Vitamins - Berg

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VITAMINSA CRITICAL SURVEY OF THE THEORY

OF ACCESSORY FOOD FACTORS

B Y

RAGNAR BERGD I R E C T O R O F T H E L A B O R A T O R Y O F P H Y 8 I O L 0 G I C A L C H E M I S T R Y

A T W E I 8 8 E R H I R S C K

T R A N S L A T E D F R O M T K ( E G E R MA N B Y

EDEN AND CEDAR PAUL

LO ND ON : GEORGE ALLEN & UN W IN LTJp

RUSKIN HOUSE, 40 MUSEUM STREET f W , £



TABLE OF CONTENTS N>

PAGE

TRANSLATORS' PREFACE . . . . . . . 9CHAPTER

# I. INTRODUCTORY . 1 7

II. T HE BIOLOGICAL VALUE OF THE VARIOUS PROTEINS . • 29

1. The biological Value of the Amino-acids . . . 29

2 . The Relationship of the. pr6teid to the non-proteid

nutritive Substances , . . 1 . . . . 37

3 . The Importance1

of inorganic (Constituents in Metabolism 40

4. The biological Value of the various vegetable Proteins . 41

5. The biological Value of the animal Proteins . 52

6. TheConditions requisite for the full Efficiency of thevarious

Kinds of Protein . . . . . . . 58

III. T HE IMPORTANCE OF INORGANIC SUBSTANCES . . . * 61

1. The Supply of a Sufficiency of nutritive Salts . §2

2 . The Importance of individual inorganic Substances . 67

3 . The Importance of an Excess of alkaline Substances . 70

4. Acidosis 76

5. Paradoxical Effect of Calcium Salts in the Organism . 83

6. The Administration of Alkalies as a Preventive of Acidosis 87

7. Forms of Combination of inorganic Substances ; their Mode

of Action . . 88

8. Mutual Interdependence of the inorganic Substances ." 90

9. TheUtiKsation of Calcium in various Forms of Administra-

tion . „ . . . . • • . 9 2

fb . The Effect of Oxidation upon the biological Value of the

Acid-formers . . . . • * . 9 4

IV . BERIBERI AND OTHER FORMS OF POLYNBURITTS . . . 100

1. Etiology . . t . . . . . . 1 0 0

2 . Isolation of Vitamin . . . . . . n o

3. The Properties of Funk's Vitamins . . . . ti6

4. Occurrence of the Vitamins . . . . • • • 124

5



6 VITAMINS

CIIAITKK? * f #

5 . The ConHequfmces td an tm»1Uti*wy *~i V J U ^ J J * • ***

a. Clinical » . . • * • T r*

&. Pathological A«at«>»-«v . . • • . M*£. The Forms t*l thr I^.r^*- • f***

6. Analysis of th*» mfrrbH M;itt»f* t*tr-'i3!s , . • ; *;

a, Sigmiu anc «• fi( the Svmj4-*««n . . • . **• J

6. FJIrrtn of Fu!*k%* Vit,*«m^ . ;**

c. I H t i v t v u i r n h v t v k - c r n t h r l U r , \ *> i t * • • ) * % * V . " * » ? ,v * ' ^ - I

t h t i t ut mitr t> :u> \uU\r l\ *r lJ«. i t * J ^ ^ ' f ? ' - ^ 'r ^* ! i f*

d . IHHnvittvH l#rtwrr« watri • <,hit<> Jl *'. 1 wA^f

e.

< • • * * *

7. Earlier AtUmfiiH nl Ivx]4ati4ti»?» . - - • *r^

8. Summary . . . . . f ^ ?

V. THE C O N D I T I O N S UI? GUCAVTII , . . . • »

t. Introductory . . . , , * . i;#

2. Importance of I-*r«4.rjn . . , . . %t%

3 . Importance u( itiutgtunr $n\m%*t\<r* , , ,. . »:i#

4. Importance f»l tIscr M tJii lfi «4 I*fr|^#fiif |-

:

* -*5 , . t» t5 . The fat-sulubi^ <***m|iltftim A , , . - **#

6. The

6. Occttrrt*nce of II

^. Qtxantttjtttve tf

§#f tbr trini|*!»*ll*M IV , ,

7* Behaviour of tli*» rr*ii**crmr (*hn*U , #*i#

S. Ifflport&na* ol tin* Nwfr*t.if*ri t,*| tfo« Mîhrr . , .. #*»i

9. Effect of the If}hibitic4i td l>ttm\U \<I*JU mfamp$mi t**^**xh * ;l a S u m m a r y • • . , . . . $m#

A d d e n d u m t o C h d ^ l e r F o u r -: H p t m , # * #

a* C U n k a J P k t u r c » . . , , , s # # #

fc. P a t h o l o g l a i l A r i i i t a t u ^ , i # |

« . F m g n o i i i , . , , , , • * , # • #

d . T r e a t m e n t t • • . » , , . f | |

; ;

V I . T H E * A T « s o L t m u i C o M f M r r t w A . . , . f # #

1 . H k t o r y ; i t » I n d a t i o t i . . . . . . i t t

2 . O c c u r r e n c e . • . . , , i # t

A und \



CONTENTS 7

C H A P T E R P A G K

4 . R e l a t i o n s h i p to o t h e r C o m p l e t t i n s . . . . 2 2 6

5 . P r o p e r t i e s of the C o m p l e t t i n A . . . . 227

6 . P h y s i o l o g i c a l A c t i o n of the f a t - s o l u b l e C o m p l e t t i n A . 230

7 . A in r e l a t i o n to X e r o p h t h a l m i a and to K e r a t o m a l a c i a

r e s p e c t i v e l y 231

8. A in r e l a t i o n to O s t e o m a l a c i a 233

9 . A in r e l a t i o n to R i c k e t s . . . . . ' . 235

1 0 . A in r e l a t i o n to P e l l a g r a , . . . . . 2 3 8

i r . A in r e l a t i o n to m a l n u t r i t i o n a l O e d e m a . . . 2 3 8

1 2 . A c t i o n u p o n the e n d o c r i n e G l a n d s . . . . 2 3 9

VII. THE A N T I S C O R B U T I C C O M P L E T T I N C 242

1 . H i s t o r i c a l . . . . . . . . . 242

* 2. S c u r v y Ep i d e m i c s d u r i n g r e c e n t Y e a r s . . . . 247

3 . O c c u r r e n c e of the a n t i s c o r b u t i c w a t e r - s o l u b l e C . 2 5 1

a. O c c u r r e n c e . . . . . . . . 2 5 1

b . N a t u r a l V a r i a t i o n s i n C c o n t e n t . . . . 2 5 3

c . feffect of G e r m i n a t i o n u p o n the C c o n t e n t of S e e d s . 255

4 . P r o p e r t i e s of the C o m p l e t t i n C . . . . . 256

5 . C o m p o s i t i o n of the a n t i s c o r b u t i c C o m p l e t t i n C. . . 262

6 . The p h y s i o l o g i c a l C o n s e q u e n c e s of C d e f i c i e n c y . . 265

a. C l i n i c a l P i c t u r e . . . . . » . 2 6 5b . Pathological Anatomy . . . . . . 266

c. Reciprocal Relationships between C and inorganic

Substances . 268

d. Forms of Purpura in relation to C deficiency . . 269

6. Mode of Action of the antiscorbutic Complettin . . 269

VIII. MALNUTRITIONAL OEDEMA 27*

1. Clinical Picture 271

2 . Pathological Anatomy 273

3 . Prognosis . 2 7 4

4. Metabolism . 275

a. Nitrogenous Metabolism 275

b. Sodium-Chloride Metabolism 275

5. Dietetic Factors of the Disease 277

a. The pathogenic Diet 277

* b. Wartime Feeding ' 278

c. Prison Dropsy • 279

d. Ship Beriberi < . 279

6. Contributory Causes of Malnutritional Oedema . . 281

a. Microorganisms . 281b. I n a d e q u a t e S u p p l y o f E n e r g y . . . . 2 8 1

c . Complettin Deficiency 282

d. MalniitritioEal Oedema akin to Mehlnahrschadei* . 284



5 VITAMINS

H A P T K R P A G E

7 . Ca u se s o f D r o ps y . . . . . . . 284a . C h e m i c a l C a u s e s 2 8 4

b. C h o le st er in I m p o v e r i sh m e n t . . • . . 2 8 5c. A n o m a l ie s o f i n o r g a n ic M e t a bo l is m . . . 2 8 7

d . E f f e c t o f H y d r a e m i a 2 8 8e . C a r d i a c A s t h e n i a 2 8 9/ . B e h a v i o u r o f t h e K i d n e y s 2 8 9

g . T h e E f f e c t o f t h e v a r i o u s I o n s o n t h e K i d n e y s . 2 9 0

h . T h e R e d u c t i o n o f B l o o d - p r e s s u r e . . . . 2 9 2i. T h e E f f e c t o f B d e f i c i e n c y 2 9 2k . T h e L a c k o f P o t a s s i u m a n d C a l c i u m . . . 2 9 3

8 . S u m m a r y . . . . . . . . . 2 9 3

A d d e n d u m t o C h a p t e r E i g h t : K i n d r e d N u t r i t i v e D i s o r d e r s 2 9 5a. M e h l n a h r s c h a d e n . . . . . . . 2 9 5

b . M ilc h n a h r sc h a d e n . . . . . . $9 7

c. F a t a s a n o x i o u s F a c t o r i n I n f a n t F e e d i n g . . 2 9 7

I X . P E L L A G R A 2 9 9

1 . C l i n i c a l P i c t u r e . . . . . . . . 2 9 9

2 . P a t h o l o g i c a l A n a t o m y . . . . . . 3 0 1

3 . T h e P e l l a g r o g e n i c D i e t . . . . . . 3 0 4

4 . V i e w s t h a t h a v e h i t h e r t o p r e v a i l e d c o n c e r n i n g t h e E t i o l o g y

o f P e l l a g r a . . . . . . . . 3 0 6

a. M ic r o o r g a n i sm s a s t h e Ca u se . . . . 3 0 6b. T h e E f f e c t o f t h e c o l o u r i n g m a t t e r o f M a i z e , k n o w n

a s Ze o c h in . . . . . . . 3 08

0. T h e E f f e c t o f t h e M a i z e T o x i n . . . . 3 1 0

d . T h e I n a d e q u a c y o f M a i z e P r o t e i n . . . . 3 1 2

e . N o rt h - Am e r ic a n E x p e ri e n c e . . . . - 3 1 3

/ . S pe c i fi c I m p o r t a n c e o f P r o t e i n D e f i c i e n c y . . 3 1 5

g . P el la g r a a n d M a l n u tr i t io n a l O e d e m a . . . 3 1 6

h . V i t a m i n D e fi c ie n c y . . . . . . 3 1 61 . C o m p l e t t i n D e f i c i e n c y . . . . . . 3 1 6

h . T h e E f f e c t o f i n o r g a n i c N u t r i e n t s . . . - 3 1 7

/. T h e E f f e c t o f S i l i c i c A c i d 3 1 8m . M e n t a l I n f l u e n c e s . 3 1 9n . C o m p l i c a t i o n s . . . . . . . 3 1 9

5 . S u m m a r y . . . . . . . . . 3 2 0

X . C O N C L U S I O N . . . . . . . . . 3 2 3

1 . D i f f i c u l t i e s a t t e n d a n t o n m o d e r n E x p e r i m e n t s c o n c e i v i n g

N u t r i t i o n . . . . . . . . 3 2 4

2 . T h e C o m p l e t t i n C o n t e n t o f F o o d s t u f f s . . . . 3 2 6

3 . N u t r i t i o n i n C o m p l e t t i n E x p e r i m e n t s . . . . 3 2 7

4 . T h e i m m e d i a t e P r o b l e m s o f C o m p l e t t i n R e s e a r c h . . 3 3 6

5 . T h e N e e d f o r S t a t e A i d n E x p e r i m e n t s o n N u t r i t i o n . 3 3 7

B I B L I O G R A P H Y . 3 3 8



T RANS L AT ORS ' P RE F ACE

RAGNAR BERG'S book marks the close of an epoch, the epochduring which the knowledge of vitamins was almost whollyconfined to those who were engaged in the experimentalsttidy of the subject, and the epoch during which the dataof the new science of nutrition were hidden away in the" tra ns ac tio ns " of learned societies or scattered al m os t'irrecoverably in the columns of polyglot periodicals. Berghas summarised all this matter within the compass of a singlevo lum e; has contributed new ou tloo ks ; and has provideda platform for th e work of future inv estig ato rs. Incid enta lly,he has written a book which, though adapted for specialistuse, is anything but abstruse, and cannot fail to be of supremeinterest to the general public—which is awakening to theimportance of vitamins, and is in search of a guide through^the dietetic laby rinth. There hav e been several att em pt s oflate yea rs to popularise th e mo dern outlook s on dietetics.Notable among those in the English language are Vitamins andthe Choice of Tool, by Violet G. Plimrner an d R . H . A . Plirnmer(Longmans, London, 1922), and Vitam incs: essential food

factors, by Benjamin Harrow (second edition, Routledge,London , 1923). Eit he r of these m ay usefully be read b y th elayman and the beginner as an introduction to the vsubject,t u t no serious studen t can afford to ignore Berg's m asterlyand comprehensive volume.

Ouf* quo tation of th e respective tit les of H arrow 's andth e Pliramers' books brings up th e qu estion of terminology .Th e word " vi tam ine " was introduced ten years ago byCasirnir Funk (one of the pioneers in these investigations) fto denote the antineuritic factor discovered a nd partially 'isolated by him . H e chose the nam e in th e belief th at th esubstance belonged to the class of chemical compoundi known



io VITAMINS

as " amines" or " amins." We follow good precedent in

dropping the mute " e " from the word used as the title of

Berg's book. But this does not solve the difficulty*occasionedby the extension of the term vitamin to denote a whole class

of substances most of which certainly contain no nitrogen—

whether " Funk's vitamin" does so or not. That is why

some authorities prefer to speak of these substances as

" accessory food factors/' and this name is used in the title

of an excellent governmental publication {Report on the Present

State of Knowledge concerning Accessory Food Factors, H.M.

Stationery Office, 1921). But the proposed name is worse

than cumbrous; it is vague; it might just as well describethe contents of an ordinary cruet-stand. The vitamins

A, B, C, etc., are doubtless " accessory food factors " ; but

so are pepper, salt, and mustard; so is the " roughage"

without which we should perish even though our food were

to contain an abundance of proteins, fats, carbohydrates,

and salts, together with an overplus of vitamins. Ragnar

Berg therefore proposes to restrict the use of the word

"vitamin" to Funk's vitamin (or vitamins), and to speak

of the general class of substances to which the antineuriticprinciples, the antiscorbutic principles, the growth-factors,

etc., respectively belong as the " complettins." Thus the

general name for the maladies decarence, the deficiency diseases,

is to be, not " avitaminosis," but " acomplettinosis." And

our author is fairly successful in his attempt to be consistent

in the use of his own terminology. But it will be noted that

ttie title of his book is Vitamins, although the exhaustive

chapter on " Beriberi and other forms of Polyneuritis," which

is a detailed study ofAthe nature and action of Funk's vitaminor vitamins, occupies only one fifth of the volume.

Here, in fact, as so often, usage rides rough-shod over

attempts at linguistic purism. The picturesque word

" vitamin/' as a general term, has come to stay. The*current

employment of a. word rather than its derivation, or its

definition. by a precisian, ultimately decides its meaning.

The public imagination has been fired by the idea of these

substances so recently discovered, so absolutely essential

to life. In the first syllable of the word "vitamin" there

is an •appeal to a universal effect, to the instincts of



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| } i r ,|\|- a!^ I| r»| ||t4ir* i4 fh^ *|rjl« $«vfiir V iJt'^MM**!, AgliCit}'*f ««•<!* f4fn1li.it with th** flHrtfri'iottt* riftctl^*sl \V)i4t w<" h;iVf* t« tfiitiHt* in tiuit we

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12 VITAMINS

appears to be a contributory cause of rickets and otherdeficiency diseases.

A no the r p oint in which Berg is an innovato* relates tothe num ber of the vitamins or complettins. H itherto m ostauthorities have spoken of three only. Writing in 1922,Leonard Williams says (Encyclopedia Britannica, twelfthedition, vol. xxxii, p . 931) : " There are prob ably a greatmany vitamins in natural foods—live or quick foods as theyare called—but up to the time of writing three only havebeen isolated. These are: (1) the antiscorbutic factor;(2) th e water-soluble B ; (3) the fat-soluble A ." Only three

vitamins are considered by the Plirnmers and by Harrow inthe books already mentioned—although Harrow, in theappendix to his second edition (p. 245), does indeed refer toCasimir F un k's recent contention th at " vitamin B is reallya mixture of two vitamins, which he proposes to call vitaminB an d vitam in D ." Similarly McCarrison, one of th e mostnoted investigators in this field, writes as follows in his Studiesin Deficiency Disease- (Henry Frowde and Hodder andSto ugh ton, Lon don, 1921, pp . 244-245) : " I hav e w rittenof three vitamins, because three are known, not because ithas been proved tha t there are only three. Bu t whetherthere be only three or legion, they will be found to exist—andthis is the important point—in the foods made in nature'slaboratory, in quantities and combinations adequate for thedue digestion and assimilation of the natural foodstuffs withwhich the y are associated in natu re. The subdivision offitamins into many classes is not without the risks attendant

on decen tralisation. Vitam ins, like other essential con stituentsof th e food, are no t to b e regarded as independent of theassistance derivable from their associates in the maintenanceof nu tritiona l harm ony. Each vitamin is bu t a member ofa team, and the team itself but part of a co-ordinated whole."

Now Ragnar Berg is well aware of the importance of thisconception of tea m work. (And, like McCarrison, he repea tedlystresses the perpetual interaction between the " t e a m " ofthe v itam ins and th e •' team " of the various endocrine glands

in maintaining the balance of healthy nutrition.) B ut h ethinks that the time is ripe for a somewhat more elaboratedifferentiation of the complettins. Provisionally, therefore,



TRANSLATORS' PRE FAC E 13

he distinguishes five groups. The table showing our presentknowledge of the complettin content of the various foodstuffs

(pp. 328-331) is arranged in as many columns. The firstof these deals with vitamins in the narrower sense of theterm, and shows the richness of the different nutrients inFunk's vitamin (or vitamins, for Berg opines that they aremultiple), which is the chief antineuritic principle of thefood. Next—though not in the order named—come columnsshowing the quality of the foodstuffs as concerns their richnessin the complettins which, pending their elusive isolation anda determination of their chemical composition, are known byletters of the alphabet: A, fat-soluble, often referred to as theantfrachitic principle; B, water-soluble, whose predominantimportance according to Berg is as growth-factor; C, water-soluble, the antiscorbutic princ iple; and D , water-soluble,differentiated by Berg both from B and from Funk's vitaminor vitamins, but like the la tte r functioning mainly as anantineuritic.

So much for the outlook upon the problem from the point

of view of the substances known as vitamins, complettins, oraccessory food factors. But Berg also considers the topicfully from the point of view of the deficiency diseases. First,of course, comes beriberi with the other forms of polyneuritis,for it was a study of these disorders which initiated the newscience of dietetics. Arrest of growth demands a specialchapter, and as an appendix to this comes a discussion whichthrows a little light on the nature of the still obscure tropicaldisorder known as psilosis or sprue. Scurvy, naturally , has

a chapter to itself. Rickets and osteomalacia, xerophthalmiaand keratomalacia, receive full consideration in the chapter onthe fat-soluble complettin A. The penultimate chapterdeals with various forms of oedema as deficiency diseases,and establishes the substantial iden tity of the " malnutritionaloedema '* of wartime experience with the " famine dropsy "of India, with " ship berberi," and with " prison dropsy.1'The concluding chapter is devoted to pellagra, and to theauthor's final summary of the whole position of the enquiry at

the date of his writing. How recent th is is may be deducedfrom the fact that his bibliography of more than 1,500 entriesis carried well on into 1922, and th a t on p p . 326-327 he Quotes



i 4 VITAMINS

a passage from Sherman and Smith's book The Vitamins,

published in New York only last year.

Apart from these " major" ailments which are classed inthe nosology as definite " diseases," Berg's presentation of

the evidence abundantly confirms the contention of those

dieteticians who hold that an enormous amount of " minor "

ill-health is due to what French writers have termed carence

fruste or hypocarence. Many, perhaps most of us, suffer,

not only iu wartime, but under the comparatively favourable

conditions of peace dieting, from what may be termed " larval

deficiency diseases"—or from the effects of such diseases

during our infancy and childhood, or from the effect of suchdiseases in our progenitors. On the paper cover of Otto

Ruhle's book Das proletarische Kind (The Proletarian Child,

Langen, Munich, 1922) is a picture of two children who might

be matched from any slum district of Europe or America.

Both have the typical facies of acomplettinosis in childhood.

The originals of these portraits would probably be found

to present the stigmata of rickets ; but, short of actual rickets,

hypocarence causes stunting of poorer urban children as com-

pared with the children of the well-to-do. Yet even the

latter are stunted, thanks to the futility of our " civilised "

methods of preparing food. Take, for instance, Berg's state-

ment on p. 189, based on the observations of Delf, Aron,

Erich Muller, and others, that " in children . . . supposed to

be thriving, to supplement the diet by fresh vegetables, extract

of green vegetables, extract of carrots, or extract of bran,

could always bring about a further increment of growth.

These observations show how defective the nutrition of ourchildren must be in contemporary life, even under what appear

to be favourable conditions."

McCarrison, in especial, has emphasised the importance

of this aspect of the new science of dietetics. He says we must

, always be on the look-out for avitaminosis, thanks to the

pestilent way in which we habitually denature our food.

" It seems to me that ' loss of appetite' is one of the most

fundamental signs of vitaminic deprivation. It is a pro-

tective sign : the first signal of impending disaster. It should

at once excite suspicion as to the quality o| the food in any

patieift who may exhibit i t" (op. cit., p. 57),



T R A N S L A T O R S ' P R E F A C E 15

The doctors of an earlier generation, who practised among

those prone to overfeeding, used to sa y " we dig our g raveswith our tee th." B ut contem porary diet is jus t as likely toerr by defect as by excess, and there is equally good reasonto say that the foundations of premature death are laid in theflour-mill and in the kitchen, by the various processes withwhich profit-hun ters an d ignoram uses spoil our foods. " Fi reis a good servant but a bad master/ ' and man must learn touse fire less on his food and to use it more wisely, if he wishesto enjoy th e best of hea lth. E ve ry intelligent read er will

draw his own conclusions as to the practical application ofth e new knowledge to th e regulation of his own diet. If asimple formula be requisite, it may be enough to quoteMcCarrison once again (p. 244) : " T he re are no more im po rta ntingredients of a properly constituted diet than raw fruit andvegetables, for they contain vitamins of every class, recognisedan d unrecognised." If a crucial exam ple of th e sort of thi ngto avoid be desired, take that cited by Berg (p. 268) from

McClendon. The craving for fresh nu tr ie n ts , says McClendon,und oub tedly has a survival value. " Am ong the Am ericansoldiers in the trenches, when their rations were restrictedto chocolate, eggs, dried milk, and sugar, worked up into asort of biscuit, he noted that this craving became over-powering within two or three days, and led them to refusetheir rations." (Apparently the idea of the U.S. armyauthorities was that soldiers in the front trenches were like

Ro bots. " You can feed them on pineapples, straw, wh ateveryou like. It 's all the same to them ! ")Many of us go through life with no serious risk of rickets

or osteom alacia; we shall no t get scurvy unless we visit th eSou th Pole or the Klo ndik e; our chance of beriberi or m al-nu tritio na l oedema is infinitesimal. B u t pe rha ps m ost of u ssuffer a t one tim e or anoth er from deficiency di sea ses ; pe rha psall of us * under extant conditions, are affected during theyears of growth by tares which are wrongly supposed to betares h6r6iitaires9 or due to " weakness of con stitutio n."Many of these troubles are, indeed, due to the follies of ourparents or our parents1 parents ; bu t they a re by no meansinstances of " the inheritance of acqu ired cha racte rs," an dye t quite as definitely as congenital syph ilis th ey are t a s e s



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VITAMINS

CHAPTER ONE

I N T R O D U C T O R Y

FROM the days of Liebig down to the year 1910, only fourclasses of nu tritive substances were recognised: proteins,fats, carbohydrates, and salts. I t is true that Liebig alreadydrew attention to the fact that development cannot run itsnormal course, either in plants, or in animals, should thesupply even of one of the necessary constituents of a complete

diet be inadequate. The development of livin g beings is r egu-lated by the supply of whichever element is least bountifullyprovid ed. In a word, this is the " law of the minimum." Sopreponderant, however, is the importance of protein as themain factor in the building up of cell substance, that investi-gators speedily came to overlook all other matters, and toconcentrate upon the supply of protein. Rubner, therefore,took a great step forward when he proved th at it is not enoughto furnish a sufficiency of protein, and that our aim must be

to provide the body with the requisite modicum of energy.But here was a new fundamental principle to monopoliseatten tion. As soon as a definite relationship between thenitrogenous and the non-nitrogenous ntitritive elements hadbeen experimentally established, the general belief prevailedthat the edifice of the doctrine of nutrition had at least beenfinished in the rough. The various rooms of the structuremight still require decoration, but no one anticipated anyfurther extensive additions to the general body of knowledge.

In this reckoning, the fourth class of nutritive substanceswas, however, entirely overlooked, The inorganic constitu-ents of the food, or, as they are usually named, the nutritive

2 17



18 VITAMINS

salts, had been so much discredited by the unproved assump-tions of unqualified curemongers and quacks and by the

premature practical application of their ungrounded theories,that no one ventured to undertake serious research in thisfield. I myself, more than half a generation ago (instigatedthereto by the pioneer work of my sometime chief, therevered Carl Rose), emphasised the importance of the inor-ganic constituents in nutritio n. But whereas people werequite prepared to recognise that the law of the minimum wasvalid in the case of carbohydrates, and even in the case offats, no less than in the case of proteins, there was little incli-

nation to admit the practical working of the same law asfar as the inorganic constituents of food were concerned.The amount of the total ash, the amount of sodium chloride,and subsequently too th e amo unts of calcium and of phosp hate s,were considered—these were the only inorganic constituentsto which any atten tion was paid. I t was at most concededon the theoretical plane that the so-called ash contains anumber of other substances which must be included amongth e genuine nu tritiv e elements. The practical inference fromthis admission, that the law of the minimum must be validin the case of every one of these additional substances, wassometimes disputed but more frequently ignored.

The most grievous defect of the old theory of nutritionwas the way in which that theory overlooked the universalvalidity of th e law of th e minimum . Investiga tors ignoredthe extent to which every tissue builder is dependent uponall the o the rs, They failed to realise th at w hat is decisive

for development is, not so much the absolute quantity ofthe various nutritive elements, as their relative proportions.They did not understand that the bodily need in respect oany one constituent ojE a die t can be determ ined only wheiwe simultaneously take into account all the other factors o:nutrition.

An additional defect, one to which I called attentionfifteen years ago, was that in experiments concerning nutritionthe duration of the experiment had invariably been far too

sho rt. My o # n experim ents lasted at first for a week. Subse-quently I extended them to a fortnight, and ultimately toseveAl months. It thus became evident to me how intim ate



INTRODUCTORY 19

is the connexion between the individual constituents of ourdiet. I learned that it is impossible to ascertain the body'sneed for any one substance, or to learn the way in which thatsubstance acts upon the body, unless all the other constituentsof the diet are being supplied in optimal quantities.

The third defect in the earlier study of nutrition was,finally, the primary assumption tha t the ordinary diet ofcivilised peoples contains all the necessary constituents inthe necessary quantities. This assumption was supposed

to be confirmed when in the course of a brief experimentno immediate or considerable loss of weight could be detected.It became the practice, therefore, to adopt as the basis ofexperiments upon the requisites for nutrition the very thingwhich had to be proved; the average supply of the variousconstituents of a customary diet was assumed to representthe bodily need for these constituents.*

The present work was begun in 1920, when we were entitled

to celebrate the decennary of a new epoch in the doctrine ofnutrition . In 1910 the liveliest antagonism would have been,aroused by the assertion that our diet contained, in additionto the familiar four classes of food constituents, quite a numberof other substances of a still uctknown nature, substancesabsolutely essential to the welfare of the organism. WhenSchaumann here in Germany first began to speak of suchessential accessory food factors, I was for a long time adverse

to the assumption, and I attempted to explain the phenomenaattributed to t&e alleged accessary food factors as the effectsof the inorganic constituents of our diet, these being my ownparticular hobby. I t seemed incredible th a t accessory foodfactors could have been overlooked for three quarters of acentury. Beyond question we were only at the beginningof our knowledge of the effects of the inorganic constituentsof food, and many surprises must still await us in this field

• Th i s i s t h e m e thod wh ic h Rubner h a s em p loyed qu i t e r e c en t ly w henendeavour ing t o a s c er t ain wh e the r t h e war t im e and po st -war d i e t s of Germ anyconta ined a suffi ci ency of ca l cium . He s im ply as sum es th a t th e pre -ward i e t bo th o f Germany and o f Japan was adequa t e i n t h i s r e spe c t , and t hush i s c ompar i s ons enab l e h im t o dr aw the c onc lu s i on t ha t our pr e s en t d i e tcon ta ins enough ca l c ium . Unfor tuna te ly , n o t on ly doe s h e use for h i s ca l cu la -t i on s e s tima t e s o f c a lc ium c on t en t wh i c h a r e s om e t im e s e r roneous and s om e -t imes mere as sumpt ions , but he l ikewise over looks the fac t tha t s j j e c ia l i s t sh av e te pea te d iy proved t l ia t th e pre-war d ie t w as def ic ient in caJtc*ur# | ,



2 0 V I T A M I N S

of research. Ev en a t th a t da te , how ever . th«*i '" v< *•' j - * ' -'

num erou s indica tion s, m ere ly aw aiti ng confirm-**** **< *j * * \ , I

foregoing explanat ion was inadequate , hit^l «1 •>•• 1> r***

was the ev idence th a t the subs ta nces in qw st i* <» ^ < 1 • } » r *' !

in alm ost infinitesim al q u an ti ti es , like the sir of * 1.**. * I -

m ed icin e; secondly th ere w as th e far t th at iK- * ^ • -* < •

were therm olabile, w ere easily de stro ye d t y I K »t \S •- *? *

indeed, th at th e a pp lica tion of m od eiati- h«Mt * « *'- 5** •!.

could exercise an inf luence upo n flu inwR aii* ' "**•< * ' ' - •

of a d ie t . Fo r ins tance , we knew tha t w h m tm % i I < n^-

fo r t o o lo ng a t im e th e co mp le x c a rb c ip h ^p f i - ^* •«• ? ' • * . . *

and magnesium un derg o deco m posi t io n, and th ,*f .i j t* i * " r

of i nsolub le c a rb o n a te s a n d p h o sp h a t e i s c k j ^ M* 4 -p u

the wall of the containing vessel . 11MM* t h i»4«-l.*1'-' - .• **

ar e esse ntial to th e b o d y of t h e ne w bo rn in f a n t , !}«**! %*:**»

drawal from the milk leads to a defirienrv of Inn*- >« 'I*** <-* «J.

and this may endanger the l i fe of the nt t r^hnc l<*x ^ ' -

withdrawals of inorganic substances fr*m lh«- h 1 -**r **

ha,ve a decisive influence upo n nut rit io n, th e q n a it j i r* ?. , ,- t

be m ea su ra bl e in ce n ti g ra m m es o r ev en iu «l**nfMN it.1^* -

whereas the ant ineuri t ic const i tuents of t in* f«**l JI <~

no ta b le effects in q u a n t i ti e s of milligram*?}* s **r fi-irft#•*>•• < ia mil l igramme.

When ye t o the r c lasses of food - ron M tturn i^ W l !** i t

d iscovered , hav ing an ana logous bu t nevcr th rk^ 1 . s j - r o f . ^ J ! v

different inf luence upon nutr i t ion, my hypoth* 1" .^ \ * < * % u * r

untenab le . I wa s fo rced to ad m i t tha t our d ie t twist *' .ni*iu

smal l bu t ve ry impor tan t quan t i t ie s o f many l i t th r* t< i unhn«*n$%

kinds of substa nce. T he chief reason wh y t h r y \**-tr t;<,i

discovered sooner is on e th a t h as been al re ad y $ftdu.i«r«l

the unduly br ief durat ion of experimtntH u\mn t i u t n f i ' ^

Dur ing the las t few years , the l i t e ra tu re r m U t U m t fhf

resul ts of these researche s h a s a t t a i n s ! conMrlrr; i14^ j>i* ^ t

t io n s . T h e wo r ld wa r , a n d th e c o n se qu e n t s e v n , u A * 1 fh r

nati ons , hav e ho we ver g re at ly hin de red th e gr rm t h <*f fct* ' %

ledge. I t ha s been im pos sible for th e indiv idiuil tf»v™ti£.,<«f

to keep h imse l f adequa te ly in formed conreming tm^nh^

similar to those upon w hich h e himself w as cng agr t l , V %jirt mil y

i n Ge rma n y h a v e we suf fe re d from th i s l a c k, a n d t l u t M n -

t a i n l / o ne of th e r e as o n s w h y t h e G e n t i an s h a v e hem m



I NTR ODUC TOR Y 2 1

greatly outstripp ed in the field of st ud y w e are now considering

—although Germany may be regarded as the scientific father-land of vitam in research. H ence th e Germ an publicationsduring the war had in most cases been long forestalled by theAmerican, to say nothing of the fact that the writings ofthe German investigators lacked the fertilising influenceresulting from th e stud y of foreign mode ls. Fu rth erm orethe literature of the subject is very widely dispersed, so thatyears of work are requisite to secure a competent knowledge

of what has been achieved.Since from the very outset I took a keen interest in these

researches, I have been able to secure a fairly complete collec-tion of the relevant litera ture . F or this reason, at th e closeof the first decennium of the investigation, I feel entitledto attempt a comprehensive survey of all that has hithertobeen learned concerning vitamins. I t must be admittedthat the task is almost beyond the powers of any one person,

seeing that at least a cursory knowledge is essential in them ost diverse fields of chem istry, phy siology, in tern al m edicine,patho logy, and m orbid ana tom y. In view, further, of th econfusion that prevails upon this subject, it should hardlybe necessary for the author to plead for the reader's indul-gence. Such a first at tem pt will h a rd ly be free from a fewmistakes.

The confusion to which I refer is extremely conspicuous

in the matter of nomenclature. At the outset of theseresearches, when investigators were still almost exclusivelyconcerned with beriberi and the kindred experimental poly-neuritis, there was a certain justification for considering boththe curative and the preventive effects of the newly discoveredsubstances on parallel lines with the familiar medicaments.Consequently, each newly discovered substance (or rather,mix tu re #of substances) received a spec ial na m e. T he firstof such nam es was " X acid," used b y Hulshoff-Pol in hispa pe rs of 1902 38 and 1907 68 for the antineuritic principleisolated from the bean katjang-idjo (Phaseolus rad ia tus ).The earliest Japanese investigators who attempted to isolateth e antin euritic substance likewise reg arde d i t as an acid,an d nam ed it " aberi acid." li6 Funk, however , found thathe was dealing with an organic base, an d spoke of* it as



22 VITAMINS

" vitam in." As a m atte r of course, numerous a ttem ptswere promptly made to turn the new discoveries to practical

account. A flood of- antin eur itic preparations invaded th em ark et, and the tide is still rising. I t was equally a m at te rof course that each of these preparations should receive itsown patented designation. Thus we h av e: or yz an in 2 l 0 ;torulin 22 0; orypan 884 ; ant iber ibe rin 320; oridin I13C

3; sita-coid 7J4; etc . Meanwhile, additional vital ly essential nu trit iveelements were being brought to light, substances requisiteto adequate nutrition. Ro hm ann 473,52i therefore proposedto give them t he comprehensive nam e of " accessory food

factors " (Erganzungskorper). T he practical-minded Am eri-cans evaded the difficulties of nomenclature by refrainingfrom th e coinage of specific n a m es ; they were con tent tospeak of " the fat-soluble factor A ," of " water-solub le B , "or " water-soluble C ." Abderhalden 8o3,1*30 used the term" eutonin " to denote th e an tineu ritic sub stances as a class,this implying the possession of a knowledge of their mode ofaction—a knowledge which is unfortunately still lacking.Equally unfortunate was this investigator's choice of the

name " nutram in " for th e w ater-soluble growth-complettin,seeing th at this substance con tains no nitrogen. Variousother names have been suggested, with a varying measureof success. I m ay instance th e am bitiou s " b io p h o r" *3«among the less successful efforts, inasmuch as every suitableconstituent of our diet may be termed a " life-sustainer."Drummond,Il 67 hoping to bring order out of chaos, has actuallymade confusion worse confounded by the proposal to useth e oldest name " vitam in " for the accessory food factorsas a class, to retain th e term " vit am ine " (this being th eway in which the word has hitherto been spelt in England,although the Americans w ri te -" vitam in ") for F un k's anti-neu ritic substance, and to drop th e qualifying adjective" water-soluble " or " fat-soluble " in th e case of tlie othe rsubstances.

There are several objections to thi s proposal. An objectionto the use of vitamin as a collective name is that some of the

substances under consideration contain no nitrogen, andtherefore axe certainly no t amins. F ur th er , it seems fairlycertaifi that there is a second antineuritic substance, free from



INTRODUCTORY 23

nitrogen, and distinct from Funk's vitamin, though like that

body it is readily soluble in water. But by the rules of prioritythe original* name belongs to the substance which was giventha t name by its discoverer; and there can be no doubt th a tthe use of the term vitamins, to denote a whole class of sub-stances of this kind has, in actual practice, given rise to graveconfusion. If, however, the antineuritic substances are tobe known as vitamins, a still worse confusion will arise shouldthe same term now be collectively applied to various other

constituents of our diet. There is good ground for the conten-tion that the misunderstandings still prevalent in the scienceof nutrition are mainly due to the improper use of the wordvitSmin. In physiological chemistry no less than in everyother science it is essential that names should be perfectlyfree from ambiguity, that there should be no possible doubtas to their denotation. In view of these considerations,preference must be given to the collective name " accessory

food factors/' introduced by Rohmann, for this name impliesno more than that the substances in question are essentialcomplements of an adequate diet, that they are accessoryto the four classes of foodstuffs with which we have longbeen familiar—proteins, fats, carbohydrates, and inorganicsalts. But if this term is to secure acceptance in internationalscience, it must be translated into the international languageof science. In the present study, therefore, the author will

use the designation " complettin.'1 The term " vita m in"will thus be reserved (in conformity with Funk's originalintention) for the nitrogen-containing antineuritic substances.Should any non-nitrogenous antineuritic substances be provedto exist, these must receive a distinct name. The water-soluble growth-promoting substance will be spoken of as" complettin B," bearing always in mind that it has veryrarely been studied apart from the vitamins ; the fat-solubleaccessor^ food factor will be termed " com plettin A " ; and theantiscorbutic factor will be spoken of as " com plettin C." Thisnomenclature will secure complete freedom from ambiguity.

The diseases that arise from a deficiency of the accessoryfood factors must be similarly dealt with in the matter ofnomenclature. Funk 3*3 proposed to speak of these as" avitaminosis," but if the use of the nam e vitantin be



24 VITAMINS

restricted to the nitrogen-containing antineuritic principle,it would be extremely misleading to speak of scurvy (scor-bu tus ), pellagra, and similar disorders, as avitamino sis. Forall these disorders due to a deficiency of one or more accessoryfood factors I shall, therefore, henceforward use the name" acomplettinoses "—the German vernacular equivalent "being" M angelkrankheiten," th e F rench " maladies de carence,"and the English "de ficienc y diseases." There is all themore reason for the use of such a collective designation,inasmuch as it is somewhat exceptional to find one of thesemorbid processes in a pu re form. In mo st cases of deficiencydisease there is more than one class of substances lacking,

although the overwhelming lack of one or other of them gfvesthe illness its specific stamp.

As already mentioned, the literature of the accessory foodfactors has now become so extensive that the individualinvestigator finds it barely possible to read without delayand to turn to practical account in his own work the publica-tions that are poured forth almost daily from the press.Moreover, anyone who stands a little aside from the maincurrent of research will often find it extremely difficult to

decide to what extent an ostensibly new contribution reallycontains novel elements. In experimen ts concerning nu trit ionevery de tail is of im po rtanc e. Th e m ost trifling chan ge m ayrevolutionise all th e cond itions of an experim ent. In m an yinstances authors fail to recognise, or do not recognise readilyenough, the real source of the new or divergent results theyrep ort. Th is is only too na tu ra l. In earlier researches upo nmetabolism, students were content to consider the effects ofproteins, fats, an d carboh ydrates ; and when exceptionally

scrupulous they would also take into account the result of asum m ary addition of salts. To-d ay we have further to makeallowa nce for four or five acces sory food fact or s; and inaddition, in the modern and protracted experiments uponnutrit ion, we have to reckon with factors which in formerday s were completely ignored. The va riety of pro teinemployed, and its richness in tissue-building constituent,must be allowed for, although our knowledge of the composi-tion of prote in is still far from p recise. There is no t evenone of the best-known proteins of which we can say that we



INTRODUCTORY 25

know all the factors requisite for its existence in perfection.Similarly as regards the fats, for we still do not know which

of these substances are absolutely indispensable to the organ-ism. Even more complicated is the problem of the inorganicconstituents of nutrition, so manifold in their variety. Fromseven to ten metals at least and as many metalloids haveto be taken into account. Each of these may exist in theanimal body, either in ionisable (i.e. salt-like) forms, or elseas a masked constituent of some extremely complex organiccombination which is perhaps itself essential to life. Fornorm al growth, for normal wellbeing, it is not enough to

furnish by rule of thumb a diet containing certain quantitiesof %11 these substances. Liebig's law of th e minimum appliesto each individual substance, and in part to each type ofsubstances. But the mutual relationships of the substancesare so intricate that it seems almost hopeless to undertakeresearches concerning the individual minima.

The further back we go in the history of the accessoryfood factors, the simpler do we find the experiments to have

been, but for the same reason the earlier technique was compara-tively defective and the results were consequently morequestionable. To-day such experiments, if they are to berightly planned and if their results are to be correctly inter-preted, demand the most careful and extensive preliminaryconsideration. Furthermore it is essential, in these pro tractedinvestigations, to make due allowance for what has beentermed " the laboratory factor/' whose importance has been

quite recently recognised. We have to remember that th eanimals we are subjecting to experiment are living in confine-ment, and are therefore far more infirm and far more exposedto noxious influences than their congeners living in a stateof nature. Especial consideration must be paid to the"cage-factor/' to the physical conditions under which theanimal!1 are placed, not forgetting the circumstance that amonotonous and uniform diet is being enforced upon them.Purely psychical factors likewise affect the wellbeing ofanimals. Fo r instance, in some animals, the mere takingout of the cage once or twice a week for weighing will makeit impossible for them to thrive, even though their diet isall that can be desired.



26 VITAMINS

If, therefore, we wish to appraise the upshot of individualexperiments, we must bear in mind that the earlier investiga-tions are often vitiated ~by errors which inv alidate th e entire

result. I t m ust also be remembered that not a few experi-menters exhibit a certain mulishness, so that for one reasonor another they will not modify a wonted method ofconducting their researches, refusing to recognise or failingto understand the improvements made by a rival. To sumup, we rarely encounter perfectly unambiguous results. Inmany cases an acceptable result can only be secured afterdue allowance has been made for the defective conditions ofthe experiment, or after errors have been eliminated bycomparison with the work of other investigators. In Uiis

task, the critic must not be frightened by any name, howeverillustrious. Why should h e be frightened ? Th e wholescience is still in it s initial stages, and only by making m istakescan we learn how to avoid them. Fa r be it from me to m aintainth at my own technique as critic is wholly free from objection,but only by strenuous though benevolent criticism can wehope to achieve something as near perfection as human beingscan attain.

For several decades, Germany was the citadel of nutritiveresearch. The most noted names in this domain, those of

Liebig, Pettenkofer, Voit, and Rubner, are German. Butprecisely because their leadership had been so outstanding",the German science of nutrition became gradually enmeshedin rigid dogmas, which were ultimately regarded as indisput-able. I t has probably been for th is reason that of late, in sobrief a time, Germany has been hopelessly outstripped in thescience of dietetics. The Germans are still dumbfounded a tthe revelation that there are nutritive substances that cannotbe included in the familiar four classes, and that consequentlyall that has hitherto been learned concerning nutrition can

have no more tha n conditional valid ity. We have in Germanysofeiong been accustomed to regard protein as a uniform entityfrom the nutritive outlook, that we now find it extremelydifficult to recognise in practice w hat has long been adm ittedas a matter of theory, namely that there are diverse sorts ofprotein and that their diversity of values must be recognisedfrom tke biological as well as from the chemical standpoint.



INTRODUCTORY 27

First of all, therefore, it will be necessary to study the latestviews concerning the biological importance of the various

proteins, that we may realise how fundamental this matteris in relation to the planning and the interpretation ofexperiments upon accessory food factors.

I have already emphasised my opinion that—owing tothe fact that the importance of protein as a tissue builder,and the essential need for supplying energy for the m aintenanceof life, are so easily understood—there has been a widespreadtendency to overlook and to ignore the importance of theinorganic salts, although this fourth great class of nutritiveconstituents has long been known to us . Let me insist oncemore that for these substances, too, the law qf the minimumis fully valid. The results of earlier researches supply ampleevidence of the physiological importance of the variousinorganic ions. In the history of the evolution of our know-ledge of accessory food factors, the value of the inorganicconstituents of our diet repeatedly forces itself on the attention.We* learn likewise that their interrelationships are vital to

the effective influence, not only of the accessory food factors,but also of the three primary classes of organic nutritiveconstituents whose place in metabolism had been assumedto have been perfectly understood. These problems mustalso receive close attention, if we are to be enabled rightlyto appraise individual expepments concerning accessoryfood factors.

What is true of philosophy and of history is equally trueof the science of nutrition . The further we advance in ourstudies, the more vividly are we made aware of the way inwhich one happening is dependent on another. In the endwe recognise as a fundamental principle that the significanceof any occurrence can never be properly estimated in isolation.In suchjan estimate, all the cooperating factors must be takeninto the reckoning before a final judgment is formed. Inthe science we are now studying, this principle applies to theproblem of the bodily requirements of each* individual nu tritive

constituent.During the study of this book, the reader will perhapsfind the innumerable references to authorities disturbing,and may be inclined to regard them as superfluous. Cet him



28 VITAMINS

r e m e m b e r t h a t " t h o l a b o u r e r IN W O M I ^ , "f *.:

t h a t i t w o u l d be* u n j u s t to m e n t i o n < n • . • : } < ;

o t h e r s u n n a m e d . M o r e o v e r , f lu iv «- a J M * . J. !

b e i n g p r e c i s e i n t h i s m a t t e r o f f i t . i t ; :: V. ],*

t h e p ro c e s s e s of n u t r i t i o n 1 h a v e n**f iia fi- . : * : f»v )

w i t h i g n o ra n c e o f t h r i r i iH »H ? aI . i i^ l ; ! / . . I •

N o w t h a t m y i d e a s h a v e l » r i i \ u ^vi4*l*, - ; 1

c o n f i rm e d by iiK K lt-rn d i e t e t i c ' j r ^ r a i i h * . i t ; «

I s h o u l d s p e c i f y w l u r h r e s u l t s ;nr t$4v » w j. ,-.;. '!

t h o s e o f o t h e r i n v e s t i g a t o r s . I i. ii 3 iu i : t ! , r . i*'« j :

m i g h t s i m p l y b e s he l v e d a s " f)i«- f a n t , :• • J . .

L a h m a n n . " M y bo ok w ma l t i t h t -n J .u i t ^ .•. 2 . i- •

p u r p o s e , w h i c h is t o s t i i n u l a t r , t h e hnu^n -is c i e n c e o f n u t r i t i o n . *

• I m u s t tsikf t h J - » o p i ^ .o f D r . L a h m a u n

%< ^ m a t ^ n u i u r» »4«* w.rr K . ] * J •:

i n m y b o o k , h a r U u u \ i t , J«*i t ^ , 4 f ' U * ^ « ? < t * ^L a h m a i H i ' « s t c M t h i n f : n n o w oh- iMjrf i - , 4 i ^ | *f>A'?a s r c g ; m l » t h e i f i o i $ * , u u r f n ? U i ? r * r « i , - . ? - ^ ^ r -d i s m i s s e d , , a n d m y h n r i i r t i i n r

1J . j l i ^ i f . * ? ' n I ^ - J f r

m o r e a c c o n l a u t w i t h t h e * ' p u * <«f t*^<- ?»*.«••:I t f o l l o w s t h a t I a m u U m r t r-j ;r-}}> |, t u *\



CHAPTER TWO

THE BIOLOGICAL VALUE OF THE VARIOUSP R O T E I N S

i . T H E BIOLOGICAL VA LUE O F THE AM INO-ACIDS

THE reader must first be reminded that, according to thepioneer investigations of Emil Fischer and his pupils, theproteins are largely or mainly constituted out of ester-likeamino-acids compounded to form polypep tids. It is rema rk-able to find how little variation there is in the compositionof th e most diverse sorts of pro tein. As yet on ly a sm all

number of amino-acids have been isolated from the naturalproteins. Here is the list of these, the conventional n am ebeing given in the left-hand column, and the structural namein the r ight-hand:

glycocollalaninserin

valinleucinisoleucinasparaginic acidasparaginglutainic acidglutaminargininornithinlysincystincystein/J-phenyl-alanin

amino-acetic acida-amino-propionic acidjS-oxy-a-amino-propionic acid

dimethyl-a-amino-propionic aciddimethyl-a-amino-butyric acidmethyl-ethyl-a-amino-propionic acida-amino-succinic acidthe anhydride of the samea-amino-glutaric acidthe anhydride of the sameS-guanidin-a-amino-valerianic acida, S-diamino-valerianic acid

a, c-diamino-capronic acida-amino-/3-propionic acid disulphidea-amino-/?-propionic acid sulphhydrnte0-phenyl-a-amino-propionic acid *

29



3 0 VITAMINS

tyrosin oxy-phenyl-alanintryptop han jS-indol-a-amino-propionic acidhistidin îmid-azolyl-a-am ino-propionic acid

prolin a-pyrrolidin carbonateoxy-prolin oxy-a-pyrrolidin ca rbon ate

Leaving* out of consideration the anh yd rides and cy st ri n(which are in all likelihood no m ore than deco m positionproducts formed in the course of the experiments), we arethus concerned with only eighteen arnino-acids, out of whichthe innumerable proteins are con structed . Of course evvftthis limited number of constituents gives ample scope for

varieties in combination. Out of the eighteen aiaino-adidS |no less than 6,708,373,705,728,000 proteins could theoreticallybe built up. Were we to take no more th an ten of th e am ino -acids, with these we could form 595,071 varieties of protein.But the differences between the proteins do not depend solelyupon differences in the arrangement of these particular con-stituen ts, for unquestionably most pro teins likewise co nta invarious quantities of other substances besides the amino-acids,Finally we have to reckon with structural differences, whicltmust certainly arise during the formation of optically activeamino- acids.

It has long been Imown that the digestion of proteinsinvolves their decomposition, and that when the influence oftrypsin is sufficiently effective this splitting-up may proceed!as far as the formation of various amino-acids. Conversely,

'Abderhalden has been able to prove 45* tha t dogs can bequite as efficiently nourished upon completely disintegratedprotein as upon protein in the natural sta te. I t w as, indeed ,subsequently shown that during the process of normal diges-

tion the disintegration of protein does not usually go so faras the formation of free arnino-acids, being arrested in thepolypeptid stage. Still, Abderhalden's experimerfts havedemonstrated as a matter of principle that the animalorganism is at any rate competent to build up its own specificproteins out of the requisite amino-acids. Q uite a num be rof investigators had anticipated AbderhaMten in this demon-stration (though somewhat less drastically), inasmuch as inexperiments upon animals they had shown that when a variety



BIOLOGICAL VALUE OF VA RIOU S PR OT EIN S 31

of protein lacking in some constituent indispensable to normal

growth is given as a food, this protein may be renderedbiologically adequate by adding the desired constituent tothe diet .

In th e before-mentioned work, A bde rhalde n likewise p rov edt ha t cer tain tissue-building constituents of pr otein ar e abso-lutely indispensable to the body. Above all, this is true ofJ^ryptophaf , which cannot be substi tuted by any other pro-du cts of pro tein disintegration. I t is tr u e also of Lztyrpsin,

which can be replaced b y its ante ce de nt 1-phenyl-alanin,but not by any of the al iphatic amino-acids nor yet by thecorresponding keto-acids. Thereby Abderhalden confirmedwhSt Osborne, Mendel, and Ferry 2*5 h ad previously m ain-tained, that the animal organism is incompetent to effect " ring-closing " (cyclopoiesis).

Glycocoll, which can easily be produced by the oxidationof alanin or even of serin, need not apparently be provided

ready-made in the food. Prolin, again, which is readilyproducible in the body by the oxidation of histidin, need notbe supplied if the last-named antecedent material be furnishedin the diet in sufficient qu an tity . Fin ally , it was pro ve dlater that Ircystin is essential. B u t in m y opinion it stillremains to be ascertained whether this substance cannot besubsti tuted by the corresponding sulphhydrate cystein,since the latter can unquestionably be oxidised to formcystin within the body.

Abderhalden was unable to show that d-lysin, arginin,ornithin, l-histidin, and d-glutamic acid, are indispensable.

In this chapter I have given the premier place to Abder-halden's researches because his name enjoys exceptionalrep ute in Germ any. B ut he was far from being the first toun dertak e experiments of the kind. I n th e U nited S tates,experiments in the artificial feeding of animals were longago inslitiited, Osborne and Mendel, in pa rticu lar, h av em ad e extraordinarily comprehensive and far-reaching researchesin this, field—researches which are directly re la ted to M etschni-koff's view s concerning " ntitritive pills " ; b u t th e en qu iryas to the validity of the theory was undertaken long beforeit had become widely know n. Osb orne an d Mexidel ha v ebeen greatly interested in the question whether ahimfils can



32 VITAMINS

carry on their vital economy with the aid of comparativelysimple m e an s ; wh ether, for instanc e, phosp horus in purelyinorganic combination will suffice. In these experiments,as soon as their duration was extended over many days orseveral weeks, the varying biological importance of thedifferent pro teins began to become manifest. As ear ly as1912, Osborne and Mendel were able to prove that the dietTmust contain certain minimal quantities both of tyrosin and]of tYyj)ioj)h(in?%5

In th e work just m entioned, an d again later,349 these investi4gators showed also that glycocoU is not an essential factor inidiet; Lewis, 653 and Lewis, Cox, and Simpson, Il83 came tothe same conclusion. Co ntrad ictory , at first sight, is* thestatement of Nitzescu,8°4 that the protein of maize is incompe-ten t to prom ote proper growth, owing to its lack of tryp top ha n

and its inad equ ate con tent of glycocoll and ly si n ; bu t th eRumanian forgot to make a control experiment, adding theaforesaid substances to the diet in order to ascertain if anyor all of them were truly indispensable. I have alread y adducedtheoretical grounds for the opinion that glycocoll is not essen-tial, inasmuch as this substance has such a composition thatit must be formed in the organism by simple oxidation out

of all th e oth er aliphatic a-amino-acids. Such, too, is th ebearing of Ivar Bang's discovery,5<>8 that proteins poor inglycocoll, and perhaps also in alanin, have in the rabbit noeffect upon th e amino-acid content of the b lo od ; these sub-stances, when present in very small quantities, are promptlyused for building up the pro tein of th e anim al bod y. W hen,on the other hand, foodstuffs rich in glycQcoll were given,

an increase in the amino-nitrogenous content of the blooden sued ; obviously because, when th e bodies rich in glycocollor alanin were worked up within the animal organism, amino-nitrogenous substances were produced in excess of the needsof the tissues. I t is well known th a t w hen an "aliphaticcarbon chain undergoes oxidation in the animal body, theoxygen seizes the terminal carbon atom—or, if this be already



BIOLOGICAL VALUE OF VA RIOU S PR O TE INS 33

affects the jS-atom, and the chain is broken with the formationof NH 3 . C H 2 . COOH—glycocoll, to wi t. There is, how ever,little likelihood that alanin can be formed in the body, seeingth a t in alanin the j8-atom is no t oxidised. Th rou gh ou t th eliterature- of th e subject, in fact, we can find no indica tionth a t it is possible to dispense w ith alan in. Sure, indeed,tells us la63 that the addition of alanin to a protein of verylow nutritive value did not bring about any improvement.

But in this experiment there were so many other unfavourablefactors that the ineffectiveness of the addition of alanin doesnot justify any inference concerning the indispensability ofth%t substance.

Just as, during the process of oxidation within the animalbody, glycocoll must arise out of the aliphatic amino-acids,so, and for the same reason, must prol in arise out of histidincompounds as a terminal product of biological oxidation.

In actual fact it appears that this amino-acid is not a vitallyessential constituent of our diet, Iz6 3 provided that a sufficiencyof histidin be supplied.

Indispensable, on the other hand, are valin, leucin, andisoleucin. Leucin (amino-isocapronic acid) cannot be substi-tuted by norleucin (normal amino-capronic acid).1200

As far as the so-called hexone bases are concerned,peculiar conditions appear to prevail, an d th e m a tt er ha s no tyet been cleared up . Num erous exp erim en ts seem to JtiavdLshown beyond dispute that lysin is an essential dietetic factoff;

and that the animal organism must be supplied with considersab le quanti ties of th is substance. > (Cf. 349, 43*, 49a, 55°. 5***<59 8, 6 13 , 6 34, 680, 804, 1095, IOOO \

It is different as regards arginin land histidin. When boththese bases afe lacking, normal development is impossible,

and it is even impossible to maintain the body-weight.Nevertheless, although the two substances differ so greatlyin composition (arginin has an open carbon chain, fromwhich there is no prospect of passing to the heterocyclichistid in), Ackroyd and H opk ins 535 and Geiling 65° agree inreporting th at adequate growth can be secured w hen either farginin or histidin is supplied in the absence of the other, iThe explanation perhaps is that the bodily requirements are



34 VITAMINS

ronceivable that either cun he transformed infn the otherthe organism.

is of peculiar co m po sit ion, and tnun einir* «»!»• fivit-ha ve show n it to be, indis pen sab le tn nntiiium ; M T ,

however, the reêivatinn made on \K ; n , I'.vrii pt*»teinsrich in iVMin, such as cast-mM•*« u*i and lart.ilbuunn,1 '*'*squire an enhanced nutritive value when Mnall *|naiifili«Huf cvhtin air siimiltanrnu-Jy aclinini^ti-rrd,

liuiMmu h as th*1 an im al otâm Mn Mi-nis !*• lit iur^nijH -trntin atliit'Vf- ryrhijxiirsis, it is obvious that phni\l aLwtn musthv an tiuiisjionsalih* factor of nu tri tio n/ "^ M ittl nl l tfHotdsan ohNcrvation to th v op{Hisitr effect,f« hut. in fhh i*X|''«th«? arluiiiiistratiou ui auuno-arids alt«'n$at«-«l with \^%]trott*itt starvatum dtu-inj; wh ich am um -a ri tli vvni? i>flaiiig formed within th r bod y. In hunger st at ic thr sr •itumt>-arid n art* vigo rously re ta in ed , and this m ay ha ve KalMffetl th eresults fiurinjK tl w sutiM»qiK^tit perif*-d wht-n afium«-;ic-i(K werehrinm supplied in the fomh

It is equally ohvinus that, tyrovn mn\i be an r\\rnti;tl

d k ie ti c fac to r; th e m j t n ^ t e quaiiUfi*-, «4 tj«s '•.tiii^fanrrare small^M hut vitally iiiij«»rtant.J;*^ Mit« hrlYn rd t^ ivaUoi ttu ttie contrary <•**> is# as in the cane of phe.nvl al.uun, ejcpli*ablefront th e pei'nliar co nd ition s of th e cxperim rtif. As * \u%u\y%ii i i9 the iitrcf:**sary a tnut it it i** very sm all. v* This i* acc:t«inted(«r by A btlw haltkrn 'sohsri 'valiun *f^ that iytmm ioxy-|*Jiriiyl-

in to Kf*nm «rxt*"itt repla t'e ai ile In* it f ante cedent pb**nyl-whkh imdergum uxuhium withtri the bfirty, T he

of a hen/,r.il ring, MI «itflkuh tu effret in the blmiitfory,

ii a fannliar occiirrejici* in the animal nt$>*mkin>. t nw*l onlyri?tinintl the reader of thetra.n^furm;ttiim of i^tjjeoJ into p

f have rnorr tlian OUCK itiMMitJ that hypfapfutnindts|ieiiîW i: tliete tir factor. O n thw iref ka l gromid?i it\m m $ owing to the complicated rompt»>itttm of thti»and owing to the tnc:mnp<?trncf* of the hnitian or^rir$$i*in to*ynthf!tt!itt cajrbon chain s, 1'lie in fr rt ti r^ in *:oiij*rtnrd b y

tMervatim}^ f€f. if>* *H- ««». i*«* **H ^** >r^t «**ij

to th e iitrffirt* in rn tii in tti inca pa ci ty of th r body, it$* obvtotMi th a t tryp toph &n ctannot be n*p l^r« l im dietet icpurpuM^ by its dKintef^ration prmbicf cvntirk jici«.l^^f Sincethe organism needs fairly large amounts of iry}>t<*ph.m, we



BIOLOGICAL VALUE OP VARIOUS PROTEINS 35

find that, when the proteins in the food contain only smallqu an tit ie s of th at constituent, growth runs parallel, to a certain

ex te nt , w ith th e tryp top ha n content.49*, 613 j ^ i s part ly explainsth e sup erior ity of m oth er's milk to cow's milk for infantfeeding, seeing t h a t t h e lactalburnin of hum an milk ispecu liarly rich in tryp toph an. Although hum an milk con-tains a smaller percentage of protein than cow's milk, theabsolute tryptophan content of the former is considerablylarger. *w 11 is not ew orth y th a t when the re is a long-continueddeficiency of tryptophan in the diet, the endocrine glandsde ge ne rat e just as they do when th ere is a com plettin deficiency.T in s will be furthe r discussed in th e sequel. Enoug h forthe moment to point out the superlative importance, inexperiments upon the effects of the complettins, of attendingto the satisfactory composition of the dietetic proteins.ro55

Mo investigations concerning oxy-prolin have come undermy notice ; but we can hardly be mistaken in assuming that,like tyrosin, it is replaceable by its unoxidised antecedent.In the case of oxy-prolixi this antecedent is prolin, and perhaps

also histidin . So com plicated a sub stan ce, being heterocyclic,can hardly be replaced by any other food constituent thanthose just named.

Before closing this brief survey of the biological importanceof the ammo-acids, we must refer yet again to Mitchell'swork,549 which shows that during brief experiments even graveerro rs in di et can. be com pensated. Ex perim enting on TvHtemice, M itchell gave the m a diet consisting of a mixtu re contain-

ing 34 % of starch, 28 % of protein-free milt (providing B,C, an d inorganic salts), 10 % lard, 18 % bu tte r (providing A),6 to 7 % sugar, and 4 to 6 % of a mixture containingvario us amin o-acids; this alternated with the same m ixtureexcept for the last-named ingredients, the arniao-acids beingreplaced by a supplementary 10 % of sugar. H e found th a tthis alternation of a protein-free diet with one in which theprotein content was manifestly inadequate gave better resultsthan either the protein-free diet or the diet containing amino-

ac id s given uninterruptedly* Obviously th e defects in th ecomposition of the amino-acid mixture (which wheaggivenunintermittently could not "but lead to overfeeding with some

, cf t h e amino-acids and to underfeeding w ith others) were m iti-



36 VITAMINS

gated in this way, that in the intervals when a nitrogen-freediet was given the body was forced to draw upon its own

stores of m ateria l. We know th at in such circumstancesthe most important constituents are vigorously retained bythe body, and that on the other hand an intensive nitrogenhu nge r is induce d. By these tw o factors, during the periodswhen the ammo-acids were given to the; white mice a betterutilisation of the nitrogen was ensured than wan possiblein the instances in which the arnino-acicls were given umnter-m itt en tly . Of course the organism 's powers of self-help inthis respect are strictly limited, and Mitchell could not keep

an y of the: w hite mice alive for more th an ()H days. W e see,however, that in brief experiments the organism has numerouspossibilities of self-help, numerous ways of compensatingfor defects in di et. Brief exper im ent s, therefore, do no tafford valid conclusions concerning the offerts of an experi-m en ta l diet* If gro ss fallacies are to be avoided, the expe ri-ments must be continued for so long a time that the sourcesof self-help in the organism run dry. K xpw im cnts upon th e

utilisation of proteins have commonly infringed this rule •especially when domestic animals have been the Mibjrcts ofexp erim ent. T h us only can we explain how, in fk*rntanydurin g the w ar, yeast (a substa nce of very low nutritiv e v a lu e !an far as its p ro tein is conc erned) could t>e recommended as *an adequate source of protein.

Inasmuch as the ammo-acids c^n only be utilised by theorganism in so far as the diet contains other con*ttttu»ntnenabling these acids to be amplified into protein* proper tothe animal under consideration, the supply (whctlier by mouthor hypodermically) of ammo-acids that cannot be thincom plem ented is a useless burd ening of th e body. This isproved by the rise in the amino-acid content of th*» bloodin such circumstances, and by the increased excretion ofam m o-ac id s in th e urines*** $*»

In view of all these considerations, a discovery made byA bd erh ald en «s» is easy to und ers tan d : it in almost indifferent

whether we give as food the protein specific to the animalconc erned , or p rotein from so m e extra neo us source ; on t heother hand, the aggregate protein of an animal is greatlysuperior to the protein derived from any individual organ,



BIOLOGICAL VALUE OF VARIOUS PROTEINS 37

2. THE RELATIONSHIP OF THE PROTEID TO THE

NON-PROTEID NUTRITIVE SUBSTANCES.

Of course in all such experiments the investigator muststrictly observe the conditions that were found essential inthe very earliest studies of protein metabolism. There mustbe an adequate supply of energy, measured with a liberalrather than with a sparing hand; and a suitable ratio mustbe preserved between the nitrogenous and the non-nitrogenousnutritive constituents. A vast amount of writing has been

devoted to this ratio, and the most contradictory views havebeen put forward. Especially conflicting are opinions con-ceAing the question whether nutrition can be adequatelysustained by proteins and carbohydrates in default of fats,or by proteins and fats in default of carbohydrates. Thisproblem is intimately connected with two others. First,can fats and carbohydrates be manufactured out of proteins ?Secondly, are fats and carbohydrates really built up into thesubstance of the organism, or do they merely serve to supply

it with energy ?The latter question is the more important of the two,

for if fats and carbohydrates do not form essential constituentsof the living tissues, their manufacture out of proteins ismanifestly superfluous. Proteins unassisted could then providefor the requisite supply of energy. For a long time, physiolo-gists were inclined to assume that fats and carbohydratesserved merely as fuel or reserve. The German experience of

war nutrition has, however, pointed towards the conclusionth at fats have a certain value as tissue builders supplementaryto their value as energy providers. I t might be contendedthat the ailments attributable to a deficiency of fat in thediet were mainly due to a lack of fat-soluble A, and the infer-ence mi&ht seem warrantable as far as the great majority ofthe population was concerned. But Similar ailments occurredin vegetarians, despite their daily consumption of such foods

as spinach and carrots, which contain large quantities offat-soluble A. We are therefore led to infer th a t fats areindispensable as tissue builders.

The objector may still point out that symptoms of fatdeficiency are not seen when there is a very liberal supply



38 VITAMINS

of protein. B ut , on the one ha nd , almost all food rich inprote in is also rich in fat (pulses, an d even lean m e a t ) ; and,

on the other hand, it may now be regarded as proved thatfa t can be formed out of superfluous protein . The ill-effects \of a fat-free diet can, therefore, only become apparent when!the supply of protein is reduced to somewhere near them inimum . Unim peachable experim ents of such a cha racterare not yet forthcoming.

However, the experience of various investigators accordswith th e da ta furnished by w ar dieting. Bierry957 was led

to the firm conviction that fats must actually serve as buildingmaterials in the animal organism, and that there must there-fore be an essential minimum of fat in the food no less thanan essential minimum of protein.833, 973, *™6 A specialist inthis field, Maignon, emphasises his view that the reason whyit is so difficult to a sce rtain thi s minimum is th a t f ats can be*manufactured out of proteins within the animal organism.744On the other hand, the same investigator has found that apurely protein diet is directly toxic to the animal organism..The to^c influence is not solely explicable as the outcome of *the effect of acids, for it cannot be prevented by the adminis-tration of alkalies; but it can be prevented by adding fator carbohydrate to the diet.778, 882, 883, 1081 Amar comes tothe same conclusion.779 B ot h Maignon and Am ar opine th a tin these circumstances the fats have a protein-saving influence.Maignon 87o, 9°3 at te m pt s to expla in this by suggesting th a tthe missing amino-acids may by aminisation be formed out

of the fatt y acids. (An objection to this theo ry is, th a t th eanimal organism is incompetent to build up amino-acids outof fat ty acids by am inisation.) Th ere m us t, however, becontributory factors, for the toxic influence of the proteinsexhibits ma rked periodic ity; it is mo st appa rent in springand autu m n, least app arent in winter and summ er. Possiblyth e more vigorous growth t h a t occurs during spring anci au tum nha s a be arin g upon t h is matter.941,1081, n*8 Carb ohydrate s,

likewise, can counteract the toxic influence of proteins.Bierry, Maignon, and their pupils are all in agreement here.778>779* 833> 936,957, 963,973. i°39, *™6 The addition of lard to theextent of one-fifth of the weight of protein is already enoughto improve the utilisation of th e pro te in ; bu t the best result,



BIOLOGICAL VALUE OF VARIOUS PR OT EINS 39

namely nutrition with the lowest quantum of protein andof energy supplied, is secured when eûal weights of proteinan d fat are given. 778> 883, 941, *™*Furthermore, a s imilar

improvement in the utilisation of proteins can be securedby supplementing them with carb oh ydr ates ; bu t in t h a tcase the supply of calories and the consumption of proteinwere higher with a diet containing equal weights of pro-tein and starch than with one containing equal weights ofpro te in and fat.77*. 941, "28

This view, that fats induce a better utilisation of proteinsthan carbohydrates do, is directly opposed to the opinions ofAtw ater, Mendel, and L ev i; and it is contested by T e r-

roine,^ 1 who, however, has no evidence to offer in rebuttal.Maignon,87°, 903 in order to explain th is m ode of actio n, a ss um esthat there is increased formation of amino-acids out of both,th e glycerine and the fatty acids of th e fa t s ; th e effect o fcarbohydrates is accounted for by their competence to supplythe demand for energy .93 Whereas it is difficult to believethat ammo-acids can be newly formed out of either glycerineor fa tty acids (see above), in m y view th e observe d facts a r ereadily explicable. We may suppose th at , w hen fat is lackin g',

proteins mu st be used up for the formation of fat. T h e re b y ,first of all, there ensues a greater consumption of protein§;and, secondly, the consequent products of protein decompo$i*-tion m ay very well account for th e toxic pheno m ena ^ tare witnessed in the bloodvessels and the kidneys ;

simultaneously (in accordance with Maignon's view) asiderable proportion of the protein mu st be expended t o ,supply the requisite energy. C arbo hy drate s, finally, t a k eeffect as savers of protein chiefly in v ir tu e of the ir pow er t ofunction as readily utilisable sources of energy. Th us t h eprotein-saving effect of carbo hyd rates is direc t, th a t of f a t sboth direct and indirect. These considerations likewiseexplain svhy it is that the best results as concerns both theutilisation of the protein in a diet and the calori e consumptionof a di et are secured when the diet contains fat and carbohydr ateas well as protein, and when the weight of fat is at least equalto that of the protein, whatever propor tion of carbohydrate th ediet may contain.

It is or should be obvious that valid and unambiguoxxs



40 VITAMINS

results can only be expected from such experiments whenthe supply of food constituents is kept down to somewhere

near the minimal requirements, above all as far as proteinis concerned . The defect of th e researches of A tw ate r andhis collaborators is that they gave quantities of protein greatlyin excess of the minimal requirements, thereby obscuring theinfluence of the fat upon the calorie consumption and stillmore its influence upon the protein consumption—for fatcould be manufactured out of the surplus protein.

It used to be believed that very large quantities of protein

were requisite, and those who still cling to that view will besurprised to learn that a diet containing equal quantities offat an d protein is the most economical. Am ar, however,showed as long ago as 1909 that in man the best utilisationof the food is secured when the diet contained equal weightsof fat and protein . Th e pro tein requirem ent will the n beminimal, and even the fat requirement will be only a fourthor a fifth of what was formerly assumed to be necessary.

3. T H E IMPORTANCE OF INORGANIC CON STITUENTS

IN METABOLISM.

Before we proceed, attention must be drawn to anotherfact which in Germany has been strangely overlooked andha s to a great ex ten t been even directly denied. I refer tothe effect of the inorganic constituents of the diet upon theutilisation of th e protein it con tains. The Am erican specialistsrequired nearly a decade to learn from their experimentsthat not only the total quantity of inorganic constituents,but also the quantities of the individual inorganic constituentsand their mutual quantitative relationships, and in especialthe relationship between anions and cations, are of decisiveimpo rtance in relation to th e dem and for protein. B ut, incontradistinction to their German colleagues, the Americansdid learn this in the end, and the consequences of the lessonare manifest in the incomparably better results secured bythe Americans, not only in respect of the utilisation of theprotein content of the experimental diets, but also in respectof the mean duration of life of the animals subjected toexperim ent. It is indeed strange tha t in th e land where thelaw ofcthe minimum was discovered, this law should be denied



BIOLOGICAL VALUE OF VARIOUS PR O TE INS 41

as far as the inorganic constituents of a diet are concerned.In 1912, ba rely two years after myself, Osborne and Mendel 22Sexpressly declared that a minimum of the various inorganiccon stituents is essential to the m ainten anc e of life ; a co m para-tively small supplement of each then suffices to ensure normalgrow th. A further increase of these inorg anic co nstitu en ts,

even an imm ode rate increase, exercises no furth er influenceon growth. In the next chapter this m at te r will be m oreclosely considered, but it was necessary to refer to the questionhere because without some knowledge of it the investigationsconcerning the biological value of the different proteins cannotbe properly appraised, and because these relationships throwlight* on m uch th at would otherwise be ob scure. I n eedmerely remind the reader how long the belief prevailed thatmaize protein is poisonous, until at length the realisationcame that the toxic symptoms which had attracted attention^were merely a form of acidosis consequent on the lack ofcertain inorganic constituents.451/ etc«

4. THE BIOLOGICAL VALUE OF THE VARIOUS VEGETABLE

P R O T E I N S .

The most important of vegetable foods are the cereals.They are diffused all over the earth, wherever plant-life is

possible. Many persons are of opinion th a t they co nst itut eideal foods, and Hindhede declares that wholemeal breadcomprises an adequate diet without any supp lem ent. Th isis by no means the case.

Rice demands consideration first, although comparativelyfew investigations have been undertaken concerning thebiological value of rice protein . Boyd Il 87 found its worthto be four-fifths that of meat protein, but his experiments areopen to criticism because he was not aware of the importanceof the inorganic constituents of a diet, and because his experi-m en ts were of too brief a duration. On th e whole it w ouldseem that rice protein is of a rather low grade, for Buckner,Nollau, Wilkins, and Castle 877 repo rt, in agreem ent w ithAbderhalden,8^ that rice as the exclusive source of protein^does no t suffice for normal growth. In especial, th e develop-ment of the genital organs is impaired, and reproduction is \hinde red. T he insufficiency of th e agg reg ate rice pro tein



42 VITAMINS

would seem to be qu an ti tat iv e rather than qualitat ive. I tcontains all the substances requisite for tissue building, but

some Of them are not present in adeq uate anw u nK If th eanimal can be supplied with a sufficiency of ri«'e protein (byadding isolated protein to the rice consumed), normal develop-ment and normal growth take place. P»uf, acmrdinj* !oOsborne and Mtfndrl,?*6 for this result to be arhieved flu*rice protein must comprise from t(> to tj % of the total f«jod.Seeing t h a t polished rice co ntain s on ly 0 ";, of pint* in, andunh ulfcd rice no more* th an 4.7 % , rice* an such v- inrninpr tentto promote normal development or to maintainBoruttau77* declares that ground rice (i.e. the mco nta in s a higher percen tage of pro tein th.m whole Tic«»,There must be some error of observation here, U n the experi-ence conflicts with tha t of all oth er investigators. O therwisethere is general agreement that in the rue grain the £ttmcontains the highest grade and the endosperm the fourst-gradtprotein.

In like manner, Osborne and Mendel i& decrtair that inthe case of maize tin* embryo alone contains protein ftdeqti.U*?for nutrition, whereas neither the whole grain imr thr Uwiirin competent even to maintain weight in animals frtl ujwnit . Tho n: hav e bc*en nu m en ais rene airljei rfinrrrn ing th«*biological value of maize protein, the subject having agreat attention because the inadequacy or tnxkity ofha $ been regarded as th e ratist? of {X'lla^ra"- -m atters tomore fully considered in the chapter on that rli*ttt.si*.

toni and Tullio w and Sherman lf tia agree in stating that inm an a nitrogenou s balance! ca nn ot be* m aintain rtl w ith m a k fa s th e on ly source of pro tein in tin* di et . Affo rding toSherman, Wheeler, and Yates,?*1 and according to hheottanand Wintcrs,7<* maize protein in for human being* eventhan tho a lready inaderjuate wheat protein, The q yof maize protein for growing p i ^ has \mm drftniteijr provedby Hart and McCoIlum,*1* H<igiJi/*\ McCollttm< Stmmond«

and Pitzji* and Hart, Stct*nbockp and l .*>tr \m*». *MI ; itdo es not e ven suffice to main ta in weight in thr* ad ul t pig.W*Baglioni,**0 Hogan,^ 1 Mr,(!olhtm and Saminomk^)41 a n dA bderh alden V hav e provt«d th a t maize protein will n otsufiico to m aintain growth in ra ts . According to AM crha lden ,



BIOLOGICAL VALUE OF VARIOUS PR OT EIN S 43

the biological value of maize protein is no greater than thatof th e endosperm protein found in polished rice. H ar t,

Halpin, and Steenbock,6

55 and also Nitzescu,8

°4 sta te thatmaize protein is inadequate even for grain-eating birds likethe barndoo r fowl; sooner or later th e anim als becomeemaciated and perish. Boyd Il 87 likewise considers the proteiiiof maize to be of a very poor quality, having only one-thirdor one-fourth of th e biological value of m ea t protein . Maizegluten, isolated as a by-product during the preparation ofmaize starch, is also, according to Osborne and Mendel,55°

of extremely low biological value, although much largerquantities of it than of crude maize can be administered asfoocfc Nevertheless, maize contains ce rtain p ro tei ds (maizeglutenin or glutelin), which are fully adequate to promotegrowth in animals. But the utmost amount of these inthe grain is 30 %, whereas at least 50 % of maize consistsof the quite inadequate zein,2I7,349, 393, 423, 1075. **9S. **63 so tha tth e ne t resu lt of maize feeding is un satis fac tory . Of course by

giving a sufficiency of the aggregate maize protein, a tolerableresult could ultimately be secured, but this would be a veryirrational way of feeding, seeing that two-thirds of the proteinare more or less completely lacking in essential tissue-buildingconstituents. Zein is especially characterised by the almostentire absence of lysin and tryptophan.55°> 6l3> 634 Conse-quently it is possible to supplement maize protein effectivelyby adding to the diet blood, egg albumin, edestin, cottonseed

protein, casein, and, above all, lactalbumin—the two lastbeing peculiarly rich in lysin and try pt op ha n. Superheatingmaize protein in the autoclave does no t bet te r i t ; on theoth er han d, in the case of m aize as in t h a t of cereals in gen eral,the process of germination appears to enhance the value ofth e protein. Attention may here be again draw n to th efact that the maize grain, like all other seeds, is inadequatein respe<!t both of the total quantity and the composition ofits inorganic consti tuents^, 451* 5

68> 578> 6l*, 655> 9°°, "43 I n the

case of the higher animals, the lack of calcium has a verymarked effect on growth.34* Unmistakable, too, is a gravedisproportion in the relative quantities of acids and bases,and Baglioni45* expressly states that the animals he wasexp erim enting on (guineapigs) died of acidosis. The • sam e



44 VITAMINS

observer draws attention to a fact which seems to be connectedwith the foregoing, and one which I myself demonstrated

ten years a g o ; when an animal is fed upon an in ade qua teprotein, a retention of nitrogen may occur despite the declinein body-w eight. If th e ma ize diet be supplem ented by asufficiency of fat, etc., then (in the absence of growth) anincrease in weight may occur through the deposit of fat andthe retention of water in the tissues, but the retention ofnitrogen is appa rent merely. W ith the substitution of anadequate protein and the addition of a sufficiency of alkali

(or even with the latter alone), there ensues a discharge ofthe accumulated nitrogenous and acid residues, with a resultantab ru pt fall in weight. As long ago as 1909, I referred to thi sretention of nitrogenous residues as being the outcome of theretention of acid residues which must occur when there is adeficiency of alkalies in the food.

As regards wheat protein, McCollum and Davis 425 declare

that 6 % in the food suffices to ensure normal growth in youngrats ; but these results are in sharp conflict with those of allother observers, such as A bderhalden *96 and Osborne andMendel.873,1082 When working in conjunction with othercollaborators (Hart,409 and S immonds and P itz 579,598), McCollumis constrained to admit that wheat protein does not sufficeto maintain growth in rats ; and Johns and Finks, Il8 9 experi-me nting under v ery rigid conditions, come to th e same conclu-

sion. H a rt and McCollum,4<>9 and H art , Ha lpin , and Stee n-bock,655 found that wheat gluten, the residue from thema nufacture of wh eat sta rch, w as inadequ ate for growth, inr a t s ; Drummond 876 came to the same result with chickens.H art and McCollum 409 found w heat ina dequ ate to pr om otegrowth in pigs, and McCollum and Simmonds^ 1 found itinad equ ate to prom ote grow th in dogs. Sherm an, Wheeler,and Y ates 720 found th a t whea ten bread made of a 74 % flour *

was insufficient to maintain body-weight in human beings,and their results were fully confirmed by the investigationsof Sherm an and Winters.74* According to Sherm an, W heeler,an d Y ates , and also according to McCollum and h is co llab-orators, wheat protein has unquestionably a somewhat higher

• A f lour re su l t ing from a mi l l ing process in wh ich 100 lbs . of wheatyie ld ed 74 lbs. of f lou r .



BIOLOGICAL VALUE OF VARIOUS PR O TE IN S 45

biological value than maize protein, but they seem to supple-m ent one anothe r to some extent. A m ixtu re of th e tw o

is still inadequate, but it gives better results than an exclusivediet of maize or wheat.When we consider the separate proteins of wheat, we

find that the relationships are much the same as with maize.According to an early (and therefore somewhat untrustworthy)investigation by Osborne and Mendel,2I7 glutenin, one of thetwo chief constituents of wheat gluten, is adequate for growth,whereas gliadin, the other chief constituent, is quite inade-qua te. To convert the latter into an ad eq uate protein, lysin

must be added.1200 But although gliadin is not competentto promote growth sufficiently,I27» 393.1075 i t is apparen tl ycompetent to maintain weight.^5. 24*. 4*3 I t seem s qu es tion-able, however, whether gliadin can really maintain the body'sstores of pro tein . According to Baglioni,393 it ca n brin g ab ou tthe maintenance of the nitrogen content of the body, andcan even increase th is ; bu t just as in feeding wit h m aizeprotein, so here, the increase in nitrogen content is a spuriousone dependent upon the storage of residues, and is attendedby an inevitable loss of weight. Since th e inad equ acy ismainly referable to a lack of lysin, and perhaps to some degreealso to a partial lack of tryptophan, wheat protein can beefficiently supplem ented by substances rich in th es e am ino-acids,such as gelatin, meat, eggs, milk, or considerable amounts ofcasein, or even by the protein of the e ar th -n u t (Arachishypogsea). Th e lowest-grade protein of w he at is th a t in th eendosperm. The protein of the bra n is of m uc h higher value ,

even superior to that of the germ as far as concerns richnessin substances essential to the maintenance of the animalorganism ; on the other hand, for the purposes of growth thegerm is somewhat superior to the aggregate grain, and twiceas good a£ th e endosperm protein.77*, 873, *°83 According toBoyd,Il 87 the biological value of the endosperm protein isonly about 39.5 % of that of meat protein.

Abderhalden found in his experiments *96 that the aggre-gate rye protein was inadequate for the maintenance of growth;it was inferior to barley protein, but certainly superior towh eat protein. Osborne and M end el Io8a also s tate that # r y eprotein is unsuited for the maintenance of growth in rats,



46 VITAMINS

but according to these authors it gives better results thanbarley. W e mu st leave the question undecided whether th e

divergency between these two authorities is to be explainedby the varying conditions of the respective experiments(the Americans certainly had a better mixture of salts as acon stituen t of their trial diet ), or by accidental differencesin th e specim ens of gra in u sed. As early as *<JU> * W J W

myself able to show beyond disp ute w . *r». 7K*. *:$ tha t inhuman beings, both during growth and in adult life, the nitrrh>\genous balance is better maintained by rye protein than by'wh eat pro tein. In the case of rye prote in, too, we find th a t

one of its constituents, gliadin, though fairly roinpotejit tr>maintain body weight,"7 is quite inadequate as a factor oigrowth."5> 4*3 The chief lack in rye p rotein would nwrn t obe lysin, but possibly tryptophan is likewise wanting, for theaddition of small quantities of casein or still better of Istctal*bumin makes comparatively small amounts of rye proteincompetent to promote normal growth, t oKl

Oats pla y a grea t par t in m odern di etetic s. It is all th*?

more interesting, therefore, to find that the strictly scientificexperiments of McCollum, Simmomls, and Pit/.^ fA ****> ihhtmwand Mendel,?^, loHl and Abtkrhalclen V> hav e proved clear lyand incontestably that oat protein is incompetent to main*tain normal growth in rats . According to Alxlrrhald en, it sbiological value is less than th at of rye* pro tein . M uckner,No llau, W ilkins, and Castle *77 found tha name th ing in t h ecase of chickens. Sherm an, Win ters, an d Phillips w go mfar as to say that the biological value of oat protein in human

nutrition is no greater than th at of m a k e protein, In oat&,as in the grains previously considered, it would M*v m t h a ithe proteins of the endosperm are of much lower grade thanthose of the whole grain.1011* By general agreement* ge lati nis an adequate supplement to oats ; but whereas Oiboroe andMendel 7s* found th at th e add ition of casein mtffkfd to m a k ea diet of oats adequate, the experiments of McCollum in thisdirection gave negative results.

Barley, too, plays a notable part in modern dietetic*.But in this case likewise the unexceptionable experiments ofBucjcner and his collaborators ^7 with chicken s, and th o seof AbderhaJden%* and Osborne an d Men del"** w ith rats.



BIOLOGICAL VALUE OF VARIOUS PRO TE INS 47

showed that when barley protein was the sole protein in thefood, grow th was not m aintained. Th is becom es explicable

when we learn that hordein, one of the chief proteins in barley,contains no lysin, and is consequently quite inadequate.21?*us, 423 Apparently, however, the lacking tissue builders arepresent in the other proteins of barley, for with a diet con-taining 5 -4 % of isolated barley pro tein S teenb ock , K en t, an dGross 740 find th a t weight can be su stained, an d th a t when th epercen tage rises to 13-6 a slight growth beg ins. Acco rdingto Osborne and Mendel,736 normal growth takes place whenthe food contains from 16 to 17 % of bar ley pro tein .

Recording to Hogan's researches,6 80 th e kafiirin of milletcontains too little lysin and cystin to suffice even for themaintenance of body-weight.

W e see, then, t ha t none of the cereal pro teins are com petentto maintain the growth of the animal body,3*9 and that onlya few of them (rye and barley) are adequate to keep up thenitrogenous balance in the adu lt. Since all th e pro teinsare different, it seems theoretically possible that in a mixtureof various sorts of grain there will be a mutual compensationof deficiencies. Th e experiments of McCollum an d Sim mond sshow that this compensation does to some extent occur, formixtures of the kind have as a rule a far higher biologicalvalue than the proteins of the individual cereals used inisolation.6 8**8a* Nevertheless, even the m ixt ur e of as m an yas eight to ten varieties of grain proves inco m pete nt to pro m oteperfectly normal growth, although such a mixture can ensureth e m ainten ance of body-weight. The rea son for th e inade-4

quacy is tha t the cereals have the comm on defect of con taining!too little lysin and cystin, and in most cases too little trypto-iph an as well. Furtherm ore, the cereals con tain to o low a*percentage of protein, so that without isolating the proteinsit is impossible on an exclusive cereal die t t o ensu re anadequate supply of these. In this connexion, ,we secureanalogous results as when inadequate mixtures of amino-acidsare used, as experimental diets,54? for better effects are attainedby ringing the changes on different kinds of cereal proteins than

by persistent feeding *%vith any one kind.*9s

Pea legumin in sufficiently, high doses is a ble t o m ai nt ai nbody-weight,**5> 4*3 but is inad eq ua te as a grow th fa cto r. The



48 VITAMINS

aggregate protein of peas is, on the other hand, utterly inade-quate, and according to McColIum and vSimmonds its biologica!

value is very low.6În my o wn e x p e r ime n t s^ . *M, 7H, %* I when haricot hmns

were used as the sole source of protein in the diet, even theapproximate maintenance of body-weight was impossible.McColIum, Simmonds, and PitzW also agree in forming avery low estim ate of th e biological valu e of bean pro tein ;the replacement of the protein in an adequate diet by onlyI 9 # 8 % of bean protein already suffices to upset the nitro-

genous balance m arkedly. Bu t a com paratively sm alladdition of casein makes good the defects of bean proteinin a marvellous m ann er. In later exp erim ents, McColIum an dSimmonds 6 s8 ascertained that bean protein and maize proteinare to some extent complementary, for one-third beans andtwo-thirds maize will determine a moderate amount of growth,which is, however, of brief duration, and is only half as exten-sive as th e growth brought about by milk protein. Boy d %t%t?therefore takes a far too favourable view of bean protein whenhe ascribes to it an efficiency 60 % that of meat protein.

Very rem arkab le is the discovery of Adkins,"** th a t th egermination of beans greatly promotes the digestibility ofthe protein they contain ; but during the drying of the beamthis improved digestibility entirely disap pears. Ac cordan t inthe observation made by Johns and Finks,10** that the ad dit ionof cystin to beans leads to no more th an a trifling im prov em entin the value of bean protein ; but that when the beans are

predigested, cystin is an adequate supplement to their protein.Conflicting, however, with Adkins' observation is the furtherpoint made by Johns and Finks, that the addition of cystinrenders the bean protein adequate even when the beans havebeen boiled for a long time and subsequently rcdricd.

According to Osbo rne and Mendel,**5> w ihm phumdinof beans is quite incompetent even to m aintain the nitroge nou sbalance of the animal body.

The same authorities inform us that the conglulin oflupines is equally inadequ ate. Accordant with this is t h efact that , in Abderhalden 's experiments^ lupines wereincompetent to maintain growth in rati .

The vignin of the fodder pea, which makes up the greater



BIOLOGICAL VALUE OF VARIOUS PR OT EIN S 49

part of the protein of that pulse, is likewise quite inade-quate ™ s* 423 ; and , speaking generally, O sborne a nd M endel 665regard the protein of pulses as of an extremely low grade.B ut the re is no rule without ex ception. Two of the pulses?have high-grade protein, the soy bean and ttxe earth-nut.

Experimenting on rats, Osborne and Mendel 6 l3 were ableto secure norm al growth in these animals by feeding the m w ithsoy beans. Elsewhere 665 they agree with Daniels andNichols 659 in describing the soy bean as a so urce of high -grade^protein suitable for hum an nu trition . Osborne an d M endel ai7were also able to secure normal growth by using glycenin

isolated from th e soy bean. Abderhalden, ^ 6 indeed, refers tothe soy bean as inadequate to promote growth in rats, butth e failure here m ay hav e been due to' some other cau se th anprotein insufficiency.

Daniels and Loughlin 6 S l found that the aggregate proteinof the earth-nut (Arachis hypogaea) was of great value forhum an nutrition . According to Joh ns and Finks, Il 89 in thecase of w hite rat s, th e replacement of 15 % of t he w hea ten

flour in the food by earth-nut meal sufficed to secure nearlynorm al gr ow th ; and when 25 % of earth-nu t meal wa s used,grow th was entirely satisfactory. I t follows th a t ea rth -n utprotein must have twice the biological value of wheat protein.The result seems all the more remarkable seeing that arachinand conarachin, two of the chief proteins of the earth-nut,prove quite inadequate, whether given separately or in con-junction, and that they cannot be rendered adequate by theaddition of cystin, tryptophan, prolin, alanin, leucin, valin,

or histidin. Sure suggests th at th e inad equ acy of the seproteins may be due, not so much to the lack of this or thattissue-building constituent, as to some inner chem ical peculiar-ities, somfc struc tur al isomerism. W e know of similar instances*Two of th e amino-acids are readily saponifiable in one com bina-tion, but in another combination are almost unsaponifiable.

Other adequate seed proteins are found in hemp seeds,pum pkin seeds, cotton seeds, and certain n ut s. Th us, Osborne

and Mendel reportai

7 tha t hemp edestin is competent tom ain tain gro wth iti ra ts . B u t its efficiency is only on e halfth at of lactalburnin,54i and is no tably enh anced b y th e add itionof a small (ju^tity of cystin. 55°

4



50 VITAMINS

According to the same authorities, the globulin ofpumpkin seeds is a perfectly adequate growth factor.*25> w

Osborne and Mendel 493 were also able to maintain growthin rats by using cotton seeds as the only source of protein, andRichardson and Green SM rep ort a similar success. Acco rdingto the last-named investigators,654 18 % of cottonseed meal inthe food suffices to prom ote gro w th ; b ut if the pro portio nbe less tha n th is, an arrest of grow th occurs. T he y found,however/48 that the rats' general power of resistance wasincreased and that the animals reproduced their kind more

frequently w hen, in addition, 5 % of casein was given . Con-formably with these results, it appears that the globulin ofcotton seeds, the chief protein of these, is an,adequate growthfactor.*35> 4*3

Nuts are often recommended as an admirable nutrient(" vegetable mea t " ) . Th e recom m endation is confirmed bythe experiments of Cajori,1*66 who finds that (in rats) walnuts,alm onds, hazel nuts, and pine kernels are competent to promotegrowth, development, reproduction, lactation, and the rearingof th e young. Osborne and M endel 2*5,433 repor t th a t th eexcelsin of Para nuts is an adequate nutr ient . Joh ns, Finks,and Paul8?* found that the globulin of the cocoanut was anadequate growth factor in rats, and that cocoanuts werealmost completely sufficient as the sole source of protein inhum an beings. Subsequently they ascertained th at by th eaddition of cocoanut, maize could be made an adequate foodfor hum an beings. Bu t th e hickory nut appears to contain

only low-grade piroteins, for, if growth is to be maintainedon a diet of these, two -thirds of the protein m ust be su bs titute dby casein.1*66

I** Sug iura an d Benedict,775 feeding w hite ra ts on bananas,were unab le to secure norm al grow th. W hen piire caseinand a little yeast or extract of carrots were added to thebananas, normal growth took pl&ê and reproduction waseffected, but a normal milk could not be produced on this

diet. The effect of th e casein does n ot depend upo n a com ple-mentary effect upon the protein, for meat protein cannot takeits place. In a later series of experiments,9 8° the sameobservers were able to confirm th e a de qu atin g influenceof casein. Lewis,968 feeding guineapigs on bananas alone*



BI«L *G ICA L VALUE OF VARIOUS PRO TEINS 51

found that the animals died in from twenty to thirty daysfrom failure of n u tr it io n ; when oats , "bran, milk, or casein,

and inorganic salts, were added to the bananas, the animalsthro ve. Any one accustomed to the critical stu dy of experi-ments of this character will derive the impression that whatwas wrong with the exclusive diet of bananas was not theinsufficiency of the banana protein, but some other defect;perhaps there was not only a lack of calcium, but also a lackof th e com plettin A. Bailey Asford I29 relates that indigensconvalescing from yellow fever, eat nothing but bananas,

consuming from thirty to forty of these fruits daily withoutany sup plem ent whatever, health an d strength re turning in amarvellously sho rt time . I hav e myself prov ed th a t, afterhabituation to the strange diet, it is possible to live very wellon bananas and butter, with a much lower consumption ofprotein than is requisite, for instance, upon a wheaten diet.

Feeding rats on potatoes, McCollum, Simmonds, and Par-sons 777 found th a t grow th was insufficient, even when th epotatoes were supplemented with bu tte r an d salt. They

estimate that the biological value of potato protein is onlyab ou t half th a t of cereal protein. B ut this repo rt conflictssharply with the results of numerous experiments, lasting insome instances for years, made on human beings by Rubner,Thomas, Hindhede, and myself. These experiments showedthat potato protein was an adequate growth factor, and alsosufficed to ensure th e m ainten ance of bod y-w eigh t. In m yown experiments, the biological value of potato protein was,,

under certain conditions, even greater than that of meatprotein, and was surpassed only by that of milk protein and

pro tein . The discrepancy in th e respective series ofobservations is perhaps explicable by the inadequacy of thesupp ly of inorganic salts in McCollurn's ex pe rim en ts. I t ispossible, also, thatjpotato protein has verjr different biologicalvalues for different species of aixunajfe.

McClugage and Mendel,748 experimenting on dogs withcarrots and with spinach, found that the protein of both these

vegetables was quite inadeq uate. According to Br un tz andSpillman,7^ when rats are put upon a diet of carrots, normalgrowth can (M y be secured by th e ad ditio n of casein. «^'

It was mentioned above that conclusions as^to ti



52 VITAMINS

biological value of a protein determined by experiments uponanimals of one species are by no means necessarily applicableto animals of ano ther species. A strik ing illustra tion of t h eneed for caution in this respect is afforded by the varyingeffect of yeast protein in hum an beings and in rats . F un k a n dMacallum/6 4 in conformity with Osborne and Mendel,^7report that yeast (supplemented with A in the form of butter)supplies a protein which is a fully adequate growth factor inrats, and also suffices to ensure the reproduction of theseanimals. In hu m an beings th e result is different. F u nk , th is

tim e in collabo ration w ith Lyle an d McCaskey,5^7 found t h a tfor thejtmman species the biological value of yeast protein isvery low. W intz 53° ha d earlier come to the sa m e co nclu sion,finding^that human beings could only tolerate the replacementof other proteins in the food by yeast protein up to an amountof from 20 to 25 % ; bey ond th a t, a loss of nitro ge n from t h ebody began. H aw k, Sm ith, and Ho lder g7* likewise reportthat in the human species the nutri t ive proteins can only he

substi tuted by yeast protein to the amount of from to t o30 % — to say nothing of th e fact th a t only very small qu an ti-t ies of yeast can be administered to human beings withoutdisagreeable results; 4 grammes of yeast will inducediarrhoea.

5 . TH E BIOLOGICAL VA LU E OF THE ANIMAL PR OT EIN S.

Animal eggs resemble vegetable seeds in many respects,

especially as rega rds their inorganic co ns titu en ts. In th ematter of the proteins, however, there must obviously be afundamental difference, above all when animal eggs ;trecompared with the seeds of cereals. W herea s the la tte r ar equite incompetent to function as adequate growth factors inanimals, the anim al egg m ust perforce con tain ev ery thin gessential to the development of the growing animal embryo,Consequently, egg protein (as the sole source of protein)

completely suffices for the needs of growing animals—rats,for instance.425 E ve n in ve ry sm all q ua n tit ie s, it ca n fullycom pen sate the deficiencies of ma ize 393 or wheat.*7J B u t t h eremarkable thing is, that both the chief proteins of the bird 'segg sxe ade qua te in this respe ct. Osborne an d M endel **5. «*lhave proved it as regards vi ieUin; according to Hart and



BIOLOGICAL VALUE OF VA RIOU S PRO TEIN S 53

McCoUum,4<>9 and also according to Osborne and Mendel,349trifling amounts of egg-yolk can render maize an adequatenu trien t. This power is mainly dependent on the abundanceof fysin and tryptophan in the yolk, but the cystin of theyolk m ust likewise play an im po rta nt pa rt . Osborne andMendel 217> *2S> 423 also confirm th e adeq uac y of ovalbumin,which is competent to ensure normal growth, and can inaddition make good the deficiency of maize protein,45° althoughnot quite so well as casein 568 (which is richer than ovalbumin

in lysin and tryptophan), Maignon's observation

6

^*

I I2 8

t h a tra ts , Myers and Voegtlin's observation 9ZI that rats, and Maig-no n's observation 743 th a t dogs, canno t live on an exclusivediet of white of egg, does not conflict with the foregoing, forthe speedy death of animals in such extremely one-sidednu trit ive experim ents is no t due to prote in insufficiency, b u tto a general lack of other nutrients, and especially of inorganicbases.

Blooi protein, like egg protein, is an adequate nutrient.Comparatively small quantities of it suffice to make maizecom peten t to sustain growth in th e pig.346 According toHogan 568 its value largely depends on lysin and tryptophan,but also to some extent on cystin. Blood-serum, in especial,is so rich in cystin, that when casein (already fairly rich incystin) is used a s th e soured of prote in in feeding dogs, a triflingaddition of blood-serum to the diet leads to a d istinct imp rove-

ment in growth.Il83 On the other han d, Maignon 6& finds thatfibrin is quite unsuitable as an exclusive nutrient for whiterats , and that this diet soon leads to the death of the animalsunder experiment; but I have frequently pointed out that,since the aim of Maignon's experiments was to show that theanimal organism needs other nutrients in addition to protein,and that an exclusive diet of protein is poisonous, his experi-ments do not really tell us anything as to the respectivequalities of the proteins with which he experimented.

The rapidity of growth in mammals during the periodwhich immediately follows birth, suffices to prove that milkcontains an adeq uate protein, and indeed one of extrao rdinarilyhigh nu tritive value. The qu antities of th is pro tein requiredin th e food are marvellously small McCollum and Davis 4*5found that 3 % of milk protein (from cow's milk) in the*food



54 VITAMINS

sufficed to ma intain body-we ight in ra ts . An increase of the

percentage of milk protein in the diet was attended by aproportional increase in the rate of growth, until a proteincon tent of 8 % was re ac h ed ; an increase of the percentagebeyond this figure had no further influence on the rate ofgro wth. Owing to the presence of th is high-grade proteinin milk, it is possible to make proteins, that are otherwisequite unsatisfactory, perfectly adequate by the addition of

small qu an tities of milk to the diet. Thu s, McCollum andhis co llabora to rs ,^ , 9°°> IJ43 feeding pigs on an exclusive dietof maize, found that the replacement of io % of the aggregateprotein in the food by milk protein resulted in growth becomingfairly satisfactory. When the substitution amounted to30 % , growth was perfectly norm al. Sherman I0

5* obtainedsimilar results in human beings ; when adults are being given

an exclusive diet of wheat, maize, or oats, the replacementof onfy 10 % of the aggregate protein by milk protein sufficesto restore norm al nu tritiv e conditions. Like observationshave been made by others experimenting with wheaten diet 873and banana diet.96 8 B o y d I l87 gives the relative biologicalvalues of cow's milk protein and meat protein as 96-5 :100;in my own experience, milk protein has a decidedly higher

biological value than meat protein, both in adult and in younjsubjects. Edelstein and L an g st e in ,^ experimenting 01children, found th e following rela tive values : cow 's milkcasein, 73 ; cow's m ilk lactalb um in, 82 ; aggrega te cow's milklproteins, 73; aggregate human milk proteins, 88. Fiirthiand Nobel J3°7 likewise found hu m an milk proteins markedlysuperior to cow's milk p ro te in s; th e former contain so much

cystin and tryptophan that human milk, though its richnessin total proteins is lower than that of cow's milk, containsmore of these amino-acids th an cow 's milk. I t m us t no t,however, be forgotten that full milk contains in addition toproteins a number of other bodies competent (even whenadministered in very small quantities) to exercise a powerfulinfluence in promoting growth. Hopkins,*0* for instance,



BIOLOGICAL VALUE OF VARIOUS PRO TEIN S 55

th e diet by o nly 4 % ) sufficed to ensure no rm al grow th. W emay suppose that the chief cause of the improvement was

that the milk provided complettins, and especially A, thatwere previously lacking in th e diet. This is striking proofthat even a high-grade protein cannot sustain life in theabsence of a sufficient supply of complettins.

S«me earlier experiments on rats made by Osborne andMendel 217> ^s> 4*3 conflict w ith th e foregoing, for caseinwithout the special addition of complettins sufficed to bringabout satisfactory development. But, in the first place,

^the duration of the experiments was only 30 days, and this

period is too short to permit of valid conclusions being drawn;and, in the second place, there is some ground for assumingthat Mendel was using casein as ordinarily manufactured,i.e. an impure casein containing fairly large amounts of A.At any rate, Lewis, Cox, and Simpson Il 83 found that in dogs,when a really pure casein was used, the results confirmedH op kins ' observations on ra ts . M aignon's failure to securesatisfactory results by the use of casein as an exclusive diet

in rats

6

4* and dogs 743, 941, «*8 {Sf a s previously mentioned,explicable on grounds which have nothing to do with thebiological value of the protein.

An additional proof t ha t casein is a very high-grade proteinis furnished by the fact that proteins otherwise inadequatemay be made adequate by the addition of casein, sometimes invery small quantities. This has been dem onstrated by experi-ments with gliadin,349 maize,409, 568* 578* 6 l3, *>55*658 wheat,579beans,636 carrots,784 and oats 736 ; but, as regards oats, seealso 6*5. According to Hogan, where maize is concerned,the add ition of casein is m ore effective th a n th a t of w hiteof egg. Ev en in the case of so high-grade a prote in as cotto n-seed prote in, Richardson and Green 648 no ted an improve-ment through the addition of casein, insomuch as the animalsunder experiment acquired a higher power of resistance, andtheir m or ta lity was lessened. In t he case of bananas,775»968, 980 too, th e add ition of casein to th e d ie t wa s followed

by m arked im prov em ent; bu t here a considerable pa rt ofthe effect must be ascribed to the complettin A, which isalways present in casein as ordinarily manufactured, and tosome ex ten t perh aps to th e calcium in th e casein. According



56 VITAMINS

to Osborne and Mendel,1082 however, the biological value of

casein is only two-thirds that of lactalbumin.In their earlier experiments on rats, Osborne and

Mendel 217» ^5» 433 found lactalbumin to be an especially high-grade pro tein. According to E m m et and Luros,879 protein-freemilk plus lactose plus 10 % of lactalbu m in comprise anadeq uate diet, guaranteeing normal growth. B ut the twoobservers last named are mistaken in regarding the lactose

in th e protein-free m ilk as th e growth, factor. Do ubtless theaddition of carboh ydrates is very im p o rt a n t; bu t Osborne'sresearches have shown that the effective factors in protein-freemilk are, over and above the complettins, chiefly the salts,and more especially the overplus of alkali in these. In asubsequent paper,898 Emmet and Luros state that the biologicalvalue of lactalbumin is not impaired by drying or by pro-

longed hea ting, even under 15 po un ds ' pressure. Accordingto Osborne and Mendel,541 10 parts of lactalbumin will furthergrowth as efficiently as 15 parts of casein or 19 parts of edestin ;and in various other reports,55°, 6l3> 877, ^2 they emphasiseth e superiority of lactalbum in to casein. Subsequent researchesby Sure I264 have, however, shown that the remarkably favour-able results of Osbome's experiments must be in part ascribed

to errors in the quality of the supplementary extracts heemployed (the nitrogen content and the sulphur content ofthese). Exact experiment showed that chemically purelactalb um in, tho ug h rich in lysin 349 an d ex trao rdin arily richin tryptophan,I3»7 is poor in cystin and to some extent alsoin tyrosin. Osborne's protein-free m ilk con tained 0*2 % ofsulphur, chiefly in the form of cystin, and also (with an aggre-

gate nitrogen co nten t of only 0-6 % ) considerable qu an titiesof tyrosin, whereby the lactalbumin was supplemented.W ithou t protein-free milk, 18 % of lactalbum in in th e d ietproduced only poor g ro w th ; wh ereas a food containing n omore than 12 % of lactalbumin supplemented by only 0-12 %of cystin ensured normal grow th. W hen th e am oun t oflactalbum in in th e food was reduced to 9 % , th e add ition of



BIOLOGICAL VALUE OF VA RIOU S PRO TE INS 57

tional evidence as to the extreme difficulty of providingunimpeachable conditions in these experiments.

The experience of the war has abundantly shown thatwithin wide limits the composition of milk is independent ofth e food supply. As long as the req uis ite tissue-buildingconstituents are present in the maternal organism, the mothercontinues to produce milk of a definite composition . Thisapplies not only to proteins, fats, and carbohydrates, but alsoto com plettins and inorganic salts . W hen the su pply ofany tissue-building constituent is inadequate, the quantityof the milk falls off, bu t its com pos ition is unaffected. Of

course this statement is true only so long as the maternalorganism can provide the requisite materials, and, more espec-ially, so long as no pathological changes have occurred inthe mother's organs. The lacteal glands ha ve no more powerto synthetise arnino-acids than have the other animal organs.McCollum and Simmonds I0*6 expressly declare that if onlyone tissue-building constituent is entirely lacking, the secre-tion of milk is arrested. Th roug h illness, however, and in

the human species through the inheritance of morbid predis-position, the lacteal glands may be so modified that evenwhen the diet is the best possible their secretion may bewanting, or they may furnish milk of abnormal composition.

F#r a very l#ng time, mi*b has been regarded as the bestsource of protein, and it is universally known that for humanbeings m eat protein is perfectly adequate.337 Ac cording toOsborne and Mendel,663 this is true even when the meat hasbeen boiled and subsequently dried after expression of the

juices ; and M aignon 744 finds th a t th e vi rtu es of m ea t pr ot einare unimpaired when the meat has been boiled and thenextracte d w ith alcohol and ether. T he othe r anima l orga ns,such as pig's liver,663 p ig 's heart , or ox ' s h e a r t y are adequategr#wth factors, and so is fresh or preserved fish,? r3,690 Never-theless, Lewis 653 finds th at the va lue even of m eat pro teincan be greatly enhanced by the addition of small quantitiesof cystin. It should, morover, be m ent ion ed th a t my own

experiments, as also those of Pezard^ and Kraft,

IO

39 showthat meat protein does not suffice even to maintain nitrogenotisequilibrium unless the diet contains inorganic salts in definitequantities and proportions. This has, indeed, long been



58 VITAMINS

know n. If a dog be fed on m ea t from w hich the juices ha veI been expressed, emaciation ensues after a time, toxic symptoms

I set in, de ath speedily follows, and pos t-m orte m exam ination* shows in th e skeleton th e changes characteristic of osteom alacia]Or osteoporosis. Carnivorous an imals living in a st a te ofnature ensure a supply of inorganic bases by drinking theblood of their victims and devouring the bones and thecartilage s as well as th e flesh. I t also appea rs th a t wildcarnivora consume at times considerable quantities of fruits,leaves, and bu d s ; they do this especially in the au tum n,

whereas in th e spring the y live almost exclusively on animal food.Boyd regards meat protein as the most valuable of allforms of protein,Il87 but this cannot be accepted as a positivefact as regards the protein of individual muscles, only asregards the aggregate protein of an animal body used as food.Abderhalden 45* learned this in his experiments on ra ts . Myown researches show that the aggregate protein of eggs, thatof cow's milk, and to some extent that also of potatoes, aremore efficiently utilised th an me at pro tein. In these experi-ments, however, the meat was given with an excess of acids.In some hithe rto unpublished experiments ma de by Rose,in which c are was ta ke n to sup ply an ade qua te excess ofalkalies, m eat pro tein was found t o h av e a value app rox i-mately equal to that of milk protein.

It has long been known that the biological value ofgelatin is low. Th e older experiments th at proved this hav ebeen confirmed by the comparatively recent work of Osborneand Mendel,**5> 4*3 Totani,6 00 and Lecoq.IO75> 1076 Gelatin ispoor in cystin, and therefore ca n be used to supplem ent proteinsthat are rich in cystin, or at least contain a fair quantity of thatsub stance, such as m aize pro tein 598 or arachin.x*53 B ut gelatinis rich in lysin, and therefore ve ry m ode rate qu antities of gelatinenable it to supplement proteins th a t are in adeq uate becausethe y contain too little lysin (such as wh eat protein and oat pr o-tein), thus converting them into adequate nutrients.598, & $, 736

6 . T H E CONDITIONS REQUISITE FOR THE FULL EFF ICIEN CY

OF THE VARIOUS KLNDS OF PROTEIN.

A protein is not rendered adequate merely because allth e requisite amino-acids are presen t in it in sufficient qu an ti-



BIOLOGICAL VALUE OF VARIOUS PR O TE INS 59

ties. Attention has already been drawn to the part thatmust be played by the mode of combination of the individual

tissue-building constituents. Fischer and A bderhalde n showedsome time ago that alanyl-glycin can be split up bytiypsin, whereas glycyl-alanin cannot be decomposed byferments. Some such pecu liarity of com position m ay explainwhy arachin is so utterly inadequate a protein, althoughanalysis would seem to suggest that this substance ought tobe of high biological value. Similar conditions mus t ac coun tfor the very inadequate way in which zein can be utilised byra ts , even when it is supplemented by the addition of thelacking tissue-building constituents, whereas zein can beefficiently utilised after preliminary hydrolysis.6 00 Likeconsiderations must explain why freshly germinated beansare b etter digested th an dried beans I I 6 6 ; why phaseolin cannotbe efficiently supplemented by cystin unless the phaseolinhas first undergone a tryptic digestion or has been boiled andthen redried IO94; why a mixture of equal parts of soy bean,wheat, wheaten bran, sunflower seeds, hemp seeds, and rye

meal (a mixture which is perfectly adequate in the crudestate), proves conspicuously inadequate after it has beenmade into a paste with water and then baked.877 In suchcases, therefore, the student of nutrition must have an eyeto these details. ;

It is likewise necessary to point out that (in accordancew ith the law of the m inimum) when there is a lack of complettin,even the highest-grade album in will be incompetent to prom ote

satisfactory development ™ w*J

*6

4 Th ere is no mean s of ascer-taining the requirements of the organism as regards anypar ticula r constitu ent, unless in respect of every oth er cond itionth e diet is all th at can be de sire d.^ , 664

On the other hand, in experiments on nutrition, it wouldbe a mistake to supply any constituent of the diet in quantitiesexceeding the optimal am ount. Th ere are two ob jections ;*first of all, this needlessly overloads the organism; a&d Jsecondly, it increases the minimal requirement of other!constituents. The diet must contain a sufficiency of all necesJfsary ingr edients, but there must be no notable excess of any.For example, in experiments upon the effects of complettins,it would be a mistake to give an excess of protein in order to



60 VITAMINS

ensure that the results shall not be invalidated by protein

deficiency. Inasm uch , however, as the biological va lue ofthe different proteins varies enormously, and the minimalrequirement of protein will vary in accordance with the natureof the supply,836 , 837, Io6

7, i*88 in such experiments the mostsedulous attention must be paid to the biological value ofth e pro teins supplied in th e food. Of course th e best w ay isto have a preliminary series of control experiments in order

to ascertain the quantities of proteins that are necessary, orthe nature and amount of the requisi te supplements.

The investigator must also bear in mind that the proteinrequirements vary at different ages. In adult animals andhu m an beings, it suffices t o give qua ntities of pro tein com petentto maintain the body-weight throughout experiments ofconsiderable du ratio n. D uring grow th, however, ve ry different

cond itions prevail.*^* 423, 425 A t th is tim e of life, besides th equantity of protein needed to maintain body-weight, theremust be given enough protein to ensure that developmentand growth shall proceed at least as fast as if the animalwere free to choose its own food from an unrestricted supply.The first requisite, then, is a thorough knowledge of the normaldevelopment of the experimental animal under the most

favourable cond itions, and this presupposes abu nd an t statistics,such as Robertson and Ray 483> 484 hav e supplied in exem pla ryfashion in th e case of th e w hite ra t. N ex t, there mu st b ean increase in the protein supply sufficient to provide for theincrease in th e tissues. T he requ isite increase, again, va riesat different periods of growth, and may at times be very large.In my own experiments^^ I found that the protein require-

ment of the growing youth exceeded that of the adult maleby from 50 to 80 % ; Benedict,993 Holt ,IX I7 and others recordsimilar results. In yo ung persons from 13 to 19, du ring t h eholidays, the protein requirement is almost twicer as greatas that of adults.

In the earlier studies we are usually informed th a t th ebasic turno ver is lower in wom en tha n in m en. To -day we



BIOLOGICAL VALUE OF VARIOUS PRO TEINS 6 1

minimal requirement will rise considerably when reproductionand the rearing of offspring have to be provided for in addition

to self-maintenance.995,I0

5* During the present chapter wehave repeatedly learned that a protein may be adequate forthe maintenance of body-weight, but inadequate for theneeds of reproduction and rearing.

As regards human beings, as early as 1913 I pointed outthat, when the conditions are in other respects optimal, theamount of protein requisite to maintain body-weight is farsmaller th an ha s hithe rto been supposed. Am erican investi-

gators have confirmed this contention when their experimentshave JDeen carefully designed . Boyd ,Il87 for instance, givingmeat as the source of protein, estimates the minimal dailyamount of protein requisite to maintain body-weight at30 gr am m es ; whereas in m y own experim ents, under moreaccurately adjusted conditions, the requirement w as^^ grajm nesof m ea t p ro te in ; and Rose, providing a be tter supply ofalkalies, found the meat protein minimum to be 24 grammes.Sherman,I0

5* in a critique of all previously published results,

and after conscientiously making allowance for all accessoryfactors bearing on the various experiments, came to theconclusion that the protein requirement in a person weighing70 kilogrammes averaged 40-6 grammes (ranging from 30gram mes to 50 grammes) ; being 0*58 grammes of proteinper kilogramm e of body-weight. In another co m m un ica tion ,^this observer declares that from 35 to 45 grammes of proteindaily (0-5 to 0*6 grammes per kilogramme of body-weight)

are quite sufficient to maintain weight in a healthy humanbeing weighing 70 kilogrammes, even though the proteins beno t carefully selected, nor of a specially high grad e. A supplyequivalent to 1 gramme of protein per kilogramme of body-weight, when a mixed diet is taken (i.e. when there is nocareful selection of particular nutrients), provides a marginof safety of from 50 to 100 % . Fo r grow th an d rep rod uctio n!larger quantities are, of course, requisite, and it is also desir-!

able in that case that the proteins should be of highbiological value.



CHAPTER THREE

THE IMPORTANCE OF INORGANIC SUBSTANCES.

i . T H E S UPPLY OF A SUFFICIENCY OF NUTRITIVE

SALTS.

I N German scientific circles, the te rm " nu tritiv e s a l t " isin bad odour ; its mere presence in a scientific essay sufficesto discredit th e work. No r was this attitu de entirely un -founded, at one time . Th e imp ortance of the proteins andof the supply of energy was so conspicuous to all studentsof human dietetics, that the importance of inorganic salts tonutrition was entirely overlooked by scientific observers.All the more, therefore, did these salts win the favour of thelaity and of quack-doctors ; they were regarded as a panacea,recommended indiscriminately for the relief of all troubles,from heartburn to cancer and consumption, so that nutritivesalt preparations sprouted in the market like mushroomsafter rain. We m ay question, however, wh ether the m edicalprofession was well advised when, in the hope of checkingth e evil, it tabooed a ll reference to th e problem. Be yondquestion the wiser course would have been to ask what firethere was behind so m uch smoke. Th e result of th e tab oowas that as recently as ten years ago not a single completeand accurate analysis had been m ade of th e inorganic con stitu-en ts of a ny organ in m an o r th e lower anim als, of »any of th ebodily juices, or of an y of th e excretions. Qu ite an ou tcry

was raised when at that date I ventured to maintain as much,and it is but a melancholy consolation that last year the factwas fully confirmed by the Experimental Stations Office inthe United States. Cha racteristic of the situation is it th a t(with the exception of Rose's fundamental investigationsconcerning the calcium requirement of human beings, which

62



IMPORTANCE OF INORGANIC SUBSTANCES 63

were supplemented by the work of Emmerich and Loew)all the research in this field was undertaken by students ofanimal physiology, whereas specialists in human medicineheld aloof.

In excuse it may be mentioned that even when physiciansdid occupy themselves with the problem (as H einric h L ah m an n,for instance, endeavoured to do), no satisfactory results wereobtained. Trustw orthy data could no t possibly be providedby the analytical methods then available, in experimentalstations and experimental laboratories, for the inorganiccon stitu ent s of food and th e organs of th e bo dy . More precise

m ethods of analysis had to b e elaborated before such researchesofferSd any hope of success.Naturally, therefore, the first studies of the complettins

were all affected for the worse by our ignorance of thesem at te rs . Such skilful experimenters as Osborne and M endel,or in Germany Rohmann, were entitled to congratulatethemselves when the animals under observation (rats) couldbe ke pt alive 80 day s on an artificial diet . Eve n in Ko ch-mann's and Fingerling's researches, this ignorance had avery disturbing effect, and largely obscured the results.Roh ma nn tried numerous m ixtures of inorg anic salts beforehe at length secured a fairly satisfactory outcome. 4*, 7* Thesuccessful mixture is of historic interest, and its compositiontherefore worth recording here. It con sisted of: tricalciu mjghosphate, 19 . graxomes; bipo tassim n,^p hosp hate, 37 g , ;sodium chloride, 20 g .; sodium citrate, 8 g . ; calcium l ac ta te ,{Tg7; irori'"Uffate, 2 g. Th e investig ato r who w as able

empirically, out of numerous failures, to arrive at such amixture, must have been sagacious, and must have had thebenefit of wide experience. I t is espec ially significant t h a tthe mixture contains an excess of bases, this excess amountingto 130*2 milligramme-equivalents in every 100 grammes ofthe mixture of salts, thus fulfilling what I have from thefirst regarded as an essential requirement of a properly arrangeddiet. Nevertheless, the mixture has grave faults. It isoverldtded with phosphates and sodium chloride, and the

ratio betjveen potassium and sodium is only 0-64 to 1 insteadof abo ut 3 to 1. Th e ratio of calcium to m agn esiu m is likewisefar too low, being only 0 -67 to 1 instea d of 5—7 to 1. F u rt he r-



64 VITAMINS

mo re, th e composition of Ro hm ann's mixture of salts sharesthe defects of almost all the mixtures hitherto recorded:it is completely lacking in manganese, zinc, and soluble

silicates.Osborne and Mendel J5° have shown th at Ro hm ann 'sm ixtu re is far from perfect. Their successes w ith a milkdiet led them to use protein-free milk as the provider ofinorganic salts. Th e milk having been acidu lated withhydrochloric acid until all the protein had been precipitated,was then warmed and filtered, the clear filtrate being subse-que ntly neutralised with soda solution. In ioo gram mes ofdry sub stance , this preparation co nta ins : Ca, i ^92; Mg,0-20; N a, 2-1 8; K, 2-82; P 0 4 , 3-52; Cl, 4-4 4; SO 4 /o-27.Hence 100 grammes of inorganic substances contain 934-2niilligram m e-equivalents. In respect of excess of bases, asregards the ratio of potassium to sodium (1-52 to 1), and asregards the ratio of calcium to magnesium (5-9 to 1), therehas been great improvem ent. The method of analysis wa s,how ever, fau lty. This is manifest at the first glance, for100 gram m es of th e prepara tion gave only 15-02 g. of " as h, "wh ereas the enu meration of the ions gives 15-35 g. Fu rth er-more, no determination was made of the other inorganic

con stituen ts of the mil k: iron, manganese, zinc, aluminium ,an d silicic acid. Th is is a typical instance of th e defects ofthe analytical methods hitherto employed.

In view of Osborne and Mendel's results, it is interestingto recall that Heinrich Lahmann made the ash of cow's milkthe basis of his speculations concerning the inorganic saltsrequired by human beings, and that he was overwhelmedwith derision, mockery, and vituperation by his fellow-countrymen for his pioneer attempt to solve the problem.

Instead of following up the line of research indicated byLahmaim, people made fun of him for " proposing to nourishadults a s if the y were infants-in-arm s." The fiistory ofscience shows many strange aberrations!

The chief defect attributable to this first attempt is thatin the work of Osborne and Mendel, and especially in thatof Lahmann, the excess of bases in the milk was greatlyun dere stim ated . In both cases alike, and mo re partic ularlyin tBe analyses taken by Lahmann from the literature of the




subject, the analytical technique was faulty, so that thequantity of alkalies was stated at too low a figure, and thepresence of iron, manganese, aluminium, zinc, and perhaps

copper, was overlooked. Furthermore, the re was a theoreticalerror in Lahmann's assumption which escaped all his oppo-nents, though some of them were on the verge of detectingit . Natural milk contains acid-rich prote ins, and unless theseproteins are fully utilised by the body (as they are in thesuckling undergoing normal growth) the total surplus ofbases in the milk is not placed at the disposal of the organism—as it was in the American experiments with protein—freemilk. If the bodily requirement of protein is less than the

amoiJnt of protein supplied in the food, then the acids in thesurplus protein will neutralise the excess of alkalies in theprotein-free milk. In actual fact, it appeared in my ownexperiments 319 that when only so much milk was given aswould satisfy the bodily requirement of protein, the excessof alkalies in the cow's milk d id no t suffice either for the growingyouth or for the adult human being. In like manner, Lymanand Raymund,9fo experimenting on rabbits (which are verysensitive to acids), found that on a diet of cow's milk the

animals perished of acidosis; bu t when sodium citra te wasadded to the food, the acidosis disappeared and the urinecontained less ammonia; even when amm onium lactate w asgiven, instead of sodium citrate, the acidosis disappeared,and the urinary ammonia was reduced a lthough an ammoniumsalt was being administered.

Following in Lahmann's footsteps, McCollum used theash of cow's milk for the supply of the necessary salts, buthad to give very large quantities in order to secure tolerably

good results. Subsequently, instead of cow's milk ash, heused an artificial mixture of salts, which was somewhatbetter, but still contained too little a lkali, and also had the sam edefects as Osborne and Mendel's mix ture . Moreover, the experi-ments of McCollum and his collaborators were too brief, andwere therefore less satisfactory than those of Osborne's school.

In later experiments, Osborne used a purely artificialmixture of salts, for too many sources of error were introducedby the presence of organic substances in the protein-freemilk. This mixture had additional merits ; and sindfe i t

5



66 VITAMINS

appears to be the best yet employed, its composition may begiv en : calcium carbonate, 134 -8; magnesium carbon ate,24*2 ; sodium carbo nate (dried), 34*2; potassium carb ona te,

141-3 ; H 3PO 4, 103-2 ; HC1, 53*4 ; H 2S0 4 , 9-2 ; citri c ac id(crystals), i r i - i ; iron citrate (crystals), 6 -34; potassiumiodide, 0*02; manganese sulph ate, 0-07 9; sodium fluoride,0*248; po tash alum, 0-0245. Here th e rat io of sodium topotassium has been improved, being now 3-2 to 1 ; and th enew mixture contains iron, manganese, aluminium, iodine,and fluorine. The ratio of calcium to magnesium is lessfavourable than it was in the earlier mixture, but this is aminor defect in view of the other improvements ; and although

the excess of alkali is reduced to about a third of whaf wasformerly present, a larger dosage with the mixture of saltswill to some exten t comp ensate the deficiency. Two additio nalerrors mu st be m ent ione d: there is far too little man ganese(the quantity might well be multiplied by a hundred) ; andsilicic acid is no t represen ted. If the se defects were rem edied ,if the quantity of magnesium were somewhat reduced, andthe proportion of phosphoric acid lowered by a third, I shouldconsider the mixture thoroughly abreast of modern knowledgeof the bodily requirements of inorganic constituents.

None the less, the biological value of this nutritive mixturemay at times be improved by certain modifications, as by theaddition of bases that are inadequately represented in anatural diet—and especially when the addition changes anexcess of acid in th e food into an excess of alkali. Th us H art ,Halpin, and McCollum,612 feeding chickens on maize, Hogan,634feeding rats on maize, and Daniels and Nichols,659 feeding

rats on soy beans, were able to ensure adequate growth bythe simple addition of potassium carbonate. As a rule,lôwever, seeds of various kinds must be supplemented by theMrther addition of sodium and calcium 645* 68a> *9X# 739; an dwe have similar reports regarding potatoes,777 carrots,784and bananas.96 8 Even milk is well known to be adequatein respect of inorganic constituent^ only for the earliest periodof life ; bu t for adults it is rendered ad equ ate by th e a dditionof a little iron. In niy own experience, how ever, as far as

adults are concerned, the richness of milk in protein makesthe Excess of alkali in this food ijiadequate.




In particular cases, special factors come into play tomodify the requirement for inorganic constituents. Especiallyinteresting in this connexion is the fact that cottonseed mealmanifestly contains a toxic substance which makes it quiteunsuitable as an exclusive diet, but that this toxic substanceis rendered harmless by the addition of inorganic iron saltsto the food.66*

2. THE IMPORTANCE OF INDIVIDUAL INORGANIC

SUBSTANCES.

There is still a great gap in our knowledge of the partplayed by inorganic substances in metabolism and in animalphysiology generally. In addition to the inorganic substancesmentioned in the previous section, there are certain others,present more or less regularly but in far smaller quantities,whose importance still remains obscure. Any investigatorwho would bestir himself to throw light on the matter, wouldcertainly do good service. Some substances, such as the

rarer metals occasionally met with in various organs, maybe excluded from consideration as of no importance. But inthe case of any substance whose presence in the body isinvariable, two conflicting interpretations of its presence arepossible. We may be concerned with an element universallypresent in nature, though in very small quantities ; and wemay suppose that traces of this element are inevitably intro-duced into the body day by day with drinking water or with

food, and especially with vegetable food. Not until a certainaccumulation of such an element has occurred within thebody will the excretory organs take note of it and proceed toeliminate it from the system. But the problem th at arisesis, whether such a substance (though present only in theminutest traces) is nevertheless essential to life and wellbein§;or whether it is merely a passenger, an ingredient whose entryis unavoidable but quite unimportant—unless, indeed, it

prove harmful to the organism when the quantity exceedsa certain minimum. Of especial importance is this questionas regards zinc, copper, and arsenic, which are always present,and even* in notable quantities. Although zinc is found incomparatively large quantities, the demonstration th^t ithas positive biological importance would be a new and sur-



6 8 VITAMINS

prising fa ct ; bu t we hav e mo re inclination to supposecopper and arsenic may exert a stimulating influenceis of moment to life.

Although a mixture of inorganic salts containing no solsilicates, and perhaps no zinc, copper, or arsenic, maysatisfactory results in dietetic experiments, we mustinfer that the substances named are not essential toEven in the most carefully purified diet, traces of them :be present as impu rities of th e organic co ns titu en ts. If i

have not hitherto been detected, the failure to find them iperhaps be accounted for, not by their absence, but byinadequacy of th e analytical technique. Soluble sili ca teespecial, are often presen t where least suspected. I t mmoreover, be remembered th a t the substances in questionpresent in the body in very minu te q uantities, which m ay g nally accum ulate ou t of alm ost infinitesimal sup plies in th e f<

Earlier physiologists would have flatly denied that s

homeopathic doses of any substance could possibly hevital imp ortance. To-day we hav e learned cau tion, sincehave, for example, in iodine a substance minute traceswhich can exercise an extremely potent influence upon Intissue. Furthe rm ore, the study of the com plettins has hmwquite a num ber of similar instances to ligh t. Stric tly sctific investigation can alone justify a decision upon sm atters ; we m ust n ot jum p to conclusions und er th e sp u

mere feeling. The rejection of possibilities w ith ou texamination has already wrought sufficient havoc bothbiology and in medicine.

Aron and G ralka *3^ have recently recorded the com ption of a mixture of salts used by Aron in dietetic experimt*!The m ixture is a good one in two re sp ec ts: the excessalkali amounts to 743-1 milligramme equivalents ingrammes of inorganic io n s ; and t h e ra tio between calciand magnesium is 4-8 to x. In o th er respec ts, howaiAron's mixture marks a step backward, for the ratio of po1sium to sodium is only 0-8 to 1 ; an d th e m ixtu re contiineither manganese, aluminium (zinc), iodine, fluorine,silicic acid. The reader m ay be inclined to thin k t h a t Ioverdressing these criticisms. W e m ust , how ever, pc rpettubear in mind that the law of the minimum is fully applica




to all the substances named. Should any one of them belacking, a perfectly normal development is impossible. Inas-

much, moreover, as inorganic substances enter into importantreciprocal relationships (predominantly during excretion, butalso during the synthesis of organic substances), we areconcerned with a qualitative as well as with a quantitativeminimum. When, for example, a substance is being givenin quantities that are adequate per se, but another substanceis being also given that antagonises the former, the quantityof this is thereby rendered inadequate.

At an early stage of the investigation, this was recognisedby R6hmann,4*, 7* and also by Osborne and Mendel.ô Inanotfier paper,225 the last-named insist th at for regular develop-ment something more is essential than a minimum of theinorganic constituents of a d ie t; if developm ent is to benormal, these mineral constituents must likewise be presentin the proper ratios one to another. Elsewhere,I224 Osbornehas recently insisted that our interest in the problem of thecomplettins must not lead us into the old mistake of forgettingother important factors. He says th a t the need for the propersupply of inorganic constituents must on no account be over-^looked, and he draws particular attention to the deficiency!of calcium and iron in many common foodstuffs. Lecoq IO47|also insists that the quality of nutrition is not solely deter-1mined by the amount and nature of protein, complettins,and the supply of energy, but that inorganic constituentsmust be provided in sufficient quantity and in the propermutual proportions. Scala * m reproaches physiologists whoare experimenting as to the causation of deficiency diseaseswith uncritically referring all the manifestations to theaccount of the complettins, and with forgetting that theorganic extracts they use in their experiments contain maddition comparatively large quantities of inorganic sub-stances which likewise exercise a powerful influence. Aboveall we have to remember that when an extract is made fromuncoagulated material, chiefly the bases pass into solution ;whereas when the extract is made from material in whichthe protein has been coagulated by heat, acids predominatein the solution. This fact may in pa rt explain the reportedbehaviour of the thermolabile complettins.



7 0 VITAMINS

Reference may be made to the researches of FoiHalverson, and Schulz1188 as examples of the importanc

th e proper choice of a salt . I t is w ell know n t ha t pigson an exclusive grain diet do no t dev elo p pro perly . Sinceanima ls ultim ately become affected w ith osteop orosis,failure of development has been referred to the dcficienc;calcium in the food. If, how ever, i>rcpared bone a shchief ingredient of which is bicalcium phosphate—a third-]acid salt) be added to the food, not merely does this faiinduce improvement, but it actually makes the disease we

On the other hand, calcium carbonate, which function*the animal organism as an alkali, completely cures^trouble. The main cause of th e disorder, an d pe rha pssole cause, is, in fact, the acidosis evoked by the food,not a deficiency of calcium, for the bicalcium phosplireduces the alkaline reserve of th e blo od b y 15 % , wheian equal quanti ty of calcium carbonate increases the alkareserve by 10 %.

3 . THE I MPORTANCE OF AN EXCESS OF ALKALI NE

SUBSTANCES.

American investigators have recently drawn attentionthe need, in this matter of the inorganic ingredients infood supply, that we should distinguish on principle betw«seeds and leaves.636» 658 Leaves contain an excess of inorgabases, whereas seeds con tain an ex cess of inorg anic ac

formers.8* w , 5°7> 5*4,578, *»• W , * > * $ , *58> * > $ % 6 8 j. *%** &)*95

6 They have overlooked the fact that in my tables 1^* *I found it possible to divide all foodstuffs into two classesaccordance with this principle : excess of acid is characterôf all animal organs and every kind of muscular tissue, andfats, eggs, seeds, and b u d s ; whereas ro o ts an d tub ers , s taand leaves (" vegetables "), bulbs and fruits, are charactcri*by excess of alkali—cranberries being a notable exception.

is therefore always possible, without monotony, to choosediet containing an excess of alka li. W e need m erely rrthe acid and the alkal ine nutr iments in due proport ions.

Of course this rule m ust no t be ap plie d too rigidly. Finstance, the study of Lecksucht [var iously known in Engl ias " the l ick," " pica/ ' " wool-eat ing," etc . ] in domest icat




animals has shown that grasses, etc., which are ordinarily

rich in alkalies may in an unfavourable soil (such as moorlanddeficient in lime and potassium) acquire an acid reaction,and that animals which feed upon such pasture become seri-ously ill. In like manner, cultivated plants, when tooexclusively manured with nitrogenous fertilisers, and aboveall when treated with liquid manure poor in alkalies (Berg 3

oS>

etc. ; Liechti and Truninger,282 ; Liechti and Ritter I333) orwith ammonium sulphate, exhibit deficient alkalinity, and

may become positively acid.No doubt the same rule applies to animals as to plants:Natyre has once for all prescribed an optimum composition,which cannot be improved upon though it can be changedfor the worse. In the previous chapter, stress was laid uponthe observation that, while the composition of the maternaldiet certainly has a notable influence upon the quantity ofmilk produced by a nursing mother, the quality of the milk,

i.e. the amount of organic nutrients it contains and the compo-sition of these, is substantially independent of the mother'sdiet—so long as milk is secreted at all and the mammaryglands remain healthy. These glands exhibit great energyin extracting the requisite materials from the maternal organ-ism, and the source of milk does not dry up so long as thematerials for the manufacture of the secretion are forth-coming. Rose 69> 7° has proved this also in the case of theinorganic constituents of the milk, especially as regardscalcium in goat's milk. McCollum and Simmonds I0*6 likewisedraw special attention to the fact.

When, however, noxious influences are at work for a verylong time, they ultimately affect even the lacteal secretion.Hess, Unger, and Supple J

33* found that when cows werestall-fed for a considerable period upon fodder poor in

calcium, the aggregate ash in the milk was somewhat dimin-ished ; the reduction was especially marked in calcium andphosphorus, bu t the sulphur was somewhat increased. Thischange is parallel to that which occurs in plants when anacid grass is produced in a soil rich in nitrogen but poor ininorganic constituents generally. The question certainlyarises (and it is one which the experiments leave entirelyunanswered), whether such protracted deficiency of inorganic



72 VITAMINS

nutrients may not directly injure the lacteal glands, so thatthese can no longer be regarded as normal. Thus Rose 69, 7°found, in contrast with the data furnished by two years'

experiments on goats, that in women the capacity for lactationruns fairly parallel with the calcium content of the drinkingw a te r; in places where several years earlier a supply of softwater had been inaugurated, he ascertained that there hadbeen a notable decline in the period of lactation.

Let me take this opportunity of reiterating the warningthat, as regards the real need of the animal organism for anyparticular substance, brief experiments are absolutely value-less. Experimental animals may seem perfectly heathy,

may develop and reproduce their kind, and only in the thirdor fourth generation do degenerative symptoms make theirappearance as the outcome of deficiency of some inorganicnutrient—control experiments showing that animals underthe same conditions, except that they are adequately providedwith this nutrient, remain quite free from these symptoms.From a communication made to me verbally by Urbeanu Ilearn that he saw barndoor fowls, provided with what seemeda bare sufficiency of calcium, develop for three generations

in a way th at appeared perfectly no rm al; bu t the birds ofthe third generation were sterile because their eggs had noyolks. Control birds were still entirely normal in the fifthgeneration.

That is why the embryo has so vigorous a tendency tomaintain the calcium content of its own organism at allcosts. I t is a familiar fact t ha t during pregna ncy a wom aninadequately supplied with lime salts is apt to lose her teeth ;and, in bad cases of deficiency, she may even become affected

with osteom alacia. According to th e researches of L.Zuntz,86 1 the calcium content of foetal rats remains normalwhen the parent rats are inadequately supplied with limes a l t s ; calcium deficiency in the food did not influence thecalcium content of the offspring of these animals unless thenoxious influence had been persistently at work long beforeconcep tion. In such instance s, however, th e entire develop-ment of the offspring was seriously impaired.

I t seems expedient to remind the reader th at t he p repara tion

of the food may also influence its richness in inorganic constitu-



IMPORTANCE OF INOR GAN IC SUBSTAN CES 73

ents. I have already pointed out that, according to Frenchinv estig ators, when milk is boiled ...the. com plex calcium-^magnesium carbono-phosphate it contains is decomposedând is precipitated in an insoluble form ; and McCollum andParsons X3oo tell us th a t th e p recipi ta ted sa lts clingy to the?walls of th e container. Th ereby th e qu ali ty of th e food i$doubly impaired. In the first place a na tu ra l inorga nicproduct, directly assimilable and immediately available forbony growth, is metamorphosed into a form hard to assimi-late,

and is in pa rt actually eliminated from th e m ilk. Inthe second place, and simultaneously, the excess of alkaliin th$ milk (already low) is gravely redu ced . W hen , afterboiling vegetables, the water in which they have been boiledis poured away, the result is similar, inasmuch as the moresoluble bases are removed, so that even vegetables whichwere primarily rich in bases will exhibit an excess of acidafter such treatm ent (Cf. Berg 141, 333, 15^.) F inal ly , th e

medicinal administration of acids, whether aromatic acids oforganic composition such as salicylic acid and benzoic acidor inorganic acids such as boric acid and sulphuric acid, leadsto a dangerous loss of bases, inasmuch as these acids can onlybe eliminated from the body after combining with the inorganicalkalies it contains. v

In the previous chapter we learned that an excess of basesin the food is desirable were it only to ensure optimal condi-

tions for the utilisation of the proteins in the diet, and toreduce the liability to the formation of noxious products ofm etabolism. I should like to refer here to th e exp erim en tsof Abderhalden,45* who found t h a t alkalinis ation of th e foodwith sodium acetate brought about a more efficient utilisationof the protein in th e food; and also to t h e obs erva tion ofBened ict and R oth 420 w ho not iced that in vegetarians(human) the basic turnover was less than in persons on a

mixed diet .It has long been known that when herbivora, and sti l l

more when rodents, are fed exclusively on grain, acidosisra p id ly ensues. In rabb its on a maize diet, for insta nc e, theacid urine contains far more phosphorus than is being intro-du ced in the food. Simultaneously the am m on ia conten t ofthe urine is greatly increased, but Underhill 5

65»566 s ta tes tha t



74 VITAMINS

in spite of this the animals' nitrogenous balance is maintained.The only possible explanation is that under the influence ofthe acids a vigorous production of ammonia ensues; this

bein g insufficient to neu tralise the acids, the body , in its needfor bases, is compelled to turn to the osseous system, the lastalkaline reserv e of the organism. Anoth er familiar fact isthat an inadequate supply of food, or absolute starvation,,both of which lead to an enforced disintegration of the body'sôwn pro tein, give rise in herbivora to the sam e phenom enon 1that ensues upon an exclusive meat diet or grain diet, namelyacidosis, with alkali impoverishment of the body, and kreati-nu ria. A rema rkab le fact is tha t, during th e acidosis^ even

in the meat-eater, hypoglycaemia ensues, exactly as in thecase of direct poisoning, as for example by hydrazin sulphate.An injection of sodium hydrate will promptly render the urinealkaline once more and will simultaneously put an end toth e kre atin uria . , Inasm uch as in herbivora a g rain d iet alsQinduces acidosis, this disorder cannot, as is often maintained,be "th<^ outcome of carbohydrate deficiency.

Ra t s , again, can only endure an exclusive grain diet fora short period, speedily succumbing on such a regimen. Anabundant addition of protein to the grain does not help them.Hogan, however, tells us that an addition of alkalies preservestheir life and has a marvellous effect in furthering growth.

Hart, Miller, and McCollum^s and Abderhalden andEwald 683 ha ve show n th at an excess of acid in th e food m ustoften play a pa rt in the causation of the avita m inos es; inthe later chapters of this book the fact will again and againforce itself on our atten tion . Peckham J310 stresses the rela-tionships and reciprocal actions of inorganic nutrients andcom plettins. In this connexion we m ay allude to Aulde's

observation I259 that when there is either a lack of calcium oran excess of acid in th e food, the com plettin A is void of effect;and that conversely the assimilation of calcium and the fulldevelopment of the anti-inflammatory properties of this baseare only possible in the presence of A.

According to Steenbock, Nelson, and Hart,4i° the directaddition of acid to the food always causes an increased excre-tion of ammonia in the urine and a decreased excretion ofurea In om nivora and carnivora this decline in urea is said



IMPORTANCE OF INORGANIC SUBSTANCKS 75

to take place by way of compensation, and thru: antherstherefore assume that iu such animals an abnormal dNntrtfia-

ticn of the protein in the food already takes place in theintestine, accompanied with the formation of ammonia, andthat the body protein remains intact. In herbivora, on theother hand, it is supposed that the taking of acids with thefood involves also the disintegration of the body protein, sothat the formation of ammonia is increased to a greater extentthan the formation of urea is diminished, and the nitrogenousbalance becomes negative. In criticism of thf.se experimentsI must point out that the diet was not one in which the

ingest ion of nitrogen had been reduced to a minimum, andthat their duration was too brief. Had it been otherwise Iam sure that the observers would have found, as Rose andI found, that in human beings, and in omnivora and earnivora,direct losses of nitrogen occur in such conditions.

We have to remember that dogs and pigs, as normallyfed, receive far more protein than is essential far their minimalbodily requirements, and that thereby a quantity of ammonia

competent to neutralise the acids added to the food k liberatedwithin the system. If no more protein th an the indinpensableminimum had been given, and if the requisite supply of addi-tional energy had been provided by giving fats and carbo-hydrates, the consequences of the addition of acids to thefood would have been promptly manifest in these animals too.

Hopkins Iass points out that under certain condition*acidosis can be partially relieved by an abundant supply ofprotein, thanks to the extensive formation of ammonia out

of the surplus protein. Hut we must not go too far withthis supply of protein, for Maignon has shown aâin and mainthat an exclusive protein diet in positively toxic even in acarnivore. W hippk and van S ly kuw bad similar rr.sult* intheir experiments. Feeding on large quantifies of meat"causes symptoms of acute poisoning resembling those oeca*liianed by an injection of aibiunose, attended by .similarconditions in the Mood—thaw; charatterhiie of timid

destruction . In collaboration with Hirkncr I have, shown *wthat this decomposition of the tissues must arise Cram thechanges in the bodily juices determined by an excessiveproduction of ammonia.



76 VITAMINS

4. ACIDOSIS.

Given certain conditions, it does not take much to induce

acidosis. BossertI0I

4 points out that * in children with apredisposition to spasmodic affections (and only in these)the mere addition of one egg to the daily diet will give riseto oedem a with retention of nitrogen and inorganic con stituents,and sometimes to the occurrence of carpopedal spasms.When the egg is withheld, normal conditions promptly return.Manifestly in such cases the existence of an affection of thenervous system explains why the acidosis has so powerfulan influence ; and we mu st invoke the same explanation toaccount for various observations that, in cases of severe

diabetes, epileptiform convulsions occurred as soon as acidosisset in.I044, «74, "75 (Cf. also Elias W .) S h a w I I 8 2 likewisefound that when certain nerve degenerations were present,acidosis aro se mo re readily and h ad a m ore powerful effect—as for instance in epilepsy, severe malaria, chronic melan-cholia, and chronic alcoholism. In conjunction with theacidosis, " epileptic " paro xysm s occ urred, especially duringthe night, when the reaction of the blood is physiologicallyless strongly alkaline than during the day . A t th e same time,

th e blood exh ibits a marked excess of hydrogen ions. Insuch cases, an increase of protein in the food leads to anincrease in the frequency of the paroxysms, whereas theadm inistratio n of alkalies reduces their frequency. A tthe post-mortem examination in cases of acidosis, therewas found cloudy swelling of the pia-arachnoid, such as iscommonly observed after death from poisoning by the mineralacids.

Although in various skin diseases (psoriasis, acne, eczema,and seborrhoic dermatitis) the acidity of the blood and the

urine is sometim es found to be increased. Sweitzer an dMichelson II04 state that this is not invariably so, and theytherefore regard acidosis as at most an accessory factor ofthese diseases.

As a general rule, we have to reckon only with theinorga nic acid-formers as th e originators of acidosis. In m ypublished works, however, I have repeatedly insisted thatwhen an excess of organic acids is taken, so that the organism




is unable to effect their complete combustion into carbonic

acid and water, they must have precisely the same effect asthe inorganic acids, seeing that they too m u s t be neutralisedby inorganic bases before they can be excreted. Thus inhuman beings the immoderate ingestion of dilute acetic acid(table vinegar) or citric acid (lemon juice) may lead to typicalsymptoms of acid poisoning, as may unfortunately be oftenseen in persons who are undergoing the popular " lemoncure.1 ' Obviously, too, an imm oderate supply of carbohydrates

may arouse like manifestations, if these food-stuffs undergoacid fermentation in the bowel. Indeed Barr IO55 regardssome pi the symptoms of beriberi and of experimental poly-neuritis as consequences of an acid poisoning due to theintestinal fermentation of the carbohydrates that are tooliberally supplied in the food. It is far from improbable thatthe so-called " Mehlnahrschaden" of infants-in-arms isin part dependent on similar causes.* Th is explains why

DreifusIo6

5 found that in the rabb i t the rectal administrationof dilute organic acids in quanti t ies that were tolerated bymouth, proved fatal. The acids were quickly and directlyabsorbed into the blood through the mucous membrane ofthe large intestine, whereas when taken by mouth they couldenter the blood only through the devious route of thelymphatic system, and could on the way be neutralised—partially at least.

There are also numerous reports to the effect that theabundant ingestion of fat may lead to acidosis. This is wellknown to occur in diabetics, whose powers of oxidation arein any case impaired. Wemust, however, bear in mind tha t

• De ta i l ed account s of the s y n d r o m e s k n o w n in G e r m a n y as Mehlnahr -s chaden and Milchnahrschaden wi l l be found be low, p. 295 and p. 297.They arenutr i t ive d i sorders in bot t l e - f ed in fan t s , r e spec t i v e ly due to feedingwi th cerea l food and wi th d i lu t ed (usua l l y pas t eur i s ed) cow's mi lk . Itne i ther becomes us nor behoves us as t r an s l a t o r s to r u s h in where Br i t i s h

experts fear to t r ead . The l e ad ing Br i t i s h au tho r i t i e s on the d i s ea s es ofch i ldren have fa i l ed to different ia te what theGermans ca l l Meh lnahrschadenand Milchnahrschaden from the genera l i t y of ca s e s of i n f an t i l e mara smus .Tha t is why we h a v e to use the German names in the t e x t . The lack ofsu i table Engl i sh terms dates from ten y ea r s ba ck . In 1913,Cas imir Funk,a t t h a t t ime d i r e c t o r of tbephys io log i co -chemica l l abora tory of the CancerHospi ta l Research Ins t i tu te in L o n d o n , w r o t e : "In Eng l i sh ped ia t r i cl i t era ture , the concept Mehlnahrschaden is q u i t e u n k n o w n , the disorderbe ing usua l l y inc luded under the h e a d i n g a t r o p h y . . . . Milchnahrschadencerta in ly be longs to thesam e ca t egory of nu t r i t i v e d i s o rder s " (DieV i ta m i ne ,Bergmann, Wiesbaden, 1914).—TRANSLATORS' NOTE.



7 8 VITAMINS

as regards fats there is a difference in the mechanism by whichacidosis can be produced. Th e splittin g up of fats, w ith aconsequent liberation of fatty acids, takes place in the intes-tine . Since, as far as we know , free fat ty acids can no t beabsorbed by the intestinal epithelium, the neutralisation ofthese acids m ust be effected w ithin t he intes tine itself atthe cost of the alkalies in th e bile. Of course thi s, too, lead sto alkali impov erishment. Th e only difference is in th eplace where the loss of alkalies o cc u rs; th e net resu lt is th esame.

Uhlmann « l 6 reports instances of obstinate acidosis insevere cases of diabetes, in which the regulation of the f.arbo-hydrate supply no longer leads to any improvement, but areduction in the amount of fat ingested is followed by areduction in th e excretion of acetone. In like m an ne r, B icrryand Portier 73* and also Dubois 733 repo rt th a t in ra ts th eweight can be maintained by a diet of coagulated protein,fat, carbohydrates, and salts, in definite pr op or tio ns ; bu tthat when the proportion of fat is unduly increased, acidosisensues, leading to acetonuria and emaciation.

In view of the observations m ade by all othe r physiologists,it is rath er presum ptuou s of Bayliss »3* to assure his reaciersthat the notions of acidosis and alkalosis are apriori untenableand to declare that other explanations must be found for themanifestations classed under these names, seeing that aslong as the organism is alive it is perfectly able to compensatesuch noxious influences!

Confusions of this kind arise mainly from a lack of precisionin the definition of acidosis. Th is, in tu rn , results from th emixing up of two ideas which to some extent are entirelydistinct, the confusion having taken place during the earlyenthusiasm of the "ionic days" when investigators werefull of the joy of creation an d discovery. In ex pe rim en tswith pure salts it appeared that acidity or alkalinity corre-sponded with the H or OH concentration, and " reaction "incontinently identified with "ionic concentration.0 Inreality, we chemists understand something more by reaction,nam ely the power of neutralising an acid or a b a s e ; an d inorganic chemistry numerous substances are encounteredwhich unquestionably possess a chemical reaction in this



IMPOR TANCE OF INORGANIC SUBSTANCES 79

sense, and can certainly function as acids or bases, althoughthey do not appear to be ionised.

At that time, attempts ware made to deftiu' Hut conceptof acidosis, in accordance with the ionic doctrine, in terms ofth e physical relationships in the blo od ; but tlie.se* attem pt*were unsuccessful. We distinguish in the* blood, first of all,th e hydrogen concentration, which m ust h<: regarded as themeasure of the physical reaction. This concentration isextraordinarily constant, remaining undmngrcl uvvix whenlarge quantities of free hydrochloric acid an; aclnuuistmtiNot uatil th e aciclotic condition approaches its trrm {an in

fatal poisoning with a mineral acid, or in diabetic coma)does tfte hydrogen ionic concentration bmmu.? positively aritl.It is evident, therefore, that the. Wood mwA contain substuna'Scompetent to neutralise adds without any change in theIonic concentration. The most im portant of tlic*.su buffersalts in the blood i.s sodium bicarbonate, ami next ronu*» thephosphate in the blood. As an index of this reserve alkalinitywe can use the carbonic-acid tension in the alveoli or in theoxaiate plasma, or the ionic concentration in the plasma*

on the addition of measured quantities* of adds*.Porges, Leimddrfer, and Markovici1*^ ^ 8 regard the

carbonic-acid tension of the blood as the mast reliable signof acidosis. Van Slyke, Culten, and S ti lh iw itw report tha tin acidosis there is no change in the ionic eontumtnitinn ofth e blood, bu t tha t its reserve alkalinity Ls rt'duccd, thisfinding expression in the diminbhed carbonic-acid tttnsicm inth e alveoli. Begun, Herrm ann, and Milnxt*r4«7 iiiid, on the

other hand, in an extended nerias of rcstârdips that hirgcquantities of hydrochloric acid can be adininhtc^rcd with thisfood, leading to a marked increase in the (txcrijtion ol ammoniain the urine, without the occurrence in the: Mood of anyreduction either of the ionic concentration or of th« rcascrvrsalk alinity as manifested by the carbonic-aeitl U?n»toti. Notuntil large doses of acid have been given for a very long time,and when a general alkali impoverishment lum U ikm phmthroughout the body, does the carbonic-acid tension decline,

and moreover this decline seems to be evoked by grave tiwuealterations. These authors' researches lead them to thecoaclusion that the carbonic-acid tension in the alveoli it



80 VITAMINS

primarily dependent upon the carbonic-acid content of thevenous blood, that is to say upon the aptitude of the blood totake up carbonic acid. Consequently, this tension cannot be an

index of th e acidosis, and can decline in the absence of acidosis.Conversely, an increase in the reserve alkalinity of the

blood does not indicate the existence of alkalosis, for suchan increase may occur physiologically, as during digestion inconsequence of th e secretion of hydrochloric acid by the sto m ach.(Cf. va n Slyk e, Cullen, and Stillman438.) Neve rthe less, thealkalinisation of the blood in such circumstances will notincrease beyond a certain measure, for fresh acids are con-tinually being supplied in the food, and moreover the hydro-

chloric acid that has been secreted in the stomach isreabsorbed. How ever, grave alkalosis can be induced byrepeatedly washing out the stomach during the climax ofgastric digestion, so that the hydrochloric acid is removedfrom the bo dy and canno t be reabsorbed. McCollum and hiscollaborators I0 I° saw severe tetany produced in this wayin cases of stricture of the pylorus.

Following the example of leading authorities, we may?describe acidosis as a condition characterised by a deficiency

of fixed inorganic bases in the body, leading to the increasedproduction of am mo nia. According to N . Zun tz, the increasedexcretion of ammoni a in the urine, in conjunction with highacidity of the urine, is the only certain sign of acidosis. (Cf.Steenbock, Nelson, and Hart,4<>7,410 and also Lyman andRaymund 962.) M any observers, such as Shaw ,1100 regardacetonuria as a sign of acidosis. B ut it is cer tain th a t t he remay be severe acidosis without acetonuria, and it is conceiv-able that acetonuria might occur in the absence of acidosis.

HopkinsIO2

4 is also right in pointing out that the morbidformation of oxybutyric acid, acet-acetic acid, and acetone—a condition which can best be separately described as" ketosis "— mu st be clearly distinguished from the changesin the physico-chemical equilibrium whicE lead to a diminu-tion in the reserve alkalinity of the blood and to a declinein its capacity for neutralising acids.

Hopkins also draws a distinction between uncompensatedacidosis, in which there is a real increase in H-concentration,

and compensated acidosis, in which no change in H-concentra-




tion can be demonstrated. In chronic nephritis and otherkidney disorders, the ordinary protective apparatus of the

body (the buffer salts of the serum, the elimination of carbonicacid by the breath, and the excretory activity of the kidneys)is thrown out of gear because the production of ammonia isdisturbed, and there ensues an acidosis of renal origin, whichis usually uncompensated. Nitzescu 406 and Palmer andHenderson 434 make the same distinction.

In the light of extant knowledge, it would seem to be amistake to concentrate attention upon the composition ofthe blood. Very serious disorders may occur in which thecomposition of the blood appears perfectly normal. The bloodcertainly possesses to a very high degree the power of self-regulation, but this does not suffice to explain all thephenomena we are considering. I t is necessary to assumethat a hitherto unmentioned regulatory apparatus is at thedisposal of the blood. We learn this from the frequentlyascertained fact that in long-continued acidosis the bodyexcretes less phosphoric acid and sulphur than is ingested,but that when in these circumstances fixed bases are addedto the food, the balance of phosphorus and sulphur inclinesstrongly in th e opposite direction. I t follows tha t the bloodmust have temporarily deposited somewhere or other theexcess of acids in the food which could not be eliminated bythe kidneys or the bowel. I t should also be noted th at inthese conditions there is a simultaneous retention of nitrogen,which is likewise excreted as soon as a sufficiency of basesis administered.

Normally, it is probable that these substances, whichpossess a rather high molecular weight, are not retained inthe blood itself, or can exist there only for brief periods, whengreatly diluted. The accumulation of such residues in theblood would certainly have bad effects, and since in the condi-

tions we are considering they cannot be excreted in the urine,they are deposited wherever they will do least mischief.Suitable depositories are offered by the comparatively inactivetissues, such as bone, cartilage, and connective tissue* Afavourite site is the subcutaneous connective tis su e; and itis here, too, that sodium chloride, an excess of which is com-monly ingested, is stored pending opportunity for the excretion

6






by increased storage of fluid in the tissues. The depositedmaterials carry with them so much water (infiltration of thetissues) that the percentage content of chlorine (for instance)is perfectly normal, and the retention does no t become apparen tuntil the contents of the tissue are reckoned in the dry state.(Cf. Scholz and Hinkel 377 and Rothstein 83<>.)

5. PARADOXICAL EFFECT OF CALCIUM SALTS IN THE

ORGANISM.

These peculiar relationships furnish the key to manyenigmas in the metabolism of the inorganic constituents offood, «t>ut a more detailed discussion of the topic would takeus too far from our proper subject. Moreover, it will benecessary to return to the matter in a subsequent chapter,so the foregoing brief indications must suffice for the presentIn the same connexion, however, it is necessary to refer brieflyto a special instance of inorganic metabolism, one whose

apparently paradoxical developments must become familiarto anyone who wishes to understand and accurately toappraise many of the experiments m ade in the course of moderndietetic research.

In the chemical laboratory it is possible by the additionof neutral salts to effect extensive modifications in ionicconcentration, these modifications usually taking the form ofa diminution of hydrogen ionic concentration . In th e living

organism we are unable to do this, for, as already said, thebody has at its disposal a regulatory apparatus which is somanifold in its possibilities and which acts with such prompti-tude that the effect of doses of mineral salts is completelyobscured. There is, however, one exception, which seems allthe more amazing inasmuch as in th is instance the administra-tion of a neutral salt ultimately leads to an increase insteadof to a reduction in the hydrogen ionic concentration. The

final upshot of the consumption of th is salt by an animal isthe occurrence of marked acidosis. To th e chemist it is atonce obvious that the cause of this remarkable result cannotbut be some kind of reaction which in the living organismpursues a quite anomalous course—however loath we may-be, at the first glance, to entertain the notion that thechemical laws of the living organism can be different from those



84 VITAMINS

of inorganic natu re. In 1905, when I first drew a tte n tio n tothe paradox and explained it with the use of chemical form ula s,my exposition aroused universal scepticism, for its improb-

ability seems overwhelming. In essence, how ever, t h eexplanation involves nothing extraordinary, nor does it entailany contradiction of familiar experience or demand theacceptance of a new system of kinetics in organic chemistry.It merely requires us to make due allowance for th e fact th a tthe animal organism is, after all, som ethin g ve ry differentfrom a test-t ub e; and th at the chemical reactions t h a t ta keplace within it result from the collaboration of millions ofcells which, despite their interdependence, are to a # large

extent autonomous, so that each is competent to act after itsown fashion. If we stud y th e chemical reactio n in th eindividual cell, we find th e familiar law s in o pe ratio n ; and itis only the collaboration of numerous cell complexes whichproduces an aggregate result that amazes us by its apparentlyparadoxical character. In other words, th e ultim ate resu ltis not th e outcome of a single reac tion b u t of a series of r ea ct io ns ,and these reactions (here is the core of the matter) take placein various organs.

I am far from having been the discoverer of theseremarkable reactions. I merely gave the explanation offacts which had long been known, though their peculiarityhad not been noticed by previous inve stigato rs. E ar lie r inthe present chapter one of these well-known facts was touchedupon. I mentioned tha t Forbes, Ha lverso n, and Schulz n 8 8

found that acidosis was increased by administering bicalciumphosphate and diminished by administering calcium carbonate.There is nothing remarkable in this, seeing that bicalcium

phosphate, CaHPO4, is a third-part acid salt. The rem ark ab lepoint only conies to light when we know that we are dealinghere with a special instance of a general rule, and when welearn that with the exception of calcium carbonate and tri-

l



IMPORTANCE OF INOR GA NIC SUBSTANCES 85

Th e strang e and anom alous beh avio ur of calcium is explainedby an observation m ade a grea t m an y years ago. E rns tLehmann 4, 16 d r ew attention to the fact that the administra-tion of calcium salts leads to no more than a trifling increasein the calcium conte nt of th e urine . Still earlier, Ri es ell z

had shown that when calcium salts are given by mouth, thequ an tity of phosphates in th e urine dim inish es; an d thisobservation w as confirmed b y Schetelig * an d all s ubse que ntinvestigators. Noorden X5 and his pupils S traus s ™> 2I andHerxheimer 2 2 found, however, that the administration ofcalcium carbonate reduces the acidity of the urine, and thatthe reduction in the urinary phosphates depends upon theexcretion of tricalcium ph osph ate by th e bow el; wherebythese observers were led to the erroneous assumption that thecalcium combined with the phosphoric-acid radical in thecourse of intestin al digestion. N eve rtheless th ey recognisedthat a portion, at least, of the calcium phosphate must be

excreted by th e mu cosa of th e large intestines. H erxhe ime ralso recognised that the aggregate excretion of phosphatesis hard ly altered by th e adm inistra tion of calcium . W ha t,happens, then, is that , when calcium sal ts are given, a par tiof the phosphoric acid which would otherwise he excreted by the \kidneys is diverted to the colon ! My own researches likewise 1showed that the greater part of the calcium is excreted bythe intestine in the form of tricalcium phosphate.97' 35 6

In the urine, however, the phosphoric-acid radical isexcreted as bisodium phosphate, or (as many think) in partas monosodium ph osp hate. Th e relationsh ips, therefore, canbe expressed by the following equations:

r. 3CaCl2 + 2N aH 2 P 0 4 = C a 3 (P O 4 ) a + 2NaCl + 4HCI and2. 3CaCl2 + 2N a 2 H P 0 4 = Ca3(PO 4)2 + 4NaCl + 2HCI.

Of the results of these reactions, the tricalcium phosphateappears in the faeces, and the sodium chloride in the urine.Since free hydrochloric acid cannot exist in the blood or thetissues, it immediately undergoes a reaction with bisodiump h o s p h a t e :

3 . 2HCI + 2N a a H P 0 4 = 2NaCl + 2N aH 2 P 0 4 .

The net result is that dosage with the neutral salt increasesthe acidity of the urine.



86 VITAMINS

B u t "before the excretion occurs, the hyperacidity hast a k e n effect within the organism, for Fuhge (op. cit.i, andI m yself at an earlier date , found th at the administration

° f salciuiii-chlQxide led t a a a increased production of ammonia,T h i s is only one aspect of the paradox. The other aspectsee rn s almost crazier. Large doses of calcium chloride induces e v e re losses of calcium, which may culminate in osteoporosisa n d osteomalacia in the experimental animals. Th us Etiennew o rk i n g alone,*3° and working in conjunction w ith Fritsch,?6

f o u n d that chloride of lime does indeed induce a t the outseta.n accu m ulatio n of calcium "within the body ; bu t t h a t if it)is given for a long time, it induces severe losses of calcium,a n d t h a t bone deformity may ensue ; these evil results c>egin

immediately if adrenalin or potassium iodide is given togetherw i t h th e calcium chloride. S imilar results Lave recentlyb e e n secured in Germany. The explanation has already beeng i v e n . The calcium chloride induces hyp eracidity withint h e organ ism, and this leads in the long run to so serious analkali impoverishment that the last alkaline reserves of theb o d y , those in th e osseous system, are attached and passi n t o solu tion, in order th at th e acids may be neutralised byt h e car bo na tes derived from the bones.

T h e fundamental cause, then, is the diversion of thephosphoric-acid radical from the kidneys to the intestine,a n d t h e consequent transformation of th e bisodium phosphatei n t o monosodium phosphate. I t follows th at all the calciums a l t s con taining acid radicals that are incombustible withint h e org anis m must act in the same way—for instance, thec a l c i u m salts of the aromatic acids. To some degree, however,sulphuric acid is an exception, for the organism can get ridof sulphur, not only in the form of sulphuric acid, but also(in part, at least) as ester sulphuric acids which require only

h a lf t h e amount of alkali to neutralise them , or as non-acidc o m p o u n d s . Rose's experiments do in fact show th at theu r i n a r y acidity is not so greatly increased by dosage withcalcium sulphate as by dosage with calcium chloride. As p e c ia l exception is calcium carbonate, whose acid radicalc a n b e freely discharged in th e gaseous form th rough thel u n g s , so that no Bases are requisite to assist in its excretion.T h e s a m e considerations apply to th e calcium sa lts of the



IMPORTANCE OF INORGAN IC SUBSTANCES 87

combustible organic acids, seeing that the terminal productof their combustion is likewise carbonic acid. In both cases,

therefore, the entire calcium content of the salt remains atthe disposal of the organism as a base.

I t is true th a t the hydrochloric acid of the stomach convertscalcium carbonate into calcium chloride. But this dors notintroduce any new hydrochloric acid into the body- W ha t-ever hydrochloric acid is formed in the stomach, a corre-sponding amount of alkali is set free, and this is competentto neutralise the hydrochloric acid that is liberated when thecalcium is excreted as tricalcium phosphate, so that the wholebasic content of the calcium carbonate is, after all, availablefor the organism.

The inorganic magnesium salts exhibit the same peculiarityalthough not to so marked a dogrce as the calcium salts.The difference may depend upon the fact that the magnesiumsalts are in general more readily soluble, so that their excretion

is comparatively easy. Furtherm ore the " triple phosphate "Mg(NH4)PO4, the insoluble magnesium salt, does not appearin large quantities in the faeces except in abnormal conditions,

6. T U B ADMINISTRATION OF ALK ALIES AS A

PREVENTIVE OF ACNDOSIS,

Calcium carbonate, therefore, acts in the animal body asa free base in this respect, that it is competent to nnutrnltHe

acids, and th us to reduce acidossis. Obviously, all inorganicbases in the free state can act in the same way, provided thatthey can be absorbed by the organism in a soluble* form*The free bases, however, have, like the km acids, ami vmmmore than these, the disagreeable quality of being corrosiveThey dissolve organic matter, and can therefore not hv, tultir*atcd by the organism except in extreme dilution. Thealkaline carbonates, though their corrosive influences in less

powerful, are nevertheless not free from this influence, whereascalcium carbonate is, an such, insoluble and innocuous.Large doses of this salt can, in fact, bo given throughout along period without any injurious consequences, differing inthis respect from the othar carbonates.

It need hardly be said that the soluble bases can u\m beadministered in the form of their combinations with the






In artificial mixtures of nutritive salts, these salts areall present in a readily ionisable form. As such , however,they play the part of foreign bodies in the organism, for theyspeedily increase the osmotic pressure to an iatolerable degree.Hence th ey are eliminated as rapid ly as possible. Manyinorganic salts begin to make their appearance in the urinewithin ten minutes of their administration "by mouth, and,speaking generally, the whole dose will have been excreted^within twenty-four hours. The excretion, however, is notreffected strictly proportionally to the concentration of thesubstance in the blood, but occurs irregularly, so that the

excretion of the last traces may often be deferred for a longtim e. I have found th at in the case of calcium and phos-phorus compounds the excretion may not be completed untilafter th e lapse of five or six days. Bu t as far as a strong1

concentration in the organism is concerned, this lasts onlyfor a brief space of tim e, an d the period of efficacy of suchsubstances ia the body is therefore strictly limited. Thereaction of the urine gives the best proof of this , Whctnant acid-rich diet is being taken, and we aim at neutralising

the excess of acid by administering inorganic bases in thaform of salts, the use of litmus paper will show that thts urinespeedily acquires an alkaline reaction . During the night,however, the period when tha great cleaning up erf the organismafter the clay's exertions takes place, the amount of availablebases is greatly reduced owing to the rapid excretion of theionised salts, the result being that the morning urines (whichcontains the products of tissue change during- the night) hits

again become acid, and is rich in uric acid although its pr>w<rof holding uric acid in solution is sm all In o ther words,when the requisite bases are supplied in the form of inorganicsalts, they are excreted so rapidly that the organism suffers*from alkaline impoverishment at the time when its need foralkalies is the greatest.

Conditions are very different in the case of natu ra l nutricmtn.Here the inorganic bases are, to some extent at leant, presentin masked forms, in stable organic combination, nnd their

presence can in many instances not be detected until niterth e destruction of the organic combination. To somft ex tent,compounds of this character are even able to resist tbe dis*





IMPORTANCE OF INORGANIC SUBSTANC ES 91

bases supplied. TIic law of the minimum is here in fulloperation ; the final upsho t will be determined by th e sub-stance that is present in the relatively smallest proportions.It is hardly possible to l>e too emphatic about this matter.We have to think, net merely of a minimal requirement 0/inorganicsubstances in general, but also of a min imal requir ement ojeach inorganic substance in particular. (Cf (In bo rn e an dMendel,«5i m * * w McCollum and Simmonds,^ loiG J$arr,IO55Hess,1055 Kulz,M Grablcy97i.)

In this connexion it is necessary to refer to a considerationwhich all investigators have hitherto overlooked. I t does

not follow that because a mixture of salts lias proved a usofulsupplement to a particular nutrient or to a particular formof diet, that it is an infallible dietetic supplement which willdo equally good service in the case of any and cvvxy diet.If, for instance, a second nutrient contains a larger excess ofacids than one which lias previously been given, the naturalway of dealing with this supplementary excess will be bygiving larger doses of the m ixture of salts. But if th e undueacidity be a one-sided affair, dependent let us suppose upon

an excess of phosphoric acid in the nutrient, an optimal effectcannot be secured by a mere increase in the am ount of a generalmixture of sa lts . The phosphoric acid will need for it s excre-tion by the intestine a preponderant percentage of th&calcium in the mixture of salts, and this will unduly reducesthe quantity of calcium available for the other nueds of theorganism. Furthermore, the ratio between the availablecalcium and the magnesium or the alkalies will thereby liereduced to the disadvantage of the calcium. In such a cns«,

therefore, we must not merely increase the dosage of th e Aggre-gate mixture of salts, but must take these peculiar condition*into account by specially increasing the dosage of calcium.

In other cases, the quan tity of sulphur may be unfavourab lyaffected in one way or an othe r; the re may he too little sodium,iron, or manganese; or there may be too much chlorine;an d so on. In a word, generalisation is especially unsafewhen v/e are dealing with this matter of inorganic metabolism,

A decision as to the composition of the supplementar y mi xtureof salts m ust always he based upon an accurate analysis oj [heconstituents cf ike diets To this matter we shall return*



92 VITAMINS

v /9 . T H E UTILISATION OF CALCIUM IN VARIOUS F O R M S C

ADMINISTRATION.A special problem is intimately connected with the f

going—the extent to which the inorganic constituents ofvarious nu trients can be utilised. A s far as th e ba se sconcerned, a detailed study of the question has been ironly in the case of calcium. McClugage and Mendereport that in dogs the calcium in milk is better util:tha n the calcium in carrots or spina ch. Rose I0I9> io83 co:

to the same conclusion as regards human beings, finding tth e utilisation of calcium in carro ts is m uch less efficient tlth e utilisation of calcium in milk. A critical s tu d y of titpapers leaves a different impression on my own mind,far as the dog is concerned, we must remember that 1animal, being a carnivore, is better adapted to digest aniifoods rich in protein than vegetable foods ; the dog's intestis,to o sh or t for a vegetable diet. I n such ex pe rim en ts, d<should be habituated to a vegetable diet before the specenquiry begins. Ne xt it m ust be no ted tha t if th e do gnot habituated to a diet of spinach or carrots, diarrhoea \ensue, involving grea t losses of ca lc iu m ; this is es pe ciaobvious when we recall that to supply the amount of Ihcontained in a very small quantity of milk, large amouiof spinach or carrots will be requisite. Th e m istak e ha s b emade that is unfortunately so often made by those who astud ying th e physiology of nutrition , of regarding " diges t ior

as synonymous with " utilisation. ' ' I n the process of n u t r i t iwe must distinguish three stages which are to a consideratextent independent one of another, nainely d ig e si io n ^ b se ftjjQp.j, ajod assimilpjien. Only when assimilation is u n sa tifactory, are we entitled to speak of a substance as imperfectutilisab le. If McClugage and Mendel h a d told us t h a t spina<an d ca rro ts were not satisfactory as sources of ca lc iu m f<dogs, they^ would have been within th e mark , b u t th e

researches give us no information as to the degree to whicth e calcium is utilisable. A nu trien t m ay be ba d ly b o rib y an anim al whose digestive system is ill-adapted t o de;with it , but we are not entitled to infer that such portioiof the nutrient as are digested are badly assimilated.




Rose, keeping four healthy hum an beings under observation,ascertained the calcium balance when a diet was being taken

competent to supply appraximately the minimal requirementof calcium. In two of the cases the exp eriment lasted afo rtn igh t; in the other two, three weeks. In two instancesthere was a preliminary period in which the calcium neededwas provided chiefly from milk, whereas in the main experi-ment the calcium was supplied in a daily ration of 40a grammesof boiled carrots. The experiment is so typical of th e short-sighted way in which inferences are drawn from experimentson nutrition that I cannot refrain from a brief examination

of th^ results.

Person,

E. D. B,E. D. B.R. S. E. . .K. S. E ,£. H.

E. W.

Diet.

MilkCarrotsMilkCarrotsCarrots

Carrots

Calciumsupplied in

0-383

O * 38 ]

Q"&(il

IVrcflr»ta«ft n lC.ilriurn !n>m

CArrrtts.

0

$50

5.184Sa

4- 4

From this it appears that in E. I). B. the calcium fromcarrots was quite as efficiently utilised as the calcium frommilk, whereas in R. S. E. a deficit occurred during the carrotdiet. But the retention of calcium during the milk diet was5° % grea ter in R. S, E, than in JL IX B. This imm ediatelysuggests that what occurred in R, S* E, during the milkperiod was not an assimilation of calcium but a simple reten-

tion of calcium. Every investigator who has been engagedin researches on calcium metabolism must be aware; that thissubstance is not rapidly excreted, and that a quantity ofcalcium introduced with the food m not fully dischargedfrom the body un til at least five or six days have elapsed. Insuch investigations, therefore, a standard diet must beselected, and must be given far a preliminary period duringwhich the utilisation of the substance under considerationhas been ascertained. Then follows the main period of theexperiment, during which the test substance is added to thestan da id diet. In a final period, when the adm inistrationof the test substance has been discontinued, the process of



9 4 VITAMINS

its elimination is kept under observation. Thus only can

some safeguard be secured against surprises due to retarded

excretion. This simple measure of precaution was not takenin Rose's experiments, and it is therefore probable that the

well-marked positive balance during the milk period was

partly due to such a retardation of excretion, and that the

quantities of calcium that had previously been retained were

excreted after the milk had been discontinued, that is to say

during the carrot period, so that the balance was then falsified

to the apparent detriment of the carrot calcium. We infer,

therefore, that the experiments on E. D. B. and R. S. E.,

in which a comparison between a milk diet and a carrot dietwas made, afford no justification for declaring that there is

a difference in the utilisation of the calcium from milk and

carrots respectively. In the cases of E. H. and E. W., there

was no initial period of milk diet, and therefore no direct

comparison between milk and carrots is possible. Apart

from this, the experiments show such remarkable irregularities

that we are entitled to challenge the accuracy of the results.

In E. H. the increment is only 4 %, whereas in E. W. it is

27 %, although the difference in the amount of lime given in.the two cases was only 14 %. A strict criticism of the experi-

ments therefore leads us to infer that in two cases the

utilisation of the calcium of vegetable origin was as great as

or 70 % greater than the utilisation of the calcium in milk—>

which is the very opposite of what Rose contends. Con-

versely, in the other two instances, the utilisation was less

efiective in the case of the calcium of vegetable origin. We

may infer with some probability that the calcium in these

two nutrients has the same "biological value.

As a result of the observations of other medical practitioners

we are eatitled to draw the general conclusion that the inorganic

bases are always fully utilisable so Jong as they are administered

in such a form that they can be assimilated by the organism.

10. THE EFFECT OF OXIDATION UPON THE BIOLOGICAL

VAXTJE OF THE ACID-FOHMERS.

Even when a precise analysis has informed us concerningthe natute and quantities of the inorganic constituents of

the food, so that we are enlightened as to what supplementary



IMPORTANCE OF INORGAN IC SUBSTANCES 95

inorganic nutrients may be required, our difficulties are byno means at an end. All th a t the analysis tells us is the

aggregate amount of phosphorus, sulphur, etc. It may,however, very well happen that in one case this or that inor-ganic substance is present mainly in an oxidised (that is tosay in an inorganic form), and that in another case it is presentin the form of some complex organic compound. In thelatter event, it may sometimes be one of the components ofa readily oxidisable substance, and sometimes one of thecomponents of a substance difficult to oxidise. The bearing

on the amount of the inorganic nutrient that is requisite willvary iji each case. If, therefore, we wish to ascertain ananimal's requirement in respect of any inorganic substance,preliminary researches must be made to ascertain whether(when the diet is otherwise adequate) the selected method ofadministering the inorganic nu trien t be a suitable one. Notuntil we know this, can we proceed with the main subjectof research. The problems are further complicated becausethe requirement of inorganic nutrients varies in different

species of animals, and also because the requirement is exten-sively modified by the state of the animal as regards growthand other physiological conditions, such as procreation,!menstruation, gestation, lactation, etc . Above all in the case?of phosphorus and sulphur we have to reckon with, not merely'the absolute quantity in the food, but also the nature of thecompound in which these elements are supplied. We knowvery little concerning the modes of combination of sulphur,

and contributions to our knowledge in this respect would bemost welcome. Apart from th e purely inorganic compoundsof sulphur, we know this element in the organism only in theform of cystein or its "anhydride" cystin, although therecan be no doubt that quite a number of sulphur compoundsare represented in the " neutra l sulphur " of th e urine. Froma private communication I learn that Hopkins has recentlysucceeded in isolating a number of new sulphur-containingorganic substances. If this is confirmed, the importance of un-

oxidised and organically combined sulphur will be yet furtherenhanced, bu t nothing has as yet been published on the subject.

I have already mentioned that the peculiar importanceof the two sulphides to the animal organism is made manifest






still retain a thoroughly inorganic character. This is manifestinasmuch as simple hydrolysis or double decomposition suffices

to liberate the inorganic component, so that its presence canimmediately be detected by analysis. We have, indeed, asuperfluity of proofs that such a combination can readilybe effected within the animal organism through the simplesplitting off of water or ammonia.

From these organic phosphates which are easily formedand easily destroyed in the organism, from these salt-likecompounds, we must distinguish as a matter of principle thesubstances in which the phosphorus exists in an unoxidisedor imperfectly oxidised form as a constituent of a purelyorganic complex, this being the form in which (in part, atleast) the element is met with in the nucleoproteins. Forthe building up of such compounds, the phosphates as foundin inorganic nature must first be reduced, that is to sayhydrogenised; and in such compounds the phosphorus subse-quently enters into so intimate a form of combination, thatthe presence of the element can only be detected after a

preliminary destruction of the organic complex by oxidation-So far as the more highly organised animals, at any rate, areconcerned, we do not know a single instance of such a genuinereduction of phosphorus, and the incompetence of the animalorganism to achieve this reaction is the probable explanation ofthe inability of the higher animals to synthetise carbon chains.

Consequently, when Fingerling X99 found that, on a diet

very poor in organically combined phosphorus, hens continuedto lay regularly and to produce eggs containing a normalquantity of lecithin, he had merely discovered a fresh demon-stration of the familiar fact that the animal body can buildup phosphorus into compounds of the ester series; but theexperiment throws no light on the possibility of a synthesisof genuinely organic phosphorus compounds.

Innumerable investigators have studied the problem, andalmost all of them have come to the conclusion that no suchsynthesis can be effected w ithin the anim al body. Against

some of the earlier experiments, those of Steinitz,*7 Zadik,*9Leipziger,3° Ehrlich,3* and others, it is possible to lodge theobjection that these experimentalists did not succeed inproviding a diet free from organic phosphorus, or to complain

7



9 8 VITAMINS

th at the duration of the experiments was to o short. T h enegative issue of their researches has, therefore, n o de m on stra -tive force. In other instances, as in the ex pe rim en ts of

Gregersen/43 the duration was ridiculously brief, no a t t emptwas made to avoid errors due to delayed excretion, and noexamination of the excreta was continued after t h e close of th emain period of the experiment. The same critic ism s ap pl yto the experiment made by H o ls ti I I 6 upon his own person.The positive results secured by Gregersen and H o ls ti m ay ,therefore, be interpreted as simply due to errors of ex pe rim en t.

Only four decisive series of observations bearing on thism atter ha ve been recorded. P a t on 3* has shown that when

salmon are on the way to the spawning-ground, and whenduring this period the testicles or ovaries undergo a n eno rm ou senlargement, the phosphorus content of the ripe reproductiveorgans increases just as much as the phosphorus content ofth e muscles diminishes. Now the muscles co n ta in a m ixed -

*organic phosphorus compound, whereas in the ovaries andpie sperm there are nucleoproteins, which must have beenbuilt up out of inorganic phosphorus. Bu t the d em on str ati veforce of Paton's observation rests upbn the old assumption

that salmon take no food while on their way up river.Put te r 87 has, however, shown tha t this as sum ptio n is un -founded ; during their migration u p river it i s tru e t h a tsalmon are less inclined than usual to feed on other fish, butthey consume plankton, and this fact cuts the ground fromunder Paton's reasoning.

McCollum95 experimented on growing rats with a dietvery poor in phosphorus. The rats grew in a fair ly no rm alfashion, but th ey lost weight, so th at M cCollum's inference

that the rats did not need any organic phosphorus for thepurposes of their growth seems a trifle hasty.H art , McCollum, and Fuller 86 experimented on pig s w ith

a diet containing very little organic phosphorus. T h e anim alsgrew, bu t they suffered in th e same wa y as t h e ra ts inMcCollum's experiments. W hen the pigs were ki lle d, th eosseous system was found to be only about one-fifth as welldeveloped as it would hav e been on a norm al d i e t . Since,moreover, the experiments were not continued until the

animals were old enough to reproduce their kind, they lackcogency.




All that remain, then, are the experiments of Qsfeprnc,Mendel, Fe rry , and Wakeman 7*9 on ra ts . B ut in ft&r case

the diet was not free from organically combined phosphorus,and since the work of other investigators ll9> *99> &* has shownbeyond dispute that the need for organic phosphorus is verysmall in comparison with the need for inorganic phosphorus, .these experiments, too, lack demonstrative force. We mustremember that even edestin, the protein which is most easilyprepared in a pure form, is never free from phosphorus—although some of the American investigators contend thatit is. I have been led by the publication of the Am erican

researches to examine a number of the eclestins of commerce,and haVc found them all to contain phosphorus, sometimes inconsiderable am ounts. The firm of Merck manufactured toa special order a sample of edestin of the utm ost pu rity. Thiscontained o-06 81 % of phosphorus (estimated as P8O3). Onfurther enquiry, the manufacturers said they could not supplyany thing purer. My own atte m pts to produce an edestinfree from phosphorus were equally fruitless. If a pu re crystal-Usable protein contains so large a percentage of phosphorus,

we are certainly entitled to assume that the commoner sortsof protein ordinarily employed in experiments on nutritionmust contain even larger amounts of organic phosphorus.Although is so many instances we are assured that the experi-mental diet was free or almost free from organic phosphorus,there is adequate ground for believing that the assertionswere based upon a defective ana lytical technique. Or, indued,the experimentalist rnay have accepted the manufacturer's

guarantees at their face value,Elaborate experiments made on dogs by Rogozinski 11<l

and Durlach a87 gave negative results. Here, however,deficiency of complettins and bases may have been acontributory cause,

All our extant experience would seem to point to theconclusion that the amount of organic phosphorus requiredby the organism is very small, tut that the higher animalsare incompetent to synthetise such genuinely organic phos-

phorus compounds as they actually want. In experimentsconcerning complettins it is therefore essential to see thatthe bodily need for phosphorus in organic combination isduly satisfied.





FORMS OF POLYNEURITIS 101

touch European food, and lived entirely on polished rice.The Goanese, who were working in the same place, but who

ate European food, remained healthy. Among the Chinesecoolies employed in Mesopotamia, beriberi had broken outduring their transport to the country, so that this was likewisea true ayitaminosis. There was, however, no improvementin the health of the Chinese coolies when they were put uponEuropean diet; and there now ensued among the Europeantroops, who ate abundant meat in the customary fashion,repeated epidemics of beriberi, some of them very severe.Sprawson was of opinion that the epidemiology of the disease

could (jnly be explained on the theory that among those wholived on European food it was spread by infection, seeing thatthe generous meat rations must have contained sufficientvitamin. The theory received official endorsement, for inthe discussion on the avitaminoses,1066 even the noted Britishscientist Hopkins described infection as* not altogetherimprobable in such cases. For similar reasons, Marchoux "55came to the same conclusion regarding the causation of the

epidemic among the Annamese soldiers in AngoulSme.In both these instances, however, the fundamentalassumption that the diet had contained sufficient vitaminwas cQntested by other authorities. Willcox,I0*5, Io66 Humeand Chick,1066

and also W allis,1066 pointed out that the beriberiepidemics in Mesopotamia only occurred when difficulties inthe supply of fresh meat had made it necessary to feed thetroops on corned beef, and that the bread in the soldiers'rations was made from the finest white flour and was thereforevery poor in vitamin. In the corned beef, the vitamin hadbeen destroyed during the process of sterilisation. (The laststatement may be correct, but it is interesting to note howamong the Entente States as well as among the CentralEuropean States theprofit-hunting of the owners of the canningfactories entailed the death of countless human beings. UdoKliinder J3*4 has shown tha t, during the war, in the preparationof corned beef in America, the water of the first boiling,

which is known to contain an abundance of vitamins, wasseparated from the meat and made into meat extract. Inthe weakly acid medium of the fresh meat it is quite probablethat, but for this, a sufficiency of vitamins would have resisted



102 VITAMINS

th e process of sterilisation.) Re garding the epidemic amongthe Chinese coolies in France, Leggate I01* reports th at thestaple diet consisted of polished rice, and though a meat rationwas given once or twice a week, the meat was tinned.

So many instances were known in which intoxicationcould be excluded, that it was necessary to look for othercauses. Th e m ost notab le fact in th e epidemiology of beriberiwas that when the disease occurred in rice-eaters it was onlyin those who consumed fully hulled and polished ri c e ; andthat partially hulled rice, still invested with the pericarp orsilver-skin, was actually ab le to cure th e disease. A firstglance at the composition of polished rice seemed, therefore,

to those medical practitioners who continued to believe inVoit 's dogmas concerning nutrition, to support the theorythat the cause of beriberi was an insufficiency of protein andfat. Th e observ ations of Cham berlain and Vedder J56 werein harmony with this, for they found that persons fed on aninadequate supply of unhulled rice, or suffering from actualfamine, developed symptoms resembling those of beriberi,and that in this disorder just as in true beriberi, the firstsym ptom wa s a loss of weight amounting to at least 21 % .

Eijkman 5 l6 likewise found that polyneuritis occurred in fowlswhose diet was quite inadequate, and that this polyneuritis,too, could be cured by dosage w ith vitam in. Segawa,3*3however, regarded the malnutr i t ion as no more than asecondary symptom dependent upon the gradual developmentof a repu lsion for the mono tonou s diet.369 Th is theo ryconflicts with the universally known fact that the body-weightbegins to decline directly the subject is put upon the patho-genic die t, long before any repulsion arises. As long ago as

1902, Hulshof£-Pol 38 drew attention to this initial loss ofweight, and his data have been confirmed by all subsequentobservers.

Nearly twenty years earlier , Urbeanu 8 had shown thatin dietetic polyneuritis the phosphorus and potassium balancein exp erimen tal animals became negative from the very outse t.Chamberlain, Bloombergh, and Kilbourne X45 pointed o ut th a tall the nu trien ts known to cause beriberi axe poor in phospho rusan d po tas siu m . Vedder 314 confirmed th is, bu t was of opinion

that the deficiency of these substances did not suffice to



F OR MS OF P O LY NE UR ITIS 103

explain ou tbre ak s of the disease. In 1904, D urh am 44 h adshown that the nitrogenous balance became strongly negative

with the appearance of the first symptoms of the disease.These points were not fully cleared up until the comprehensiveresearches of Schaumann I23» 36x had shown that directlythe experimental diet was begun, the balance of nitrogen,total ash, and (above all) calcium and phosphorus, becamemarkedly negative, and grew continually more unfavourableas th e disease progressed. Ob servations m ad e by Aron a ndHocson,I49 and by Breaudat,*72 that the addition of meat tothe diet did not cure beriberi, ran counter to the theory that

the disease is due to m alnu trition in th e ord inary senseof th e te rm . According to Tasawa,33* a pecu liarly typic alpolyneuritis ensues upon a diet in which polished rice issupplemented by white of egg or thoroughly boiled meat;and Lovelace 2 6 2 has seen a number of cases of beriberi inwhich the supply of protein in the food had been abundanteven in accordance w ith the older dietetic sta nd ard s. Ed ie,Evans, Moore, Simpson, and Webster2 2 0 found, indeed, that

the addition of casein somewhat retarded the onset of thedise ase; bu t th e most plausible interp retatio n here is th atthe casein of commerce used by the experimenters was notperfectly free from vitamin.

In one respect there is something to be said in favour ofthe opinion of those who have held that the inadequacy ofrice protein is responsible for the occurrence of beriberi, forBarrIO55 has drawn attention to the fact that experimental

polyneuritis closely resembles the diseases that result fromfeeding with an inadequate protein—for instance, one charac-terised by a lack of try pto ph an . Th is, how ever, can onlybe an accessory factor, for were it the efficient cause theaddition of protein to the diet would prevent the disease,and we have learned that it fails to do so.

Br6auda t 3C7

2 found also that the addition of fat or carbo-hydrates was ineffective. Indeed, in monkeys sufferingfrom beriberi, the addition of butter to the diet hastens the

end.IO56 In part this remarkable result may be explainedby the supposition that the provision of additional combustiblematerial imposes upon the body an additional task with which,in its weakened state, it is unable to cope, so that the acidosis



106 VITAMINS

induce in fowls a polyneuritis which closely resembles humanberiberi. In this connexion it ma y be of intere st to notethat polyneuritis gallinarum has recently occurred on a large

scale, as an outcome of wartime feeding, in Holland amongord ina ry domesticated fowls.975 This prove s th a t th e experi-m enta l polyneuritis pre vio usly observed was no t simply anartificial product of lab or ato ry conditions, bu t a nutr itivedisorder perfectly ana logou s to beribe ri. I t has now, therefore,become possible to study in animals the complicated problemsconcerning this enigmatic disease more intimately and morespeedily than could be done in human beings in hospital.

Hois t and Fro l ich 6a> 6 3, *4,6 5,100, 105, 107,186 h a d ^Jready

noted that not only polished rice, but most other cerealsfrom which the bran has been very thoroughly removed andwhich have been finely ground and sifted, induce scurvy inpigeons and barndoor fowls. W hen unhulled, thes e cerealsare harmless to such birds, but bread made from fine flouris extrem ely injurious. T h e same observers discovered th atraw meat does indeed cause general disorders in fowls, butthat the birds become affected with polyneuritis only whenthe meat had been boiled for a long time, or superheated

(uo° to 1200

C ). In lik e manner, potatoes th at ha d beenlong boiled induced polyn euritis in fowls. H ar t, H alpin,and McCoUurn6 l* also showed that unhulled cereals wereharmless to fowls, provided that calcium carbonate wasadded to the food in order to prevent the incidence of otherdiseases th an beriberi. Acc ording to Weill and M ouriquand,6 27hulled maize and sterilised maize both cause polyneuritis,whereas the hulls of raw maize have an antineuritic influence,an d, according to Clementi,5*9 fowls which hav e been affected

with polyneuritis by being fed on rice can be cured by givingth em wholemeal from m aiz e. According to Schaumann,36itoo, the whole maize is harmless to pigeons.

Nevertheless, cases of beriberi have been reported in whichthe pathogenic agent was unquestionably unhulled rice, andnot polished rice. IO77, "55, II 8* Th e most reasonable explana-tion of these instances is to suppose that in such cases therice had been kept too long in store.

It has long been known that gêen peas and fresh beajisare rich in vitamins. This is especially true of the katjang-idjo



FOR M S OF PO L Y NE UR I T I S 107

bean (Phaseolus radiatus), renowned as a remedy for "beriberi.As ea rly as 1902, Hulshoff-Pol 3* pr ep ar ed a n ex tra ct of

katjang-idjo which w as successful in curing be ribe ri. Mosz-kowski X74 expressly declares th a t w hen a n exclusive d iet ofpolished rice is producing beriberi, the occurrence of thedisease can be prevented by the addition of comparativelysmall qua ntities of this bean to the daily ratio n. Sch aum ann 3^confirms the statement that katjang-idjo has both a prophy-lactic and a curative action in be rib er i; b u t add s th a t therem edial influence of th e bean declines as it gets older, an dthat beans which have been stared for five years are quite

ineffective. Th is accords w ith th e report of W eill, M ouriquand,and Michel,^6 that sterilised meat will induce polyneuritisin cats more rapidly in proportion to the time the meat hasle en stored. Th e same observers found th a t ra w frozenmeat or salt meat was well borne by cats if fresh, whereas-when it has been long kept it is known to be free from vitaminsand to have a pathogenic influence.

I rnxist repeat that in the case of seeds, too, the method

of pre pa ratio n is of much im po rtanc e. Osb orne an d Mendel 493found that there was abundant vitamin in cotton seed, "butRommel and Veckler^r report that fine cottonseed meal,as an exclusive diet or as an extensive supplement to hay,induces polyncuritis in cattle . In like m an ner, pigs fed onhulled rice, cottonseed meal, or a mixture of maize mealand cottonseed meal, speedily became affected with poly-neuritis . In conformity with the observations of Hoist andJrolich, Litt le i6 t repo rts the occu rrence of "beriberi in S t

Anthony (Newfoundland) and Labrador in persons nourishedalmost exclusively on fine wheatea flour. In the pig, too,according to Hart, Miller, and McCollurn,5*5 large quantitiesof fine wheaten flour give rise to polyneuritis.

The q uestion is greatly complicated b y th e circumstancethat the same nutrient has very different effects in differentspecies of animals. We hav e seen th a t maize is harm less tofowls and pigeons ; and according to H ois t and F r 6 li c h M

xats rem ain h ealth y on a maize diet,—an obse rvation confirmedfcy Schau m ann. Conversely, Sch aum ann 's expe rimen ts showth a t maize induces marfo^d polyneuritis in ra b b it s; Hoistand FrQlich, and also Schauraann, have found that it causes



108 VITAMINS

scurvy in guineapigs; whilst Weiser *58 states that pigs fed

on m aize perish from general m alnu trition. Again, accordingto Hart, Halpin, and McCollum,612 fowls fed on wheat remainhealthy, whereas pigs and rats develop polyneuritis on thisd i e t; and H oist and Frolich inform us 65 th at guineapigsfed on wheat suffer from scurvy.

The varying reaction of different species of animals to anidentical diet is still a complete enigma, and in my opinioninsufficient at ten tio n has been paid to the m atter . Speaking

generally it would seem th at graminivorous birds th riv e onwhole grains, but suffer from polyneuritis when the grainis hulled. I n m am m als, on the other hand, grain feedingmay cause polyneuritis in certain circumstances, especiallyin rodents (except for the omnivorous rat), which are highlysusceptible to acidosis. In m any mam mals, however, a graindiet indu ces scu rvy instead of polyneuritis ; while some animalsperish from general malnutrition owing to the inadequate

sup ply of inorganic nu trients in the grain. W hen grain hasbeen very thoroughly hulled, almost all animals, human beingsincluded, become affected with polyneuritis. Are thesevariations due to varying requirements in respect of vitamin;or are the polyneuritic disorders due to the absence of variousvitamins which act differently in different species of animals,or are essen tial to different species in a vary ing degree ?

Hoist and Frolich (op. cit.), experimenting on guineapigs,

found that these animals on an exclusive cereal diet invariablysuccum bed in from fifteen to forty-six days. In sixty-fivefatal cases, sixty-three were well-marked instances of scurvy,and o nly tw o were instances of polyneuritis. I t is tru e t h a ta large number of the animals dying of scurvy were found onpost-mortem examination to have degenerative changes inthe finer ramifications of the peripheral nerves, but there hadbeen no pa raly tic sym ptom s. Considering this observation

in the light of'what has previously been said, its interpretationbecomes easier when we recall that rodents are extremelysensitive to acidosis, which in these animals always leads tohaemorrhages, and frequently to the occurrence of oedema.If their food be characterised by a lack both of vitamin and ofthe antiscorbutic complettin, the effect of the latter deficiencywill be reinforced by the acidotic influence of the food, so



FORMS OF POLYNEUR ITIS 109

that scurvy will develop unless there be some special predis-position to nervous disease, a predisposition either congenitalor acquired. I t is in these exceptional instances of predisposi-tion th a t polyneuritis develops. But the fact that in suchcases, also, the bones were found to be " as thin as paper,"shows that scurvy or acidosis existed as a complication.

We have already learned that beriberi in human beingsand polyneuritis in other animals are not solely associatedwith an exclusive rice diet, but may occur when various other

nutrients are given. Even when these pathogenic nutrientsare given in conjunction, and even when they are given (ofcourse in preponderant quantities) in association with nutrientsthat have a curative effect on polyneuritis, polyneuritis willensue, as happened in the case of the British troops inMesopotamia, and as was observed by Dufouger£ "44 in FrenchGuiana. Lovelace26 2 reports a case of beriberi observed byhimself in which the patient had been taking a mixed diet.

Dickenson,4*6 and also Smith and Hastings,286

noted theoccurrence of this disease in persons taking an extremelyvaried diet which seemed to comply with all the hithertoaccepted essentials of an adequate nutrition. " Ship beri-beri," which also arises in persons taking a mixed diet, cannotbe considered here, since nervous symptoms are entirelylacking in this form of the disease. The whole clinical pictureof ship beriberi assimilates it rather to malnutritional oedema,

and we shall return to the matter in that connexion.When beriberi occurs in persons taking a mixed diet, it

will be found: (a) that some of the important nutrientshave been subjected to a preserving process involving exposureto excessive or unduly prolonged h ea t; or (6) th at the cerealsin the diet have been subjected to too extensive a hullingprocess in the m ill; or (c) that other important constituentsof the food have, in preparing them for the table, been boiledand that their vitamin content has passed into the cookingwater and been thrown away.

This account of the etiological importance of diet inrelation to the onset of beriberi may conclude with a referenceto the fact that both Cooper 269 and Vedder235 have foundthat the use of alcohol does not appear to accelerate theonset of beriberi or to aggravate the course of the disease.



n o VITAMINS

2. ISOLATION OF VITAMIN.

The first attempt to isolate the antineuritic principle was

made by Hulshoff-Pol 38, 68, 626 in jgoz. Having prepared awatery extract of katjang-idjo beans, he added lead acetate

to form a precipitate; the filtrate was then freed from lead

by means of sulphuretted hydrogen ; "by subsequent evapora-

tion at the ordinary temperature he secured an acid crystalline

substance to which he gave the name of X acid. It had

prophylactic virtues against "beriberi, and was a useful remedy

in cases of that disease. McCollum and Sirnmonds67° subse-

quently isolated vitamin from haricot beans. Having extracted

these with 95 % alcohol, they got rid of the alcohol by evapora-tion, freed the residue from fat by treatment with ether,

mixed it with dextrin, and precipitated the active principle

in conjunction with the dextrin by means of absolute alcohol,

These observers recorded as a remarkable peculiarity that

vitamin, which is ordinarily insoluble in acetone and benzene,

can be extracted from the dried dextrin precipitate by the

use of acetone or benzene. This statement has not been

confirmed by any other investigators.

It was natural that other early attempts to isolate vitamin

should have teen made in the case of rice grains or the silver-

skin of rice (rice polishings). In 1910, Fraser and StantonIo8

reported that the active principle could be extracted from rice

by means of alcohol. Tie next year, Funk *55 extracted the

hulls of rice with alcohol, freed the solution from alcohol,

dissolved the residue in dilute sulphuric acid, and then

precipitated with phospho-tungstic acid ; the precipitate was

treated with "baryta water, and after the excess of baryta had

been removed by the addition of sulphuric acid, the filtrate

was first purified with an excess of silver nitrate, and then

the vitamin was precipitated as a double salt with silver

nitrate by the use of baryta water. Prom this precipitate

it was possible to extract a crystalline preparation, which

proved to be the nitrate of an organic base.

Subsequently the method" was much modified, but the

essentials of the process remained unchanged—the crude

vitamin was isolated by the precipitation of a sulphuric-acid

solution by means of an exactly adequate quantity of phospho-



FORMS OF P01YNEURITIS in

tungstic acid. Tsuzuki and Shimamura * s6 improved themethod. Having driven off the alcohol from the first

alcoholic extract, they removed the fat from the extract bjr

the use of ether. They were then content with decomposingthe phospho-tungstic-acid precipitate by means of baryta,subsequently freeing the solution from baryta by treatmentwith sulphuric acid, and then evaporating to a syrup. Bythis process they secured a thick syrup, acid in reaction, andrepresenting 0 . 3% of the material originally extracted.They named the product aberi acid.

Schaurnann I2 3 prepared his crude vitamin in the firstinstance by extracting the silver-skins of rice (rice polishings)with albout ten times their weight of 96 % alcohol, drivingoff the alcohol by evaporation on a water-bath at a moderatetemperature in a strong air-current, and removing the fatfrom the extract by the use of acetone. He subsequentlysecured a purer product by the following process. Havingmade an extract with water, orbetter still with dilute (o-z %)

HC1, he treated the extract with 96 % alcohol, precipitatedthe filtrate with sublimate solution, and decomposed thisprecipitate. At a later date,36 1

he seems to have used 0-3%HC1, but he states that extraction both with this and withalcohol is far from being successful. Hence we can under-stand the experience of Abderhalden and Lamp<3,289 whofound that extraction with alcohol did not notably impairthe curative virtues of rice bran.

Since Funk's method involves serious losses of the activeprinciple, Tsuzuki 3*° attempted to secure a crude preparationmore highly charged with vitamin. Having extracted with60 % alcohol, he evaporated to a syrup, which he saturatedwith ammonium sulphate until the proteins it contained wereprecipitated; the filtrate was then freed as much as possiblefrom ammonium sulphate by the plentiful addition of alcohol ;

the solution having been once more concentrated, was againprecipitated, this time with absolute alcohol, and the filtratethen concentrated by evaporation at a temperature of from6o° to8o° C. to form a thick extract, brownish in colour. Tothis, Tsuzuki gave thename of antiberiberin. Onekilogrammeof rice polishings yielded fifty grammes of antiberiberm.According to Schaumann 3** it was almost entirely ineffective.



112 VITAMINS

F u n k 273 ende avou red to purify his own crude vitam in byfractional crystallisation, thus securing two crystalline sub-stances. One of thes e w as appa rently nicotinic acid, and th e

other was a hitherto unknown nitrogenous body of highmolecular weight.

Before this, Tsuz uk i, Shimam ura, and Odake *10 had triedto obtain pure vitam in. Th e crude product resulting from th edecomposition of the phospho-tungstic-acid precipitate wasprecipitated with tannic acid and subsequently purified inthe form of a crystalline pic rate . The substance thus obta ined,known as oryz anin, was found b y Drummond and F un k 39°to be quite ineffective.

The purest preparation hitherto secured is that made byHofmeister.11 ^ H e trea ted rice polishings and rice hus ksthree times in succession w ith twice their bulk of 80 % alcoholin the cold, evaporated the extracts in vacuo, treated theresidue with hyd roch loric acid even as strong as 3 % , an dthen extracted the fat ty m atter with ether; the ether wasthe n driven off in vac uo at a low tem pe ratu re; a thick s yru presu lted, an d th is was purified by precipitation with 80 %alcohol. T he filtrate, hav ing been freed from alcohol in va cu o,

was rendered slightly alkaline by the addition of sodiumcarbonate, and then precipitated with Kraut 's potassium-bismuth iodide solution, care being taken to avoid thedeve lopm ent of a stro ng ly acid reaction. After five ho ur s,the precipitate was removed by siphonage, decomposed bytrituration with silver carbonate, and the preparation wasth en prom ptly filtered. T he filtrate was freed from silver byweak acidulation with hydrochloric acid, filtered once more,and evaporated in vacuo to near dryness. The residue

consolidated to form a faintly tinted, deliquescent mass witha ra diatin g crystalline str uc ture , and from 5 to 10 milligramm esof this sufficed in pigeons affected with polyneuritis to removethe paralytic and convulsive symptoms for from 8 to 10 days.By the gold hydrochloride method a pure substance could beprepared from this material, and to the purified preparationHofmeister gave the name of oridin (probably a dioxipiperidin),wh ich how ever prove d qui te inefficacious. Hofmeister su p-poses that the efl&cacy of the crude material must depend

upon the presence of small quantities of some constituent



FORMS OF POL YN EU RITIS 113

which is lost d ur ing th e process of purification (in th a t case

it m ust possess am azing potency). H is alterna tive explana-tion is that the virtues of the crude material are destroyedby the purification.

Most investigators, however, in their attempts at theisolation of vitamin, have recourse to yeast as a more readilyaccessible substance . As early as 1910, Schaum ann "*secured an effective ex tra ct as follows. H av ing rem oved th e

fat from the yeast with ether, he extracted the residue with0 *2% HC1, precip itated th e ex trac t with a n ab und ance of96 % alcohol, repea ted th e solution and precipitation , andfinally, washed th e precip itate on th e filter with alcohol andethe r. E die , E va ns, Moore, Simpson, and W ebster,2*0 havingextracted the fat from yeast with ether, treated the residuewith cold 96 % alcohol, and evaporated the alcoholic extractin an air cu rren t. T he residue was then dissolved in 0-2 %HC1, purified by F un k 's phosph o-tungstic acid an d silver-nitrate process, microscopic crystals amounting to 0-0038 %of th e original yeast being ultim ately secured. According toSchaumann,a3* if th e process be arre sted at th e stage of decom po-sition of the phospho-tungstic-acid precipitate, an effectiveproduct is secured, but this contains considerable quantitiesof an im pu rity (perhaps cholin) which has a toxic action. H e

has therefore modified the process in th is way.361 T h e filtrateafter p recipitation of th e ba ry ta b y sulphuric acid is eva pora tedat a low temperature to a syrupy consistency, dried with silicain a vacuum exsiccator, finely powdered, and steeped twicein succession for forty-eight hours in absolute alcohol withthree drops of dilute sulphuric acid. On dry ing th is alcoholicextract, he secured an active crystalline residue, which was

manifestly a m ixtu re. B u t in this case, as in t h a t of th erice vitamin, the activity of the preparation was destroyedin the purification of the separate components of the mixture.(Cf. Seidell M43.1484.) Funk , m oreover, ha d earlie r h ad th esame experience with yeast vitamin.273 H e ha d isolated fromthe crude vitamin three crystalline substances, one of whichappeared to be nicotinic acid, whilst the other two were



H4 VITAMINS

certainly -exist in a combined form, probably as the union ofa pyrimidin base with nucleinic acid, for the full efficacy ofth e extract was not developed u nt il after hydrolysis. Th eyfound, also, that Funk's method of preparation must beattended with great losses, for the original hydrolysate wasfrom twenty to twenty-five times more effective than thevitamin that could be extracted from it.

In the case of yeast, likewise, it appears that the fullefficacy is only developed after the autolysis of the yeast.

As a rule, therefore, in subsequent investigations autolysedyeast has been used as raw material, and here again Williamsand Seidells6 0 noted that the crystalline crude vitamin lostits efficacy completely during the process of recrystallisation.Abderhalden and Schaumann 8o3 subsequently prepared aneffective crude substance by simply precipitating the alcoholicextract of the hydrolysed yeast with acetone or mercuricchloride.

Sugiura776 reports an entirely new way of obtainingvitam in. H e pu ts th e dr y yeast in a collodion bag, and fillsup w ith w ater, or b et te r with 5 % sodium-chloride solution.The vitamin gradually makes its appearance as a crystallinepowder on the outer surface of the bag, and can be securedby merely bru shin g it off. I am no t aw are th at this m ethodhas been checked by any other observer.

Osborne and Wakeman978 attempted to secure an active

highly concentrated crude vitamin in an extremely simplemanner. They gradually scattered dry yeast into boilingwater to which ten cubic centimetres of 1 % acetic acid hadbeen added . After tw o minutes* boiling, the whole wascentrifuged, and th e ye ast was washed once more with w ateracidulated with acetic acid. The purified solution wasgradually diluted with alcohol, and precipitates were securedwith a content of 52 %, 79 %, and 90 % of alcohol by weight

respectively. The bulk of the vita m in was in th e secondprecipitate, and represented about 6 % of the total dry matterin th e yeast. R ecen tly Fra nk el a nd Schwarz X3*3 haveattempted to secure vitamin in a pure state, but with theaid of a qu ite unsatisfactory control process. Having m adean alcoholic extract of yeast, they removed the fatty matterwith ether and precipitated the residue with lead acetate*




The filtrate was freed from lead with sulphuric acid, andprecipitated with concentrated mercuric chloride solution,

the precipitate being then treated once more with sulphuricacid. The filtrate from mercuric sulphate was freed fromsulphuric and hydrochloric acids with lead oxide and silvercarbonate, and then concentrated in vacuo. By degrees,there crystallised out a substance, which, however, provedinactive. The highly active mother solution was purifiedwith picrolonic acid, the filtrate was precipitated with asufficiency of phospho-tungstic acid, and the precipitatedecomposed with baryta water. The filtrate was freed frombaryta^ by the addition of 50 % sulphuric acid, refiltered,and concentrated in vacuo. The yield was 0*2 % of a veryactive syrup. Attempts to extract the free base from thisby treatment with amyl-alcohol after alkalinisation withbicarbonate, were fruitless.

A somewhat new method has been adopted by Myersand Voegtlm,IX44 who omitted the precipitation with phospho-tungstic acid. Dried yeast was powdered, and boiled repeat-

edly in methyl alcohol containing 1 % of concentrated hydro-chloric acid, the alcohol was distilled off, the residue wasdissolved in the smallest possible quantity of 1 % hydrochloricacid, the solution was shaken up with ether, and the chlorinewas then precipitated with hot aqueous silver acetate solution.The filtrate was treated with a considerable excess of silveracetate solution, and baryta water was added until analkaline reaction began to appear. The resulting precipitate

was decomposed with sulphuric acid and sulphurettedhydrogen, the solution being freed in the ordinary mannerfrom these two ingredients, and then concentrated in vacuo.From the concentrate, histidin and similar substances wereprecipitated with mercuric sulphate, and the filtrate was thentreated with absolute alcohol. The resulting precipitate wasfirst freed from mercury by the use of sulphuretted hydrogen,then freed from sulphuric acid by the use of lead acetate, andfina lly freed from lead by the use of su lphuretted hydrogen.When the liquid was concentrated in vacuo in the presenceof caustic soda, spindle-shaped crystals gradually formed,and these were extremely active. If, however, the crystalswere removed from the mother liquor, and an attempt made



n6 VITAMINS

to purify them by washing with absolute alcohol, they

completely lost their activity and became transformed intoprisms.

We see, then, that there is no difficulty in preparingeffective ex tracts from vario us foodstuffs. B ut th e purificationof these extracts is attended with a notable loss of material,and the activity of the preparation seems to disappear atthe very moment when the last stage on the way to purityis reached. The meaning of this remarkable behaviour willbe considered later.

3 . T H E P R O P ER TIES O F F U N K ' S V ITA M IN S .

All th a t we as yet know concerning the antineuritic p rincipleassures us that it is readily soluble in acidulated water oralcohol. In p u re wa ter, o r 95 % alcohol, it is soluble w ithgreat difficulty, so that these menstrua extract it quiteincom pletely. I n abso lute alcohol, ether, acetone, benzol,benzin, chloroform, and acetic ester, it is quite insoluble;and yet McCollum and Simmonds 67° make the rem arkableassertion that acetone, though it cannot dissolve vitamindirectly out of plants, can dissolve it out of the concentratedalcoholic extracts of these. The same authorities declarethat when vitamin has been precipitated by dextrin andalcohol an d the p rec ipita te dried, the vitamin can be ex tractedfrom this prec ipitate b y benzin. Should the statem ent beconfirmed, we shall have a far simpler method of isolationthan the laborious and wasteful procedures hitherto employed,namely precipitation by phospho-tungstic acid, silver, ormercury.

Chamberlain, Vedder, and Williams *96 were the first tono tice th e absorption of vita m in by animal charcoal. I t ispossible that this might be made the basis of the method forit s isolation; b u t we ha ve to note tha t these authoritiesdeclare that the vitamin cannot be re-extracted from thecharcoal either by water, alcohol, or ether. .Various

6 66



FORMS OF PO LY NE UR ITIS 117

th at m astic emulsion will absorb vita m in. Th is is especially

im portan t in view of t he fact th at Voegtlin and Whitehave noticed that adenin and kindred bases are not takenup by this abso rbant. Fro m such an abso rbate, by dissolvingit in benzin and shaking it up with acidulated water, a fairlypure product could be speedily obtained.

The enormous losses attendant on the various methodsof purification do not seem to depend only upon the peculiarinstability of vitam ins. Perhaps the m ain reason is th a t

vitam in is, as Cooper *69 tells us, prec ipitated from its solutionsin conjunction with any precipitate of a nascent metallicsulphide. W hen we remem ber th at a tte m pt s to purifyvitamin always entail its precipitation as a double salt ofsilver or mercury and its subsequent freeing from the metalby treatment with sulphuretted hydrogen, or else that thesolutions are purified by treating them with lead salts and

subsequently precipitating the lead with sulph uretted hydrog en,it will be readily understood that extensive losses cannotfail to ensue.

Vitamins are not precipitated from acid solutions by leadace tate, calcium chloride, barium chloride, o r silver salts ;nor from alkaline solutions by phosp ho-tungstic ac id. Onthe other hand when the vitamin solution has been renderedalkaline by baryta water, the vitamin is precipitated both

by barium chloride an d by silver sa lt s ; and in th e foregoingsection we have frequently noted that it is precipitated byphospho-tungstic acid in solutions weakly acidulated withsulphuric acid. According to Schaurnann,1*2 copper acetateinduces abundant precipitation in the crude vitamin solution,but inasmuch as Funk 3 05 tells us that no precipitation isinduced by copper salts in purified solutions of vitamin, the

precipitation observed by Schaumann must have dependedon the presence of impurities.Regarding the reaction to mercury salts, Osborne and

Wakeman 978 state that vitamin is precipitated by mercuricchloride, whereas Myers and Voegtlin IJ44 actually free vitaminsolutions from other bases by the use of mercuric sulphate.Probably the precipitation observed by Osborne and Wakemanwas likewise due to the presence of such bases as adenin,



n 8 VITAMINS

According to Tsuzuki, Shimamura, and Odake,510

vitamin

forms precipitates with picric acid and with tannic acid.

According to Osborne and Wakeman 97& the precipitation with

picric acid does not occur unless the reagent is added insuitable excess.

The vitamins are dialysable/S6*

l8* and are comparatively

resistent to acids. Dilute sulphuric, hydrochloric, and nitric

acids, have no effect on them, and according to Schaumann

vitamin is unaffected by long treatment with 10 % sulphuric

acid. On the other hand, most investigators agree in stating

that it is very sensitive to an alkaline reaction, especially to

caustic alkalies. Still, even by these, vitamin is not instanta-

neously destroyed; its destruction requires a time whichvaries in accordance with the concentration of the alkali,

But there are two observations sharply conflicting with these

statements. According to Williams and Seidell,56° the absorb-

ate into fuller's earth is insensitive to alkali, and the

vitamin can actually be extracted from the absorbate by a

dilute alkaline solution. Daniels and McClurg834 tell us that

the vitamin in haricot beans, soy beans, and cabbage will

even resist superheating (1200C.) in the presence of sodium

bicarbonate. In this instance we are not told whether theamount of sodium bicarbonate added was sufficient to make

the menstruum markedly alkaline.

Reports concerning the sensitiveness of vitamins to heat

are contradictory. According to Fujitaniia i

the vitamin of

rice is destroyed by prolonged heating of the rice bran at

ioo° C. Funk 3*3 reports that the boiling of milk suffices to

reduce its vitamin content, and the same authority 334, as

,. also McCollum and Davis 455 agrees in stating that casein no

longer contains vitamin after it has been boiled. Abderhaldenand Lampe

a89 report that fowls fed on rice become affected

with polyneuritis sooner when the rice is boiled than when

it is raw; but Funk 357 points out in this connexion that

fowls consume a larger quantity of boiled rice than of raw,

and we have repeatedly noted that an excess of carbohydrate

food accelerates the onset of polyneuritis. When the fowls

are given a definite ration of rice, it does not matter whether

the grain is boiled or raw.334 A remarkable observation is

that of Hoist, who found that fowls fed on boiled potatoes

6

*




became affected with polyneuritis, whereas fowls fed on driedpotatoes 65 developed scurvy. The vitam in would seem,therefore, to be thermostable in comparison with thecomplettin C.

Higher temperatures definitely injure vitamin. Weilland Mouriquand,47<>, 495 Voegtlin,536 Hogan,646 and Hopkinsand his collaborators Io66 agree in reporting that an exclusive

diet of cereals, meat, or vegetable foods that have beensterilised at 1200 C , inva riably gives rise to polyneu ritis.Weill and M ouriquand 497 no ted th e same th ing in th e case ofsterilised unhu lled ri c e ; and it ha s also been noticed in thecase of sterilised maize.632

Various observations seem, however, to conflict with theforegoing sta tem en ts. According to Chick and H um e 596

yeast co ntaining 6 5 % of wate r loses no more th an an insignifi-cant amount of its protective influence through being keptfor one hour at a tem pe ratu re of ioo° C. Th ey say th a t thevitamin in the wheat germ can bear without damage twohours ' exposure to a tem perature of ioo° C , b u t a t 1200 C.it is rapidly destroyed. I n the already qu oted pa pe r byDaniels and McClurg we read that the vitamin in haricot

beans, soy beans, and cabbage will bear heating for half anhour at ioo° C, and even at 120 0 C, although bicarbonate ofsoda has been ad d e d ; b u t after this trea tm en t m ost of th evitam in has passed into th e w ater. According to Rohmann,47*the baking of food for one and a half hours does not destroyth e vitam ins. Barsickow3<>4 rep or ts th a t yea st t h a t ha sbeen heated to 1200 C. is still able to cu re po lyneuritis ; andFigueira IO46 succeeded in curing beriberi with sterilised beans.According to Osborne and Mendel, 102 boiled meat still containsconsiderable qu an tities of vitam ins . The conflict of evidenceis explained when we recall that in the sterilisation of largemasses of compact foodstuffs, after exposure for one and ahalf hours to 1200 C, the heat in the centre does not exceed



120 VITAMINS

F u n k 5" found radium to hav e no effect upon the activityof v i tam in; and that Zilva 9 l6 makes a similar report asregards ultraviolet light.

Not much is known regarding the colour reactions of

vi tam in. W ha t seems to be a fairly pur e preparation assumesa deep blue colour when treated with phsopho-molybdic-phospho-tungstic acid ; but it gives no colour reaction withph osp ho -tun gstic acid alone in acid solution 488 • whereaswhen rendered alkaline with soda solution, a blue tintdevelops.56° W e mu st remem ber th a t these reactions arecommon to a very large number of substances, so that we canconfidently assert that they are not specific, and we maywith considerable probability attribute them to the presenceof impurities.

In the foregoing we have seen how extraordinarily difficultit is to prepare a vitamin that is even moderately pure.Hence our knowledge of the composition of the vitamins issc an ty Th e literatu re of the subject, for instance one ofSchaumann's papers , IW contains elementary analyses ofactive preparations, but it is obvious that these latter wereimpure, so that the results of such analyses do not justify anyinferences as to the real composition of the vitamins.Fiink/SS, 205 w ho secured his vitamin as a nitrate, gives itscomposition as 55-63 % C, 5-29 % H, and 7-68 % N, deducing

the formula C 7H l6 N 03 'HNO 2 . H e rega rds it as a pyrimidinderivative, and considers it to be either a constituent ofnuc leinic acid or to be com bined w ith nucleinic acid. The reis much evidence in support of this view, especially the state-ment of Chamberlain and Vedder J5 6 that vitamin is formedfrom the decomposition of bean protein, and also the frequentlyobserved fact that autolysed yeast has a more powerful actiont h a n yeast in the original sta te. Hofmeister II J3 gives a similarcom position for his oridin hydro chlo ride. The formula isC 5H xx NO a • HC1. I t has a me lting-p oint of 2400 C, and may

pe rh ap s be a dioxypiperidin. Pe rha ps connected with thisis Abderhalden and Schaumann's observation 8o3 that amongt h e hydrolysis products of autolyse d yeast there was" aschamin/' which appeared to be a dimethylpropenylamin.

A survey of the whole series of investigations and of theattempts to obtain the antineuri t ic principle in a pure state




makes it perfectly clear that we have not to do with one single

vitamin, but with a whole class of more or less similar com-pounds. In one of his subsequent publications 273 Funkreports that he has been able to isolate from rice hulls twonitrogenous products, one of which seems to have been nico-tinic acid, wh ilst th e other appeared to hav e a far more complexcomposition than had hitherto been supposed, the formulabeing C26 H2ON409. Fro m the extract of autolysed ye ast hesecured, in addition to nicotinic acid, two other bases, with

the respective formulas C24H I9N5O9 and C29H23N5O9.When it became clear that these active bodies whose

absence was attended by the occurrence of polyneuritis werenitrogenous, it was natural to think of studying the relationshipto neuritis of the other nitrogenous compounds known toexist in the animal body or to be frequent constituents ofth e food. Th ym in, cytosin, uric acid, and guanin,265, 317 also

cholin,*84> 361 purin,*84 neurin , and betain,3*i arginin, aspa ragin •histidin, and oth er amino- acids, J96 and adrenalin,289 provedqu ite inactive in this respect. On th e other ha nd a num berof substances were found competent to postpone death frompolyneuritis for days or hours, though not positively curativelike vitam in. Th us strychn ine 3« delayed the fatal iss ue ;and chinin and cinchonin, in contradistinction to cinchonidin,

had a t least a tra ns ient efficacy.*^ According to Abd erha ldenand Lampe,289 allantoin was inactive ; bu t F unk 3*7 sta testhat its administration was followed by definite improvement,so th a t life was prolonged for two or three days. H yd an to inactually prolonged life for nine days. According to th e sameauthority uracil led to an alleviation of the paralyses, andprolonged life for from two to six days . W hereas W illiams an dSeidellsô declare adenin to be quite inactive, according toFunk, this substance, and also hypoxanthin and xanthin,though they have no effect on the paralytic symptoms, cannevertheless prolong life in pigeons for from thirty hours tofive days. Paraxanthin had a certain antineuritic effect onone occasion, b u t in thr ee other cases was ina ctive. Th ym o-nucleinic acid led to marked improvement, and prolongedlife for from nine to fourteen days, whereas yeast-nucleinic-



122 VITAMINS

beneficial effect, 73, «* is, however, right in insisting* t h a t inview of the great variations in the duration of life in such

cases, a brief retardation of the fata l issue can hardly justifyany inferences. Nor has the intensity of the para lytic sym p-toms much significance, for these vary greatly from case tocase.361 The same criticism applies to the observation ofAbderhalden and Ewald,683 that atropin, in contradistinctionto pilocaxpin, seems to mitigate the attacks to some extent.

Weight must, perhaps, also be ascribed to the objectionwhich Cooper 269 has made to Ms own experiments on the

effect of chiTnn and cinchonin. He found th a t these su b-stances could sometimes relieve the paralytic symptoms, butthat they were quite ineffective in this respect when they hadfirst been kept for six houis at a temperature of 125 0 C. Heinfers from this that in the manufacture of the quinine basestraces of vitamin from the cinchona bark sometimes cling tothe product, and this impurity gives the bases an illusoryappearance of activity as antineuritics.

Funk 974 had entirely unfavourable results with phloridjzin,and also with adrenalin, thyroid extract, and parathyroidextract, which all hasten the onset of the disease, increasethe loss of weight, and sometimes hasten considerably thefatal issue.

New parths of enquiry were opened when Funk publishedMs supposition that vitamin was a derivative of pyximidin,an d still mo re when he was able to detect nicotinic acid am on gth e constituents of crude vitamin. H e ascribes th e c u ra tiv e

effects of rice vitamin and yeast vitamin to the compoundformed b y nicotinic acid with one of the bases of th e v ita m in .It. R. Williams 481, 513, etc" repeated Fun k's atte m pts t oobtain the vitamin in a pure st at e; bu t the only pure pro du cthe succeeded in isolating from Funk's vitamin mixture witha melting-point 2330 C. was, once again, nicotinic acid. H ethen began experimental dosage with kindred substances.P ure trigonellin (methylbetain of nicotinic acid), p-oxynico tinic

acid and nicotmc-atid-nicotine-ester gave quite indefiniteres ult s. Somewhat bette r curative results iollowed t h eadministration of ill-defined condensation products of oxy-nicotinic acid with phosphoric pentoxide or acetit anhydride.As far as any antineuritic influence could be ascribed to



FORM S O F POLY NETJRITIS 123

/}-oxypyridin, a-methoxypyridin, a-methylpyridon, trigonellin,nicotinic acid, and betain, this was manifestly associated with

the presence of a betain group in the preparation, so thatWilliams was inclined to believe that some such group mustexist in. vit am in. In further ex perim ents, a definite impro ve-m en t in th e para lyti c sym ptom s of pigeons suffering frompolyneuritis was secured by a-oxypyridin and by 2-, 4-, 6-,and 2-, 3-, and 4-trioxypyridin. Ina ctive were nicotinic acid,cinchomeronic acid, chLnolinic acid, 6-oxynicotinic acid,citrazinic acid, glutazin, and the anhydrides of 2-, 4-, and6 -tiioxypyridin a nd tetraox ypy ridin. W illiams w ent on tomake j.n observation which is likely to be of great importancein the furthe r stu dy of vitam ins. H e found th a t th e effectivesubstances lost their efficacy very soon after they had beenprepared. H e inferred from this th a t these substances, onkeeping, underwent a metamorphosis from the active forminto a tautom eric inac tive form. H e was, indeed, able toprove that a-oxypyridin exists in two keto-forms and oneenol-form, and that only one of these three, the keto-form

which crystallises in needles, has a marked antineuritic effect,th e enol-form in pa rti cu la r being" qu ite ina ctive . Similarrelationships obtain in the case of jS-oxypyridin y-oxypyridin,y-hitidin, and the anhydrides of methylpyridon, trigonellin,and betain. I n th e case of these substan ces, only th ecorresponding forms ha ve a cu rati ve influence, and inde edthe last three have no protective influence of any kind.The protective form seems t o b e a pseudob etain form,

and it is a matter of the utmost importance that theanimal organism is not com petent to m etam orphose th einactive form into th e active form. W illiams supposes th a tthe leading characteristic of the vitamins must be a com-pound which in respect of its structure or of its energy-contentis closely akin to such a pse udobe tain ring . Com pound s ofthis kind may form part of most of the simpler nitrogenoussnts tan ces contained in th e anim al organs. Especially th eym ay be presen t in the nuclein bases ; an d it seem s likely t h a tFunk's vitamins owe their efficacy, in part at least, to somesuch pseud obetain form of nicotinic acid. W illiam s' account,of the various forms of the oxypyridins was confirmed byHarden and Zilva, who, however, could not find that these



12 4 VITAMINS

substances had any beneficial effect in cases of polyneuritis.Further researches must be undertaken before this problem

will be ripe for a decision.The investigations of Hofmeister, who found that^ the

active preparations contained at least traces of impurities,and that the activity of these preparations disappeared whenthe purification was advanced a stag e, seem to jus tify th esupposition that vitamins are unstable substances which arecapable of being preserved in a labile form as long as certainimpurities are present, but undergo a metamorphosis in to astable form as soon as these impurities are removed. H ither towe have paid too little attention to this possibility, vftdch. islikely to prove of decisive importance in th e further s tu dyof the vitamins.

4. OCCURRENCE OF THE VITAMINS.

Vitamins are present in almost all anmial and vegetablesubstances used as food. In the animal body they are lessabundantly stored in the muscles (which, when fresh, always

contain a sufficiency) than in the parenchymatous organs.In plants we find them especially in the leaves and o th ergreen parts, that is especially in the vegetative o rgans; whereasthe parts used by the plants for storage, such as bulbs, t ub er s,and roots, contain them in less abundance. Still, the am ou ntof vitamin in potatoes, for instance, is so large th at evenboiled potatoes are useful, not merely as a remedy, but also asa prophylactic. Fruit, too, in the kitchen sense of the te rm ,is rich in vitamin, and so are seeds. W ithin th e ind ividu al

organs, the vitamin content of the various tissues differsgreatly. Especially does this apply to seeds, whose endospermcontains so little vitamin that its use as an exclusive diet,or even as a predominant constituent of the diet, is thecharacteristic cause of beriberi. The giams, of seeds a reespecially rich in vitamin. In like manner" % e vit am incontent of eggs, which are the animal counterparts of seeds,is concentrated mainly in the yolk.

We can readily understand, therefore, how harmful it iswhen, in lands vhere bread forms the stap le diet, the dem andsof a crazy standard of luxury should lead people to consumebread made only of endosperm. We have already learned th a t




in North America epidemics of beriberi have followed theuse of such brea d. We saw also th a t in 1911 th e Jap ane se

maintained that the spread of the railway system in theircountry must be responsible for the increase of beriberi alongth e new lines of comm unication. Since th ere ha d been nochange in the mode of life of the Japanese peasants, thesescientific authorities believed that the diffusion of an infectiveagent was responsible. B ut the y overlooked the fact th at ,thanks to railway developments, the peasants had not merelyacquired increased facilities for marketing their own agri-cultural produce, but had also become contaminated withthe refinements of urban life, and had heen provided withfinancial resources enabling them, to buy polished rice milledin the towns and to abandon the use of the partially hulledrice formerly prepa red in the ir own ha nd mills an d foot mills.WillcoxI0*5 has shown that among the European troops inMesopotamia during the recent war (men who were fed mainlyon meat, and on bread made from the finest wheaten flour),epidemics of beriberi repeatedly occurred when circumstances

made it necessary to replace the ration of fresh meat by tinnedm eat. The fine w hite flour contained extrem ely little vitam in,which was, however, sufficient when supplemented by thevitamin in fresh m e a t; b ut when the m eat had been sterilisedhy prolonged exposure to heat (probably the juices of themeat, and therewith the vitamins,J38

3 had also been removedby pressure) the supply of vitamin was altogether inadequate.

Apart from these canning processes, the vitamin content

of food can "be so greatly reduced by excessive sterilisationor by some othe r faulty m ethod of prep aration (as b y thro w ingaway the water in which the food has been boiled) that itis no longer adequate to prevent the onset of polyneuritis.Over-roasting, likewise, can seriously reduce the vitamincontent of meat, although the other vitamins in the diet willin general m ak e good th e deficiency. If, how eve r, in suchcases the amount of food taken be reduced owing to axniteindigestion, or if the bodily requirement be increased by theonset of some febrile disorder, or the like, the vitamin contentof the food may no longer suffice the needs of the weakened"body, and the re m ay ensue, if no t be riberi, a t least a m oreor less m arked atta ck of po lyn euritis. Such cases are



it6 VITAMINS

commoner than is generally supposed, especially in Europe,but owing to defective knowledge of their etiology th e y a re

apt to be confounded with other diseases.Amongst the poorer classes of the population, such occur-rences are fairly easy to interpret, but it is no tew orth y t h a tattacks of polyneuritis are by no means ra re in Euro pe am o n gwell-to-do persons belonging to the cultu red s tr a tu m ofsociety. If in such instances we investigate the c au se s ofthe disease we shall usually find that the patient has recentlyhad an acute gastric or intestinal disorder. He has th er euponbeea prescribed a very rigid diet, consisting of food th a t sh a l l

be easily digestible and simultaneously as " nourishing " a spossible. In consequence of this the stomach and bowelhaw beta increasingly disaccustomed from their propertasks—tht patient, who is usually a neurasthenic, paying

...sedulous, attention to the behaviour of .his body .all th e w hil e .




as minor digestive troubles, disinclination for work, and aproneness to excessive fatigue. B y degrees, weakness in thelegs and unsteadiness of gait appear. Pa raes thes ia is noticedin the nerves of the lower extremities, and circumscribedanaesthetic areas can usually be discovered in various partsof the skin below the knee . T he knee-jerks, which are a p t

to be somewhat exaggerated in the initial stage, are by now



128 VITAMINS

disappearance of the patellar reflexes, extensive hyperaesthesiaof the skin, and severe paraesthesias of various kinds, thesesymptoms indicating grave disorders of muscle and nerve.

Only in the later stages do we find complete anaesthesia andreactio n of degeneration. Intellig ence is unimpaired to th ela st , although fits of depression ar e frequent, and wherepredisposition exists even mental disturbance may ensue.The later stages are always attended by profound apathy.

b. Pathological Anatomy.

If we examine the nerves in human beings that have diedof beriberi and in animals that have succumbed from

polyneuritis, we usually find marked degeneration of thefinest nerve endings—a degeneration gradually spreadingtowards the centre, and ultimately showing itself in the spinalcord and even in th e brain. In the peripheral nerves, th echanges consist of degeneration of the medullary sheaths, andof degeneration and subsequent complete destruction of theaxis cylinders, until in the end the latter are completelyreplaced by nucleated neuroplasma cylinders, which Diirckrega rds as a nervous matr ix tissue. Th is view is doubtless

correct, for even though complete restoration of the nervesmay take a long time, the administration of vitamin willreestablish nervous functioning in a marvellously shortperio d. Moreover, we frequently find exten sive degen erationin nerves supplying muscles that have been working quitesatisfactorily.

The next most striking feature to the pathologist is theatrophy of the muscles in the affected parts of the body, inwh ich sometimes a typ ical my ositis can b e noted . The atroph y

is distinguished from the ordinary atrophy of inanition bydefinite signs of degeneration : th e cros s-striation is obsc ured ;th e sarcolemma sheaths hav e often b u r s t ; their contents aresoftened, contain fat-droplets, and have here and there exudedfrom the sheaths. Th e nuclei of the musc le cells are markedlyincreased in number.

Similar conditions are observable in severe attacks ofneuritis due to other causes, and notably in those dependenton intoxication. Hence it has been widely believed th at the

disease must be a primary polyneuritis due to intoxication.




Nocht,74 however, pointed out as long ago as 1908 that thereare certain fundamental differences between the degeneration

typical of toxic neuritis and that typical of beriberi, and hetherefore considered that the nerve degeneration of the latterm ust be regarded as pu rely atrophic. This theo ry is sup po rted,above all , by the fact that even in the nerve bundles thatare most gravely affected, certain fibres still appear intact,whereas in toxic degeneration all the fibres of a nerve aresimultaneously affected.

Medical observers in general are of opinion that the nerve

degeneration is the primary lesion, and that the atrophy ofthe nmscles is merely a consequence of thi s. I n my opinion ,there are important grounds against such a conclusion.First of all, atrophy of the muscles, with subsequent degenera-tion of the muscular fibres, frequently occurs before there isany visible lesion in th e n er v e s; and, secondly, the ne rvelesions are not proportional to the severity of the pareses orparalyses. It is tru e t h a t K oninger 7 m ainta ined in 1884

that the nerve lesions were primary, and that the typicalsymptoms of the disease did not appear until after the onsetof the nerve lesions. Ved der a nd C la rk ,^ , 307 aga in, w hostudied the lesions in the brain, deny the peripheral natureof the disease, and consider that the primary source of thesymp toms is in th e central nervous system. B ut these sameobservers, and also Eijkman, Cooper,3 JI and Schaumann,3i<>have repeatedly insisted that there is no demonstrable connec-

tion between the intensity of the paralysis and the degreeof nerve degeneration. A tten tive stud y of published casesshows that there have been many in which severe paresesor complete para lyses occurred, cases which pro ve d fatal,without there being any nerve lesions discoverable on post-mortem ex am ination ; or at most there was a deg enerationof the medullary sheaths, but in cross-section of the nervesno degeneration of th e fibres could be dete cted . On t h eother hand, cases are frequently encountered in which thenerve lesions are most extensive, so th a t hard ly a single he alth yfibre can be detected even in the big nerve trunks, and yetbefore death no paralyses have been noticed and hardlyeven slight pareses.



I 3 o VITAMINS

c. The Forms of the Disease.

We must infer from these considerations that we areconcerned, not with conditions that bear a causal relationshipone to the other, bu t with parallel manifestations of a com m oncause. The pareses and paralyses are obviously not a co nse -quence of the nerve lesions ; or, at a ny r at e, are not nec essarilyso, for they can just as well be explained as the outcome ofa primary affection of the muscles. Indeed, some haveattempted to argue that the nerve degenerations, when these

are slight, are a consequence of the degeneration and theputting out of action of the muscles supplied by the âffectednerves.

The most probable explanation is that the nerves and; the muscles degenerate and a trophy more or less sim ulta ne -

ously owing to some defect in nu trition. Th is theo ry is su p-ported by the fact that the disease is always introduced bya marked falling off in weight, and we have already learnedthat both the nitrogenous balance and the total-ash balanceare negative long before the outbreak of the illness.

In association with cases of beriberi of the type we havebeen describing, known as dr y beriberi, we frequentlyencounter instances of the so-called wet beriberi, casescharacterised by oedema. The oedema, like the pareses,appears distally, spreading upwards from the toes or fromthe finger-tips. Gradually the entire lower extremities areinvaded, then the lower part of the trunk, then the thorax

and the neck, until ultimately the face may be so much swollenth a t the features become unrecognisable; hyd rope ricard ium ,too, is exceedingly common. In th is form of the disease,there is usually cardiac dilatation without valvular lesionsand without hype rtrophy. The pulse is regula r, bu t feebleand frequent. In prolonged and severe cases, when the h e a r tis overworked, there may be actual insufficiency at the dilatedcardiac orifices, and m urm urs may become audible. T h e

urine is always greatly diminished, rich in urates, but usuallyfree from albumin and casts, this showing that there is nore na l irritation. In wet beriberi, th e mu scular atro ph y isnecessarily masked by the dropsy, and even the pareses maybe more or less obscured. If, however, by res t in bed a n d



FO RMS O F PO L Y N EU RITIS 131

suitable diet, the dropsy be relieved, it becomes plain thatmuscular atrop hy is present in such cases also. W hen th e

treatment is successful, there is an enormous discharge ofurine, the oedema disappears w ith marvellous rap idi ty, and th epatient now presents the typical picture of atrophic beriberi.

Sometimes we encounter a third type of beriberi, whichshould really be regarded as an aggravated form of dropsicalberiberi. W hereas th e nor m al course bo th of atrop hic an dof dropsical beriberi is chronic, so that the cases sometimeslast for years, the acute cardiac form of beriberi is very rapidin its onset, and may even terminate fatally in a few hours

from lêart weakness. Th e exc iting cau se is, as a ru le, som esudden demand upon the energies, as through very unusualbodily or mental exertion, the onset of an acute disease, ora major operation. Th ere pro m ptly ensues a feeling of seriousillness, with extreme precordial anxiety, greatly increasedfrequency of the breathing (which is convulsive and anxious),marked cyanosis, violent retching, and sometimes haemate-mesis. The tem pe ratu re is usually normal, the pulse is full

but compressible and extremely frequent, with a loweredblood pres sure ; th e he artb ea t is violent, convey ing a sho ckalong the great bloodvessels. A na tu ra l consequenc e of th iscondition of the circulation is a marked reduction in theurinary excretion, culminating in suppression of urine andthe onset of w idespread oedema. D ea th tak es place incollapse, with diaphrag m atic paralysis, pu lm on ary oedem a,a galloping pulse, and in many cases a clouding of the intelli-gence ; in some instances, d eath tak es place in com a.

If we wish to analyse the etiology of beriberi, we haveto reckon with thre e m ain groups of sym pto m s. M ostcharacteristic, in m y opinion, are th e atro ph y an d deg enera tionof the muscles, leading to th e pareses or par aly ses. Sec ond lywe have to consider the nerve degeneration, which we shallincline to regard as a contributory cause of the paralyticsymptoms only when the nerve degeneration is stronglydeveloped—unless, indeed, we accep t th e view of m a n y

authorities who hold that the pathogenic factors give rise toa disorder of nervous functioning long before any anatomicalchanges hav e tak en place. I t seems to m e difficult to c red itthe existence of such a functional disorder, seeing that the



I 3 2 VITAMINS

reports of experimentalists repeatedly mention that theconductive power of the nerves for stimuli was reta ined . The

third group of symptoms comprises the cardiac weaknessand the onset of oedema.

6. ANALYSIS OF THE MORBID MANIFESTATIONS.

a. Significance of the Symp toms.

In the previous section we have learned that these threegroups of symptoms may occur almost independently each

of the other, although muscular degeneration appears to bea constant feature of beriberi. I t is invariably present, also,in th e polyneuritis artifically induced by an ill-balanced die t,but this form of the disease is almost always characterisedby the presence of more or less oedema. Some invest iga torsaffirm that the following three types can be distinguishedamong cases of po lyne uritis: simple neu rit is ; ne uritisaccompanied by general enfeeblement; and extrem ely acute

polyneuritis without neuritis properly speaking but character-ised by grave debility. As regards the first of these, whichis rare , I cannot help suspecting tha t atrophy is really presen t,bu t is masked by the oedema. For in experimental poly-neuritis, also, we invariably find that the other symptoms donot appear until great bodily wasting has occurred, am ountingto from 23 % to 30 % of the weight. Many authors ha vebeen disposed to refer this wasting to a loss of appetite in

animals kept upon an ill-balanced diet. In answer to th iscontention, it has repeatedly been shown that the loss ofweight usually begins directly the experimental animal isput on the pathogenic diet, and may be considerable beforethere have been any signs of a loss of ap pe tite . Eve n w henChamberlain, Bloombergh, and Kilbourne *45 had recou rse toforced feeding (cramming), they found that the onset ofpolyneuritis was always preceded by a loss of weight am ounting

to at least 21 %•. It is true that in Fraser and Stan ton'sexperiment, in which forced feeding of pigeons with polishedrice was practised,™* the weight of the birds remained almostconstant—with the result, we may parenthetically remark,th a t the onset of polyneuritis was speedier than ever. Nopost-mortem examination appears to have been made in



FORMS OF POLYNEUR ITIS 133

these interesting cases, but it seems not unlikely that thebody-weight was maintained, partly through oedema, andpartly through the putting on of fat, although grave musculardegeneration may have ensued. However this may be, theconditions were so exceptional that Fraser and Stanton'sexperiment cannot help us to decide the problems of etiology

in the absence of post-mortem examination.The occurrence of oedema in beriberi is a secondary

symptom, one which has nothing to do with the essentialdisease. The eighth chapter of this work is devoted tomalnutritional oedema, and in that chapter we shall have torefer once more to the onset of oedema in cases of beriberi.We certainly have to do here, with an intercurren t affection,and are reminded of the frequent associtaion of beriberi with

scurvy.If the muscle degenerations and the nerve degenerationsare to be regarded as parallel symptoms running an indepen-dent course, we may perhaps assume that our food containstwo classes of vitamins, the absence of one of these givingrise to the nerve lesions, and the absence of the other givingrise to the muscle lesions. There is much evidence in supportof such an assumption, a notable point being that mostauthorities incline to assume the existence of two distinctclasses of vitamins. However, these respective classes seemto have different effects from those we might expect in accord-ance with the foregoing assumption. To clear up th e m at ter,a more detailed examination of the data contained in theliterature of the subject must now be undertaken.

First of all it is necessary to bear in mind the unanimoustestimony of authorities that a natural nutrient, in so far asit is active at all, does not merely cure this or that symptom

of beriberi or experimental polyneuritis, but relieves theentire syndrome. In beriberi, for instance, it does not m at te rwhether we give rice bran, beans, or green vegetables, all ofwhich are very active remedies, or whether we give one ofthe less powerful agents, such as milk. Provided the dosageof the remedial food be sufficient, a complete cure promptlyensues. But the results are very different when for curat ivepurposes we use extracts made from the remedial nutrients

and Schaumann tf

l

emphasises the assertion that the qualita-



134 VITAMINS

tive no less than the quantitative effect of such extracts isless in proportion as the purification of the substance has been

m ore thorough. Vedder 3*4 po ints ou t t h a t crude v itam insemployed as antineuritic remedies are from 20 to 30 timesless effective than the foods from which they were originallyderived containing the same amounts of these substances.At the same tim e, the univer sality of effect has disappea red fromthe extr acted cru de vitami ns, and each of these has an effectpeculiar to itself.

T ha t i s w hy so m an y au th or i t i e s *84, 375,5*6, 619, 666, 683, 691,

731, 874> 1040,1066, etc j i a v e c o m e t o consider tha t a t l eas t twovitam ins are indispensable for a cure . W e m ay recall th eobservation of F un k *73 th a t th e bases he isolated from ricebran and from yeast respectively were inactive when usedseparately, but were able to cure the paralyses whenadministered simultaneously.

b. Effects of Funk's Vitam ins,

Certain investigators regard t h e vitam ins as active remediesThus, according to an early paper by Funk,375 they definitelycure experimen tal p olyneu ritis i n an im als ; Segawa 3*3expresses th e same opinion. Th e lat ter , however, noticedthat the marasmus attendant on these cases was not relievedby the vitamins, and this led him to regard the marasmusas a secondary symptom, an outcome of the malnutritionconsequent on the lack of balan ce of the diet. W e hav e

already seen that there are numerous indications against anysuch theory. M arasmus is no t a secondary symptom inthese cases; it is the first and most fundamental symptom.Pareses and paralyses are superadded as further characteristics.Marasmus and the nervous symptoms taken together combineto form the typical picture of beriberi.

In 1911, lecturing in B erlin, S chaum ann for the first tim erecounted the experimental evidence to prove the almost

miraculously beneficial effect of vitamins in pigeons paralysedby polyneuritis. B ut this cautious investigator pointed ou tthat the birds' restoration to health was apparent merely.He said that rice bran must contain other substances whichhad to be given in addition to the vitamins if a real cure wasto be effected. In default of the se, th e animal would die



FORMS OF POLY NEU RITIS 135

notwithstanding the relief of the paralyses. About a yearlater, Strong and Crowell ™3 reported that when experimental

animals were fed on polished rice, the addition of alcoholicextract of rice bran to the diet sufficed to prevent the onsetof paralyses ; and th at in animals suffering from experimental ipolyneuritis the extract would dispel paralytic manifestations,even when severe, within a few hours or days ; bu t theadministration of the extract did not prevent the death ofthe experimental animals. Vedder and Clark 23%> 3°7 foundthat alcoholic extract of rice bran gave relief only in thefulminant form of polyneuritis, being then competent to remove

the paralytic symptoms. Later, Vedder and Williams 284noted that the different symptoms of beriberi required differentvitamins for their cure. The Funk 's vitamins precipitableby phospho-tungstic acid relieved the paralytic symptoms,and these only ; on the other hand, the filtrate after precipita-tion by phospho-tungstic acid was useless for polyneuriticparalysis, but had an unmistakably beneficial influence uponthe atrophy. In his important paper of 1914, Schaum ann

again and again insists that Funk's vitamins are only of useto relieve the paralytic symptoms, whereas alcoholic extractsof bran exert a complete prophylactic and curative influence.

Even more effective than alcoholic extracts of the bran,;are extracts of rice bran made with water or with weaklyacidulated water. Besides promptly relieving the pare ticand paralytic symptoms, such extracts bring about markedimprovement in the general condition, and lead to an increasein weight though not to a complete return to the normal^*

An extract of yeast similarly prepared with water containingo • 3 % of hydrochloric acid acts in the same way, but farmore powerfully. If yeast, after removal of the fat, is firsthydrolysed with 10 % sulphuric acid and then extractedwith water, the resulting extract is found by Schaumann s^to be peculiarly efficacious against the paralytic symptoms,both as curative and prophylactic, but it is not otherwisevaluable. In like manner, extracts made from katjang-idjobeans after predigestion with pepsin and hydrochloric acidare useless to prevent loss of weight and emaciation thoughactive against pareses and paralyses. According to V oegtlinand Towles,365 a watery extract of the spinal cord of



X 3 6 V I T A M I N S

th e ox w as effective only agains t th e par aly t ic sym pto m s.

V ed de r 3°7 noticed th a t insufficient sup plies of v it a m in can

tetard the onset of pareses and paralyses , but do not prevent

loss of weight an d emaciat ion ; th e per iod of inc ub at io n m ayfee prolonged to as mu ch as a y e a r ; whe n de at h com es a t

"fast, i t i s usually sudden. Sch aum ann 3 6 * h a d t h e s a m e

exper ience. Adding inad equ ate qua nt i t ies of a lcohol ic ex t ra ct

of yeast to a diet of polished r ice, he found that the onset

of pareses was thereby retarded, and yet the loss of weight

was greater than in cont rol animals fed on pol ished r ice

unsupp lemen ted. S t il l, the an imals receiving th e ye as t

extract l ived longer , and (except for the loss of weight)

apparen t ly in good hea l th—unt i l sudden ly g rave para lys i s

supervened, and death soon fol lowed.

c. Differences between the Effect of Funk's Vitamin and that

of water-soluble B or that of water-soluble D.

Williams and Seidells6 0 report some interesting observa-tions. In animals fed on polished rice, th e fuller's-earthabsorbate from autolysed yeast was adm inistered; thereu ponthe paralytic symptoms disappeared, and concomitantly therewas a notable improvement in the general cond ition. If th e

absorbate, before being added to the food, was treated withdilute alkali, it ceased to affect the general condition, thoughit was still comp etent to relieve the paralyses. I n th eoriginal auto lysate of yeast (before the fuller's-ea rth ab so rbatehad been prepared from it) the effect of alkalies was theopposite; if the autolysate was allowed to remain in analkaline solution for a considerable period, th e effectivenessagainst the paralyses as a prophylactic and a curative dis-appeared, but the solution continued to bring abo ut notab leimprovement in the general condition of the animals fed on

polished rice. These observations hav e no t been confirmed,but we know that vitamin is absorbed in a fairly pure stateby fuller's ea rt h; and since this absorption app ears to be aphysical reaction in which no decomposition of the vitaminneed be expected to occur, we have theoretical grounds forsupposing that the vitamin in this absorbate will really bepure. Now Emmet and M cKim 6 6 6 have been able to provethat in pigeons suffering from polyneuritis the fuller's-earth




absorbate, though it relieves the paralytic symptoms, isquite without influence upon the loss of weight and theemaciation. These authorities therefore infer th a t the prophy-

laxis or cure of the marasmus requires the presence in thefood of certain hitherto unknown substances, over and abovethe vitamins.

Sugiura776 states that both the alcoholic extract ofcarrots and the crystalline substance prepared from jêastin accordance with his method have a powerful remedialinfluence in acute cases, as far as the paralytic symptomsare concerned, but do not relieve the marasmus; in chroniccases these preparations are of no use whatever. Weill and

Mouriquand 731

likewise found vitamin effective in acutecases of paralysis only ; in chronic cases of beriberi, moreextensive pathological changes must have taken place, changeswhich vitamin could no t influence. Abderhalden andSchaumann 8o3 expressly declare that the eutonins (see p. 22)rapidly and effectively relieve the nervous disturbances, butotherwise are devoid of beneficial influence; whereas ricebran and yeast (substances from which eutonins can beextracted), are strongly curative. I t is interesting to note,

moreover, that although an alcoholic extract of yeast 361 canrelieve paralytic symptoms or prevent their onset, its adminis-tration tends to have unfavourable effect as regards the lossof body-weight. On the other hand, yeas t which had beenextracted with large quantities of alcohol—even four timesin succession—was able to prevent or cure the disease, theloss of weight in these cases being only from 6 to 7 %.

McCollum and Simmonds 69* have been led by theirresearches to believe that only the nervous disturbances are

referable to lack of vitam in. Hopkins and his collaboratorsIo66

come to the same conclusion.We have quoted in this connexion no more than a few

extrac ts from the literatu re of the subject. The reports ofthe other observers all have the same trend, and it is needlessto cite them more copiously. Cooper,*69 whose experiencewas similar, attempted to ascertain the minimal quantitiesof a nutrient that must be given in order to prevent, in oneseries of cases paralytic symptoms, and in another series of

cases loss of weight, on a diet of polished rice.



138 VITAMINS

Fish was comparatively ineffective. Ten grammes of

pike had no effect either on the paralyses or on the loss of

weight.Many investigators were, however, strongly disinclined to

admit that there could be other vitally important substancesin the food, substances still unknown to us. The presenceof a fundamentally important substance in fat had beenproved. This was absolutely distinguished from the anti-neuritic principle by its solubility in fat, and had thereforebecome known as fat-soluble A. Stepp 5*7 had given experi-

mental proof that vitamin could not substitute fat-soluble A,and that the latter could not substitute the former. r Sinceall the other essential substances were soluble in water, it

B a k e r s ' y e a s tY o l k ofeggBar l e y , d e co r t i c a t ed

„ u n d e co r t i c a t edB u l l o c k ' s h e a r tSheep' s bra inI - en t i l sLean bee f

Prevent Paralyses.

Fresh.

Grammes.

33* 755

1 2

152 0

Dried.

Grammes.

2 * 5I # 53 ' 2

4* 52

35

Prevent Loss of Weight.

Fresh.

Grammes.

2 * 51 0

7*51 0

53 to 63 02 0

Dried.

Grammes.

°"5.5

92

0•6 to 1•2

65

was assumed that there was only onevitally essential water-soluble principle— vitamin. McCollum and his co llaborators 490

were loath for a long time to tolerate the supposition thatthere are other unknown substances in the food which areindispensable to life and health. But inasmuch as McCollum'sown work had shown beyond doubt that natural nutrientscontain water-soluble substances essential to growth, Americanauthorities did not hesitate to identify this growth-factor,this water-soluble B, with Funk's vitamin. The water-soluble antineuritic substances and the growth-factor did, in

fact, react similarly in many respects towards heat and otheragents, so that the assumption of their identity did not lackjustification. Ed dy 5*4 showed some years ago that , justlike vitamin, the growth-factor could be absorbed from anextract of pancreas by Lloyd's prepared fuller's earth, and



F O R M S O F P O L Y N EU R ITIS 139

could be precipitated by phospho-tungstic ac id ; an d heproved that both preparations had an antineurit ic influence.Drummond 6l9 arrived at similar results in his study of theantineuritic principle and the growth-factor in yeast, and hetherefore came to the conclusion that the two substances wereidentical. Lecoq IO76 describes the growth-factor as solublein water and alcohol, insoluble in fatty menstrua, resistantto acids, sensitive to alkalies, absorbable by colloidal aluminiumoxyhydrate or iron oxyhydrate, and destroyed by prolongedheating at 1200 C.

There was, consequently, considerable evidence in favour

of the; view tak en b y Drummond,8

74 and by other Brit ishauth orities "94. 1554 as rec en tly as 1922, th a t th e w ater-so lubleantineurit ic principle and the complett in B are the samesubstance. Bu t th e objections to any such assum ption arestill stronger. As long ago as 1913, F un k 324 ha d shown th a ta diet may be rich in vitamin and nevertheless inadequateto prom ote grow th an d even to m aintain body-weight. Abder-halden and Ewald 683 and also Abderhalden an d Schaumann,8o 3insist that the addition of extracts rich in vitamin to polished

rice does not make of the latter an adequate food, whereaspolished rice supplemented by a sufficiency of extract ofrice bran is able to maintain life upon a normal footing*H o p k i n s a o a had shown as early as 1912 that whereas thevarious preparations of vitamin could not sustain growth,aqueous extracts of bran or yeast promoted normal growth

d. Differences between water-soluble B and water-soluble D

These results might be interpreted as showing that thereis a dist inction between vitamin and the growth-factor, butthat the growth-factor is identical with the still unknownwater-soluble substance which is essential in addition to thevitamins to the complete cure of beriberi and experimentalpolyneurit is. Bostock s i6 assumes this identity as regards theactive principles in rice, Byfield IJ53 as regards those in orangejuice, and Eddy and Stevenson I2O5 as regards those in riceb ran . wAbderhalden I04° ha d proved in the case of y eas t

that the antineuritic principle, in contradistinction to vitaminbut in conformity with the growth-factor, was practicallyinsoluble in alcohol. W hen , however, we carefully stu dy such



140 VITAMINS

researches as those of Osborne and Mendel concerning thecomplettin content of various parts of the wheat grain, a

different result is reached. We hav e already learn ed t h a t i nthis grain the antineuritic principle is concentrated in thegerm, whereas the pericarp is somewhat less richly suppliedthan the germ, and the endosperm contains exceedingly little.According to Osborne and Mendel, however, in young ratsloss of weight can be prevented when wheat germs are usedas the only source of complettin, but in these circumstancesgrowth does not occur. Although endosperm co nta ins asmaller quantity of water-soluble complettins, when given

in conjunction with the germs endosperm can sustain growthin rats. This observation can only be explained on theassumption that, as far as the growth-factor is concerned,the endosperm of the wheat grain must contain more thanthe germ. The water-soluble complettins in the germ m u stconsist mainly of Funk's vitamins and the as yet unknownwater-soluble antineuritic principle. In endosperm , on th eother hand, there must be an adequate supply of the growth-factor, but Funk's vitamin and the antineuritic principle

must be almost completely lacking.An observation m ade by Sugiura and B ened ict 98° can be

similarly explained. A diet of bananas and casein is a deq uat efor the maintenance of lactating rats , especially if supp lem en tedby the antineuritic principle in the form of yeast added tothe food to the amount of 0. 5 % . B ut th e milk secre ted insuch a diet does not sustain growth in th e sucklings. T h etrouble cannot be ascribed to the protein, inasmu ch as we h a v elearned from other experiments that banana protein is ren-

dered adequate by the addition of casein. No r can the defe ctin the diet arise from a deficiency of inorganic nutr ie n ts ; forthe abundant supply of bananas is a guarantee that the foodwill contain an excess of bases, and although there may bea partial lack of calcium salts, these could be adequatelysupplied from the osseous system of th e mothe r ra t. T h eobservers found that in these cases the addition of 0-5 % ofprotein-free milk rendered an adequate production of milkpossible, and they therefore assumed that the milk thus added

must contain some organic substance essential to growthwhich had been wholly or partially lacking in the unsupple-



FORMS OF POL YN EURITIS 141

mented diet. This substance could not be the antineuriticprinciple, for there was an abundance of that in the yeast.

It would, of course, be possible to suppose that the antineuriticprinciple is able when administered in comparatively smallquantities to prevent polyneuritis and to guard against lossof weight, but that in order to secure normal growth largerquantities are requisite than can be supplied by the amountof yeast actually given. On that theory, the requisite supple-ment of antineuritic principle had been furnished by theprotein-free milk. We shall see, however, in a moment th a tthis plausible interpretation is untenable. The experiments

of Oshprne and Mendel "S 1 have, in fact, shown that yeastalso contains the growth-factor, so that when the supply ofmilk is inadequate, normal growth can be sustained throughsupplementing it with small doses of yeast.

Loeb and Northrop 569 found that the growth-factor inthe yeast was far more thermostable than the antineuriticprincip le; but whereas the latter was resistant to alcohol,the former was destroyed by it. However, this observation-

was made on the larvae of flies, and we are hardly justified-in regarding it as convincing evidence in the case of higher'animals. A fortiori this criticism applies to the researches ofEmrnet and Stockholm,I2O3 Eddy and Stevenson, I30

5 Miller,1286

and Whipple,I287 who used yeast as the test object in theirexperiments on gro wth; for subsequent investigations haveshown that the modifications they observed in the growthof yeast were referable to numerous other factors, such as theprovision of a better mixture of salts, the supply of carbo-

hydrates, etc.Nevertheless, the researches of Emmet and Luros,120*

who fed pigeons and rats on tmhulled rice, have shown clearlyth at there are differences between the water-soluble antineuriticprinciple and the growth-factor B. They found that theantineuritic principle can tolerate one hour's heating at1200 C. under a pressure of 15 lbs., but that it is partia llydestroyed by two hours in an air chamber at the same heat

and pressure, and completely destroyed by two hours' exposureto the same hea t at a higher pressure. In ex tracts, the anti-neuritic principle was even more sensitive to heat. Thegrowth-factor, on the other hand, was not notably affected



142 VITAMINS

by exposure to the same conditions. McCollum andParsons X3«> were led subsequen tly t o a different view , find ing

that when milk was boiled, the antineuritic principle wasdestroyed more rapidly than the growth-factor.

Funk and Macallum563 tell us that the growth-factor isless stable and is more readily destroyed than the antineuriticprinciple in th e process of purification by pho sph o-tun gsticacid and silver precipitation. W e can ha rdly acce pt this asa proof that the two substances are distinct, seeing that themethod is obviously unsuitable for the isolation of the growth-

factor. Th e m ethod is th e one employed by Fu n k for theisolation of vitamin, and we may therefore presume that theterminal product is simply a vitamin containing growth-factoras an imp urity . W e are all the more justified in such a co nten-tion seeing that, on the one hand, Funk and Macallumthemselves tell us that the terminal product is very likeFunk's vitamins, and on the other hand other observers haveproved that both the growth-factor and the antineuriticprinciple are merely obtained in small quantities as an acci-denta l im purity through precipitation by phospho-tungstic acid.

More convincing, in my view, is the statement of Sugiuraand Benedict 967 th a t the growth-factor is destroy ed by expo-sure to radium , whereas th e antineuritic principle, as wehave previously learned (p. 120), is unaffected thereb y. Veryim po rtan t, likewise, is the fact observed by Verz&r an d Bogel I27°that when growth-factor is subcutaneously injected it has noeffect on either the glandular secretions or the blood-pressure,whereas the antineuritic principle, as will subsequently beshown, has a specific influence on the glands.

Summarising all these considerations, we are led to endorsethe view first expressed by Mitchell 979 that the v i tamins,the water-soluble antineuritic substances, and the water-soluble growth-factors, form three distinct classes.

e. Behaviour of the Glands.

To complete the picture, we must give an account of theanatomical and physiological effects of a lack of vitamin andth e supply of vitamin. In supplement of wh at ha s alreadybeen said it should be mentioned that Funk has found changesin th e brain. In cases of polyneuritis, th e brain conta ins




considerably less nitrogen an d 20 % less phosphorus th annormal.J97 Schaurnann points out tha t the glands, no lessthan the muscles, undergo gradual atrophy. Portier,1]co3Tan Driel,ri39 and Bierry, Portier, and Randoin,IX97 report,in conformity with numerous other observers, the same facts. ,When there is a lack of vitamin, there occurs atrophy of the;testicles, spleen, ovaries, pancreas, heart, liver, Iddneys,stomach, thyroid, and brain, the onset being practically inthe order named. In the glands, th e parenchymatous tissu e ;

gradually disappears, being replaced by connective ti ss ue; ithe spermatazoa vanish from the testicles. The secretion of

saliva,, gastric juice, pancreatic juice, bile, and intes tinaljuice, declines. In con trast with the other glands, the pitu i- ;

tary body and the adrenals become enlarged, bu t the secretion of \adrenalin is greatly reduced, although the adrenals apparently*contain more of this substance than usual.

The administration of vitamin rapidly changes thepicture ; the glands resume their secretory activities, and bydegrees the atrophic changes disappear. In young animals,

the testicles, even though they have degenerated so extensivelythat the active cells have heen almost entirely replaced byconnective tissue, return to the normal and produce sperma-tazoa once more.TIO7 With the reappearance of the digestivesecretions, the appetite, which has been in abeyance, returns,and is often ravenous. Extremely characteristic is an observa-tion by Fletcher, quoted by Fraser and Stanton.108 At theheight of experimented polyneuritis, "when pigeons refuse

food and are forcibly fed, the rice remains unchanged in thedistended crop. B u t if, now, a small quantity of rice polishingsbe introduced into the crop, the accumulated rice is speedilydissolved, and the normal powers of digestion return, with arevival of appetite. Uhlmann,63^ 755 using the commercialpreparation known as orypan,884 has made a detailed study ofthe effects of the administration of vitamin in birds andmammals suffering" from experimental polyneuritis. Ingeneral, he found that vitamins have the same effect whetheradministered "by mouth or by subcutaneous or intravenousinjection. Above all, there is a powerful stimulation of th eparasyrapathetically innervated glands, the action resembling(though not identical with) that of pilocarpin, mnscarin J or



1 4 4 VITAMINS

chol in , and s imi l a r ly a r re s t rtl by atfMjnn. A<> j a rh* t i l . t r

e ffec ts , Uhlmann tviws i* > i u n v a x n i M - n r i i r m --! n .4-4 nut, > yu

t e a r s , sweat, saliva, ga.strir jm«:«-, In!*.*, jv.ui ^-.iia« imn -, ,m4

i n t e s t i n a l j u i c e ; in fr^nrt »4 thr 1-r-t f-'nr - < i ^ i t - i r . , hi-,

obse rva t ions ha w Imn vnt\imw<i hv V**n;!jm a a 4 M \ M - . ^

and also by Willc:«x.Jwl-H An:n i4 i i i i : t<« l -h lm- tu i i , th«- ••iinin-

lating influence; on tin* i«im*r*M*i is a k i n t«* th.u *4 •••«* i<-tm,

though less powerfu l .

Wi l lcox re jH)r t s tha t the in«-r«-!«*ry i** ti v*ti r- . nf fh«- Kl-*mK

are re s to red by the a d n i i m ^ t r a t t ^ n *»I vif4ii4iii# l^t I ii.w*- nu%

been ab le to find any tncmttmi «4 flic *-iL-ii nu^n i }**- hvj«-r-

t r o p h i c d p i t u i t a r y b o d y and tin? atlrnMl--.. \ \ > -a*- i#»4 trji-j

whether these remain en l ; i r i4î4 *a y e t n r n i " th* a n^tnîJ - .3 /^

The unst r ia ted » ius«vl«^# tm h*^ Hum tb**- ^ in . i t r . j i n i i ' ^ i r -^

a re powerfu l ly s t imu ln t rd t*y imj ' ^ t ^mv *4 x-ii.mnn. I l i r

ac t i on re sembles t ha t ul inj**<is^n^ <4 j « i l ^ . i t }^

or chol in , and in similarly inhibit***! l»y ûrall d^^-^ «4 4f i<f '

O n theh e a r t , v i t a m i n wo r k s by way t?j j^#wrihU v.*f%*] \tuiiti

t i on , and the enhanced v igour uf tlur tifij^n r . t i . i i r . « i i t ! r 4

the a r t e r i e s in the fa rm r4 a *4r**iif» j - ^ j j ^ \

e x p a n d an d the hlotKi-presMtri: falls,

The fac t t ha t the p i t u i t a r v h*W an*l th«4 -Mh«-n.»l.. in

c o n t r a d i s t i n c t i o n to all thr ritlu-t ^liful*, tiiH»*»i:»i Iivi^'iuoj4iy #

cannot fai l to attrart sjn-ci.il 4ff«iji$oji, Jt r. ;i)| t^«- tn««f»*

r e m a r k a b l e , t h e n , t h a t in thf wh«4f Iit« 'ri tm<- *4 \l^ % t l . j # . t

no fur ther re ferrnn* should be ?iw*l«* t* > ihx, | r < n l u r »«*.*< it o «

of the p i t u i t a r y b o d v , a l t h n u q h th«- i*-s«i$f n nw»t i iMinf*".ily

b e the express ion of MHIV. sp'Oal r!r!<i^,ivr inr,i%^f«", «»n t l i r

p a r t of the org anis m. Tin* la r k «•( vt tamt i t imis t |44 i«H r l i - n r

caused some sor t of dHtt t rhat i rt* in thr «tntiti.il rrMiitiniv win* h

d e m a n d s e x c e p t i o n a l a c t i v i t y ftwin thr jYtttt i taty \**W »n«l

the ad rena l s , and t i n t s Ivmh to t h w r h y i i r r U u i J i y 4t •iiiy

rate we can imagine no oth«T t<xp)«m»»tt(«!t. Itnt wr kutiw

nothing of the part pkyed in tin? mattt-r t*y thr |utmt«iry

internal secretion, although the phenoiiini»i fhrvrritx'tt t lu

investigation. In tin* n*xt rhajitrr, whrtt wr «om*- t*i

the growth-complrttin, wu «Ji»)l Irarn that flu* pttmuty

forms an internal .secretion whose effects ar*1

in many ^

similar to those of complettin B# and who** functton may

possibly be to increase the activity of the tatttti.il



Kf>KM< OKFOI.YXKUKITIS 14$

rif thr tii..".u

(f- It r- j-*«'i1i:ij^* l i i^ ' i tu*- ' . ' t h r a r t i w j * i m « i p l r ha*

n u t \ H )<'-*-J» r-3.tt<---l \ u t h « r i t . * i n t v , t h a t w«' k iu *v v v* l i f t !**

r o m T f t s j j j t : th*.- j ' . u ij .* l*v*-4 hv t h r p i t m t a r v h«**!v in r r i a t i u i i

la j t o j v n v ' j u t r - . Wr 4i«- -4 i l ! t n n n t a m w h H h r t t h r . * . u ! r 4 a m ' « ?

k f * " t t t t »*- f*-?J'>* :' hn <infra p. .*•<>-:} \ i r r \> , i tv* l }»v K i i h t ' i i ' - . t i i i a nd

K , i V f l ^ O I th^ . * t - i t « l j ^ j 1'ih*' »4 t h r p l t U t f . i t " V t»*i*Iv is llu' f*%tl

i f.

, n ' . . ( i r v « - r v * l i f ! % - i * - n t a*. r « - F » u * l - ' * t h * * u t l r r i

U i ? h * r i ! 4 n i » v t h . i t r , i « h i»f t h « * t \ V n J i a f f s

j ' i " H f J u » v ^ ,%w r ! I * i ' * ! u j * " * ! M I ! - - t ^ n * *\ i * ' i c * i u

r ! K * ^ i ^ r - i n l r i c i s ^ h n , w h i « l i i ^ u t r a t f - ' t h * * 1*1*V r ^ . r l - * , i l i 4 f r u \ r , l * h * ^ < l j * ? « " . - M i r ; , i l | t | f l u i n t h r i n r t

r r l l * - * r - < * f i i « * ^ « I p 4 i « , \ v h * 4 \ r i j i r t f / i , i l « * f l i r t * | i | i t r t l f r u | t h

I ' y i l l * ' r «v

i i } > J * - * " * i l * ^ f i v i i i « " . r » i i h r f w « i % n h % t a u « • * " ' , t h « * h l

p | r v , t | f r i s | | i , i l ! l t . i | | $ « - 4 a t | t ' » ! V » f ! J ' M l J r V r l . J j | f l i r f H ^

t«Avar?.l^ 3U**|4iy . M a n y iiivr.stiâtMr1* h a v r th*.*rr{iin* \n*%m

lr*l tu iiifvt tfi;it an mi:rra**.-*l furtnatum of adt

j*l;trr in !*rni**i$, Mr.C a r r i v a l MH «'X|tlains tin: w

tmh'tmi m ca.vH *>f f#jlyn**ft!r$ti<* an ft^ltoWH, fit!

t i i a t tmtnn iu thir **xr:t^vivr supply of a i l rn taUr i tlw s m a l l

r b a n* > t m n t ; l y o m t r a r t r f l , itritt t h a t by tin* const*-

m m M w -ti liIfNtKi-prr^Mitv fli«* h ln fi tl ^ rr u in in U*tm\

thr»fir4h fhi!w a l l s of tin- vr*»sH* ;nu\ infiltrati^ tin* ti%Mit^.

H a t r t w f t ha*-, h^Wi'V**?', f?mr$trr| rît t h a t , wiiil**! tfi r r n u t r a r t u m

of tli<* ait'-n«•!«-•« fanM*rJ t*y;iflt*iialfii t\*ws mrtri'fi Ir4ii toan

in*Jr;r-r n{ j]rf',',Iirr $?) tfir af1r||r'(, tit t.ll«fartrticilr*. thf nNrlVf'H

a n 4 jn tli-*- *4|-al!4i tr'% th«* p r rva i r r is Ir twrrrrl ami thr blotui--

Httram a"«-l«"i-4t*^l, "I"It** i'rtiT t at a.tfrriia lin m u s t , th«Ti*fort*,

|w tw fii?1*!rr thr nii'vrt. r#f nrrlrfna, If rrnVrr, it Ii;i-^ brrtl

provf t l tha t in p«4yn* furitr-i th«« bln<»ilj-*rr'H^frr i.

rather than iiK.rr;r-!.*-<l, NU t h a t wr jinr4 a.'v-uinr th«r

cif a vn.Mim«»!<?r pa rrî :.,, l i n t thr fall m arfrrial prr.NStiri* thu*

to rr laxati t t f i «4 th«* art»':n«*U^ t> aft.i«nf'lr«] t*y an inrrtsiMrtl

ctnpil!;iry pr«*vatrr4 {a vr iur ui^ tr an M id at tr m atu l tIs*- rt#irii*cpi-riil

tmm*t tA ru t l r f i ia . Mf ' f 'u rmt in has,th^rr fun*, formal ly wi th*d r a w n his h y p i t l i f ^ H . ^ ^

Craftier î 1 * fMic o m e * to ano the r vu*w# w h i t j j n cc r to i r t ly



146 VITAMINS

be tter founded. He assumes th a t th e intern al secretion ofthe adrenals is, like that of all other glands, reduced by adeficiency of vitam in. Th e hy pe rtrop hy is to be exp laine d

as an outcome of the attempts of the adrenal to ken-p up thesupply of adrenalin, a substan ce essential to life. Th e v ita m insrequisite for this are obtained by the liquidation of materialfrom other glands of less vita l im po rtan ce . U ltim ate ly, ofcourse, the supply of vitamin from these sources is exhausted,and then no more adrenalin can be produced notwithstandingthe hypertrophy of the adrenals.

The hypothesis is strongly supported by the behaviourof the body temperature in beriberi and experiment;^ poly-

neuritis. The tem pera ture falls, though very slowly, and th ismay be interpreted as a sign of the reduced formation ofadrenalin. Suddenly, just before the end, the tem pe rat ur efalls by as much as 3 0 C , and death thereupon ensues. Innormal circumstances, the body makes an effective responseto a fall in tem peratu re by th e increased formation of ad ren alin ,and we m ay therefore infer th at the sudden fall in te m pe ra tur eat the close of the illness is due to a failure in the formationof adrenalin. In conformity w ith this theo ry we find t h a t,

whereas during the general course of the disease the adrenalincon tent of the adrenals is found to be norm al, or even som ew hatincreased,».v>, »$>7# »*$ when th e collapse of te m pera tu re occu rsjust before death there is a sudden decline in the adrenalincontent of the adrenals.

/ . The Ener getics of (he muscular System.

We have now come to what may perhaps be regarded asthe most important chapter in the pathology of polyneurtt is ,

to the question of the energetics of the m uscular system. Ithas long been known that there is a gradual fall in temperaturein polyneurit is , and Dutcherw has recently provided experi-m en tal confirmation of th e fact. Raimono ,*?8 too, showed in1916 that the respiratory quotient slowly declines, ultimatelyreaching a level which is barely half th e norm al. Th is obse rva-tion ha s been confirmed by Tanji.745 In conform ity th er ew ith ,study of isolated muscle has shown a marked falling off Inthe internal respiration of the tissues. Abderhalden,*M$

whose observations show that extracts r ich in vitamin



FORMS OF POL YNEURITIS 147

promptly restore tissue respiration to the normal, is of opinionthat the substances he terms nutramins act after the mannerof co-enzymes, inducing conditions which direct tissue respira-tion and the other activities of the cells into normal channels.Freudenberg and Gyorgy 12Sl have also been able to show thatnumerous vegetable extracts, and also codliver oil, linseedoil, and cream, must contain substances able to increase therespiratory activities of animal cells.

I t is, however, necessary to note th at the previouslydescribed behaviour of the muscular tissue is by no meanspeculiarly characteristic of polyneuritis. Abderhalden andSchmidt I3°^ have detected a like decline in the energy oftissue respiration in all diseases attended with muscularatrophy, the change taking place only in the wasted muscles,and being discernible only when these are examined quitefresh. If the experiment was not made un til after the musclehad been kept for from nine to twelve hours, it could not beshown that vitamin had any influence on tissue respiration

Even if Abderhalden's observations are accurate (andthere is no reason to question them), the causal relationships

may be entirely different in the various diseases. We mayassume, for example, that in consequence of a febrile disorderthe catalase content of the tissues has been used up, and thatthereby a weakening of the muscles has ensued, leading toatrophic changes in these organs. Naturally in such casestissue respiration will be rendered more active as soon ascatalase is produced once more thanks to th e effect of vitamin.We might, on the other hand, accept the prevailing view thatthe nerve lesions are primary, and that the muscular atrophy

is a secondary change. But in tha t case it would be difficultto see why tissue respiration should become less active aslong as there is an adequate supply of blood, for the primarynerve disorder could not easily affect the catalase content ofthe muscles. The conditions are different if we assume themuscular degeneration to be a primary lesion dependent uponthe absence of the co-enzyme vitam in. In tha t case, it isnatural that the activity of tissue respiration should graduallydecline in proportion as the co-enzyme disappears from the

muscles, although the catalase content of these may beunaffected, and the catalase is ready to be restored to activity



1 4 8 V I T A M I N S

as soon a s v it a m in is su pp lie d. H ut t*w n th is th»-«»rv «!*«"*

n o t to u ch t h e ro ot of th e m a tt e r. T h e rr*«Nirrhr*. <«f }- jjkiu,«ii

an d Huishoff-Po l, a nd also tho se of D u t t h r r , : ^ '«•» h.iv«« - h -w it

t h a t in po ly n cu ri ti s th e catalasi* r o n t m t of th** inn-.* I*--, i*by no m ea ns unaffected, bu t rapidly i l t r l i n rs nfi inît t-K-

fal ling to bare ly hal f the no rm al D u n l i n ' s work , .md »- p* »J

al ly th at c lone b y him in col laborat ion with r o H a t / . - v !i r

shown th a t t he adm inis t ra t io n of vi tam in K sfnn , th»*

influence of ca tala se, no t b e r a t e (as Ab*!«ih.iH* n 4 nii^

cata lase al re ad y p rese nt in tin* nniM lrs is ac tiv at ed l»v th<*

vit am in , bu t beca use und«T tin* in ll n rm r *4 th«- vi ta m in >*

new fo rm at io n of th e abs<?nt cat.-ila.si* t a k r j»!,u»\

£, Differences between Polyncur ith and *4<trrj!h»n situ\.

T he re i s no do ub t a res em hl an cr in th«* «nnditi«*u **f t h r

muscular system in l>**ril>f 1 i an d t'Xjwriim-n fa! j»*hii»

as compared with that in other dise.iM-^ limdin^ tu rm^\<%

More (^specially, the energetics of the br«ly ;wr t iUwly

in be rib er i a nd po iy ne ur iti s t o w hat obtaisiN* its înipl*- Î?MV.»*

t ion. T he re are , how ever , im po rta nt diffrivm;rN hrivvn -n fh*-

economics of the maintenance of bodi ly IHMI in ûnpl*- vf-iiv.^

t ion and in avi taminosis , i rsprr t ivr ly , as w«? 1«MIH ji**in ih**

admirable .studies of Novam.1*1^^ m " - i U i i Th«* »m|itiriam-r «-4

th e m a tt e r justifies i ts de ta ile d discu^ 1**11. In b o th *.r<%,

th re e pe rio ds can be? ciihtinKui^hecl; an in itia l * % w \ w h ^ h

lasts one or two days in s tarvat ion, but a fo r tn igh t * * t m** tr

in av i tam ino s i s ; then com es a long t»u*rm^di ;i t^ n t w , t in

is succeeded in both cases by a brief final *4^«: t-nttnw

in dea th .

In simple starvation (in pigeons) t in: daily \m% ut w

during the init ial stage ranged from 4 % to 7 % per Hirm 4

in the in te rmedia te s tage , the U m clm?n no t eicc rfd 2 % <#r

3 % d a i l y ; in the f inal s tage, i t r ise* once won? to th«- s i m r

level as in the initial st ag e. B oth in th« initi;il and in th«- liri-il

st ag e, the d aily loss of h ea t i s conH tdcrnbly Mreitir.r tli;in m

th e inter m edia te s tage . A t fi rs t the bnr ly te tu j^ rat i i i f $%

unaffected, the n a gr ad ua l decline* j^ tn in, and in tin? fitiiil

st ag e th er e is a sud de n fa ll W « §r«% t h w , th a t tht* f;iH i n

tem pe ra t ure does no t ran para l le l wi th th rh%% ui \mtt

fth**

temperature may be almost normal even winn t he hm * A

**



FORMS OF POLY NEURITIS 149

heat is from 50 % to 60 % above normal. If follows thatduring the initial stage the production of heat must be con-siderably greater than normal, but that a decline in heat

production must gradually set in ; ultimately the heat produc-tion falls off so much that it is barely possible to keep thebody temperature high enough for the maintenance of life,until at last the balance between production and loss is sogreatly disturbed as to induce the catastrophic fall intemperature th at immediately precedes the fatal issue. .

In the avitaminoses, however, the temperature and theloss of heat remain normal for a time. The body-weightgradually declines, the decline becoming rapid after a while,in conjunction with a commencing failure to absorb nutriment.The weight falls off far more rapidly than in simple starvation,and subsides to a much lower level. The loss of heat is muchreduced during the intermediate stage, until after three or fourdays the loss amounts to only about half the norm al; thence-forward the loss continues at this rate even in the final stage.The temperature, which (in pigeons) is normally 42-2° C ,sinks rather rapidly to 41 ° at the outset of the intermediatestage, but thereafter the decline is slow, so that at the endof the intermediate stage it is still as high as 40 0. When thefinal stage sets in, the temperature falls rapidly to about370, when death ensues. I t follows tha t at the outset of theintermediate stage the production of heat must be consider-able ; thenceforward, heat production must slowly declineand in contradistinction to what happens during starvationit must permanently be less than normal. Moreover, th ecollapse in temperature at the close does not depend (as in

starvation) upon increased loss of heat, but upon a furthersudden fall in, or perhaps an absolute arrest of, heat production .When the experimental animal is put upon an adequate

diet in time to save its life, the return to normal occurs inmuch the same way after prolonged starvation and afteravitaminosis. It is true that after starvation the return ofappetite is gradual, whereas when vitamin is given to ananimal suffering from experimental polyneuritis, the creaturebecomes ravenous almost immediately. Still, the difference

soon disappears, so that after a few days the quantity offood taken is in both cases about 50 % above normal. Not



I 5 o VITAMINS

un til after th e normal body-w eight has been rniitainnl clnrsth e takin g of food become norm al in amou nt. Wh*n flu-

change for the better is made in thr diet, tin* btidv ûrlitincreases rapidly by from 10 % to 20 % ; th ru it i^ iu str *stationary for a while; thereafter a slow ami sîu^vkitirregular increase proceeds until the normal wriÎit i* rr^.nnrtlThe loss of heat also increases, thoug h it n m i i n s U * t a tntm5 % less th an normal after starva tion , and 2 o " i 1* (* thannorm al after a vitam in-free diet. Tlu*n the loss **f b'-i fgradually rises, and rises somewhat more quickly than the

body-weight, so that, by the time the normal body-wi•iglit h«**

AVTTAMINOSIS. — STARVATION .

I . B o d y w e i g h t H I . B o d y (II . He a t lo ss . IV. Hea t |'i roUut t t«m .

been regained, the loss of heat may \m as much its 115 %above norm al. Thereafter it gradua lly sink* to th« tummil*During the first twenty-four hours of recovery, the tx#lytem peratu re rises to abo ut 41 ^, th e rise being Hufottquwtfiyslower, un til in four or five day s the p igeon's normal tempera-tu re of 42 • 20 is regained. Thu s the hea t production is cornpara*tively small during recuperation ; the food that is assimtiatw!is mainly transformed in to the tissue th a t replaces what h ubeen lost, and is not used to any considerable extent for thesupp ly of hea t energy. N ot until the bodily condition ha *become n orm al once mo re is an excess of hea t product innpossible upon a food consumption that still remains excessive



F O R M S O F P O L Y N E I T R I T I S 151

fur a timi\ so that an increased tans of heat is now manifest,VVh^n xhv dp\nAiiv }. o n r r m o r e normal, tin* food consumption;I|MI U'rnnv-^ tp.atthil t and lit it p rod uc tion sinks to the

miibiusy l«*vrl,Thr rurvr* in thu figuu* Rive a graphic rqjreantation of

th r rlMn^tvs in uvitaininoHts and star va tio n respective ly. Th ett\%t\rv nm.st notf that, just as in thti case of geographicalTirljrf r o n ti m rs th»? v rr tk a l d em en t in the cu rve s is gre atlyrx;ijf*^'rated in comparison with the horizontal element, forw rr r th«* vert ic al «'lnnt*nt repn*sf»ntt»d in due proportionwithin fh** hori/tinU! ;I|J;UH: availal^h? in such a figure, thevi *r tk 4 Kradatit^n would hr ha rdl y notice ahle. Tlie courseaf the wd^ht curvtt suffices to show that in herihert wtr cannotMittply IK: ro n tm ie d with m alnutr i t ion depen dent upon anill-Ii.ilinr<*(l dii;*t, hut that then* mu%t \m lacking in the food*omt? (trinstttucnt which n orm ally re nd ers its full utilis atio npm *ib !i\ wheriMs in st ar v at io n there* is a simj>le com bu stioniif thr \nuiy material withfiut tlie pdHHihility of any substitute ;tli.tt m why the t.nrvt* in beriberi is far less steeply graded fora tune, until the body'n own supply of the requisite materialin nil a'HisMim*!, wherrupon a steeper gradation is shown.Inse pa rab ly ninntctiHj with this is heat pro duction. Infttarvatiftn* the bcidy must meet all itsi needs out of its ownsiibfctamr. Sinci* the h ra tin g m aterial thu s ava ilable con sistsmainly of protein, and ninmi protein cannot be adequately

for all thr piirj>o^»s of the body, there must be much* in tfam prr»c:t*Hs, an d th e com bu st io n of th e w as teK lîd^ in an increas ed heat (Mroduction. B ut as soon

n.% Ihf? {HI I in th r bo dy run.H sho rt# the heat production suddenly

d«cltn(*», falling farh v U m

no rm al. In poly neu ritis, th e condi*tion^ an* rwi-tmtl* Heri.% there: h a supply of mere fuel,an d d u rin g this initia l ^tage t hi s fuel IH utilised in a fairlynormal fa.*hir»n ; but m mum ®s the specific peculiarity of thedisease, dimtni»lu?d faculty of utilisation, comes into play,heat production falls oft in proportion to thin h&ftcned facultyfor utilisation—-very rapidly* at first, until the body hasaccommodated i twlf to c ircumstances , and then more s lowly;until at last a complete incapacity for utilising the food sets

in # and heat production suddenly falls to a minimum,T he ob vers e of he at produ ction is he at loss . In s tarv atio n



152 VITAMINS

sta tes the la tte r is always increased. A t first the increaseis due to increased heat production ; subsequently heat lossstill remains above normal, although heat production has now

fallen below n o rm a l; finally, just before de ath, there is arenewed sudden rise in he at loss. In avitaminosis, he at lossrun s a very different course. At first, like hea t produc tion,hea t loss remains nor m al ; then, when heat production isreduced, hea t loss exhib its a sudden decline ; an d thence -forward it remains unchanged at a low level.

The body temperature depends upon the relationshipbetween hea t production an d heat loss. In starvation states,heat production is, as we have seen, increased in the r initial

stages ; but since heat loss is likewise increased, the tempera-tu re remains no rm al for a considerable period. No t u nti lheat production is greatly reduced, so that it is no longersufficient to compensate heat loss, does the body temperatureundergo a gradual decline ; in the final stage, when heat lossis very rapid and heat production has ceased, there is acollapse in the body temperature. In the avitaminoses,likewise, the temperature remains normal, here for the reasonth a t a t first he at produ ction and heat loss are both unaffected.

Subsequently, when heat production falls off, there is amarked regulative decline in heat loss, but the compensationis excessive, and a rather rapid fall in temperature results.In the final stage, when heat production ceases and heatloss continues, a sudden and fatal fall in temperature ensues.

The differences between the behaviour of the animalorganism in starvation states and in the avitaminoses, respec-tively, is manifestly due in part to differences in the adrenalinproduction. At the outset of the starvation period, hea t

production is excessive, and the body temperature musttherefore be regulated by a dilatation of the bloodvessels topermit increased heat loss, this involving no exceptionaldem and for adrena lin. Subsequently, when heat produc tiondeclines, the normal tendency of the body is to react byincreased production of adrenalin, in order to promote vascu larcontraction and thereby reduce heat loss. By this time,however, the adrenals have been so much injured by thestarva tion th at the adrenalin production is inadequate. Th e

temperature therefore falls, and the fall is more extensive in




proportion as the adrenal inadequacy is greater—until atlast a critical collapse of temperature ensues.

In the avitaminoses, also, adrenalin production is obviouslysoon impaired, this resulting in a sudden fall of body tempera-ture . However, as Bierry, Portier, and Randoin IX97 haveshown, the body uses its last reserves of vitamin (perhapssecured by the liquidation of material from other glands) tom aintain to the utmost the activity of the adrenals. Thelatter undergo hypertrophy in consequence of the increaseddemand made on their energies, but do not succeed in producingmore adrenalin than is requisite to maintain the body tempera-

tu re at .t he lower level to which it has now fallen. U ltimatelyth e adren als can no longer function. Perha ps there is nolonger anywhere in the body vitamin-containing materialavailable for liquidation. Another possibility is th a t he atpro du ctio n ha s become quite insufficient. Anyh ow, a criticaland fatal fall of temperature now ensues.

7 . EARLIER ATTEMPTS AT EXPLANATION.

These facts have additional implications, which willperhaps enable us to gain a more intimate understanding ofthe essential nature of the disease and of the way in whichit comes into being. B ut before I tu rn to m y own specula-tions concerning these problems, I must give an account ofthe views published by other observers anent the significanceand the functions of the vitamins.

First let us consider the theories of Portier and his collabo-r a to r s . They hold that the three stages of the disease are

mainly determined by the vitamin provision of the body andits influence on adrenalin production. In the initial stage ithe organism still possesses a store of vitamin adequate tosu pp ly th e need s of all th e glands. In th e second st&ge, thevitamin content of the organism is no longer adequate, an<tthe adrenalin production is falling off, but the latter troubleis more than compensated by the hypertrophy of the adrenals|so that in this stage the body actually contains an increasedpe rce nta ge of adre nalin . Th ank s to the increase in thefadrenalin content and the resulting persistently high tensionof the vascular walls, there ultimately results the frequentlyobse rved sclerosis of th e finest capillaries. In t he thir d stage,



VITAMINS

a d r e n a l i n p r o r i u * t i » » n M M - n i t u r h , \ \ s - w i . t h * ~ t r j $ < • *

c a t a s t r o p h i c f a l l *»f ) * * » \ \ t m ^ n ^ r ' . : ^ .: i ' ^ L i - I ' V .

T h i n r x p l a n a t i n u . a!

« « • - ^ m U » * - • t * * : 3, «,« . < ! . ; • *

a l l r n v a n r i ' f u r t h '4

« h . t i i | , « - . i n ? h < -f* '» ^- - i ••" '• ' -" ^t h r m a t l t * a u t l f - . « f ' 4 «f 1 '^ . ' »* %

i - . : M ^ 4

t l i * ' a t t o i i l ^ v » » n d * i « ' ^ « * i v J . j i 4 v 4 , 5 ! ' < * 3 . v " .: 4 % '.

pfacts. Arr»#i«h»j: to th«- th« r. in fK ;:

p

f l u * t h e o r y m a y%

r*%

n\ tu » i ' < ^ y n ! f«^ tK^ i f h - i w - . ix%tanpt*r ;i tur«* olfM-tVfti in j*< S J * » " U » < I *li- i >? • *t

d«?(rsctiv« in n t h r r w . i v * t h . i l it i , unv» t !•«* ** < 4 ! d r

it w o r k i n g ; h v j » i t h i ^ i v .

A n o t h r r . t t t f i n p t in iw\\* * % \ r ij>r i n ^1^ «j . iv n

v i t a m i n* i I M H l wi *n m a Ir liv l l a - r . - . l ' - t , 1 ' " i%5.«* i it- |

t h r e e a l t r r n a t i v f h%*i*dhr\r- i |ij-j f,t-? M•>'*• n n

p e r h a p s t h r j ^ L i f u l s p . u t t M p a t u s ^ in t hr ». :! * «' n i

r a n n o t p r o d u c t * t h * i f a ^ f r t i < ^ t i \ \ \; t! * ' %t il.

v i t a m i n s . * I h r sr« r « n « l s n i ^ - j i * . ! * $•• t!,4i !}•<-p a r t i t k i ! of thf n a t u r e *4 f n m r n t ' * . an4 t^ A\,

t h e prori*jiM*H ri{ t n t n m ^ l t . i i v i n ^ t . i l * * h-in J

n a t i v e U t h ; i t tin v i t » » m m t i « 4 V t * r t%rt t ! ; .« l it*

of ho nn a n t * * , M* t h a t h*4 im * n* "^ <• .#nn*>t t* ffut^*!

arc lack ing . Uat i s \ l r r is w r l ld o not ta k f IIH v r t y f**r# an<t

mere iy rcmovi? thr q tuay answer. It i% trivltit»st^tt«l«* th^t thr

by an ad<si|uatt* d i r t , \mt thin 4**^ $)t»i rnj i.un h**«r 4pif ton ii t n a k h d to fly within a frw hmitn of it?r 44ttniir.iof vitamin, Thr wr<#nct hyj^*t}ir\i'i 11 rxrn te-w hrtj»jiit thanthe first, m*fl perhaps th<- thit«l hvji««<hr%i% 11 m %*«< m%ms€MMt for (apart from th* fact t lut ihc mrvh^ntntft ut trtmmtaction, and abo tht* formatiun,, r»4ttifr. nn4 ftiirii«4i$n^ «|the hormonal , art#tilt a %r4l«l W*kk^ nrt th« t *4ih*-*r tii'iîlnHn^tells us anything r rgt r t lmg th«: |4n« r whrr<* tl>r v ita m sn *take effec t or conce rn ing tbe i r m o d r of a c t i o n .



FORMS OF POL YN EUR ITIS 155

while the hypotheses might explain either the symptoms ofvitamin deficiency or else the positive effects of vitamins,they cannot explain both of these.

It is not possible to speak much more favourably of theassumption of Abderhalden,1255 who believes that the vita-mins, functioning as co-enzymes, must create conditionswhereby tissue restoration and other cell processes aredirected into normal channels. For although this theoryindicates a point of attack and conveys some ideas regardingthe mode of action, we have no evidence that catalase needsa co-enzyme to activ ate it . Nor does Abd erhalden's theoryexplain why, in this disease, an insufficiency of catalase isformed in the muscles, or why, perhaps, catalase is not formedthere at all .

By far the most notable attempt to explain the mode ofactio n of t he v itam ins is th a t m ad e by Schaumann,73» 9°» x*2»X57» *73* 177, 219, **6,3™ and by Schaumann in conjunc tion w ithAbderhalden.8o3 As long ago as 1904, D urh am 44 showed th a tthe excretion of phosphates is greatly diminished in beriberi.Schaumann was the first to point out that polished rice isvery p oor in phosp hates as compared with unhulled or partiallyhulled rice. I n th e course of his further researches he foundthat poorness in phosphates was characteristic of all thenutrients inducing beriberi or experimental polyneuritis, andhe was therefore inclined for a time to regard a deficiency ofph osp ha tes as th e effective cause of the disease. O therinvestigators, such as Frase r and S tanton,108 Aron and Ho cso n/ 1

etc., m ade similar observations. Bu t it became ap par ent,especially in the course of Schaumann's own work, that theaddition of inorganic phosphates to a pathogenic diet hadno good effect whatever, and Schaumann was therefore com-pelled to modify his theory that a deficiency of organicphosphorus compounds was of primary importance.

These were the days when lecithin therapy was still highlyfav ou red ; although the discovery of ph ytin had furnishedlecithin with a powerful rival. In view of th e scantiness ofthe chemical information possessed by most medical men, itw as not surprising t h a t people should ha ve believed them selves

to have discovered in these mixed-organic compounds thelong and arduously sought organic phosphorus compounds.



156 VITAMINS

But Schaumann's attempts with phytin and lecithin wvw no

less fruitless than those with better drlined phosphorus

compounds. Only nucleinic arid, and especially tin

1

formderived from yeast, gave positive results, though tint rfirrt

of these substances was far less powerful than that of extract

of rice bran. When it was now discovered that Funk's vitamin*

were in fact devoid of phosphorus, Schaumann had to ietnmh'1

his hypothesis again, and he assumed that the vitamin*

played a part in intermediate phosphorus metubuliMn, func-

tioning as a kind of phosphatases. This M*emed all t.h« more

plausible seeing that Schaumann's own romprehensiw sludirs

of metabolism as well as those of other investigator*M:, r lc«had shown beyond dispute that in polyneuritic disorder* the

phosphorus balance is strongly negative despite the mluctcl

excretion. It has subsequently appeared, however, that,

even when Funk's vitamin is administered, and the jttmw of

voluntary movement is restored, the phosphorus balance

remains negative, and this observation puts the: la,st explanation

out of court. But besides Schaumann (who not bring a

medical man, had to be guided in medical matters by tin*

opinions of the faculty), all the leading medical authoriti**

regarded the nervous paralysis as the primary lr*ion.

Moreover, in the nervous system and in the glands there roukl

be detected, not only an atrophic degeneration, but also a

disturbance of the phosphorus metabolism which it wan

natural to regard as the cause of the failure of ncrvou* func-

tioning. From 1912 onwards, therefore, Schaumann indifittJ

to regard the role of the vitamins in intermediate jihtiNphtiriw

metabolism as mainly one of activation. Hi; therefore %u%*gested for these substances the name of

Mactivator.*/* but

subsequently withdrew the suggestion in deference to the

priority of the name vitamin.

Tschirsch *o°4 was doubtless influenced by SchattrffitmT*

researches in formulating the hypothesis that the mum of

beriberi must be the incapacity of the body, in the* absence

of vitamins, to effect the cydopoicstH that h requbtitt* for the

formation of the nucleoproteins. He thus regards Iht* vitamttiH

as ring-closing ferments, without whose aid thi* food cannot

be utilised for the upbuilding of nuefcoprotein*. Apart

from the fact that this theory does not provide* &ny explanation




of the almost instantaneous restoration of mobility whichensues when animals suffering from experimental polyneuritisare dosed with vitamin, it cannot be taken as proved thatthe human organism is incompetent to effect cyclopoiesis,and that human beings would simply starve to death if thenecessary ring compounds were not provided ready-made inthei r food. This attem pt a t explanation must, likewise, berejected.

It is worth mentioning that in 1916 VoegtlinSS* endeav-oured to explain the action of vitamins on the theory thatthey served to neutralise the toxins resulting from an excess

of rarhphyrirates in the food and the consequent intestinalfermentation. Inasmuch as Voegtlin's own work contributedpowerfully to promote a better knowledge of the mode ofar t ion of the vitamins, there can be no doubt th at thisauthority spontaneously recognised the untenability of hishypothesis, f° r w c find no further mention of it in hissubsequent writings.

8. SUMMARY.

I am not a medical practitioner, and the independentviews I shall put forward in this section are therefore advocatedwith all reserve. In my opinion, however, there are certainfortts which may guide us in our search for the causes ofpolymwritic disorders. I have repeatedly insisted that thenerve degenerations cannot be the primary causes of theparalyses. For, first of all, the latter occur in cases where onpost-mortem examination we can detect no nerve lesions.Secondly, even in the worst cases, the nerve degeneration is

never complete, seeing that some fibres always remain ingood condition. Thirdly, the restoration of mobility is analmost instantaneous affair, so that there is absolutely notim e for the recovery of a damaged nerve. Finally, we learnfrom anatomical evidence that the general improvement isspeedy, whereas nerve regeneration in the best event requiresm onths. (Cf. Vedder and Clark,*3* and Schaumann 3«>.) Forthe same reasons, it is impossible to regard muscular degenera-tio n or atrophy as the primary cause of the symptoms. The

instantaneous restoration of the mobility of a degeneratedmuscle is as unthinkable as the instantaneous restorationof the conductivity of a degenerated nerve; and we have



158 VITAMINS

learned that a definite interval must, in fact, elapse beforethe muscular system is fully restored to the normal.

It is therefor e necessary to assume that, degener ative changesnotwithstanding, the possibility of functioning is preserved

should it be possible, either to remove an inhibition, or else

to supply some substance that is lacking. An obv i ous a s sum pt i on

is th at the vitam ins are indispensable stimuli. I t has beenshown in the foregoing that similar effects to those producedby vitamins can to some extent be produced by well-knownorganic bases, although the influence of these is not lasting.An electric current, however, has similar effects, and we are

certainly n ot entitled t o contend th at the absence of ranimalelectricity is a cause of the paralyses, or that animal elec-tricity is produced by vitam ins. Similar effects are no t alwaysdue to identical causes. In no science is the va lidi ty of th isprinciple more conspicuous than in physiology.

Matters will perhaps be cleared up by a consideration ofthe general determinants of muscular movement. Thismovement is a manifestation of energy, and presupposes the

prior existence of th a t energy. Now the motive power of theanimal organism is combustion, and in animal life we cannotconceive any manifestation of energy in the absence ofcombustion. The formation of lactic acid and carbonic acid,products of combustion, during muscular movement, showsthat oxidation is an essential determinant of such movement.If, therefore, we inhibit the combustion, no movement cantake place even though the nerves and muscles are intact—unless energy be supplied from without, as for instance inthe form of electricity.

In polyneuritic disorders, the combustion in the musclesis, as we hav e repe ated ly learned, reduced. Th is defectivecombustion has been experimentally shown to be mainlydue to the lack of a sufficiency of catalase. Exp er im en t h aslikewise proved that the catalase content and therewith thetissue respiration, i.e. the possibility of com bustion, is resto redby the supply of vitamin. Finally, there is exp erimental

evidence that what happens in the muscles in polyneuritiswhen vitamin is supplied is, not so much that already existentcatalase is activated by the vitamin, but rather that th eprovision of vitamin actually increases the catalase content of




the muscle!;. In a word, the vitamin must lead to the newformation of catalase.

T h i s , then , is the core of my theory. Under the influence

of vitamin, the catalase content is kept at the requisite level.We m u s t still leave open the problem whether the vitaminsplay an active part in the building up of catalase as necessaryconstituents of that substance, or whether they are to bere gard ed as directly operative catalase-forming ferments, orwhether (as Abderhalden suggests) they represent co-enzymesessential to the formation of catalase.

This merely provides an explanation of the polyneuriticsy ndro rp c. The origin of the atrophy and degeneration of the

muscles and nerves still remains to be explained, and herewe m u s t invoke the action of a substance of which we as yetknow very little, the water-soluble antineuritic complettin,which fo r short I shall now call D.3^8 i t has been shownth a t F u n k 's vitamin, the real antineuritic principle, willrelieve the paralytic manifestations, but only these, it doesnot cure the atrophy and degeneration of the muscles and the |

nerv es ; and death inev itably ensues in such cases eventh ough F u nk 's vitamin be given, unless D be also added to*

the d ie t. Numerous attem pts have been made to describethte sy m p to m s as no more than the results of inanition. Thereare, doubtless, plenty of grounds for such an assumption.R e c e n t ly , Simonnet *3« pointed out t ha t both in beriberiand in experimental polyneuritis the diet is extremelyill-balanced, and must certainly be inadequate in more respectsth a n o n e . This authority errs as regards beriberi, for in tha tdisease, though we speak of its origination by a rice diet, wedo n o t usually imply tha t the patient has taken no food butrice. T h e diet may have been varied, bu t the mistake hasbe en t h a t the staple article of food has been polished rice.Moreover, beriberi broke out among the European troops inMesopotamia, and the diet of these well-fed Englishmenmust certainly have been a varied one. Underfeeding asre g ard s protein, fat, inorganic salts in general, and alsocomplettins A and C, may therefore be excluded as a causeof be r ib e ri , and we must seek another etiological factor. Wemust certainly approve Simonnet's proposal that in futureex p er im en ts a diet should be given th at shall be fuUy adequate



160 VITAMINS

except for the absence of the antineuritic factors, for we may

hope in this way to secure clearer and more trustworthyclinical pictures. H ith e rto these clinical pictures hav e oftenbeen confused by intercurrent disorders, especially by mani-festations of the haemorrhagic diathesis and by oedema, sothat the disorder which was the primary object of study hadbeen rendered almost unrecognisable. On the oth er ha nd anartificial diet such as Simonnet experimented with (meat

thoroughly boiled and pressed, and subsequently extractedw ith alcohol and ether ; Osborne's salt m ixtu re ; aga r powder ;earth nu t o il ; bu tter f a t ; qua ntitative filter paper [as roughage— see below p . 1 9 0 ]; po tato sta rc h ; and distilled* water)will, indeed, be vitamin free, but is likely to contain D afterall. In fact, in the diet named, there is D in the agar powder,th e fats, and the p o ta to starch. The result was th a t this

diet rapidly induced severe paralytic symptoms with tetanicspasms, but the animals' loss of weight was much smallerthan is seen in cases of beriberi, and the typical atrophicform never developed.

It would have been much better to retain the familiarexperimental diet, supplementing it with specific substances— salts ; A, B , and C ; pro te in ; superheated fat.

Almost at the same date as Simonnet, Karr,I293, ^94 madesimilar experiments which were invalidated by the sameerror and led to the sam e result. The main fault of K ar r'sexperiments was that, when giving an abundance of B, hedid not realise th a t he w as giving D as well. I t will be neces-sary in such experiments to turn to account the recognitionof the differences between B and D, and thus to plan a diet

which shall contain a sufficiency of B without any notableadm ixture of D . I t is no t, however, necessary to troublevery much about the supply of B, since experience shows thatadult experimental animals deprived of B can remain healthyfor a period far longer than that which proves fatal fromatrophy when D is lacking.

Attention has several times been drawn to the fact that



FORMS OF POLYNEU RITIS 161

manifestations experimentally induced by Simonnet andK ar r i n their respective series of experiments, was not accom-p an ie d b y any such signs of glandular atrophy or suppression

of se c re ti o n . Ka rr expressly reports that in his experimentala n i m a l s digestion ran a normal course. This is a plain indica-tion t h a t the absence of I) (which is usually found in associationw ith t h e complettin B) is really responsible for the atrophicm an ife st at io ns . Even had Simonnet's and Karr's researchesbeen o f no other use, we should have to thank them for theclear demonstration they have given that beriberi and experi-m e n t a l polyneuritis are not simple but complex disorders.

When Funk's vitamin is alone lacking, -paralyses without

atrophy ensue ; when 1) is alone lacking, the result is mar asmuswith characteristic degenerative manifestations ; when both arelacking, the result is typical beriberi or polyneuritis , in whichthe varying quantities of the respective complettinsaccount fo rthe mor e or less mar ked development of one or other syndrome.

N o w that these relationships have been cleared up, wear e f a c e d with a new and important -problem. W hat is them ode o f action of the complettin I) ? Since the symptomscan appear on a diet which is in other respects adequate, thisa t r o p h y can hardly be due to a lack of tissue-building constitu-ents . JBesides, there is a fundamental difference between thea t r o p h y we are now considering and that which ensues in af a m i l i a r form when some well-known constituent is absentfrom t h e diet, or in simple starvation . In D deficiency, weh av e som eth ing more than atrophy due to lack of proteinor energy, for there is simultaneous degeneration. Event h o u g h we assume tha t in consequence of the want of D theu ti l i s a t i o n of new material and therewith the maintenance ofth e e x i s ti n g tissues are impaired, this hypothesis by no means

su ff ices to explain the symptoms of degeneration. Asp r e v io u s ly said, we have no difficulty in conceiving of atrophyw i t h o u t degeneration. But since the two appear in conjunction,th e re m u s t be some sort of connexion between them ; and inas-m u c h a s atrophy does not per se induce degeneration, we are ledto i n f e r an inverse order of causation, and to suppose that thea t r o p h y is the outcome of the degeneration. The organism haslost t h e faculty of maintaining its extant substance, and hast h e r e w i t h lost the faculty of making good the used-up material.

TT



VITAMINS

Life, movement, secretion—in a word, all the manifesta-tions of life—are dependent on the using up of the materials

of the body. We must not imagine th a t in th is process everycell, or every group of cells, throws off part of its molecularstructure, as the dried coats peel off a sp rout ing onion. W emust rather assume that reactions occur within the mass sothat the fundamental substance is modified. N or mu st wesuppose that these changes occur with equal intensity every-where. According to the nature of the particular vitalmanifestation, the organ or organs chiefly concerned will bevariously modified in their innerm ost st ru ctur e. Now the

essential feature of life is that whereas the spontaneousdecompositions of the inorganic world are irreparable, thosethat occur in living matter are more or less completelycompensated. In ma lnutrition, and even in actu al starva-;tion, the wastage of the organs primarily essential to life isrepaired by the withdrawal, from less important organs, of;the materials required by the more im po rta nt one s. If in \the case we are now considering, no such rep air take s p lace, !if the innermost structural elements do not merely atrophy,

bu t also degenerate, we have to infer t ha t— in con trad istinc tionwith the state of affairs in malnutrition or simple starvation-there is a definite lack of something whose presence w ould renderpossible the imm ediate restitution of t he u tilised m ate ria l.

We are led by these considerations to discern that the funda-

mental activity of the complettin D must he a contribution to the

restoration of the used-up material. One way o f se t t l i ng the

whole question would be to describe the complettin I) as a

restitutive hormone, as the substance which makes repairpossible. B ut, apart from the fact th at we are m erely prov idinga new name instead of giving an explanation, we s h o u l d h a v eto account for the remarkable fact, unparalleled in the v i t a lprocesses of the organism, that a hormone indispensable t othe individual is, by this supposition, not m anu facture d bythat individual but has to be introduced from without. Fo rjust as little as vitamin, can D be synthetised in the animalbody.W36 The best proof of th is is th a t t h e xniUc of m o t h e r s

suffering from latent beriberi is so lacking in these substance*th at the infants fall ill sooner than th e moth ers, (On t h eother hand, such a synthesis is within the competence, notonly of the higher plants, but also o f t h e s ch i zomyce t e s and




the yeas ts For instance, the intestinal microorganisms can

effect such a synthesis. Consequently, as Portier and

Randoin xo63 have shown, the faeces of animals sufferingfrom polyneuritis contains so large a quantity of vitamin that

it will suffice to cure the animal if suitably administered.)

More detailed knowledge of these processes is very

difficult to acquire, for we are concerned with the most

in timate reactions of life, which have hitherto been completely

ignored . In the matter of nutrition and repair, modern

physiologists, and above all Jacques Loeb, have done a great

deal of work, but their labours have by no means sufficed toclear xx$> the difficulties. The main reason for their failure is

that t he members of this physiological school are completely

under the spell of a physical chemistry. Their studies are

therefore restricted to two special fields; the effect of the

ions on the cells; and the reaction of the living colloidal

substance of the cell upon other colloids. Obviously such

researches will not unlock all the secrets of the matter, as has

indeed been proved once more by Carrel's attempts to induceanimal tissues to grow outside the body. For Carrel found

that such growth would only take place in natural serum,

in the natural fluids of the body.

Moreover, the process of assimilation whereby the cell

builds up the constituents of the food into its own substance,

and t h e utilisation of this substance for the purposes of life,

can b e explained neither in the terms of ionic reactions nor

in t he terms of colloidal chemistry. Both these fields ofresearch have contributed much towards the elucidation of

the bodily processes, but only a purely chemical science can

make such processes comprehensible. Here we find our-

selves in unexplored country, lacking the guidance of even

one established fact.

The explanation of the matters we are considering encoun-

ters additional difficulties owing to the entire inadequacy of

our anatomical and physiological knowledge for this purpose.It appears to be a fact that to some extent the breaking up,

removal , and rendering innocuous of the products of vital

reactions is effected by the blood through oxidation, but this

s ta tement sums up all that we know of the matter. It is

uncertain whether the nutrition of the tissues is achieved

by t he blood or by the lymph, (I think there are grounds



3 6 4 VITAMINS

for giving the preference to the lymph, although the participa-tion of the blood can by no means be excluded.) O urknowledge of this process is all the more inadequate inasmuchas the ultimate course of th e finest blood capillaries an d lym phcapillaries is still unknown to us. Our ignorance m akes itvery difficult to study these reactions, and physiologicalscience has not yet ventured to approach this fundam enta lprohlem.

For example, we do not know where the transformationof the albuminous tissue "builders into the body's own sub-stance takes place, and the probability is that there are nospecial organs for this function. I t is unquestion able th a tnot merely every species of animals, but also within eachanimal every organ, has its own peculiar kind of prote in ;and it seems unlikely that primarily there should come intoexistence some sort of standard protein which the individualcells can then metamorphose into their own pro tein . T his

would be doing the work twice over, and would render thedigestive process superfluous. F a r more likely is i t th a tthe cells themselves build up their own varieties of proteinout of the tissue-building constituents of the food, and thetheory that that is how the process takes place has beenreinforced by Carrel's success in growing the living tissues.But here we encounter a new contradiction, for this growthwas effected in serums which contained, at most, traces of

amino-acids in addition to serum album in. W e m us t no ttherefore reject the supposition that the cells of the organshave at least some power of transforming an extraneousprotein into their own protein. The rapid disappearance ofthe amino-acids from the fluids of the body after meals iscontributory evidence in favour of this view.

If we are in search of explanations of the inner mechanismof the action of the water-soluble antineuritic D, the.foregoing

theory will seem quite inadeq uate. There are th re e factsto bear in m ind : the cause of the atroph y or degenerationis, the lack of a certain sub stanc e; this substanc e is n otsynthetisahle in the animal organism, and it is renderedinactive by heating, especially under pressure in a moistmedium; finally, the locality where the substance takes-ieffect must be in the cells.

Starting from the last consideration, we can think of



FOR MS OF POL YN E UR I T I S 16 5

three ways in which the absence of a substance might hinderthe rebuilding of tissue. First we m ight assume tha t th eproper mode of action of the substance in the cell is to promote

the synthesis of the cell-substance itself. Secondly we mightassume that when the cell is intact and the food is otherwiseadequate, the function, of the missing substance is to promotethe linldng of the nu trien ts to the cell-substance. Th e thirdpossibility is that through the absence of the substance underconsideration, the mixture of nutrients has somehow beenrendered inadequate.

To "begin with, let us consider the first of these assumptions.The sjsnthesis of the cell-substance proper is achieved in the

animal organism with very modest adjuvants—so modestth a t the process m ight seem hard ly possible. Du ring synthesisin the plant cell, hydration plays a leading part, the additionof molecules of water, or the elimination of groups of atomsby the action of hydroge n. In the organism of higher animals,not a single instance of the kind has been proved to occur.(There are cases of so-called reduction, as when aldehydesare transfo rm ed in to alcohols w it h unsatisfied affinities.But these reactions depend upon the addition of water to a

compound an d i ts subsequent de tac hm en t; they do notdepend up on th e action of hydrogen.) Nor is there known inthe organism of higher animals any instance of the synthesisof carbon chains. Animals obviously lack the power oflinking a carbon atom to a carbon atom, of effecting whatchemists ter m a pure condensation. The only condensationsthe animal organism can achieve are those which take theform of couplings in which carbon is linked to nitrogen oroxygen with the splitting off of ammonia or water, or some-

times with the splitting ofi of salts—the process wherebyethers, esters, or pep tids are formed. On th e other ha nd ,th e organism is also compe tent to break u p existing com poundsby the introduction of a water group or an ammonia groupof elements. B y these simple reactions, b y th e alternatingaddition or subtration of water or ammonia, the most complexproteins ca n b e built up b y th e animal organism, providedthat the necessary carbon chains and amines are suppliedin the food.

In the light of the first hypothesis, therefore, we supposeth e m ode of action of I> in the an im al cell to be such th a t



i66 VITAMINS

this substance, behaving as an enzyme, either promotescombination or else hydrolytic or aminolytic decomposition.

We may, of course, suppose that there is an indirect actionlike th at of a co-enzyme ; b u t inasmuch a s the ba sic con ceptionis still purely hypothetical, this supposition would involvea superfluous complication. A part from th at , th er e are goodgrounds for questioning the accuracy of the whole assumption.First of all, it is hardly conceivable that the animal cell (whichfundamentally resembles the plant cell and has come to differfrom the lat ter only throug h ad ap tation t o a different env iron-ment) should be so dependent upon this environment andupon all the alien factors outside the organism as^to beincompetent for the spontaneous fulfilment of the very func-tions by which as a living being it is distinguished from theinorganic world—so that it is compelled to secure theabsolutely indispensable enzyme from exte rna l sources. A nadditional reason against any such assumption is that whenthe food supply is completely cut off, the function we areconsidering can still be carried out, so that in the organs of

the most vital necessity the processes of assimilation continueeven though the organism as a whole is foredoomed to deathfrom a lack of th e inta ke of energy. Doub tless th e lastconsideration has no demonstrative force, seeing that deathfrom starvation is a comparatively rapid affair, whereas inpolyneuritic disorders the lack of certain substances has totak e effect for a long tim e before the illness beg ins. T here is,however, a third reason for rejecting the enzyme theory as

very improbable, for all the organic enzymes hitherto knownare comparatively thermo labile. Th e com plettin D , in adry medium, can resist an hour's heating at 120 0 C, anexposure which destroys all known organic enzymes.

The second possibility is that there is lacking some sortof intermediate link which, if present, would couple thesubstance$ derived from the food to the cell-substance proper.If the suggestion is that we have to do here with somethinglike the amboceptors of serology, it may be incontinentlyrejected. For in th at case we should have to assum e t h a tthe different substances in the cell all constitute a chemicalaggregate which is as it were eaten away at one end by thevital reactions, its integrity being then restored by the linkingon of substances derived from th e food. B u t t h e supp osition




is certainly tenable if we presume that some intermediarygroup may be missing from the food, a group which if present

would have enabled the substances in the food to be builtup into an aggregate identical with that of the cell-substanceitself. If that is the way the second supposition is to beinterpreted, we can pass on immediately to the third theory,according to which the missing link is itself a constituent ofthe food.

The vitally essential requirements of the food would appearto be as follows. I t must contain a sufficiency of carbonchains of definite but varying lengths. In pa rt these must

be amjjiised, and in pa rt must contain certain rings. Fu rther,these substances must be sufficiently far reduced. Finally,there must be an adequate supply of groups with unsatisfiedaffinities, so that the necessary couplings may be possible.The first four requisites are deducible from the proved factsthat the organism of higher animals is incompetent tosynthetise carbon chains or to effect ring closure (except inso far as this is possible by the simple formation of lactone);

th a t only in the rarest cases can it achieve aminisation ; andth a t it is quite incompetent to effect hydration. The fifthrequisite is obvious, seeing that the new substance requiredby the organism has to be built up by couplings.

To decide where in this instance the defect may lie, wemust further make allowance for the fact that although thesubstance in question is generally believed to be fairly thermo-stab le it is certainly damaged by prolonged heating. Under

the conditions that obtain we may exclude the possibility ofa decomposition of a carbon compound by over-heating, orthe decomposition of the possible ring-closing substances.It is, however, perfectly conceivable that sensitive aminescan be saponified by heat, especially in the presence of water,the amine group being replaced by a hydroxyl gro up; andAbderhalden's researches have shown that the hydroxidescannot replace the amines of the food—cannot be re-aminised.This possibility must, therefore, be borne in m ind; bu t th e

theory is rather improbable, seeing that the amines hithertoknown to be present in the food and in our organism are notve ry sensitive to heat. Among the synthetic amines, thereare certainly many in which, owing to peculiar structuralconditions, the amine group is readily detachable, bu t no



168 VITAMINS

such substances are known am on^ the na tur al amines. Still ,the possibility must not he ahst'luff-Iv t i i \mvwA t i<* \ it $%known that tin*, water in whirl) jurat h;iv I m n b<.?|r*1 r ^ t a m - i

more am monia than wan dcni'm 4rat»l»* m ihc- np .i t, lin»question arises, however, whether tlm Nj'hitinf* % M is ii<*tcomparable to that which wwt* as a jmirly j'hy.i«4<<ir.ilaccompaniment of digestion without any t*âiiin.r **n nutrition,as when carbamides are transformed into th«f t**ir<">j*m4i$?i:ammonium compounds

There is a second group of rriinparativrJy umtabl** '-ul»'stances in natural Uunfa, rorupriîn;* what i* kn«>\vn *v* lh«-sulphhydril group. Hir^:h.Hti:iniJ'^ has «tr,nv» attîitjuji in

these. In th e hy drolys is of p ro lrin^ in th«* l»l*<fMi*«ry wefind as the pr im ary reprenrnta tivf* of th«* sulj-'hur<*ystin» which is an anhydride of tin- suJphhvdfa!^ rv^fIn our discussion of the biological valnr i4 tb«" pi^ffin-ilea rned t ha t th ese Mib*ta«ct*% ari* alrvoltjtrly f.^ -n tM l toCyst in is a very u nstable substan ce. \W ,uv »*siinl<-4 inw he the r cyste in, to o, ma y not h«* of grea t im j^ jit .ti ur fr.r th«?upb uilding of pro teins , sr iin g that it i% t-v^ti tuu if uir-44)4f*

tha n the anhydri<Ie. A j4«>s.Mble obj«-c u**nt»* ^m h ;* vir-w I.H

that a sulphur-free diet is rtiidrrrd ,p!*qn;*f* by tli** .i4di!t«nof cystin ; but thri'e is no risi.ôn why \ \*v sbouM n*#! ^Mim«that in the? body this anhyrirttlt* m ay tak** t»j# w-ii«-r ;tn«l tjmlrii»<idecom position into oxyûninr* prnpi**tiK ;Kid an d ry ^t rm ,so th a t the rea lly activ e brwiy !*• th e stiljihJiydr.ilr.., At an yrate, we know that in th«-- lom!# cyst in r\-m In* r r f t W H dycystein ; and it is certain that whrn Hth*T r*f th<-^ Milî^nriîis heated in the presence: of wairr, thr sulphur i \ **plif *4f,Thereby, both cystin and cy^trin arr «-bvi*»iiNly r^tid^frU

valueless for n utr it iv e pu rjw srs, iim^mnch #>% Hnl|»hhydr..ittoncannot be effected in tl m annual Unly , I J i r tm i ilwt thi.îdecomposition is not merely pf^%ibk in thr firriMmt^nrrs weare considering , bu t dkw** ac tuall y ocrctir, is prrw rtj by th efact that when tin* of jm*M srwd m m l an? Of -ti cJ a fm rlydefinite odour of sulp hur etted hydro^ fii i* often i^ rc qi fib ir,During the war, the stt 'riUsattoii of tinitH mrnt w,v* mi ruth*lessly conducted that complaints of thb MH«-I1 licommon.

Besides th e su lphu r gro up, we* h:iv«* r«?a.son tq p}that the food contains other group* of %ub%Utttm with a




readily modifiable composition (for instance, bodies with analdehyde-like structure), but our knowledge of these is toovague to justify definite statem en ts concerning them . W e

are, however, certain that the proteins, and especially thenucleoproteins, contain thermolabile mixed-organic com-pounds. Thu s it is supposed th at pa rt, at least, of the phos-phoric acid in the nucleoproteins must be present in theform of metapho sphoric-acid com po un ds ; and on prolongedboiling in water these, even when combined with bases toform metaphosphates, are more or less rapidly transformedinto orthophosphates. This m ay be taken as a partial

confirmation of Schaumann's views concerning the indispensa-bility of certain organic phosphorus compou nds, for the animalorganism is unquestionably competent to change the lowerstages of oxidation of phosphorus, such as metaphosphatesand pyrophosphates, into orthophosphates, but cannot effecta reversal of the process.

Simple prolonged heating of foodstuffs, especially at ahigh temperature or under pressure, may therefore be pre-sumed capable of bringing about any one of three changes

competent to render inadequate an otherwise adequatenutrient, because the animal organism cannot reverse thetransform ation. Th ese are : (1) the disam inisation of vitallyimportant amine compounds ; (2) the decomposition of similarsulphur compounds (and perhaps of substances belonging toother u nstable groups) ; (3) the metam orphosis of m eta-phosphates and pyroph osphates into orthophosphates. Reac-tions (1) and (2) will make it impossible for the foodstuffs tobe assimilated to form cell-substance, for the unstable groups

in the food m ixtu re will ha ve been destroyed. In t he caseof reaction (3) th e unfav ourab le effect is tw of old : in thefirst place the food will have been deprived of the metaphos-phoric and pyrophosphoric radicals, which are essential tonu trit io n; and secondly th e aid to the process of couplingwhich would have been furnished by these phosphorusderivatives, will now be lacking.

In the second chapter we learned that the lower-gradeamino-acids are apparently of no vital importance, seeing thatthey can be formed within the body out of higher compoundsby am pl e oxid ation. W hen, therefore, we th ink of disaminisa-tion as a pathogenic influence, it is only the amino-acids of



x7o VITAMINS

high molecular weight that come into the question, hutare present solely in ccmipnrativrly small quantities in prophy-lactic or cura tive D-containing rx tra i'ts . Hut thm * is i*vulmcc!

telling against the theory that di-samim-Nation by halting inof much importance1 in this connexion. V^t inst.uu-i-, in !hif

sufferers from beriberi in Mi'Huputamia, thr m«*at rationshad been lav ish. If, tlK?rdfon% \vt; a r r to n ^ a r d thi- I n k ofcertain amino-acids as the essential causr <>i th«« m.ilmitrjit^fi,we must suppose tha t the meat must h a w i m u rjmtr «h*m-teg ra ted by the process of sterilisatio n a far m**tr tho ru u^ hdisintegration than can IK* efi<?ctt:tl in tJw thi'tnita! Lihm*iU.t tydu ring artificia l hydrolys is. I th*?rrf«"*r«? ru m n lr r t l p t tin?

disa m inisa tion factor m ay be dismiHwtl fir»m th«* rtr rk ill ing.Again, complete disintf^ration of the nutphur rumjimimi*

is hardly conceivable even in uhra--strrih^fl iiit-al, J*«> tha tthis assumption has little probability in it-* favwur.

With regard to the third hy{*othe,s.K on ihr t*thvt hand ,the experiments of Franeb and Trowhndî*«M m nl tho*«? «fTrowbridge and Stanley lfS have* shriwn th a t whrri nir-if i%boiled even for a co m para tive ly brief pf*ricx!4 rir^rinicare transformed in to inorganic. I ronsiilrr tha t in

with the appearance of beriberi in I H * T M M * % U U a ^ r t i l i ^ d ie t,this is the factor we have rhifUy to rnnîdrr ;w:fmmt;il4r ft*rtha causation of the atrophy and tk*$mrtMi* m ut mn^.\m$

nerv es, and gland ula r tissue*. Thu s w«? c« m r b ack tw ttif.

early view of Schaumann, that th« Ltrk of ar^^nir. p\ump\mtn%compound* m ust play a leading part in t h r rtto kf ty «#f p4 y^neu ritic disorders. If dosag e with " rirgitnit: pli i^p ti^ irii '*failed to d o an y goo d, ti ns was l:M.*c;ium* th r pb*^ |ih*itr» fjivrnwere not those vitally esHcmtuil phonphatitn tiorni^Hy

in the food. The ph osph orus tom puun tfc iiM.'.d in the?m en ts h av e for th e m ost p a rt b m i m i x c l gsimple ester-like combirmlium of ordinaryacid, not containing the mittaphosphat« mud pytha t a re ind i spensab l e to the an ima l o rgan i sm*

Thi s mus t no t be in t e rpre t ed a s an aaa ter t ton tha t me ta -phospha te s o r pyrophospha te s wou ld be e f fec t i v e a i i su ch*for i t i s qu i t e poss ib le th a t w ha t coun tu b the i r m ode 0Icom bin a ti on i n o rgan ic m a t t e r . N o d ou b t wh en w e t i yd f c il y i t

organ ic substances con ta in ing phoffphorus , wt* f i n d t ho t ep h o s p h a t e ; bu t i t d o e s n o t fo llo w t h a t t h e a n im a l o r g a n i sm



FOR MS OF POL Y NE U R I T I S 171

is comp etent to produce them. W e know, indeed, th at w hendigestive enzyme acts on the nucleoproteins, phosphoric acidis split off provided the action is continued long enough;however, the latest investigations point to the conclusionthat in natural digestion no such complete splitting off takesplace, b u t th at larger and more complex com pounds areabsorbed from the alimentary canal.

Until further study has supplied us with better lights, weare entitled to accept as a working hypothesis that in theseillnesses the repair of tissue waste has been rendered impossibleby the lack of certain organic phosphorus compounds in the

food. JThis lack is in some cases due to t h e direct rem ovalof cer tain ingre dien ts, as in th e " polishing " of rice, or inthe boiling of food and the subsequent throwing away of thewater used for the purpose ; and in some cases it is due tothe destruction of thermolabile substances by excessive orundu ly prolonged heating . He nce the atroph ic changes inthe affected organs, for continued work without the replace-ment of the used-up material must in the long run infalliblycause degeneration. An additional factor is undoubtedly

the lack of catalase, owing to which the catabolic changesm ust ru n an abn orm al course. A further source of troubleis that the medium in which tissue change has to be effectedis rendered unfavourable, on the one hand by the presenceof these products of abnormal catabolism, and on the otherhand by a deficiency of inorganic constituents.

An objection which may be put forward against the fore-going theory is that in starvation states, when the supplyof the same substances is likewise absent, though atrophy

ensues, there is no degeneration. W e m ust, however, remem berthat in starvation the course is far more rapid, and that inpolyneuritic disorders the period of incubation is oftenconsiderably longer than is requisite in starvation for a fatalresult. I t ha s, m oreover, been proved th a t during starva -tion the most vital organs are nourished at the expense ofthe others, in order that the former may be kept suppliedw ith ade qua te nu trim en t. In starvatio n, therefore, the lessimportant organs atrophy, and will at most exhibit degenera-

tive phenomena towards the very last, whereas during theprolonged incubation of polyneuritis there is plenty of timefor degeneration to ensue



( H A I 1 IKK I IVK

TH E C O N D I TI O N S O F G R O W TH

1 .

THE old sche matisa tion of tin* theory ««J n nt ii ti o n. w ith itsun du e stressin g of the* im port an rr *4 th** nj>|!v of pfMtcmand energy, wrought much harm, and Muwhm* w,r« th<- hatinso manifest as in tin: dom ain of tin- frrdmit *4 t.hiM trn NiJIirt?it to recall how authorities in tii*'tHj«f-.4 innai'ini* th«v untv^wddem and for food ch-pt'iicient u|«*n i;t«*vih, wi*r«? i«4i!*iu t.ues tim ate ch ild ren's n m l frii ntitiiin«-ut a j'r««j«*iti<.4i.il tosize ami weigh t. So ImMwmm! w;i,s lh«* a]»)4i?-*itiun * 4 tin**principle tfiat we arc really ^ntitlrcl t«i woiii!**r \h ,* \ thn

nu tri tiv e rcquircnsMits trf infant?- ttw irm s dnniii* flir ftr^tweeks of life were not suj«pr*srtl t o l«* n* st ri ti ri l t*# z % «4 therequire men ts of the adu lt , A go*>*l tna iiy y«-ai'« ag« f j ôut that growth nrcir^sarily t lr imimh a far IIU-I*- ; ir t tvrover, and that for thin tvns**n flu* nutnftvt* irrj!iir*iiintf^

during growth must be* incoinparafily itfra lrr th an th «w «4ad ul ts. I showed fnrthfr th;U# thanks in the* j*r*!;intrywhich ignored thin ctmsidrrattMn, tin* n-Mtll^ «f ;t.ll fhrinvestiga tionn regard ing tlu* itu tti tto n of th<* p-*|nilalipn nf

th e United Stat es (invi^tigationH which Iwvr *mf m an ymillions of dollars) hav e been w«irthlr.ss. tlu rin g th e larfdecade there has been a change for the filter, timitgh atfirst, it would neem, only on th e c4 h ir wile* r*f th r A tla nt ic ,Thus in 1920 M, A. Brown *«** clachired that thr nutritiverequirements of the growing f^rgani^m hud hithertogreatly underestimatitd. Despite theory, in pra ctic r,children are not thriv ing, tlws** r^| jon sib l« for their car ealways ready to try and enforce mtpttwittumi by an extrava-

gant supply of nutriment, chiefly in the form of



TH E CONDITIONS OF GROWTH 173

but sometirfees in that of carbohydrate or fat. Witness th einnumerable proprietary preparations for the feeding of

children with which the market has been flooded for decades.The very multiplicity of these preparations is the best proofthat most of them are ineffective, and that those whorecommend and use them are on the wrong road. The troub leis that, as Terrien I2lS phrases it, far too much faith has beenput in the so-called dietetic test. The mere fact t hat b y anexcessive supply of nu triment it is possible to cause an increasein weight, by no means signifies that the development of thegrowing organism has necessarily been redirected into the

right channels. To justify a conviction that such an improve-ment has occurred, we must ascertain by detailed and accurateobservation that absorption and excretion are properlyrelated each to the other, and that the increase in weightis not due to a morbid deposit of fat or a morbid retentionof water in the tissues.

Here prolonged observation is requisite, and the medicalpractitioner is seldom able to undertake anything of the

kind. The pa tien t is brought to see the doctor once or twiceat the ordinary hours of consultation, and that is alL Theremay or may not be improvement. Unless improvement isimmediate and obvious, the parents are apt to growimpatient and to consult another physician, who will havea different method. While each adviser, guided simply bythe increase in weight, may be convinced that his prescriptionshave been helpful, in the unfortunate little patient gravedisorders of health are gradually developing, and thespecialist whose advice is ultimately sought may be unableto ascertain their direct cause.

The disastrous results of the present methods of childfeeding in our large towns should suffice to convince anyonethat the period of observation should be much longer thanis now custom ary. If we are to draw sound conclusions asto the value of any particular diet, it is not enough that weshould be able to show that one individual apparently thrives

upon it. Osborne ia24 is right in maintaining that in manycases the effects of errors of nutrition do not become notice-able for three or four generations, and the assertion has beenendorsed by numerous other investigators. How many



i 7 4 VITAMINS

instances of so-called degeneration, of anatomical hindrances to

childbir th, of incapacity for procr eation, conception, lactation,

etc., are referable to dietetic er ror s in earlier generations !' it is obvious that the life of the individual human beingis too short to enable any one of us to make a sufficiency ofobservations in the case of the hum an young . On th e otherhand, we m ust carefully avoid a pr em atu re applica tion tohuman conditions of the results of experiments on animals.But when it is possible to trace a close parallelism in theserespects between human beings and the lower animals, thetransference of conclusions is justified. Above all, it is jus ti-fied when the same causes produce the sam e effectsrin themost diverse classes of animals, as in birds , rod en ts, rum ina nts ,omnivora, and cam ivora, and when it is possible to pr ove th atin a comparatively short time these causes produce the sameeffects in human beings. Then we m ay a pp ly to hum andietetics what we have learned from experiments on animals.We saw in the last chapter how valuable this method hasbeen in the case of the polyneuritic disorders, notwithstanding

the fact that we may be disinclined to regard the experimentalpolyneuritis of birds as perfectly identical with beriberi inhum an beings. From this outlook, the investigations of thelast decade, and especially those of very recent years,although they have been carried out on animals, are of over-whelming importance in their application to dietetics in thecase of adult human beings no less than in that of children^

2. IMPORTANCE OF PROTEIN.In the second chapter a detailed account of the importance

of protein was given. Most of the experim ents upon w hichth a t account was based were made and confirmed upon g rowingorganisms, and as far as generalities are concerned it willsuffice to refer to what has previously been said. All th a tI need add here is that, thanks to the dominant tendency tooverestimate the importance of protein, substances shown by

a cursory chemical examination to contain a considerablepercentage of crude protein are often esteemed far morehighly than their m erits w arran t. Le t m e recall the w artim eattempts in Germany to supply a richly albuminous nutrientderived from yea st. To make " nutr itive y e a s t " (as it was



T H E CONDITIONS OF GROW TH 175

pompously styled) money was spent by the million, largequantities of sugar being wasted in the process—thoughsugar was exceedingly scarce and was urgently required for

th e feeding of th e people. This sugar was literally thrownaway, for physiological experiments on nutrition have provedth at the crude protein which " nutr i t ive ye a s t" certainlydoes contain in very large quantities, partly consists of freeamino-acids and is partly of low biological value, so thatordinary po tato protein is a far better nu trient. (Cf. Fun k,Ly le, and McCaskey.567) In brief expe rim ents on hum anbeings, Wintz 53<> did, indeed, find that when the rest of theproteinm in the diet w ees high-grade, as m uc h a s 30 to 40 % of

the protein could be given in the form of yeast protein andeffectively utilised ; but the exhaustive researches of Hawk,Smith, and Holder 87* ha ve shown th a t in ordina ry circum-stances the amount of " nutr i t ive yeast" protein in the dietca nn ot usefully exceed from 10 to 30 % . Moreover, the useof yeast protein is restricted by the fact that not more ihamone or two gramm es can be tolerated. W hen as much a sfour grammes are given, diarrhoea sets in.

In like manner the crude protein of the pulses that

ord ina rily ripen in Germ any is far too highly esteemed. Inmy own experiments,3*9, 6r4, 785 the protein requirement ofan adult human being could not be tolerably well suppliedby a smaller quantity than ten pounds of haricot beans daily.McCollum, Simmonds, and Pitz,6*5 and McCollum, Simmonds,and Parsons,6 ^ report that the protein of ripe peas, beans,and lupines is quite inadequate to maintain growth.

It is essential to remember that many varieties of proteinthat are able in an emergency to keep an adult going (the

whole rye grain, for instance8

96

), are incompetent to providefor normal reproduction, or to ensure a proper secretion ofm il k . Con sequently, when the diet is ill-balanced, and whenthese sorts of protein predominate, the offspring may sufferseriously even though the parents may seem to be doing wellon such a diet.

The following varieties of protein are known to be quiteinadequ ate to m aintain grow th: the aggregate protein frombeans, peas, and lupines 6

45>«9*> *96; phaseolin,335. 423 legumin,

and vignin (which are able at most to keep up the body-



176 YITAMINS

weight22^ 423) ; rye,*96 wheat,5*5, 579, $* , 801, 896 barley,74°, 896oats,598,635, 896 rice,8?6 maize,8^ soy beans,^ 6 z e in ^ s , 4*3 conglu-tin,235* 423 hordein (can only m ain tain w eig ht 22

5, 42-3), gliadin(can only maintain weight 3-5, 246,423. 55°), carrots,7 84 gela-tin,2^* 423 bananas.775,968

It is true that in certain parts of the before-mentionednutrients we find varieties of protein which are able tofunction as efficient growth-factors, such as edestin ("badly ! 541)excelsin,225» 423 maize glutelin,235, 423 and th e p ro te in of th ewheat germ.5°7 Bu t these adequa te proteins are n o t p resen tin quantities sufficient to supply the needs of the growingorganism. Since, however, th e variou s proteins differogreatlyin composition, it is sometimes possible to induce sa tisfac torygrowth by a m ixture of foodstuffs each of which, is se para te lyinadequate. It is impo rtant tha t the ingredie nts of such amixture should not belong to th e same class of foodstuffs,for within any one class the proteins will usually he found tohave the same general composition, and therefore to presentidentical defects. The leading defect, as a role, is aninsufficiency of certain ring compounds—such, ainino-acidsas tryptophan or tryosin, and above all an insufficiency oflysin and cystin. Hence th e cereals, which a re poo rly fur-nished with, lysin, are pe r se quite inade qu ate , b u t can berendered adequate as growth-factors by the addition ofgelatin, since this subs tance contains 6 % of lys in. 59

8» 6a5

There is not a very large choice of really adequatenutrients. Among seeds, the only ones we know to beadequate are cotton seeds, for cottonseed meal, when nottoo finely sifted, suffices to maintain growth.4939» 5*4, 55°> 654Furthermore, cottonseed globulin is adequate, as is alsopumpMnseed g lobul in .^ , 423 P o ta to protein,567 too, isadeq uate; my own experiments showed this p rotein to h a v ean unexpectedly high biological va lue . E g g s ,3 ^ 745 an d alsothe separate proteins they contain (ovalbxirnin and vitellin),are adequate growth-factors.*35> 4*3 In m y own ex pe rim en ts,the adequate protein of milk was found to resemble theadequ ate protein of egg in possessing the very hig he st biolog icalvalue.7^5 As regards lactalbumin, its high biological valuehas also been proved by experiments on animals,235, 4*3, 54*

I3 8



T H E CONDITIONS OF GROWTH i 7 7

menting lactalbumin with small quantities of cystin a furtherincrem ent of gro w th can be secured. Opinions differ asrega rds casein. In experimen ts of only 30 d ay s' duration,Osborne a nd Mendel «5 . 423 found th a t casein could m aintainnorm al growth in mice ; but subsequently they reportedth a t it was only tw o- th ird s as effective as~ lacta lbum in 54« ;by the addition of small quantities of cystin, casein couldb e rendered as good a growth-factor as lactalbum in. Thismay explain Hopkins' observation,^ that casein was notfully adequate, but could be rendered adequate by supple-menting it with very small quantities of milk—quantities so

small a3 to increase the amount of dry substance in the foodby only 4 % . Still, we must not reject th e possibility th atin Hopkins' experiments the mixture of salts employed maynot have been fully adequate, and that the beneficial effectof the addition of milk may have been due to the salts in themilk rather than to the small quantities of lactalbumin itcontained. Finally, Osborne and Mendel have draw n atten-tion to the fact that what is called " protein-free milk *' reallycontains small qu an tities of cystin. Th is m ay account both

for th e impro vem ent in the efficiency of casein no ted in Hopkins*experim ents w hen rnilk was added, and for the great superiorityof natural milk to isolated lactalbumin or casein,

I must not omit to mention the opinion of many investi-gators that, after a certain age, milk is unsuitable as the solesource of protein. Freise1006 agrees w ith Mattill andConklin Ij 85 in referring this unsuitability to the fact thatm ilk is not a sufficiently concen trated food, a nd they h avesecured far better results when fresh milk has been to a large

ex tent replaced b y dried milk. Bu t these sam e experimen tsreally show that the reputed inadequacy is not due to anydefect in the composition of milk protein, but obviously tothe modified requirements of the adxilt organism in the matterof inorganic constituents.

I t has been shown in th e foregoing th at inade qu ate proteinscan sometimes be rendered adequate by supplementing themwith other proteins which are likewise inadequate when usedexclusively. Ob viously, then , an ina de qu ate protein can b e

still more easily supplemented by an ad equate protein. F orinstance, maize may be converted into an adequate growth-



I 7 8 VITAMINS

factor by adding blood 34*, s™or milk "4 3 ; maize glu ten, b ylactalbumin or cottonseed meal55o ; cereals, by gluten, casein,

yolk of egg, or milk w ; maize b y lactalb um in6 l

3 ; rice,454or seed protein in general,579 or bananas,775 or cajrots,7*4 etc.,by casein. The amo unt of the supplem entary protein req ui re dis comparatively small, and Osborne an d Mendel 3 drawspecial attention to the fact that it is far less than would "beneeded if the supplementary protein had to function as thesole source of protein.

In the second chapter we learned that the minimal

quantities of protein needed to maintain weight have hitherto,as a rule, been overestimated. T h e sta tem en t is lessr ap plic -able to the period th at imm ediately follows bi rth , for a t t h a ttime, owing to the demands of growth, comparatively largequ antities of protein are requ ired. Still, th e differencebetween the minimal amount needed to maintain weight andth e optimal requirement for growth is no t ve ry large. McCol-lum and Davis 435 repo rt th a t in th e case of young ra t s for

the maintenance of weight the minimum proportion of milkprotein needed in the food is 3 % ; th at , a s th e prop ortio n ofinilJc protein is increased, growth proceeds more rapidlyun til the am ount of milk protein in the food reaches 8 % ;this is the optimum, for further increments of protein do notadvantage growth in any way. Several ye ars earlier, O sbo rneand Mendel a25 had come to the same conclusion.

If the quantity of protein is kept near the rniuimuin, orat any rate well below the optimum, an increase in fats orin carbohydrates, even though considerable, does not exercisea favourable influence on growth.^ 1 This observation con-flicts with the generally received opinion, "but it accordsperfectly with the demands of the law of th e minimnrn, W h enthe amount of protein in the diet is reduced, the experimentsof Richardson and Green *54 show th a t th e first effect i s t h a tthe rate of growth falls off, and that when the protein israhiced to the minimum that will maintain weight, growth

is completely arrested. If, now, th e am ou nt of p ro te in inthe diet is yet further reduced, loss of weight ensues.

Of course the level of both the minimum and the optimumis mainly determined "by the nature of the protein used asfood. In addition, however, the relationship betw een th e



T H E COND ITIONS OF GROW TH 179

protein and the total supply of energy plays a notable part. 8*?Though, as already said, assuming that a definite amount ofprotein is being given, even an immoderate increase in the

supply of energy in the food fails to exert any influence ongrowth, Bierry 833 is righ t in insisting th at a minim al supplyof protein carries with it the need for a minimal supply bothof fat and of carbohydrate.

3. IMPORTAN CE OF INORGANIC SUBSTANCES.

Nevertheless, a diet containing adequate amounts ofprotein, fat, and carbohydrate, is still far from being competenteven ta maintain the body-weight, let alone maintain normal

grow th. In Ch apter Three the importance of the inorganicconstituen ts of th e food has already been discussed. H ereI need merely point out that it is not enough for the foodsimply to contain inorganic sa lt s ; w ha t is indispensable toan adequate diet is that the supply of inorganic constituents,and the varying quantities of the respective salts, should beduly related to the age of the individual under consideration,to Ms bodily and m enta l condition, to the nat ur e of the nu tri-ment he has hitherto "been receiving, and to the present supply

of food. W e hav e learned w ith regard to the inorganic ingredi-ents, that not merely must there be a sufficient minimumof each, but that they are mutually interdependent, so thatthe various minima are not constants (as has hitherto beengenerally assumed "by dietetic exp erts). T he supply of th einorganic constituents of the diet must therefore be adaptedto the supply of the respective organic co nsti tue nts ; andabove all to th at of th e protein in the d iet, for protein containsan excess of sulphur and phosphorus, which in the healthy

organism a re oxidised to form th e corresponding acids, requ iringfor their excretion a suitable supply of "bases in the food.Th e conditions th a t regulate the bodily requirements in respectof pro tein axe alr ead y com plicated en ou gh ; bu t it followsthat the conditions that regulate the bodily requirements inrespect of inorganic constituents must be no less intricate.

I t m ust be remem bered, too, th at , in th e groining organism,metalxrtism is necessarily far more active than in the adultorganism,, and that the increased turnover in the formercreates a fax greate r demand for inorganic nu trien ts. There



!8o VITAMINS

are two substances in particular of which the adult organismhas comparatively little need, whereas in th e growing organis m

the demand for them is exceedingly active . I refer to i r o nand calcium. As far as sucklings are concerned, natu re a t t e n d sliberally to the matter : for at the beginningof its earthlypilgrimage the immature being receives an ample provisionof iron from the m aternal sto re ; and m ilk is ex trao rd ina rilyrich in calcium salts. B ut when th e sources of milk run d r y ,the prospects of an adequate supply of calcium are greatlyrestricted.

I t is a good thing, therefore, th a t, b y the very fact ofgrowth, the growing organism is enabled t o utilise t h ecalcium salts of the food in a way impossible to adults. T h eadult has to devote a large proportion of the calcium suppliedin the food (and what is said here of calcium, applies on t h ewhole to magnesium as well) to promoting the excretion ofthe excess of phosphoric acid con tained in th e diet. In t h esuckling, on the other hand, there is an active demand forpurely inorganic phosphoric acid no less than for calcium,seeing th at the former is needed as well as the la tte r for t h ebuilding up of the osseous system. In th e adu lt o rgan ism ,large quan tities of tricalcium ph osp hate are excreted a sexcess of ballast by the mucous membrane of the large intes-tine, and are eliminated with the faeces ; but in the growingorganism they are built up into the substance of the bones.Here is a characteristic difference between the metabolismsof the respective ages.

In the third chapter we learned th at , in respect of in orga nicingredients, foodstuffs can be divided into two main groups,respectively containing an excess of bases and an excess ofadds . Apart from the artificialities introduced by civilisationand by its dealings with the cultivated pla nt s, the distinction Isa sharp one and is of fundamental im portanc e. Fu rth er m or e,we saw tha t w ithin each of these m ain gro up s the differentclasses of foodstuffs have their own peculia rities. Fo r ex am ple ,

the proteins of most seeds, and especially those of the cereals,are especially characterised by inadequacy due to a lack ofcystin and lysin. In like m anner, it is a common ch ara cte r-istic of seeds, not only to contain an excess of acid, but alsoto exh ibit a deficiency of calcium. For lime is almost a lw ays





VITAMINS

chlorine as well; and Hart, and McCollum w expressly declare

that all the cereals contain an excess of acid, and that a cerealdiet therefore requires the addition of inorganic hases.Cotton seeds axe an exception to the general run of seeds,

for they contain a protein that is fairly competent to maintaingrowth. Richardson and Green 5*4 found, how ever, t h a tthese seeds likewise are inadequately furnished with calciumand other bases. According to McCollum, Simrnonds, an dParsons,^1 haricot beans are not able to maintain growthunless their protein and complettins are supplemented by theaddition of calcium carbonate and sodium chloride ; a n dMcCollum, Sinunonds, and Pitz 645 sta te th at the pulses-gene r-ally are inadequately supplied with sodium and calcium.McCollum and Davis 431 report that seeds as a class are lackingin inorganic nutrients, and must be supplemented by mixturesof inorganic salts.

Bananas, again, are too poor in calcium to be adequategrowth-factors.775. i%°> 980 Roots and tube rs are often g re a tl ydeficient in calcium, and sometimes deficient in sodium.According to McCollum, Sirnmonds, and Parsons,777 this isespecially true of po tato es ; and according to De nton a n dKohniann,784 of carrots.

Various authors emphasise the difference, from the nutri-

tional outlook, between the green pa rts of p lan ts and t h eseeds. Whereas the seeds contain a n excess of acids, t h eleaves contain an excess of bases ; and w hereas all seeds ax edeficient in calcium and sodium, leaves are often richly su pplie dwith these bases. McCollum and Davis 43r have shown inth d r experiments that omnivora (such as pigs and rats ) fedCHI grain can rear their young provided that the grain isadequately supplemented with green fodder. McColhim,Simmonds, and Pitz,645 even in experiments on birds, supple-ment grain feeding by giving leaves rich in sodium a n dpotassium ; and they point out tha t under natur al c on dition sthe graminivora do not live exclusively on grain, but ha^vea great liking for young and tender greenstuff—for in s ta n ce ,they nip off and swallow whole the fresh shoots of newlygerminated plants. In view of these facts it is ra ther re m ark -



T H E CONDITIONS OF GROWTH 183

nu tritio n. Th is strange assertion is explicable on th e groundthat for the estimation of the base-acid ratio McCollumemployed the obsolete and fallacious method of titration of

as h alkalin ity. Th e m ethod will often disclose ash w ith analkaline reaction in foods which a more accurate analysisshows to contain a m arked excess of ac id ; during th e processof conversion to ash, the greater part of the sulphur andchlorine often disap pears . This is why McCollum an d Mscollaborators, in preparing their artificial mixtures of salts,ha ve paid insufficient atten tion to the supply of bases, soth at their m ixtures are inadequate in th at respect. Owingto tha fact that their mixtures do not contain a sufficient

excess of alkali, their successes in the upbringing of younganimals cannot be compared with, those of Osborne and hispupils, who used m ixtures of inorganic salts containing am ore nota ble excess of alkalies. Th us a single defect inanalytical technique can introduce the greatest confusioninto the results!

4- IMPORTANCE OF THE METHODS OF PREP AEIK G F O O D .

It is necessary to insist once more that nutrients maynot only "be primarily inadequate in respect of their contentof inorganic salts ; they m ay be p rimarily adeq uate, butmay be rendered inadequate by the method of preparingth e food. F or exam ple, th e cereals already hav e a poorequipment of inorganic salts; if now, in preparing pap forchildren, only the finest sorts of meal be employed, we areusing a substance from which the greater part of the saltshas been discarded, so that such a food may be directlypathogenic. Again, the common practice of throw ing awaythe water in which food has been boiled, leads in manyinstances to a dangerous impoverishment in the inorganicconstituents of the diet. (Vide supra, pp. 73, 125, and 171.)Furthermore, measures that might be supposed to have noeffect of this kind, such as the sterilisation of milk, may incertain circumstances bring about important changes inthe mineral content of a foodstuff. We have already learnedthat when milk is sterilised by heat, the calcium-magnesium-

caibonophosphate it contains (a salt indispensable to theupbuilding of the bones) breaks up into its constituent salts,



184 VITAMINS

and that three of these, namely calcium phosphate, mag-

nesium phosphate, and calcium carbonate, are quite insoluble.Not merely does there result an impairment of the physiolo-gical working of the substances in ques tio n ; b u t further,as McCollum and Parsons *3<>ohave shown, a partial coagula-tion of the milk pro tein ensues during the sterilisa tion . Thecoagulated portion is precipitated with the salts, and clingsfirmly to the wall of the con tainer. Thus the simple sterili-sation of milk, as for example in a Soxhlet apparatus, leadsto a physiologically important reduction in the bone-formingsalts of the milk.

The author is, therefore, in full accord with Osbqrne, 1"*who insists , that the ur gent interest and novelty of th& com-

plettm pro blem must not lead us to forget the decisive imp ortance

of tht inor ganic salts.

5. TH E FAT-SOLUBLE COM PLETTIN A .

It has been proved that normal growth cannot be securedby the most sedulous attention to the four great classes offootstufis hithe rto recognised. An adequate supply of pro-teins, fats, carbohydrates, and inorganic salts, is far fromsufficing in this respect. The priority here m ust certa inlybe given to G. Lunin,3 who showed as long ago as 1881

that substances of a hitherto unknown character, essentialto growth, were apparently present in milk. The stat e-ment was confirmed in 1912 by F. G. Hopkins. 203 Almostsimultaneously, Osborne and Mendel 2~5 drew atte ntion tothe same fact, and investigators generally now became awarethat water-soluble growth-factors must be important ingre-dients of food. As early as 1909, W. Stepp93 recorded th e

pioneer observation that nutrients which have been extractedwith alcohol and ether canno t maintain life in m ic e ; bu tthat if the alcoholic extract has been made in the cold, itsreaddition to the nutrien ts renders them adequ ate oncemore. In this connection, physiologists were a t first inclinedto think of the lipoids, some of which are soluble in alcohol.

In the following year, however, Osborne and Mendel 3°5




fat is lar d or dripping ; bu t if a little b u tt e r be added tothe diet, or if butter be substituted for the lard or dripping,norm al growth is resumed. In these experimen ts it w as alsoproved that the fat-soluble growth-factor must be an ingre-dient of those portions of the butter fat that have a com-paratively low m elting-point. When the b ut te r w as meltedat a moderate temperature and centrifuged, the growth-factor w as con centrated in th e clear bu tyric oil. Inasmuchas this butyric oil is practically free from nitrogen and phos-

phorus, it was manifest that the growth-factor could notbelong to the lipoid class.

Much interest was aroused by this discovery, and numerousinvestigators now attempted to elucidate the nature andmode of ac tion of th e comple ttin A . Since the effects ofthis substance are not confined to the promotion of growth,it will be necessary to devote a special chapter to the fat-soluble complettin A, and for the nonce we need concernourselves only with its function as growth-factor.

T h e researches of M cCollum and Dav is, 453,454 and thoseof Drum rnond , 499 an d others , speedily showed th a t th iscom plettin A is in fact indispensable to grow th. The presenceof the substance in butter was confirmed by McCollum andDavis, also by Aron,44$ and by Langstein and Edelstein.73°,78oCodliver oil, and fish oil generally, contain it in abundance %)

6;

so does the body-fat of beeves, whereas the storage fat con-ta ins ver y little. 34 Am ong th e vegetable oils, linseed o i l 6 îs extrem ely poor in this con stitue nt; and olive oil an drape-seed oil 730, 7&>, 896 conta in but li tt le . Cocoanut o il, andthe palrnin or vegetable margarine made from it, are veryill-supplied with th e growth-fac tor 7?°» 7%° ; whereas animamargarine manufactured from oleomargarine or olein con-tains a fair amount, though not nearly so much as realb u tte r. On the other ha nd , the stearin residues obtainedby pressure as a by-product in the manufacture of animalmargarine is devoid of the complettin A.424 Seeds containvery litt le, and are therefore inadequate foods in this respect;millet, hemp seeds, 636» 682» fy* and cotton seeds,534,654 areexcep tions. Am ong the cereals, oatmeal (which ha s of la tebeen so widely recommended as a food for children!) is



186 VITAMINS

mote growth.6^. 75* Maize,5« rice,454, 5°7 and b a r le y ^ 0 arenot much better ; nor is wheat, this statement applying "both

to the whole gTain and to th e gercn.5°7> 5*5 W hereas thecereals in general contain too little A,w some of the pulsesare adequately supplied ; the soy bean is notably rich in thissu bs ta nc e .^ Banan as have too little 775; so have potatoes.777

The discovery was soon made that the A content of afat is greater in proportion as the fat is of a richer yellowtin t. Then it became apparent that thi s is likewise tr ue ofroot crops; whereas potatoes, which are colourless, containvery little A, carrots, and in especial the more richly colouredvarieties, con tain an ample supply. More careful researchesshowed, however, that the association of a high lipochrornecontent with a high A content is merely for tuit ou s; nu tri-ents containing much lipochrome may sometimes containlittle A, and conversely nutrients containing little lipochromem ay contain much A. Fu rthe r investigations disclosed thefact th a t fat-soluble A may be present in a foodstuff th a tcontains no fat a t all, or practically none. Green leaves,

for instance, which (except for their minimal supply of leaf-wax) are almost devoid of fat, frequently contain consider-able quantities of A—more than most fats contain.

Melianby 1J35 is , indeed, disposed to consider th a t th eimportance of A as a growth-factor is inconsiderable, for inhis experiments, in which dogs were given a diet containingvery little of this complettin, growth seemed to he inde-pendent of the A content of the food. He quo tes as con-

tributory evidence the experiments of Hess and Unger, inwhich the growth of children fed on dried skim-mili, sugar,cottonseed oil, autolysed yeast, orange juice, and flour, wasperfectly normal—for Melianby holds that this diet waspractically devoid of A. Bu t neith er Mellanby's own experi-ments on dogs, nor those of Hess and Unger on children, areconclusive as to the indispensability of A as growth-factor,seeing that the assumption that the complettin A is metwith only in animal fats is absolutely erroneous. L a te r

investigatioiis have shown that skim-milk, and also Osborne'sprotein-free milk, contain notable quan tities of A . E venthe casein of commerce manufactured from skim-milk, andthe lactose of commerce prepared from whey, often conta in A ,



T H E CONDITIONS OF GRO W TH 187

som etimes in considerable amo unt. If we further b ear inmind that cottonseed oil, autolysed yeast, cereals, and, in

especial, orange juice, all contain a fair proportion of A, weshall readily understand how, in the diets specified by Mel-lanhy, the summation of the small quantities of A in thevarious nutrients can easily have produced a total fullyadequate to maintain normal growth.

Before leaving the complettin A, it will be as well tomale perfectly clear that A is not identical with either thelipochrom es or th e lipoids. Th e investigations of Palm er

an d Kempster959> 9

s0

* 9

61

have shown that the substancesbelon ging to these categories have no effect on grow th. Inaddition, we must note that the complettin A exhibits ano tab le degree of therm osta bility. I t does no t seem to beany the worse for prolonged boiling (in milk), or even forprolonged heating to over 1200 C. (in but te r) . I t is, how-ever, ver y sensitive to th e oxygen of th e air. It s efficacyis seriously impaired when butter containing it is broughtto a temperature of 100c C. and vigorously s tir re d ; whileif air is forced through the melted butter, the complettin israpidly destroyed.

6. THE GROWTH-COMPLETTIN WATER-SOLUBLE B.

a. Historical.

The part played by the complettin A as a growth-factorhas not yet been fully elucidated, although it is known thatA certain ly does function in th a t cap acity. I t is m uch thesame with the water-soluble growth-factor, the complettin B.True, that the previously quoted observations of Hopkinsan d F un k refer mainly to the complettin A ; and F un k'soriginal assumption was that a diet containing both A andvitamin was fully adequate for the maintenance of growth.But this acute observer soon realised that in addition tovitamin there must be other water-soluble substances offun da m en tal im po rtanc e. More especially he learned from

the experiments he published in 1913 and 1914 that ade-quate growth could not be secured by an artificial diet richin vitamin unless it also contained the second water-solublegrowth-factor^1*. 3*3, 334, 3 ^ H is researches were soon con-firmed by other investigators, and McCollum and Davis 45& 454



i88 VITAMINS

expressly declared th a t a special water-soluble growthfactor must be indispensable in addition to Funk's vitamin

and the fat-soluble factor A . Dmmmond,499 and at an earlierda te Osborne an d Mendel,--5 found th a t m ilk containedwater-soluble growth-factor in the absence of which normalgrowth was impossible; and Drumrnond secured similarresults with the lactose of comm erce. W e m ay pa renth eti-cally remark that Funk 3** assumed that this growth-factorhad in the adult organism to be destroyed by some sort ofspecific rea ction ; he held th a t the formation of malignanttumours must be due to a failure to effect a sufficientdestruction of the water-soluble growth-complettin In theadult organism. This com plettin, he imag ined, becomingconcentrated in some part of the body which, for one causeor another, was peculiarly predisposed t o such a concentration,gave rise to a crude and uncontrolled proliferation of thetissue cells.

McCollurn and Simmonds6 6 1 made interesting andexhaustive researches on growing animals whereby the appli-

cability of the law of the minimum to the growth-com-plettins was demonstrated. From these experiments itappeared that when the food contained only A or only B,even in marked excess, the animals speedily perished . EitherA or B might be given in quantities just sufficient to main-tain weight, hut this could not keep the animal alive forlong. It soon became weak and succumbed to pro stratio n.If A or B were given to satisfy the minimal requirement,

and the other complettin were provided in excess, weightcould be maintained, but the animal died just as quicklyas if both A and B had been reduced to the minimumrequisite to m aintain weight. If bo th A and B are given inquantities exceeding the minimum requisite to maintainweight, growth now takes place, becoming more active asthe dose is increased up to a certain point. B u t th e opti-mum requisite to promote growth is not very much largertha n the minimum requisite to m ainta in weight. McCollumand Simmonds believe that it is easier to keep the animalsin good condition even if very small quantities of A and Bare given, than to ieep them in good condition when anyother factor of the diet is seriously reduced.




AronI045 showed that extract of carrots contains largequantities of B, but is inadequate as a growth-factor unlesssupplemented with A, which can "be best done by adding

a high-grade fat. Delf,"^ who found that the expressedjuices of green vegetables are rich in B, proved that thesejuices are not adequate growth-factors unless supplementedwith A. She w as able to demon strate tha t when the dosageof B rises above the minimum, the growth-curve exhibits arap id rise. Bu t th e op tima l effect is soon atta ine d, andbeyond this point a farther increase in the dosage of B hasno influence on gro w th. Aron, and also Erich Miiller andother specialists in the diseases of children, observed that

in children that were supposed to be thriving, to supplementthe diet by fresh vegetables, extract of green vegetables,extract of carrots, or extract of bran, could alwaj^s bringabo ut a further increm ent of grow th. These observationsshow how defective the nutrition of our children must bein contemporary life, even under what appear to be favour-able conditions.

Obviously, experiments of this kind must be subjectedto a very rigid criticism, especially as regards the general

environm ent of th e experim ental anim als. In earlier days,before experience of these matters had been gained, experi-menters were seldom able to breed healthy animals for severalgenerations in succession. As late as 1916, J . C. Dru m -moad498 (whose statement was confirmed by noted Germaninvestigators) declared that it was impossible to bring upchickens properly under laboratory conditions, especiallywhen the birds were fed on sterilised food. The belief gainedground that the activity of tie intestinal bacterial flora

m ust be essential to th e life of th e higher animals. B utfurther study of the conditions of life and growth in variousspecies of animals has shown that this assumption was erro-neous. The ill success of the earlier experiments was ma inlydue to a destruction of the complettins in the animal's foodb y excessive sterilisation— by overh eating. B ut , ap ar t fromthis question of the food, many of the environing conditionsare of vital imp ortance. Th e animals mu st hav e room tomo ve about na tu ra lly ; the food-containers must he pro-

tected from defilement, and yet must be readily accessible;



igo VITAMINS

there m ast be a sufficiency of light and fresh air, et c. Normu st psychical influences be neg lecte d; the anim als m ust

enjoy the pleasures of society, and must not be needlesslydisturbed. Merely taking them out of the cages freque ntly,in order to weigh them , m ay have an un favourab le effecton the growth-curve. Robertson and Ray483 have paidspecial attention to such matters in experiments on mice,with excellent results.

One factor of great importance is the supply of a suffi-ciency of indigestible material to give bulk to the faeces—material now term ed "ro ug ha ge ." Aron44^ drew at ten tio nto this in connection with nu tritiv e expe riments one ra ts ;McCollum and Davis,43i and McCollurn, Simmonds,and Pitz,5°7 in th e case of om nivo ra ; and Har t, Miller, andMcCollum,5x5 in the case of pigs an d ra ts . Osborne andMendel,^2 and Hart, Halpin, and Steenbock,3260 were ableto show that the debility of fowls fed under laboratory con-ditions could be completely cured by giving them a suffi-ciency of roughage. The bes t m ate rial for this p urpose,

better than charcoal or sand, is a chemically pure filter paper.Considerable quantities of this m ateria l are re qu is it e ; ahen needs about two-thirds of a square metre of thick filterpaper every day.

Difficulties arose, at the outset, in preparing" complettin-free proteins, and indeed in the composition of the diet ingeneral. The first really decisive successes are recorded in apaper by Osborne, Mendel, and W&keman 1O98 published in

1920, when the physical and chemical properties of the com-plettin s were fairly well understood. In a subsequent paper3x33*

Osbome and Mendel amplify their reports, mating specialleference to the preparation and administration of the indi-vidual com plettins; bu t these prescriptions are less sa tis-factory than could be wished, for the authors do not drawan adequate distinction between the various water-solublecomplettims.

It is worth repeating here that, even when the otherenvironing conditions ar e all th a t could be des ired, th evalidity of the results may be seriously endangered by theuse of too small a num ber of animals. In th is respe ct, like -wise, R obertson and R ay 's experim ents on mice 4*4 dese rve




th e closest atte ntio n. These observers have recorded theaverage development of mice during the different stages ofthe ir life. Obv iously a knowledge of such detail s in the

case of experimental animals is of decisive importance inour appraisement of the results.In conclusion, it is well to note that the tastes acquired

"by animals during the natural conditions of existence in thefree state—their instincts, if you like to use the term—helpto safeguard them agains t m istak es. O sbo m e an d Mendel 739record the observation that rats given a free choice betweentwo food mixtures which appeared to be identical in respectof tasê and physical qualities in general, instinctively pre-

ferred the mixture which was ad eq ua te ; some of th e animalsthat seemed to like a change of diet, and would not at firstconfine themselves to one or the other, concentrated theirattention on the adequate diet as soon as growth began tobe deficient.

i . Occurr ence of B.

Whereas the complettin A is not very widely diffused,the complettin B is present in a large number of foodstuffs.The following whole grains and other seeds contain con-siderable a m o u n ts : oats,635 maize,578 wheat,579 barley,74*malted grain,7& beans,636 soy beans,65?> *65 earth-mits,6 8r

pulses generally,^45 cotton seeds.654 Cajori I 3 6 6 repor ts tha tto maintain growth in rats, 0*5 gramme of chestnuts, walnuts,or hickory nuts, 2 grammes of pine kernels, hazel nuts, orPara nuts, and nearly 3 grammes of almonds, were requisite.According to McCollum and Simmonds,6 83 seeds in generalcontain large quantities of B, the husks and the brans beingespecially rich in th is substance,448, 730, i * > , 781, 896 which caneasily be ex tra cte d therefrom. McCollum, Simm onds, a ndPitz,5°7 and Osborne and Mendel,873 state that the germscontain eyen more B than the bran or husk ; but the cerealsare least favoured in this respect. B ana nas , according t oSugiura and Benedict,775 and according to Langstein andEdelstein,7&> are so poorly supplied as to be an inadequatefood ; but the insufficiency manifested in these experimentsm ay be referable to oth er causes. Aron 7*x insis ts t h a t freshfruits contain ple nty of B. Plu m s, pea rs, and apples,"47axe no t conspicuous in this re sp ec t; b u t co coanu t cake *7*



I 9 2 VITAMINS

oranges,n53 and lemons,11*? contain large q uan tities ; andaccording to Osbom e an d Mendel orange juice is as effective

in this respect as fresh milk.All observers are agreed 73°. 780, W in describing cabbage

as peculiarly rich in B ; so axe green vegetab les in general.:*1

According to Osborne and Mendel,^1 1 gramme of the driedsubstance of lucerne or spinach contains as much B as do2 grammes of wheat, soy beans, eggs, or milk ; white cabbage,clover, and timothy grass are about equal to spinach.According to Steenbock, Gross, and Sell,IO53 and according

to Osborne and Mendel,10

?8

among the last-named, clover isthe richest in B. Lucerne contain s nearly as muoh, b u tthe amount in spinach, tomatoes, cabbage, kohlrabi, carrots,and potatoes, is only half as great, and that in beetroots iseven less—all measured in the dried sta te . T he d ried sub -stance of 16 cc. of milk has the same efficacy as x grammeof dried spinach. According to Osbom e and Mendel,937 con-firmed by Whipple,I287 onions are fairly rich in B . So are

turnips, mangel-wurzels, the leaves of the same, and toma-toes, very rich in B 937; an d according to Steenbock, Gross,and Sell ,9s* in an artificial diet, 15 % of carro ts, swedes, o rthe rhizomes of Arum macula turn (lords an d ladie s), w illsuffice to ma inta in no rm al growth ; when sweet po ta to eswere used instead of th e carrots, etc., 20 % was re q u is it e ;of sugar beet or of mangel-wurzel, even more was needed.Lecoq I0

7* formulates what he regards as a general rule when

he says that all the active tissues contain large quantitiesof B, whereas the storage tissues are comparatively ill-sup-plied with this substance. Th is is in conformity w ith th eobservation that wheatmeal 873 is rath er poor in B ; an dthat polished rice 454 an d th e finest cotto nseed meal5>4 con-tain so little that they are unable to promote normal growth.It is not surprising th at, according to Oslo rne and Mendel,?37grass should contain much more B than mature hay con-tains, for the latter is already on the downward path towardsdea th at the time of reaping". McCoIlum, Simrnonds, a ndPitz 6 a5 stress the fact that all natural fodders, which havenot yet "been subjected to artificial methods of preparation,are rich in B. We have seen, however, (and Steenbock, Gross,and Sells81 are emphatic in asserting) that the quantity of



TH E CONDITIONS OF GROW TH 193

B in any natural nutrient cannot be regarded as a constant,for it varies according to circumstances.

T he lower pl an ts, likewise, are rich in B . Abder-

halden8

96

has shown that fresh yeast contains large quan-titie s ; and Lan gstein an d Edelstein 73°. 780 te l l us that therichness in B is maintained by yeast in the dry s ta te . Pacin iand Russel7°3 dem onstrated th at an ex tract of typ ho idbacilli, and the culture medium in which these organismshad been grown, were rich in B ; th is throw s a new lig htupon the frequently observed fact that after typhoid feverin children a rapid increase in stature is apt to occur.

Butcher's meat would seem, according to Osborne and

Mendel,66

3 to be very poor in B ; bu t m eat extract is ra th ermore l i tera l ly supplied. Drummond 6 ^ makes the samereport as regards the muscular tissue of stock-fish, herring,and preserved salmon. The aggregate herring seems tobe better supplied, and Drummond supposes that the differ-ence is due to a concentration of B in the reproductive andother glands. B ut th e same autho ri ty reports th at in mam -mals the testicles, th e ovaries, the pituita ry body , th e thy roid ,and the thyrnus, are very badly supplied w ith B ; and th a t

in rapidly growing tissues, such as those of the foetus andof tumou rs, no B can be found. On the other hand th epancreas,564 the liver, the heart, and the brain contain an.abundance of water-soluble B.662> 1™

Of exceptional interest, of course, is it to ascertain theB content of milk, the natural food of the growing organism.Both human milk 7Sl an d cow 's milk 737 appear to b e r a th e rpoor in this grow th-comp lettin. F or rat s, 16 cc. of milk a rerequisite to secure norm al gr ow th; when th e allowance w as

limited to 15 cc, a supplement of 0-2 gramme of dried yeastinduced a marked and sudden increase in grow th. As fa ras the promotion of growth is concerned, it does not matterwhether we give full milk, slrim-milk, or Oshorne's protein-free milk; approximately the same qua nt ity of each ofthese is requisite. I n th e case of dried milk, the do sag em ust be abou t 50 % higher.737 Be it no ted th a t t he la s tstatement applies to the dried milk of transatlantic manu-facture, which is m uch more sensfbly prepa red tha n the G erm anbran ds. German dried milk probably contains very little B .



194 VITAMINS

Since B, like D and the vitamins, is apt to be carrieddown as a precipitate with other substances, considerablequantities of B are often found in the casein and lactose ofcommerce.499* 579 If, therefore, these subs tances ar e be ingused in experiments on growth, they must first be carefullypurified.

But the B content of milk, like the B content of otherna tur al nu trien ts, is far from being a constant. Theinvestigations of Osborne and Mendel,1^1 Hopkins,I3 I4 andothers have shown that the amount of B and also theamount of A in the milk vary according to the season and

according t o t he n atu re of the fodder. Th e am ou nt islargest during spring and summer, and when the animalsare pastured or are given green fodd er; in autu m n an dwinter, and when the animals are stall-fed or are given dryfodder, the B content falls off.

c. Quantitative Estimation of B.

Williams,9*3 and almost simultaneously Abderhalden andKoehler,95* observed that the growth of yeast is notably

stimu lated by th e addition of extracts " rich in v it am in / 'Bachmann I2 29 an d W illiams "45 independently propo sed,almost at the same date, to make use of this fact for thequantitative determination of the amount of B in variousnutrients and extracts; the method received the endorse-ment of noted investigators,1*0^ "84,1297 and has been modi-fied in several directions for the avoidance of irregularities.Bachmann 958 ha d himself pointed out th a t the grow th ofdifferent stocks of yeast was very variously affected by suchadditions of vitamin-containing extracts; and Emmet andStockholm I2°3 observed that the reaction was inconstantwhen only one stock of ye as t wa& un de r observa tion. M ore-ove r, ku m ter e 11*7 no ted th a t th e ad ditio n of well-definedorganic or inorganic substances often produced better resultstha n extracts r ich in B ; and also tha t extracts th at werecertainly devoid of complettin had, none the less, a powerfuleffect. Q uite rece ntly, Fu lm er, Nelson, and Sh erw ood,3^*

have fully confirmed Lumi&re's observations ; and McDonaldland McCollum *358 have drawn renewed attention to the

familiar fact that a vigorous growth of yeast can be secured




in nutritive solutions containing little else than inorganicsubstances, and certainly no B. W e m ust ass um e, there-

fore, that the stimulus to the growth of yeast provided byvarious extracts is little, if at all, dependent upon the presenceof B. It follows that the deductions drawn by variousauthorities,1286 ' Iz87> ^98, 137* upon th e basis of su ch experi-ments concerning the B content of the most diverse nutrientsand animal organs, are entirely fallacious. Th ose w ho wishto ascertain the quantity of B in any nutrient or organ must,therefore, have recourse, as of old, to the tedious and costly

method of experiment on animals; but the results obtainedby this method are trustworthy.

d. Properties of the Oomplettin B.

The growth-complettin B (which Abderhalden, in defianceof the fact that it contains no nitrogen, speaks of as " nutra-min") is, by universal agreement, readily soluble inw ate r,4 48, 453, 454, 499, 654, 682, 730, 780, 1076, etc. a n ( j t h e r e f o r e i s

completely removed from vegetable food by the customarypractice of throwing away the water in which the vegetableshav e been boiled.784 In con trad istin ction to A, i t ap pearsto be insoluble in fat 453> 454; bu t like A i t is solub le inalcohol in a moderate degree of concentrat ions 1O

76 The

latter statement appears to conflict with a report by Loeband Northrop 569 to th e effect th a t t he efficacy of t he sub-stance as a growth-factor is " perm anently in ju re d " byalcohol. The grow th-prom oting substan ces are insoluble in

acetone, ether, and benzin ™76; but strangely enough can,according to McCollum and Simmonds,67<> be redissolved outof the alcoholic extract by benzin or by acetone after pre-cipitation with dextrin and subsequent drying. No lessstrange is the observation of Robertson and Ray, I29 6 t h a tthe growth-factor can be extracted from brain substanceby acetone, and it seems questionable whether what reallyhappens in this instance may not be merely the removal of

an admixture of A by fat-solvents.When we attempt to study the properties of the com-

plettin B, we have to reckon with a very disturbing factor,namely that most authorities have failed to draw any dis-tinction between B and D, this often leading to serious c o n -



196 VITAMINS

tradictions. For example, nearly all subsequent investi-gators have confirmed the observation of McCollum andSimmonds 67° that this complettin is unaffected by hydro-

chloric acid, nitric acid, and sulphuric acid. B ut these sametwo American authorities, in the same paper, describe thecomplettin B as sensitive to alkalies—a statement which con-flicts with the rep ort s of m ost oth er observers. Accordingto Byfield, Daniels, and Loughlin, 1^ the growth-factor inoranges will resist, not merely alkalinisation, but subsequentboiling for five m in u te s; while W hipple ia87 assures us thatin cabbage it will tolerate boiling for several hours, even ina solu tion con taining o-i % of hy drochloric acid or e cor-respon ding am oun t of sodium bicarbonate. In like man ner,

a considerable heating of animal substances such as meat,during which ammonia is always formed, has no influenceupon the water-soluble growth-complettin.

Speaking generally, this complettin, in contradistinctionto co m plettin D , seems to be fairly insensitive to heat. Anhour's boiling of meat, and even an hour's sterilisation ofmeat at 1150 C.,8^ leaves B unaffected— though Richet%3declares that an hour's boiling renders meat incompetent tom ain tain grow th in the dog. As regards this last observa-tion, however, the destruction of the complettin does not

seem to be the cause of the failure of growth, for the dogwas given nothing but meat, which is per se an unsuitablediet for a growing anima l. According to the same au tho rity,an equivalent amount of meat and bread can be heated toioo ° w itho ut th e process interfering in any wa y with thegro w th of a dog nourished on this m ixture. Th e observationconfirms th e foregoing criticism of th e previous one. Th egrowth-complettin in brain tissue will tolerate three-quartersof an hour's heating at 1300 C.,8^ but is somewhat damaged

by an hour 's heating at 135

0

. In beans it is unim paired byboiling,^ 1 and will even tolerate boiling for six hours.499The boil ing of hear t , l iver, b r a i n y m i l k , ^ tomatoes,899potatoes,773 and carrots,784 has no effect upon the growth-pro m oting qualities of these nutrien ts. In polished rice, thecomplettin B is unaffected by ordinary boiling, but is some-what damaged by one-and-a-half hour's heating at a tempera-ture of 1340 C.970




The drying of milk969 and the pasteurisation of this^ 1 have no influence; and prolonged heating at a very

high temperature is requisite to destroy the traces of B inthe casein of commerce.5 6a Orange juice can be boiled untilit becomes dr y from evaporation "47 w itho ut d estro yin g th ecom plettin; and the drying of carrots, po tatoes , cab bag e,turnips,984 sliced potatoes,773 or vegetables in general, at atemperature of from 50 0 to 6o° C.,IO98 does not seem toweaken the growth-com plettin in any way . Sliced pota toe shave to be autoclaved for several hours at a temperature

of 1200 C. to produce a ma rked ly injurious effect u pon thi scompfettin. In ordinary dried yeast, th e growth-co m plettinis still fully efficacious. E ve n several ho ur s' he a tin g a t1050 C. had no effect upon it.568, ^s 8

As we learned in Chapter Four, some authorities believethat the antineuritic D and the water-soluble growth-com-plettin B are identical, and others consider that this identitymay be assumed with considerable probability 6 l9, "53* "9 4;

but the respective reactions of these two substances toalkalies and to heat exclude the possibility of their beingidentical.979>x*w I t is proper, however, to po int o u t th at ,in experiments of this kind, trustworthy results can onlybe secured when steps are taken to ensure that during theheating process the temperature which is supposed to beoperative shall be reached in the interior of the substanceund er treatm en t as well as upon its surface. D urin g th e

customary process of sterilising masses of an experimentaldiet at a presumed temperature of no°, 120 0 C, or more,the temperature in the interior of the mass will only rise(as in the baking of bread) to about 70 0 C. Portier andRandom 935 have drawn attention to this source of fallacy,and have suggested a practical method whereby the errorcan be avoided. The expe rimen tal food is divided in to sm allportions which are placed in muslin bags that hang freely in

the interior of the sterilisation ch am be r; this will ensurethat the whole substance shall be raised to the desired tempe-rature. The experimenter must, however, be careful toplace a saucer beneath each of the bags, to catch drippings,and these must be remixed with the food after the sterilisa-tion, for otherwise grave errors may ensue.



198 VITAMINS

Sugiura and Benedict 967 found that the growth-com-plettin B was rapidly destroyed by exposure to radium

emanation.According to Eddy,564 the growth-vitamin is precipitated

by phospho-tungstic acid in an acid solution, and Funk, aswe have seen above, was originally of the same opinion.In a subsequently published paper (Funk and Macallum 563) heinclines rather to the view that when the vitamins are beingisolated by the phospho-tungstic-acid process, this substanceis accidentally entangled in the precip itate. In th is con-nexion, Drummond 6 l9 has pointed out that any precipitateformed in a solution co ntaining th e growth-com plettin^ tendsto carry down the complettin with it.

We are led to infer that the growth-complettin mustexist mainly in th e form of a colloidal solution. The sup-position is confirmed by the fact that the complettin, likeso many other colloids, is absorbed by alumina.564> 1043, "53

e. Physio logica l Effects of the Gr owth-com plettin B.

One of the most striking symptoms in animals sufferingfrom B deficiency is the almost invariable onset of gastro-intestinal disorder,IO56> I239 which appears in adults as wellas in growing animals. 1^ Experimenters were at firstinclined to believe that the absence of the growth-complettinled to the formation of toxins within the alimentary canal;these were supposed to be absorbed by the organism. Thetheory was that the action of B was analogous to the actionof the vitamins 5

63—it was presumed to neutralise these

toxins or counteract their effects.5x5, "4* I ha ve alreadypointed out that earlier investigators were prone to attributethe ill-success of experiments, with sterilised diets to theabsence of beneficial microbes.783 I t was na tu ral , therefore,to assume that the growth-complettin had a favourableinfluence on the intestinal flora.I046 Open to the same inter-pretation were the repeated observations IO55»JI1 «95> etc"that when the complettin B was deficient in the food the

animals suffered far more from prostration and were moreliable to infections of all kinds than the Controls, whichreceived an ample supply of B.

The general symptoms, however, were also accordant




with the assum ption th at the growth-complettin m igh t "inone way or another exert a direct influence on metabolism. IZ24

But when AronI

*I

3 assumed that this influence might beexerted by the stimulation of peristalsis, he overlooked thefact that the B-containing extracts contained numerousother substances which had long been known to exert astim ulating influence on peristalsis. (Cf. P la nt 12 9 l.)

The increased power of resistance to infection on a dietcontaining an ample supply of B must, however, be deter-mined by other factors than those which account for natural

immunity in the ordinary sense of the term, for ZilvaWreported that in guineapigs a lack of B had no effect on theamo unt of agglutinin and amboceptors in th e blo od ; andthat when the animals of one group were allowed free choiceof food for six months, while the animals of another groupwere placed upon a restricted diet for the same period, nodifference in the complement activity of the blood could bedetected in th e two cases. Obviously, th e increased power

of resistance when the diet contains a sufficiency of B mustbe the outcome of the general improvement in the nutrition,which enables the animals to resist noxious influences moreefficiently than when they have become weak and sicklyeither from natural causes or through a diet artificiallyrendered inadequate.

Drummond 6 87 has published an observation which hasnot been confirmed by any other investigator, that when

there was a lack of B in the diet the animals suffered fromkreatinuria. This sym ptom must have been due to a generallack of bases rather than specifically to the lack of B, for,as I have repeatedly shown, a lack of bases almost alwaysleads to an increased excretion of kreatin.

But the foregoing assumptions do not touch the cardinalpoint in the mode of action of the water-soluble growth-complettin. We hav e already learned th at F un k was led

in the first instance to assume the existence of this com-plettin by the striking observation that its absence from thefood made the maintenance of weight impossible in adultanimals, and the maintenance of normal growth impossiblein imm ature anim als. Th e first signs of a lack of B in th ediet«*4 consist of arrest of growth, loss of weight, general



200 VITAMINS

debility, and loss of appetite which may culminate in theabsolu te refusal of food. Nervous distu rbance s ha ve some-

tim es been observed shortly before de ath. (Cf. Drum -mond 6 87.) Th ey m us t probab ly be ascribed to th e use of adie t deficient in D as well as in B ; in th a t case the y wouldbe dependent upon the absence of the water-soluble anti-neuritic principle and not upon the lack of B.

The most remarkable point about the effect of B is, justas in the case of vitamin or of D, that very minute quantitiescan be shown to have an influence.10^8, Io6° W hen we find

that the addition of as little as half a gramme of driedclover or spinach to the diet can render it competent to inducenormal growth, we realise that the quantity of complettinrequisite inust be extraordinarily small.

When discussing the efficacy of A, we learned that bothfor this and for B th e law of the minimum is valid. Drum -mond 687 poin ts ou t th at , within certain limits, the exte nt ofgrow th is pro po rtion al to the am ount of B in th e food. Thefirst result of the addition of B is shown in an increase ofweight, this occurring also in adult and healthy animals I2*4;subsequently, in immature animals, vigorous growth speedilyensues. Simultaneously there is an improvement in thegeneral ap pe ar an ce ; if the tin t of th e skin has beenmo rbid, a he alth y colour is res tor ed ; in hairy anim als, th ecoat becomes thick and glossy once more.1*^ , 1268 £ u t w e

must bear in mind the possibility that the latter pheno-menon may be the outcome of the simultaneous administra-

tion of D.FigueiraI046 noted that in sucklings extracts of wheat

bran, when given in large quantities, were apt to inducediarrhoea. W e ha ve no reason to suppose th at th is sym ptomis due to the growth-complettin, for Abderhalden and Schiffi-m an n **73 have shown th a t B in wa tery ex trac ts is abso lutelynon-toxic bo th in frogs and in m amm als. Alcoholic ex trac tsof b ran gave rise to accessory sym ptom s, and especially to

tonic contraction of the bloodvessels, which were not notedwhen watery extracts were administered.

The growth-complettin, however, has certain bad effects.As Funk pointed out, i t may not merely affect the bodyand the organs favourably, but may also promote the growth




of tumours should these exist. Conversely, Hopkins hasproved that in animals fed on a B-free diet, tumours grewto only about one-fourth the size attained by similar tumoursin controls. Copeman, who reports these experiments,deduces from them a method for the treatment of cancer,and declares that he has secured good results by prescribinga diet poor in #A Mackenzie,1^ in answer to this sugges-tion,, has pointed out that Drummond's experiments havedemonstrated the impossibility of starving the tumourwithout starving the host.

# 7. BEHAVIOUR OF THE ENDOCRINE GLANDS.

McCarrisonI2

4° has shown that the endocrine glandsshare in the general malnutrition. Nearly all of them undergoat ro phy ; bu t the adrenals are an exception, for when thereis a deficiency of B they undergo hypertrophy just as theydo when the re is a deficiency of vitam in. The requirementof the endocrine glands in respect of B seems to be small,just like tha t of other org an s; bu t their needs are so vitalthat they have the preference over the rest of the body asregards the utilisation of B. This is proved by an interest-

ing experiment made by Stewart.1

*01

He gave white ratsso spare a diet for a period ranging from eleven to twenty-two days after their birth, that they did not put on weightat all from the time of bi rth . Nevertheless, the animals grewconsiderably in leng th ; and the head increased in weightby abou t 45 % at the expense of the trun k and the extre-mities. Simultaneously, the increase in weight in the visceraamounted to 46 % , th at of th e skin to 25 %, and th at ofthe muscles and bones taken together to only about 6 %.

The most remarkable point was the behaviour of certainspecial organs. As compared with conditions in the new-born animal, the liver had fallen off by 23 % and the thymusby 49 %, whilst the thyroid, the ovaries, the lungs, and theadrenals, remained of the same weight as at birth . Someof the other organs had increased in weight, the increasein certain cases being enormous: the pineal gland washeavier by 21 % ; the heart, by 26 % ; the pituitary body,by 29 % ; the^ stomach and intestines, by 40 %..; the spleen,

by 33 % ; the spinal cord, by 83 % ; the kidneys, by 90 % ;



202 VITAMINS

the brain, by 125 % ; the eyes, by 146 % ; the epididymes

by 225 % ; the testicles, by 374 %.

This led Funk, as early as 1913, to the assumption that

the action of the growth-complettin cannot be a direct one,but must be effected indirectly by a stimulation of the

activity of the endocrine glands. Abderhalden 953 takes the

same view. He regards the complettins as stimulants, each

of which has a specific action upon certain groups of cells;

in one case, upon those of the digestive glands; in another,

upon nerve cells; in another, upon the cells of the endocrine

glands; in another, upon the involuntary muscle of the

intestine; and so on. <%It has, in fact, long been known that there are intimate

relationships between growth and the activity of various

glands. For instance, the reproductive glands, prior to the

development of their reproductive functions proper, appear

to form internal secretions which promote growth. We

know of the thyroid secretion that it has a special influence

in promoting growth; on the other hand, hypothyroidism

in youth leads to an impairment of the whole bodily develop-

ment and to the most various disproportions and malforma-tions. Very instructive in this respect are some of Abder-

halden's dietetic experiments, notably those on tadpoles.

Especially important, in this connection, is the activity

of the pituitary body; this statement concerns the internal

secretion of the anterior lobe, for that of the posterior lobe

has no influence on growth. Consequently, HOchst's hypo-

physinia96

has quite a different effect from the tethelin first

prepared by Robertson and Ray from the anterior lobe.Tethelin is a well-defined chemical entity, having the com-

position of a j8-imid-azolyl-ethyl-amine; and its mode of

action has been elaborately studied by Robertson and Ray

in masterly fashion.485, 486,487, 548. 862,863,864,865,1141

The most characteristic feature of the action of tethelin

is that it stimulates the growth of the mote active cells, and

tends to inhibit tjhe growth of connective tissue. Thereby

the youth of the tissues is preserved, and a powerful influence

is exercised upon th% onset and the duration of sexualmaturity and sexual functioning. The effects of tethelin

vary greatly,Jaccoriing to the length of time for^which it




is given, and according to the phase of life during which itis administered. When given continuously from birth

onwards, it induces gigantism, but the giants thus producedhave a short life. On the other hand, when tethe lin is givenonly during early youth and then discontinued, it leads toincreased growth, and the effect upon growth lasts beyondthe period of adm inistration; but the prolongation of thestage of youth thus determined leads, further, to a generalprolongation of life. Generally speaking, these resu lts hav ebeen confirmed by Marinus,^ and by Abderhalden andBrammertz *376; in so far as there are differences between

Abderhalden and Brammertz's results and those of Robertsonand Ray, we have to remember that the experiments of thelatter were performed on mammals, and those of the formeron tadpoles. Almost simultaneously with the first experi-ments of Robertson and Ray, Clark 446 made investigationsinto the effect of the anterior lobe of the pituitary body onfowls. Not only did he note an enhanced growth in thebirds, but he believed that their laying was favourably

influenced. More recently, Simpson "93 has experim entedon the same lines, and declares that tethelin has no favour-able effect upon laying. Larson ^4 found th at in thyroidecto -mised animals, tethelin had a favourable influence upon thegeneral condition and increased the duration of life in theanimals that had been subjected to this operation.

According to Popielski,^** tethelm , or ra th er /J-imid-azolyl-ethyl-amine, does not exist ready-made in the tissues,and is certainly not found in the anterior lobe of the

pituitary body. On the other hand, he has found th is sub-stance in the stomach, and he assumes that it must be adecomposition product formed during the isolation of thereal active body. However this may be, there can be nodoubt that neither tethelin, nor the natural secretion of theanterior lobe of the pituitary body, represents the growth-complettin of which we are in search, for the effects of thesesubstances differ too much from those? of th e grow th-

complettin. Moreover, when the milk of a lactat ing animalis deficient in B, and the growth of the sucklings is conse-quently below par, we cannot improve growth by addingportions of the anterior lobe of the pituitary feodj to the



204 VITAMINS

maternal diet , whereas such improvement in growth promptlyfollows the administration of B to the mother.657

According to Robertson and Ray,

11

** cholin has a similareffect to tethelin upon subseq uent g ro w th ; b ut cholin iseven more destructive to life, for large quantities of cholinhav e to be administered. These are stored up in variousorgans and exercise a noxious influence. The effect ofnum erous other substances on grow th ha s been stud ied. Itha s been found th a t hyd roc ithin 399 ha s a fav oura ble effecton gr o w th ; and, on the o the r ha nd , th a t c holes terin 353, 53°, 53*an d lecithin 355.53° ten d ra th er to r e ta rd gro w th. N o sub-

stance with a genuinely analogous influence to that of B hashith erto been discovered. Th e na tu re of B and its modeof action still remain to be elucidated, but there is one morepoint to which I must refer before leaving this subject.

B appears to have a peculiarly powerful influence uponthe growth and the activities of the endocrine glands, forthese glands (with the exception of the adrenals) atrophywhen B is deficient. Now we hav e to remem ber tha t g rowthis the resultant of the interaction between the secretions ofcertain glands—some of which are known to act in this way,while th e effect of othe r endocrine gla nds on gro w th pe rha psstill rem ains to be discovered. T he re are, therefo re, con-siderable grounds for accepting a hypothesis put forwardby Funk. H e supposes th at B cann ot be synthetised inthe body, and is therefore not (as we have found the com-plettin D to be) directly indispensable. B , suggests Fu nk ,must be indirectly effective, by keeping the endocrine glands

in good order and by stimu lating their activity. Ad ditionalsupport to the hypothesis may be furnished by the observa-tion that—though, in general, the growth of sucklings isdependent upon an adequate supply of B to the mother—in the absence of this, normal growth can be secured by thedirect administration of B to the sucklings.

8. IMPORTANCE OF THE N UT RIT ION OF THE M OTH ER.

The proper feeding of the mother from the first moment

she conceives is of decisive importance to the growth of theoffspring. Th e m oth er's die t even before she conceives isno t w ith ou | influence in this respe ct. W e hav e, of course,




to reckon with a factor competent, in a measure, to correcteven grave errors in the maternal diet—a factor but for

which the animals we are pleased to term civilised humanbeings would long ere this have died ou t. I refer to th emarvellous energy displayed by growing animal organismsin securing, even in the most unfavourable circumstances,the nutrients requisite for maintaining life and promotinggrow th. To a degree , moreover, a like energy is displayedby the mammary glands, the maternal organs which aremainly responsible for the wellbeing of the offspring duringthe period that immediately follows birth.

As regards the importance of diet even before concep-tion, this has been clearly proved by the researches ofZuntz,86 1 who found that an exclusive diet of protein andfat, or an exclusive diet of protein and carbohydrate, ledin both sexes to grave impairme nt of the reprod uctive faculty.The animals conceived less frequently, and had smallerlitters, although the individual offspring were normal insize, structure, and weight. Zuntz also found—as R6se y> 7°

had found more than ten years earlier—that a long-lastingdeprivation of calcium has likewise a deleterious effect uponthe reproductive powers, but that in this case the wholedevelopm ent of th e offspring is seriously affected. In th isconnexion, I must refer once more to Urbeanu's researches,which showed that when the supply of calcium to fowls wasrestricted to an amount that seemed just sufficient for themaintenance of the maternal organism, sterility becameapparent after three or four generations. McCollum and

his collaborators, too, and also Osborne and Mendel, havefrequently drawn attention to the importance of a properdiet to the integrity of the reproductive po w er s; and moreespecially do they stress the fact that the thriving of a singlegeneration affords no guarantee that the diet is a satisfactoryone. In m an y cases, th e effects of an ina de qu ate or an ill-balanced diet do not become apparent for several genera-tions. Only then do we find th at the animals conceive more

rarely, and that the offspring appear more and more weakly,until ultimately complete sterility, or failure of the lactealsecretion, ensues.

If the mother's diet, though containing a sufficiency of



206 VITAMINS

proteins, contains these in a form which is not fully adequatefor promoting growth in the offspring, the maternal organism

supplies the foetus with what is lacking by drawing uponthe m aternal store. Ev en inanition in th e m other will notprevent reproduction, and the structure of the offspringseems perfectly normal, but Zuntz 86 1 states that the weightis below the average.

Insufficiency of the maternal diet in respect of proteinhas no effect upon the composition of the milk 2*6> 5 6 r ;Behre "5 6 and Stern "57 report that the inadequacy of fodderduring the war had no notable effect on the composition of

cow's m ilk. All auth orities are, how ever, agreed tha t th equantity of milk falls off when the diet is insufficient.*"1

The long-continued malnutrit ion of nursing mothers thatprevailed throughout Central Europe during the war, ledto a redu ction in th e lac tea l secretion. U ltim ate ly, defectivenutrit ion leads to a degeneration of the mammary glands,and changes in the composition of the milk then ensue.X(>4*On the other hand, McCoUum and Simmonds x o a 6 reportthat when the maternal diet is exceptionally high-grade,the secretion of milk is abundant, and the growth of theoffspring is extremely active.

Th e faculty of th e lacteal gland s which enables the m toextract from the maternal organism whatever is requisitefor the production of normal milk, renders the mother 'smilk the best nutrient for the offspring during the earlyphase of life. H ap pily a conv iction of th is tr u th h as gainedground in Germany of late, not only among doctors and

governmental authorities, but also among women through-out the popu lation. Bergm ann 835 insists that even whenthe mother 's milk is somewhat lacking in quantity, a breast-fed infant will tlyive better than a baby sufficiently fed byhand.

The inorganic salts requisite for the formation of normalmilk are likewise extracted with great energy from thematernal organism.1026 Carl RQse,6^ 7° who exp erim entedfor a considerable period on goats, could not find thatextensive variations in the diet produced any changes iathe composition of the milk of these animals. But th©mother cannot provide what she herself does not possess,




and ultimately therefore, when there is a persistent lack ofinorganic salts in the maternal diet, the composition of the

milk suffers. According to Hart and Steenbock95* therethen ensues grave debility in the sucklings.The mammary glands also have the power of concen-

trating into the milk the growth-complettins A and B thatare stored in the maternal organism, so that when thesesubstances are deficient in the mother's diet, the milk willcontinue for a time to contain enough to promote normalgrowth in the offspring.1026 Still, the influence of the maternaldiet is marked in the case of both these complettins. Refer-

ence has already been made to the fact that in cows theamount both of A and B in the milk varies with the seasonand the fodder J33<>; the milk is only adequate for the main-tenance of growth in the offspring when the maternal dietis itself adequate in this respect. Even in cases when thegrowth of the offspring is apparently taking place in normalfashion, we may find tha t th e provision of an ex tra supplyof B for the mother will be followed by a notable accelera-tion of growth in the sucklings.561

During weaning, and even later—when the young animalshave become habituated to an independent diet, the mother'smilk m a y continue to serve as a corrective for deficienciesin the diet.1026 If any further emphasis of the importanceof breast-feeding were requisite, and if anything could serveto persuade neglectful mothers to fulfil their duties in thisrespect, a general diffusion of knowledge concerning thework done during the last ten years upon this topic of the

factors of growth would suffice. In Saxony, the Sta te hasrecently instituted a special department for hygienic enlighten-ment, and it is eminently desirable that this new departmentshould pay special attention to the spread of a knowledgeof the foregoing facts.

9. EFFE CT OF THE INHIBITION OF GROWTH UPON

SUBSEQUENT GROWTH.

Another remarkable phenomenon must be considered

before dismissing the subject of growth. As long ago as1912, Osborne and Mendel **5 pointed out that when (for



208 VITAMINS

one reason or another) the diet had been such as to check

natural growth for a considerable period, normal growthwas resumed as soon as the error in diet had been remedied.Among dietetic defects leading to an arrest of growth, theseauthorities allude to th e follow ing: 370 an insufficient supplyof protein, or the lack of certain nitrogenous tissue builders;the lack of A or B ; the lack of ce rtain inorganic nu trients ,or an improper ra tio of these in th e diet. In such circum-stances, the inhibition of growth may be protracted farbeyond the normal period of growth, and yet growth mayeven then be resumed when the noxious influence ceases tobe operative.370,465 Th ereby, the to ta l du ra tio n of life m aybe considerably increased, and the animal may in the endattain its normal size.

Growth which is resumed after such an arrest proceedsat a more rapid pace than usual, attaining for a time a

m agnitude which is due to an excess of com pensation. (Cf.Osborne and Mendel *25> $* ; Tho m pson and Mendel 7*5.)

Nor throp 6 6 0 has published some interesting researcheswhich corroborate the work of Osborne an d Mendel. H efound that such a temporary arrest and subsequent resump-tion of growth were actually followed by an abnormal pro-longa tion of life—in th e larva e of flies, for instanc e. B ut

the prolongation affected only the phase of life subjected tothe experimental modification. T hu s, in the se partic ula rexperiments, it was the larval period of life which was pro-longed, whilst the life of the pupa and of the imago remainedof average du rat ion . I t would seem , therefore , as if fromthis point of view the different stages represented differentindividuals.

In their first publication on the subject, Osborne andMendel insisted that a restitution to the normal or an excessof compensation was only possible when the weight of theanimal had at least been maintained during the period inwhich growth w as suspended. W henev er th e diet ha d beenso inadequate as to cause loss of weight, the subsequentgrow th was inev itably imp aired. Jac kso n an d Stewart,IO59



TH E COND ITIONS OF GRO WTH 209

ensues after the defects in the diet have been made goodis not fully adequate, so that throughout life the animalsexhibit stigmata due to malnutrition during the develop-mental period.

An excellent idea of how important a satisfactory dietis to the wellbeing of children can be derived from a reportmad e by K. B . Rich "4 1 concerning the work of the educa-tion al autho rities in th e Chicago elem entary schools. In ve stigation showed that the treatment of tonsillar hypertrophies,carious teeth, adenoids, and fiat-foot, was almost ineffective,although great expectations had been formed. W ha t proved

decisive for physical wellbeing was cleanliness, light, freshair, exercise, and , abo ve all, atte ntion to diet. W hen theseenvironing conditions were improved, there was a concurrentincrease in weight and stature.

10. SUMMARY.

We may sum up in a single sentence what has gone beforeby saying that normal growth is preeminently dependentupon a ration ally comp osed diet. Children m us t be given a

sufficiency of food, and the protein must be as high-gradeas possible. Fr om this poin t of view, po tato es an d milkare th e b e st ; cereals are less suitable, unless th e inadeq uacyof their proteins is made good by giving milk in addition.The diet must also contain a sufficiency of complettins: Acan most advantageously be provided in the form of milk,bu tter, or sp ina ch ; fresh vegetables and fruit in abund anceare a satisfactory source of B. The diet should contain

from five to seven times as much of vegetables, potatoes,and salt-rich fruit (apples and pears are poor in this respect),as of meat, eggs, or cereal products—for otherwise an ade-qu ate excess of bases cann ot be gu aran teed . Care m us t betaken that the nutrients shall contain enough sodium andcalcium, the la tte r being especially im po rtan t. Th e sodiumcontent must be at least one-fifth of the potassium content,and the calcium content must be not less than five timesas great as th e magnesium con tent. Th e la tte r requisite

is sometimes difficult t o fulfil; in regions where the w ateris poor in lime, it will be indispensable to give about three-quarters of a pint of milk daily.



210 VITAMINS

Before I close this chapter, I must say a few words aboutthe feeding of children in Germany and Austria during the

war. The conflict brought tragedies enough in its train,but the matter we have now to consider was one of the mosttragical of all. I t has been proved th at , in Germ an A us tri aand in Germany, approximately one million children perisheddirectly or indirectly from w artime feeding, and th a t alm ostall the children who survived were more or less seriouslyinjured b y the inadequacy of the diet. Perh aps th e w orstfeature of the case is that the blame for what happened can

only be indirectly ascribed to the blockade, for the chieffactor was the stupidity of the German dietetic experts andof the government th at acted on their advice. I rep ea ted lydrew attention, both by word of mouth and in writing, tosome of the grave errors th at were being co m m itte d; b u tmy remonstrances had no effect, and it is but a poor andbelated satisfaction that the results of the British, American,and international commissions of enquiry have shcrtvn mycriticisms to have been fully justified.

Consider, first, the most outrageous of all the errors ofwartime feeding—the crazy, the utterly inexcusable, slaughter-ing of milch-cows in order to secure a few paltry pounds ofm eat. To attai n this lamentable result, and to sto p th emouths of clamorous flesh-eaters, our precious herds weredestroyed. In the m ost short-sighted fashion, milkers w erebutchered each of which within a single year could haveproduced its own weight of invaluable nutrients in the form

of milk, and no one stopped to think that thereby it wasbeing made impossible either to breed for the future su pp lyof meat or to provide for the subsequent victualling of thepeople with butter (rich in A) and with milk (rich in A, B,C, and inorganic salt s). (Cf. Mason 1011.) Almost as badwas the potato control, whereby the price of one of our mostimportant articles of diet was fixed at a figure at which itdid not pay the farmers to grow the tuber. Bu t, ap ar t from

these two errors, which are at least easy to explain, I h a v eto think of two others which can only be described ascrim inal: the removal of th e germ from cereal p ro d u c ts ;and the steaming or scalding of vegetables for conserves.

It has long be&i known that the highest-grade protein




in every grain, and nearly all the fat of the grain, are con-centrated in th e germ. Nevertheless, the re was no hesita-

tion about extracting the germ of the grain in the milkingprocess in order to use the fat thus secured for the feedingof th e already over-rationed mun ition wo rkers. I t was sup-posed that the germs, after the removal of the fat, were tofind their way back to the community-at-large in the formof meal for breakfast use. I have never been able to learnw hat really became of them . In actu al fact, throu gho utth e war, we received at Weisser Hirsch on tw o occasionsonly a ration of a germ-containing meal, each person having

abo ut enough to ma ke a small cup of gruel. One excusegiven for the removal of the germ was that the keepingqualities of the flour were thereby improved—but thesekeeping qualities were of very little importance, seeing thatwe were all forced by hunger to eat our rations with theleast possible delay. Besides, th e stat em en t is un tru e. T hewhole procedure was a robbery of the energies of the Germannation and a crime against our growing youth.

Even more serious, if possible, was the second error, thebleaching of vegetables before the y were dried. In a subse-quent chapter, this will come up again for fuller considera-tion, and it will suffice t o say here th a t th e m ere steam ingof vegetables for five minutes dissolves out so large a pro-portion of the inorganic bases that the residue contains anexcess of acids. Sim ultaneously, th e vita lly im po rta nt com-plettins are almost entirely dissolved out of the vegetables.

Chick "37 an d D al y el l, 1 ^ and also Block Ia8* (a German

investigator), in their studies of wartime diets in Germany,insist that the worst feature was the impoverishment of thefood in respect of A, B , and C. Br itish doctors and physi-ologists IO55 are unanimo us in the opinion t h at th e ma incause of this defect was the method of preparing vegetables.The before-mentioned authorities record a number of strikinginstances in which severe attacks of scurvy in children werepromptly relieved by the addition to the diet of carrot juice

or raw spinach, o r in some instance s of bu tt e r or of codliver 611.Among German medical practitioners, there are somewho have long been aware of these facts, and have turnedtheir knowledge to practicalfacc oun t. Above all, I m ust



212 VITAMINS

refer to the work of Erich Muller and his collaborators, andto that of Aron, who, in the circles entrusted to their care,

were able to secure admirable results with the scantiest ofmeans. Block, too , showed th a t in severe cases of mal-nutrition in children, the addition of fresh vegetable juiceto a milk and vegetable diet gives excellent results.

These views of mine, which to some extent had beenadvocated earlier by Lahmann, are now being widelytrump eted as a brilliant foreign discovery. I t m ay be hoped,therefore, that even the Germans will at length break the

shackles of tra di tio n; and th at , even in Ge rma ny, a curre ntof fresh air will invigorate the science of dietetics.

ADDENDUM TO CHAPTER FOU R : SPR UE .

a. Clinical Picture.

Among European residents in the tropics, especially inthe East Indies and in the Sunda Islands, there frequentlyoccurs a rem arkab le disease known as sprue or psilosis. I thas not hitherto found a satisfactory place in the nosology.In the account I propose to give of this disorder, I am guidedchiefly by the description given by Brugsch and Kraus,Handbuch der allgemeinen Therapie, section on TropicalDiseases. The illness begins with slight gastro-intestinaldisturbances, which have nothing characteristic about them,and come and go. From tim e to tim e, isolated patche s ofinflammation appear on the tongue, to disappear again com-

pletely. In the course of years, the a tta ck s grow more fre-quent, and the inflammatory manifestations on the tonguebecome more severe an d last longer. W hen the disease isfully established, the inflammatory foci on the tongue gradu-ally spread un til the y coalesce. Th e lingual epithe lium dis-appears, and on the inflamed surface can be detected verysmall suppurating vesicles or extremely sensitive circum-scribed minu te ulcers. Th us in course of tim e the surface

of the tongue is to an increasing extent denuded of epithe-lium ; the mucous m em brane is dr y and fissured; th epapillary body has vanished, the papillae being replaced byovergrowths of connective tissue. The whole m usc ula ture ofthe tongue has atrophied, so that the organ has become




extremely small, deeply furrowed, and thin . The gums andthe rest of the buccal mucous membrane may be sympa-thetically affected with inflammation; the suffering may be

further increased by salivation, or the secretion of a tena-cious mucus, o r sometimes by dryness of the mouth. Thesense of taste is greatly impaired; the saliva has becomeacid, and th e sulphocyanate may have completely d is ap-peared from the secretion.

Inflammations of the rest of the upper part of the ali-mentary trac t complicate the clinical picture, leading todifficulty in swallowing, pain on swallowing, a sense of full-ness, flatulence and eructation, heartburn, and, in exceptional

cases, vomiting . Although in the early stage of the affectionthe appetite is often excessive, it subsequently falls off, withthe onset of achlorhyd ria. Burning thirst is comm on; theabdomen is i n a state of flaccid distension. Borborygmi,and the rapid onward movement of the intestinal contents,show that excessive fermentation is going on. Colic is,however, present only in acute exacerbations of the disease*

The bowels act especially during the morning hours,and the evacuations may number ten or more, though theyare sometimes suppressed for a while. The stools are gene-rally of the consistency of pap, foamy, yellowish white incolour ranging to grey or greenish, though there is no signof jaundice. Their reaction is acid. They contain an excessof fat, but no mucus or blood.

At a comparatively early stage the liver is reduced insize, but this may be no more than an outcome of the generalatrophy. There are no special symptoms showing anyinvolvement of the respiratory, circulatory, or urinary system.The urine sometimes contains an excess of bile-pigments;and when the stools are suppressed, indigo can be detectedin the urine.

There is extrem e emaciation; the skin becomes flaccidand wrinkled ; ultimately death occurs in a condition ofcachexia in which the patient has come to look almost likea mummy.


Generally speaking the blood seems normal in spru e;but in severe cases, owing to the malnutrition, intense



214 VITAMINS

anaemia ultimately sets in, so that the haemoglobin richnessof the blood m ay fall to 40 % of th e no rm al, or even lower.

In the worst cases, the blood may come to resemble that ofpa tien ts with progressive pernicious anaem ia. B u t, ap artfrom these extreme instances, the characteristics of the bloodare those resulting from chronic toxaemia and from a plasticinhibition of haematopoiesis.

The pathological anatomy of this disease does not furnishany etiological explanation, for the pathological changesare no more than the results of the abnormal fermentationsin the intestine. In th e ileum there is a flaccid di ste nt io n;the villi of the mucous membrane have atrophied and almostdisappe ared; thus the wall of the gu t m ay be transp arentand as thin as paper, unless thickened by oedematous infiltra-tion. There are numerous punctiform ecchymoses, some-times larger extravasations of blood, and bile-stained patches;these changes give the bowel a remarkable motley aspect.The oesophagus and the stomach are always affected, thecoats being in most cases thickened, inflamed and infiltrated,or selerosed. The mucous membrane is wrink led, thickened,here and there atrophic, and often flecked with haemorrhages.The mesenteric glands are enlarged and strongly pig-,m en ted ; or, in some cases, atroph ied and cirrhotic. Theirritation of the bowel may spread to the peritoneum, leadingto local periton itis and the formation of adhesions. Th ere

are no marked changes in the bone-marrow, which is, how-ever, greatly lacking in fat. The othe r organs all manifestthe effects of the general atrophy.

c. Prognosis.

In advanced cases, the prognosis is unfavourable, andeven in the early stages it is dubious. A cure will in anyevent take a very long time, and will demand, during this

period and afterwards, from a seriously debilitated sufferer,the display of a great deal of patience, tenacity, andenergy. In slighter cases which come under trea tm en t atan early stage, th e conscientious carry ing o ut of th e pre-scribed course of tre atm en t m ay affect a c u r e ; b u trelapses will only be avoided by extrem e cau tion on th epatient 's part .




d. Treatment.

Rest in bed is needed only in severe cases. Th e m ain

thing is to promote improved nutrition, by checking fer-mentation through reduction of the carbohydrates in thediet, and by lessening the putrefaction of nitrogenous sub-stances within the bowel by restricting the supply of pro-tein—thus securing a better utilisation and absorption ofthe food. F at is very bad ly born e. A milk diet is generallythe best, the milk being given unboiled, and it must not betoo rich in cream. W e shall do well to d ilute th e milk withVichy w at er ; if it is no t borne even then , th e effect sho uldbe tried of using an even more strongly alkaline water, suchas Em s, for the dilution. Rem arkable results sometimesfollow the giving of fresh raw fruit, especially strawberries,bu t also bilberries an d gooseberries. B y degrees atte m p tsmay be made to increase the amount of protein in the food.Potatoes are well borne. W hen medical exp erts in tropicaldiseases assure us that vegetables cannot be tolerated, andmost often be withheld for many years, we presume thatwe are once more encountering the fallacy which has nowhappily become obsolete as regards the treatment of gastricand intestin al disorders in general. B u t it is certain ly ofthe utmost importance that anyone who has suffered fromsprue should for years to come shun strongly-spiced, rich,or fat ty articles of di e t ; a single indiscretion of th is kindmay prejudice the whole course of treatment.

e. Etiology.

As I have already shown, medical science is gropingin the dark where the question of the etiology of sprue isconcerned. I t is certainly presum ptuou s for a person likemyself, not being a practitioner of medicine, to express anopinion on the m a tt e r ; but I feel nevertheless th at m yknowledge of the way Europeans feed in India, in conjunc-tion with my special experience of modern theories of nutri-tion, will perhaps enable me to give some pointers.

First of all it must be remembered that, as far as diet

is concerned, European life in India is about as unnaturalas can possibly be conceived. The British hav e taken with



216 VITAMINS

them to the east their national preference for a meat diet,and have wedded it to the indigens' taste for highly seasoned

rice. Th e burn ing thir st induced by such a die t is slakedby vast quantities of iced and usually sweetened drinks(alternating with tea), which are frequently loaded withlarge doses of alcohol.

Naturally this regimen is extremely injurious to thegastro-intestinal tract. In the United States, too, iceddrinks are greatly in vogue, and we are informed that thepractice of consuming these beverages is found to be mostunwholesome, giving rise in the first instance to acute dis-turbances, and subsequently in many cases to grave chronicdisorde rs. T he excessive stimulation of the mu cous mem-brane is aggravated in India by pungent curry, and usuallyin add ition by tobacco and alcohol. How ca n we expectthe unfortunate mucosa to tolerate all this without inflam-im ato ry reaction ? Now, we know t h a t gastric disordersfrequently affect the condition of the buccal mucous mem-brane, which becomes thickened or inflamed, often with

the formation of aphthous ulcers.The wonder really is that cancer is not more frequent

in tongues th at are so much m altreated. Perh aps the reasonis that, as previously explained, for the development ofmalignant tumours there is needed an abundant supply ofB—this substance being so thoroughly utilised that thetum ou rs are themselves free from B . In a ctu al fact, thediet of Europeans in India, where fruit is scarce, is extremely

poor in B ; an d this scarcity m ay account for m an y of th esym ptom s of sprue. Firs t of all it m ay accoun t for thereadiness with which the buccal mucous membrane—whichin general is so resistant and has such remarkable powersof regeneration—becomes inflamed and ultimately atrophies;and the same remark applies to the mucous membranethroughout the gastro-intestinal tract. We may supposethat the deficiency of B leads, not merely to a lowering of

the capacity for resistance, but also to a grave impairmentof regenerative power, so that inflammation that has onceoriginated tends to persist indefinitely.

There can be no doubt, moreover, that the excess ofacids in the food plays a notable par t in the etiolog y; the




acidity of the saliva suffices to prove this . As to the partplayed by the metabolism of inorganic salts in the causationof sprue, nothing definite can be said in the absence ofdetailed investigations. It is noteworthy, however, thatthe nutrients recommended for the treatment are all charac-terised by excess of bases and richness in calcium. Theeffect of fruits in this respect must be conspicuous, for weshould have anticipated that the skins and pips of the fruitsfound helpful would have irritated the bowel quite as muchas any vegetables.

The fact that vegetables are not well borne is, of course,partly explicable by the irritant effect of the indigestibleresidues. But the re are many vegetables which are fairlywell borne in sprue—for instance, young spinach and youngcarrots, both of which resemble potatoes in leaving com-paratively little irri tant residue. I t is, therefore, not easyto understand why potatoes should be so much better tole-ra ted than vegetables in general. The difficulty is all thegreater seeing that vegetables in general are pooF in carbo-hydrates, whereas potatoes consist so largely of carbohy-drates, and yet one of the main points in the treatment ofsprue is to res tric t the supply of carbohydrates. May notthe explanation of this apparent contradiction be found inthe fact that most of the other sources of carbohydrate arecereals, which contain a notable excess of acids, whereaspotatoes are rich in bases ? We shall be the more inclinedto accept the explanation when we remember that by thecustomary methods of what is regarded as refined cookery,vegetables are robbed of their excess of bases, and that thismay be the main reason why they are badly borne in sprue.

Such a theory is supported by another consideration.Milk contains only a slight excess of bases; and yet (at anyrate in the early stages of sprue) it is not well borne unlessits excess of bases is increased by dilution with mineralwaters containing liberal amounts of bicarbonates, i.e. ofalkaline salts.

The favourable effect of fruits can perhaps be explainedby their C content, seeing that milk is rather poor in C.Perhaps the frequency of haemorrhages in sprue is referableto C deficiency, and it may be that closer examination



218 VITAMINS

(especially in post-mortems, when attention has been directedto th e point) will show further signs of mask ed s cu rvy . Im ak e th e suggestion with all reserve. In any case , fntits

may furnish a welcome augmentation of the calcium supply,for the calcium content of milk seems to be inadequate inthe long run for adult human beings.

As far as the widespread atrophy of the organs is con-cerned, the main cause of this is doubtless the generalfailure of nutrition consequent on the digestive disturbances.But when there is defective nutrition because the diet isquantitatively inadequate though qualitatively adequate,

we find general atrophy differing from that characteristic ofthe deficiency diseases in that the glands continue to func-tion. In th e acomplettinoses, on the oth er ha nd , im pair-ment of glandular functioning makes itself apparent at avery early stage. W e have seen th a t this is especiallycha racte ristic of a lack of vitam in, of B , and of D ; and theearly onset of slight acidity in sprue suggests an inadequacyof th e diet in one of these respe cts. A su rve y of t h e fore-going considerations enables us to infer that the lack is not

one of vitamin or of the antineuritic D, but that B isprobably lacking.

It would be of equal value to suffering humanity and toscientific medicine if the problem of sprue were to be recon-sidered|jwith the aid of the modern methods of dieteticphysiology.



CHAPTER SIX

THE FAT-SOLUBLE COMPLETTIN A

i. HISTO RY ; ITS ISOLATION,IN" the previous chapter, when discussing the determinantsof growth, it was necessary to consider some of the peculi-arities of the complettin A in order to fill in our picture ofth e growth-factors. But the efiects of the complettin Aon the animal organism are not restricted to a favouringin g row th; the y are so multiform tha t a special chaptermust be devoted to the fat-soluble complettin A.

The starting point in the study of the fat-soluble com-plettin was the paper published by Wilhelm Stepp,93 a pro-fessor a t Giessen, in the year 1909. He observed that adiet which had previously been quite adequate, proved afterextraction with ether and subsequently with alcohol incom-petent to maintain growth in mice and to keep the animalsalive. If the solvents had been used hot, the readditionof the ether extract and of the alcohol extract did not makethe diet adequate. If, however, the alcohol extract hadbeen made with cold alcohol, the return of this extractrestored adequacy to the diet.

The report seems to have been overlooked, for otherwiseit would surely have led to further and more detailed investi-gations. A second report by Stepp,234 published in the year1912, also failed for the time to att ract attention. In thisinstance Stepp showed that the active substances were notvery resistant to h e a t; they were completely destroyed bytwo days' boiling of an alcoholic solution, or by boiling thewhole food in alcohol for forty-eight hours, or by prolongedboiling in water . A t th a t date, Stepp was inclined to rega^fithem as lipoids. When a food had been rendered inade-

2 19



220 VITAMINS

quate by such treatment, its adequacy could be restored bythe addition of an extract made with cold alcohol from other

portions of food. It was manifest, therefore, that theorganism of the mouse was incompetent to synthetise thesesubstances, and this led Stepp to infer that the lipoids wereabsolutely essential con stituents of food. Two y e a rs later,Step p su pplemented his work w ith a repo rt 396 showing thatthe denatured food could not be rendered adequate by theadd ition of pu re fats. B ut the addition of va rio us lipoidcompounds was likewise found ineffective in this respect.An alcohol and ether extract of yolk of egg was, however,extremely active, so that Stepp continued to regard a com-bination of vitamins with certain lipoids as the active prin-ciple. T he view seemed to him to be confirmed w he n hewas able to prove 5*6 that the denaturation was effectedmainly if not exclusively by the alcohol extraction and notby the ether extraction ; and to show tha t the de na ture dfood would be rendered adequate by an acetone extract ofyolk of egg, and much better by an alcoholic extract of yolk

of egg m ade subsequent to extraction w ith ace to ne . Insome instances, the acetone extract was inactive whereasth e alcoholic extra ct wa s effective. V itamins alo ne , an dvarious lipoid compounds, were ineffective; th e co m bin atio nof vitamins and brain lipoids was effective in certain instances.

The investigation did not enter the right track untilHo pkins an d Neville *67 noted in 1913 th a t the a rtificial dietemployed by Osborne and Mendel could only maintain

weight in mice for a limited period, but that when 2 cc. offresh milk were added to the food (a supplement whichincreased th e to tal dried substance by only 4 % ) th e miceremained perfectly well-nourished. This observation wasconfirmed by Osborne an d Mendel.*95 Th ey found t h a t onthe artificial diet, as originally supplied, rats could be keptgoing for a considerable period, even with increase of weightand a moderate amount of gro w th; bu t ul t im ately grow th

ceased, th e weight fell off, and th e animals pe ris hed . If,however, during the critical period a little milk or butterwere added to the experimental diet, the rats quicklyrecovered, and normal development ensued.

Shortly afterwards, Osborne and Mendel 305 supplemented



TH E FAT-SOLUBLE COMPLETTIN A 221

their previous observations by finding that fat-free milk,and also the salts contained in the water of butter, werequite ineffective ; but that perfectly pure butter fat, obtainedentirely free from nitrogen and phosphorus by melting andcentrifuging the butter, was a very active growth-factor,greatly superior to lard. This report was promptly con-firmed by McCollum and Davis 386; and Osborne andMendel 350 were able to detect the active principles in thefat of yolk of egg and in codliver oil, but could not findit in almond oil.

Opposed to these reports was one made by Dezani^

who found that he could keep his experimental animalsalive and in good condition on a lipoid-free diet, providedonly th a t the diet were sufficiently varied. He contendedthat what was wrong with Stepp's experiments was thatthe monotony of the diet had induced loss of appetite inth e animals subjected to experiment. We know to-day th atDezani's inferences were fallacious to some extent, inasmuchas his experimental diet, though free from lipoids, was notfree from the complettin A. Almost simultaneously with

the Italian's paper there came from two widely divergentsources confirmations of Stepp's observations. Kawashina,4*7and McArthur and Luckettw who reported along almostprecisely the same lines* were able to show that the variouslecithins, other lipoids> cholesterins, and fats, are not essen-tial to life in mice [this is true, provided that the supply ofprotein is adequate] ; but that , on the other hand, a dietconsisting of casein, starch, lactose, lard, and milk salts,incompetent per se to maintain life in mice, could be

rendered fully adequate by *the addition of a substance presentin yolk of egg and soluble in alcohol and ether.An investigation made by Funk and Macallum 374 showed

that the life-sustaining substance could not be identicalwith butter fat, for the addition of a thoroughly purifiedsuperheated butter fat could not render adequate a dietlacking only in the one factor under consideration, whereasthe alcoholic extract nmde from the original butter was per-fectly competent to render the diet adequate. Halliburton 73*

therefore considers that the reason why fats are indispensableto life is that they contain this growth-complettin.



222 VITAMINS

Nevertheless, as we learned above, a large number of

other investigations had shown that there is another factor,

the water-soluble complettin B, no less indispensable for

the maintenance of life and growth. Since there is little of

this complettin in fats, or none at all, it was natural to sup-

pose that green vegetables, etc., were to be looked upon

exclusively as the providers of B, and that A was present

only in fats. Hence the two substances have been fre-

quently confounded (cf. 714). But it soon became apparent

that certain nutrients that were unquestionably rich in B,

could only maintain growth when supplemented with A;

and that others, such as green leaves, though free from fat,were adequate growth-factors without any addition of A.»35

By a large number of investigations it has now been

proved beyond dispute that for the maintenance of body-

weight and for the promotion of normal growth both A and

B are essential.453,454,874, «84,1045 More especially has this

been demonstrated by the work of McCollum and Sim-

monds,66l

>664 who simultaneously showed that both the

growth-complettins were subject to the law of the minimum.

2. OCCURRENCE.

The occurrence of A was first definitely proved in rnilk,

and its presence in this fluid has subsequently been con-

firmed by numerous investigations.** **7. *9S>305* 3**#?8|»

n%9

With the separation of the cream, the greater part of the A

factor passes away into this *95>y>$. 35°, 3 , w. 7%*, *M* ; and

when the cream is made into butter, the A is chiefly stored

in the more fluid portion, the so-called butyric oil 3°5»w>477;but considerable quantities of A remain in the skim-milk,

and when the casein is precipitated they are included in the

precipitate. Both the casein of commerce, and also chee$e,7M

therefore invariably contain A, though in small quantities,

so that neither casein nor cheese must form a component

of an A-free diet. Yolk of egg, the first source of nutriment

for the growing bird embryo, is very rich in A, for the fat

of egg-yolk contains A in a concentrated form*3S»« 5*6* 7**>i«9,1x46 j n the normal body-fat of animals, in beef fat for

instance,4*4,618,75a there are also large quantities of A,

which, as in the case of butter, are stored in the ingredients




o f the fat th a t have a com paratively low melting-point (theso -c a ll e d oleo margarine or olein 434, 618, 752) - whereas th estearin of animal fat , just l ike the part of the butter whichl i a s a high m elting-po int, is practic ally free from A.4*4 Con-sequently animal margarine, which is manufactured fromoleomargarine or olein, is comparatively rich in A,61®* J3*9

In contradistinction to the normal body-fat, the storagef a t of animals contains v ery little A.75*. XM3 Fo r this reason,l a r d is very poor in A ; 305* 374,386, 434. 453, 454, i%*, 13*7 b u t it isnot, as was at one time believed, completely free fromA . I X 4 ^ 13*6

The fat of fish, like the fat of mammals, is rich in A, sothat fish oils in general contain an abundance of thiscomplett in.6 ^

Passing to consider the individual organs, we find thatthe pancreas, the thymus, and the adrenals, contain com-paratively little A 9™ ; whereas the kidneys contain more,th e he art still more,43^ an d th e liver mo st of all. Conse-quently the oil expressed from pig's liver is as vigorous init s grow th-prom oting qualities as b u tt e r 7<>*; an d a t anearly stage in this investigation codliver oil was recognised

as pre em inen t am on g fats for i ts r ichn ess in A.35°, 374, 634, 781, 1146In contradistinction with eggs, the seeds of plants usually

contain too little A to ensure the maintenance of normalgrowth. In especial this ha s been proved as regard s oats,6*5, 7*4w h e a t 436 ,515 , 68a , ? I 4 > b a r l e y 74©, r y e 7*4, a n d m a i ze 4361 57» , 658,

***, 714. According t o Steen bock , Bo utwe ll, G ross, an dSell,I0*7 yellow maize is an exception, for 88 % of this inth e food suffices to m ain tain grow th in you ng r at s. McCollumand his collaborators^ 8 however, found that the A content

of yellow maize was inadequate to promote growth in pigs;bu t norm al growth could b e ensured in these anim als if th emaize were supplemented by an alcoholic extract fromanother portion of th e sam e maize, this increasing th e Aconten t a little. Spea king generally, th e cereals are inad e-quate 490.68a j th e germ contains a good deal m ore A th anth e endosperm an d th e bran,43^ 490 b u t no t ne arly enough.5°7Beans are very poorly supplied with A,63*, 658 this st at em en tapplying to soy beans 659,*65 a n < i earth-nuts6* * . "* 9 ; bu t

there are certain pulses that contain fairly adequate quan-



224 VITAMINS

titics.^s Brazil nu ts, bu tte rn ut s, Barcelona nuts, walnuts,and almonds, an? all \unn in A ; in like? m an ne r, almond

oil,3S« olive* oil,"81

nut oil^f

- roroaimt oil,"'** and cccoanutcake, are incompetent to maintain growth.*?4 Cotton seedsare poor in A $M. ?M ; and so, therefore, is cottonseedoil.M, ***** Since* cottonseed oil and cocoanut. oil are thechief constituents of variable marârine^ these likewisearc inadequate as Krowth-fatiturs/'1* On the other hand,linseed, millet, and hemp smLs/** are rq^rtrd to be fairlyrich in A, although the quantity is inadequate.? 1** *»*

Fr uit w ould app ea r in general to IK: w r y poorly suppliedwith the fat-soluble gn*wth-compl«4ttin. iv^piTjally is th is re-ported of bananas??* oranges,* lW l U*mons, and grapefruit,*M?

In respect of A co nte nt, seeds con trast with leaveswhich are, generally speaking, rich in A.?1*. **% *m Thus,lucerne,*'^ w hite cabbage,*'/*.. M« an d e^jw xully gm -n cal>bage,1^6 spinach, clover, and timothy gras?*,*!1 areas very rich- Q ua ntit ativ e dat a an? given byGross, and Sell^^n who tell us th a t 5 % of lum tu% clover,

spinach, and artichoke leav«vs, or to % ul white lettuce, inthe food, will suflict: to eu^tirtr normal growth and reproduc-t ion in ra ts ; hut even 15 % ul white cabbagi? proves inade*qu ate . CjsUorne ancl M rnddl fM> found th at ttmiattars weremore active than an equal wvight of liutter fat, and thatclover, lucerne, grass, and spinach were no Ic** active* Driedwhite cabbage was Irs* active.

As regards rtiot trc#ps# |Mitat«H*s pravrd quite inadequate

in thin respect ???• **»•**». *M* ; but the *,wt*t?t j ^ t a t y , th eAmerican rival of tlje j«4«4to# was* j iM a«* ac tiv e as th textremely active ramit.v*1 According to Zilva,*1^ ourrotiar e richer t h an w hite tabba ;;*?; b u t htc?ciibcick, CiroM, stnd^Sell found that turnips, numîh'wntmh, »ugar brctA, Arummaculatum (lurch and ladtt*s)f paiMii|» # and common btrt*trootwere quite* iiuidequatc,*11

3 . Ccm.I*M»TTiN A AKI>

see, then, that a l though the complett i i t A k solublein fat, th e aunnount of t h b aihstîH r in variouji n ut rie nt s isby no t tw*m% proportional to their rkhnrsn in fat,** At inearly itage in than: invent.igatiom # the opinion gained ground



T H E FAT-SOLUBLE COMPLETTIN A 225

that there was a definite ratio between the A content andthe lipochrome content of food, the belief being that thenutrients richest in lipochrome were also richest in A.I0*7Carrots, which are among the most highly coloured of theroot crops, are especially rich in both A and lipo-chrome.784, 9

8l> K»7 The careful investigations of Rosenheim

and Drummond "3* have shown, however, that althoughthere is a general parallelism in the A content and thelipochrome content of nutrients, the parallelism is notinvariably sustained:—

Foodstuff.

Milk Fa t . .Yolk of EggCodliver OilWhale Oil ..Beef Fa t . .Kidney FatMaizeWheat GermCabbageSpinach.

CarrotsChicken FatLiverHerringsCottonseed OilCodLardCocoanut OilHardened Fats .

LipochromeContent .

4 - 4 - 4 -4 - 4 - 4 -4 - 4 - 4 -

4- 4-

4-4-

4- 4-

+ 4-4- 4-

4" 4*4* 4"

A Content .

4 - 4 - 4 -4 - 4 - 4 -4 - 4 - 4 -

4- 4-

4- +4-

4- 4-4" +

- j -4- 4-4- 4-4- 4-

———

The hardening of fats seems to destroy the growth-com-

p le tt in A ; and when fat is extracted with benzin or withether, most of the complettin is removed by the process.11^Just as in the case of water-soluble B, so also in the case

of fat-soluble A, the richness of the natural nutrients isinco ns tant . In especial, this has been proved as regardsmilk and but ter by Steenbock, Boutwell, and Kent.75* Theseauthorities suppose that the chief cause of the variationsmust be the different feeding of the cows, but it appearsthat the same fodder will contain different amounts of A

a t different times. Consequently, in the case of fat-solubleA as in that of water-soluble B, we have to reckon with

15



2 2 6 VITAMINS

seasonal variations in the richness of the pastures . F u rth e rmore, as we are about to learn, when dried fodder is inquestion, prolonged storage of the fodder is attended with adecline in the A content.

4. RELATIONSHIP TO OTHER COMPLETTXNS.

Among the descriptions of the properties of the com-plettin A we find several inconsistencies, which might leadus to suppose that we really had to deal with different sub-stances in the different nutrients. A more careful exam ina-

tion shows, however, that the inconsistencies are mainlydue to the great comprehensiveness of the researches con-cerned with the complettin A, and that in some of thesethere has been confusion with the other cornplettins—moreespecially with the complettin B . In th e early stages ofthe investigation, the inclination was to regard A as a lipoid,and we have already learned that this was Stcpp's originalopinion.526 But Osborne and Mendel 3°5 have proved (ef.

also 7J

4,875,1308) that the substance must be free from nitrogenand phosphorus, or that if it contains either or both, it mustdo so in quantities th a t are almost incredibly m inute ; obvi-ously, therefore, it cannot be a lipoid. As regards o th eringredients of the fats , subsequent investigations 7*1* •?$» *J*have shown beyond dispute tha t A is not glycerine, th a t itis not a saturated or unsaturated fatty acid, and th a t itis not an undecomposed fa t; nor can the various sterins b&

accounted possible incorporators of the A influence. In th eforegoing chapter (p. 204), we learned, indeed, that the statinshad the opposite effect to A, inasmuch as they interferedwith growth, especially when given in excess. Funk 375 w asat first inclined to believe that A must be a base havin g asimilar action to tha t of the vitamins. Bu t Stepp has givenadequate prc>of,5*7 first of all that A contains no nitrogen,and secondly th a t its mode of action is quite different fromthose of the vi tam ins; Funk and Macallum have confirmedthis view>4 The researches of Rosenheim and Drum-mond«3* have shown that A, despite its kinship with th#lipochromes, is no t itself a lipochrom e; and this has beenconfirmed by numerous authorities^,959* $ & > , 9&*> 1*70, *i*3 I tremained to be demonstrated that A and E were distinct.




The distinction is, in fact, obvious, for we know of substanms(like butyric oil) which contain A ami hardly any 1$; andof others (turnips, potatoes) which contain B and no A.Furthermore we find tha t A without B or H without A doesnot suffice to rend er a diet ad equate ; also, th at the effectsof the two differ greatly in certain respects -for instance,A prevents and cures xerophthalmia and osteomalacia,whereas B does not. Finally, the question has to be mootedwhether A might not be identical with the? antiscorbuticcomplettin C. Apart, however, from the consideration th atthe effects of A and C ant entirely different, direc t proof

that the two substances are distinct has been furnished byGivens and Cohen,75i Harden and Zilva,*»s and Mellanby.uHWe are therefore constrained to admit that the compJettin Ais a distinct substance, not identical witli any of the* oth errecognised growth-promoting or itfo.snstuining substances.We shall now proceed to consider this properties of A,excluding reference* to any propertien that might be ascribedto confusion with other substances, or to impurities.

5 . PROPKKTIKS OF THtt Co M I'UiTTlN A ,

In 1909, Steppw drew attention to the solubility of thincomplettin in alcohol, «md the fact has been confirmed byall subsequent investigators, w** v% «»«• **?, %**, 7M, <***, **s<> Itis but slightly soluble in water,?** and cannot be extractedfrom fat by water.*?* I t is, however, soluble (though notvery readily) in the ordinary fat'SohwntH acetone,*1* b<*rm>I,chloroform,1 M» and iithvr,**% w. ***• 7M, *M* but cannot \m

completely extracted by the*** mum trtta. When, however, Ais first extracted with alcohol, and the* extract in evaporateddown, the complettin can then bit fully extracted from theresidue with ether . Thin provides a gooci method of purifi-cation. For example*, green virgetabtefi, having \mm\ driedand pulverised, are treated with htmzin or with cither toextract the fa t; the complettin h then extracted withalcohol; when the alcohol hm been evaporated off, theresidue is extracted with et h e r; when the ether has been

evaporated, the com plettin is left in a fairly p ure ata te. Fordietetic experiment*! it can then be dissolved in olive oilwhich has been previously freed from A, (Cf, Zilva, 1150*)



2 2 8 VITAMINS

Speaking generally, however, the complettin A (though speci-fically termed " fa t-s ol ub le ") is no t readily dissolved byfats, and cannot be extracted from vegetable nutrients byvegetable oils or by lard.7*4, "4*

Funk and Macallum374 began by isolating A by themethod then in vogue for the isolation of vitamin, namelyby extraction w ith 0 -5 % hydrochloric a ci d ; but obviouslyall they could get in this way were specimens of A contain-ing vitamin as impurity—this being, indeed, manifest fromthe other da ta of the investigation. D rum m ond 875 declares,moreover, that A is almost insoluble in hydrochloric acid.

The non-identity of A with vitamins, with B and with D,and above all with C, is best shown by the reaction of therespective substances to alkalies. W hereas th e other com-plettins all appear to be more or less sensitive to the actionof alkalies, A is apparen tly unaffected b y th em . Steenbock,Boutwell, Gross, and Sell IX4* actually declare that fats con-tainin g A can be fully saponified by 6 % alcoholic solutionof potash without the A being notably affected, even thoughthe action of the alkali has been continued for several days.

Drummond,875 however, tells us that there is a certain lossof A in this process, perhaps due to oxidation—see p. 229.By shaking up the soap solution with ether and evaporatingoff the ether, an extremely effective residue was obtained.This could be further purified by dissolving it in a mixtureof alcohol and petroleum ether (naphtha), and then addingwater, shaking up, and allowing the solution to separate-into layers. The A, together w ith the caro tin, passed intothe naphtha stratum, whereas the alcoholic xanthophyllsolution contained no more th an traces of it. This reportsuggests that the obtaining of A in a pure state ought to bepossible, and it could be wished that with this end in viewthe physiologists would seek the aid of a competent chemist.

As regards thermostability, the complettin A differsgreatly from the complettins hitherto considered, and alsofrom C. Nevertheless, as Osborne and Mendel 702 andRamsden7i4 insist, the power of resisting heat is greatly

influenced by the conditions under which the heat is applied,one of these conditions being the nature of the menstruum.Thus Mendel I223 reports that A in butyric oil is less resistant



T H E FAT-SOLUBL E COM PLETTIN A 229

to heat tha n A in aggregate bu tter. In bu tter , A will resistlong-co ntinued steam ing^w , 113* fifteen ho urs ' heatin g at95° C-,

lliz and even four hours' heating at 1200 C.IO34; but

it is destroyed by longer heating at these high tempera-tures.396, 427 Y et Steenbo ck, Bo utw ell, a nd K en t 75* foundthat when butter was shaken up with hot water for a longtime , the A it contained was seriously inju red ; and theyconsidered that the injury was due to the effect of heat.Stepp 334 repo rted th a t two da ys' boiling of th e activ e lipoids,or of the aggregate food, in alcohol, or more prolonged boil-ing in water, destroyed the activity of the substance.

According to Delf,8

°6

the growth-complettin A in greencabbage resists ordinary boiling, but it is somewhat impairedby keeping the dried cabbage for from one to two hours ata temperature ranging from ioo° to 120 0 C, and is veryseriously injured by two hours' dry heating at 130 0 C. Onthe other hand, Steenbock and his collaborators IO54 informus that the A in green cabbage is not affected by threehours ' heating in the autoclave under fifteen pounds pressure.

The contradictory character of the foregoing reports is

mainly explicable by the supposition that the complettin Ais readily oxidisable. According to Drummond,875 when thefood containing A is hea ted in thin lay ers to ioo ° C , the Ais destroyed within an hour, whereas several weeks' exposureto a temperature of 37 0 C. is requ isite to effect de structio n.Subsequently, Drummond and Coward X3*4 ga ve di rect con-firmation of the hypothesis that the cause of the destructionm us t be oxidation by atmo spheric oxygen . Th is, likewise,

is the plain inference from the experiments of Hopkins,

IO

34who found that four hours ' heating of butter at 120 0 C. hadno deleterious effect upon the A it contained, whereas the Awas completely destroyed within the same period at thistemperature when air was forced through butter all the while.In a subsequent and extensive series of experiments,^^Hopkins confirmed the theory that A is readily oxidisable.According to Zilva,x3*5 ozone, even in the dark, speedilyrenders A completely in ac tiv e; and ultraviolet l ight will

quickly destroy A in codliver oil when air or ozone is present,but has no effect when the oil is in a carbonic-acid atmo-sph ere. Th e sensitiveness of A to light was po inted o ut in



2 3o VITAMINS

1918 by Ramsden,7I4 who did not, however, recognise the

real bearing of his own observation.We may, therefore, assume that when air is excluded,

or when a nutrient is heated in compact masses, the com-plettin A will tolerate even prolonged heating at I2O°C.under atmospheric pressure or under greater pre ssu re. B u twhen air has free access (either because the nutrient is heatedin thin layers, or because it has been pulverised, or becauseit is in dilute solution, or because air is directly conductedthrough it), A is speedily destroyed by a high temperature.This explains why it is that when lactalbumin 898 or casein I I 6 8

is heated at 1200 for a long tim e in thin layers, th e trac es of Athese substances contain are destroyed, and yet that butter canbe exposed to the same conditions without app reciable loss of A.

We can also understand why the drying of vegetables,especially when the drying is effected in the customary

manner at a moderate temperature,1^*, 13** i s harmless tothe A they contain, and that the dried material can safelybe stored in large masses with th e exclusion of a i r ; bu tthat when the A-containing substances are preserved in thepowdered state, and especially in open vessels, the com-plettin A is soon destroyed.80? This explains, likewise, whybutter can be preserved in bulk for years without the loss

of efficiency of the A it contains, whereas butyric oil nolonger contains any effective A after a year's storage.477Delf and Skelton *>7 describe th e dry ing of ve ge tables as anundesirable m ethod of preserving t h e m ; bu t t h e foregoingconsiderations will show that, as far as the A content is con-cerned, this is true only if the dried vegetables are freelyexposed to the action of the air.

6 . PHYSIOLOGICAL ACT ION OF TH E FAT-SOLUBL ECOMPLETTIN A.

When there is a deficiency of A in the food, just as whenthere is a deficiency of B, the first effect is an arrest ofgrowth (in young an im als ); then comes a ra p id loss ofweight, often attended with grave debility,821* IX33 and theappe tite falls off. The general deb ility and th e lowering of




of A to enhance the resistance of the organism to microbicinfection is extremely characteristic of this complettin.8?6*920, 1116 The difference between breast-fed and bottle-fed

infants as regards resistance to infection is well known;Aron refers this to the high A content of the natural milk.The same authority I1I7> suggests that the extreme prevalenceof influenza during the last years of the war, and the malig-nancy of the disease at this epoch, may have been due tothe general lack of A in the diet, and to the consequentweakening of the constitution.

When there is a deficiency of A in the diet, just as whenthere is a deficiency of B, no change can be detected in the

serological c o n s ta n ts .^ W e m ust therefore look to a directloss of efficiency in the organism or its cells to account forth e diminished pow ers of resistance. No dou bt one of th eeffects of wartime feeding was the widely noted diminutionof th e haemoglobin richness of the blood ; b u t w ar feedingwas defective in so many respects that we are hardly justifiedin laying th e blam e up on one defect in particu lar. Ste pp 884certainly found that in dogs fed on an A-free diet there wasa marked decline in the haemoglobin richness of the blood,

although the number of the erythrocytes remained normal.Dalyell,IO55 in a Viennese child suffering from grave mal-nutrition, found that the provision of A in the diet was fol-lowed within two-and-a-half months by an increase in thehaemoglobin richness of th e blood from 38 % to 70 % .

The effects of A and B in respect of growth are of coursemanifest only in growing animals, and in like manner theeffects upon body-weight are far more manifest in youngthan in adult animals—more manifest in proportion to the

act ivity w ith which gro w th should be proceeding.459 W efind also that the effect of A deficiency in reducing resistanceto infections is less m arked in ad u lts J^ Nevertheless, A isessential to adults for the maintenance of body-weight anda good general condition.^*

7 . A IN RELATION TO XEROPHTHALMIA A N D T O

KERATOMALACIA RESPECTIVELY.

The lowering of resistance to infection gives rise, especi-

ally in youth, to an aifection of the eyes which may be



232 VITAMINS

regarded as pathognom onic of A deficiency. This diseaseis known as xerophthalmia, which usually passes on rapidlyinto keratomalacia. Of all th e tissues of the anim al body,the cornea is perhaps the most completely removed fromthe direct influence of the blood stream, and it is thereforeonly to be expected that any important change in the bodilyjuices should speedily produce effects upo n th e cornea. Thelack of A in the food gives rise to a' general dryness of theskin, and it has similar effects upon th e cornea. The morbid

state thereby induced makes it easy for all kinds of microbesto invade the tissues of the eye, producing changes whichm ay culminate in blindness. The occurrence of xerophtha lmiain A deficiency was first noticed by Freise, Goldschmidt,and F rank 459 in ra ts fed on food which ha d been ex tractedw ith alcohol. The observation w as confirmed b y Bulley,821

Hopkins,1066 and Nelson and Lamb.JI43 The prim ary cause

of the disease is not the infection of the cornea, but the dry-ing of the cornea through the lack of A, which prepares theground for microbic invasion. Bu lley ha s rep eated ly endea-voured to infect with material from cases of keratomalaciathe eyes of rats fed on a diet rich in A, but has never suc-ceeded. Or rather, among 250 you ng ra ts on an ad equatediet, 5 only became affected with xerophthalmia, and inthese instances there was reason to suppose that the extremeuncleanliness of the animals was the cause of the infection.On the other hand, rats fed on a diet devoid of A almostinvariably became affected w ith x ero ph tha lm ia or ke rato -malacia.

Among diets especially prone to induce these diseases ofthe eye, the following ill-balanced diets are mentioned:pota to d ie t 8 l 2 ; nu ts poor in A Il6 9 ; cereals 682» 796;—even

when supplemented with buttermilk, skim-milk, or vegetablem a r g a r in e s Millet an d hemp seeds are said by McCollumand Simmonds6 83 to prevent the onset of xerophthalmia;but according to Auer,81* attacks may occur when millet isbeing given. W e m ay assume t h a t in millet, as in othernatu ral foods, th e qu an tity of A is v ar ia b le ; an d since thereis at the best but a narrow margin of sufficiency in this




contain very little A if the removal of the cream has beenthorough . This explains th e discrepancy between th e obser-vations of Bloch,9*o who found that a diet of buttermilk or

skim-milk may induce keratomalacia in children, and thoseof Freise, Goldschmidt, and Frank,459 according to whombuttermilk and skim-milk will cure the disease.

When the diet is rich in A (when, that is to say, it con-ta in s plenty of bu tte r, cream , full milk, eggs,92o or cod liveroilI057), this affection of the eyes is rarely encountered, andthen only as a result of general debility and deficient atten-tion to cleanliness. Perhaps these exceptional instancesmay also be referred to a deficiency of inorganic salts in the

diet, for McCollum and Simmonds6 8

* draw special attentionto the fact that, while A can prevent or cure the disease, i tcan only do so when the diet contains an ample supply ofsodium and potassium.

For the cure of xerophthalmia or keratomalacia, extractsrich in A,I243 and natural nutrients rich in A, such asbutter,6 82* 9*°>

IO55 cre am , full m ilk, eggs,9*> and codliveroil,9*°, r°55 will be found v al u ab le ; th e same sub stances areefficacious as prophylactics.6 82* 7*4. 812, 821, 1343, 131*

8 . A IN RELATION TO OSTEOMALACIA.

Like the cornea, the cartilages and the osteogenic tissuesare poorly supplied with blood, and they too therefore areespecially apt to suffer when A is lacking in the diet. IO55 Inexperiments on animals, changes in the bones are less con-spicuous than changes in the cornea, so that reports uponbone disorders are rare. According to the experimentsmade by Mellanby IO55 in th e years 1918 and 1919, youn g

dogs supplied with a diet poor in A but otherwise adequatebecome " r ic ke ty " ; but the author's descriptions suggestrather the onset of a rachitis tarda, which may be regardedas identical with osteom alacia. According to Ba rne s andH u m e ^ th e chief characteristic of thi s disease is a rare-faction of the osteoid tissue, which in the neighbourhood ofthe epiphyses may be reduced to the thinness of paper;th e spongy tissue m ay mo re or less com pletely disap pear,b u t th e chemical comp osition of the bon e is no t affected.

In true rickets, on the other hand, there is softening of the



234 VITAMINS

bone tissue with a predominant loss of calcium salts, so thatthe bone-ash in cases of rickets exhibits an abnormal prepon-

derance of magnesium salts.Weiser,347 feeding pigs on an exclusive diet of maize,no ted the onset of " ricket-like " diseases of th e bones, andhe considered th a t rickets was actua lly presen t. I t is tru ethat in the experimental animals there could be detectedin the canial bones, the ribs, and the vertebrae, a moderateincrease in the proportion of magnesium, and that this obser-vation might be taken as confirming the rickets theoryBut in rickets the most pronounced changes occur in thebones of the extremities, and in the experimental animalsthese bones contained a normal percentage of magnesium—or in some instances even a little less th an norm al. Wecan, therefore, confidently infer that the disease was notrickets, but osteomalacia.

Scheunert, Schattke, and Lotzsch lS l reported the onsetof a similar disease in horses fed on hay of abnormal com-position. Th ey considered th at th e unus ually low propor-

tion of lime and phosphorus in the hay was the pathogenicfactor, and we know that in abnormal vegetable productsthe A content may be too low. Sch eun ert Io88 has recentlyreported another case in which osteomalacia occurred inhorses fed for ten yea rs in th e same stab le. In th is instance ,the fodder was normal as regards richness in inorganic salts,and the only obvious defect in the diet was that the drinkingwa ter was ver y poor in calcium. Scheunert thinks th a t theillness was due to an infection of the stables and the drinkingwater with a diplococcus which gave rise to digestive dis-orders in the horses, resulting in a general modification ofthe intestinal flora and in the abundant formation of lacticacid in th e intestine. B oth these instances are extrem elyinteresting in more ways than one, and I shall return totheir consideration shortly.

During the later years of the war, osteomalacia and otherforms of osteopathy were frequent, and in the large towns

sometimes assumed epidemic proportions. This tends toconfirm the opinion that the complettin A is essential tothe normal metabolism of the bones. I t has been widelybelieved that the cause of these troubles must have been



T H E FAT-SOLUB LE COMPLETTIN A 235

some lack in the diet, especially a lack of calcium and phos-phoruses , 9<>5 1031, 1078, 1290,1306 fcut other authorities havespoken of a " lac k of v ita m in ." 933,1078 Th e la tt er assu m p-

tion is confirmed b y th e following considerations. Fi rst ofall, the bone disorders were frequently associated with signsof disorder of the endocrine glands, such as amenorrhoea inadult women and a failure of menstruation to begin in girls atth e age of pu b er ty (cf. Blencke IO78), and by nervous symptoms,such as teta ny an d o ther spasmodic tro ub les .1^ , 1165 Inthe second place, the diseases were curable by a diet richin A, and especially by the administration of codliver oil933, 1078 or of ph osp hora te d codliver oil.933,96s, 3<>6

9 . A IN RELATION TO RlC KET S.

Obviously, the onset of such bone diseases when thediet is lacking in A, in conjunction with the specific anti-rachitic effect of codliver oil (a substance rich in A), hasgiven rise to the view that rickets is caused by a deficiencyof A in the food. Osborne and Mendel 35° (see also Aron 781),who were the first to discover that codliver oil contains A >

promptly thereon gave expression to the opinion that the

therapeutic value of codliver oil in rachitic disorders mustbe due to th e A it contained. The suggestion received addi-tional support when it was found that osteomalacia waspron e to arise wh en the diet was deficient in A. B u t t hehypothesis has never secured unconditional acceptance amongexperts, R6hmann47* considers that the main cause ofrickets is, either a lack of calcium in the food, or inadequateabsorption of calcium b y t h e intestine, " w ith th e possiblecollaboration of " a disturba nce of th e hon no nic secretions

th a t control the formation of bon e. McCollum, Simm onds,and Parsons,^ 1 and also Dalyell,I338 while admitt ing that thelack of A has some causative influence in the production ofrickets, nevertheless regard this influence as subsidiary,and stress the importance of other errors of nutrition (not-ably, the lack of B, C, calcium salts, and phosphorus), toge-ther with the significance of the general conditions of lifeand t h a t of th e care of th e body . As regards th e diseasesof bone that occurred in Mellanby's dogs,IO55 it is evidence

against the presumption that they were rachit ic, that a cure



236 VITAMINS

ensued when butter or full milk was added to the animals'diet for in children suffering from rickets, the ad m in is tr a-tion of full milk in the absence of codliver oil is ap t t o m ak ematters worse.

At first , misunderstanding arose in these investigationsthroug h the reite rate d confusion between A and B inplants.IJ35 But the further research went, the more wasdo ubt cast upon th e accuracy of such views. I n 1920Mendel himself said that he considered it dubious whetherA really had anything to do with the causation or cure ofrickets I 2 2

3 ; and Mackay, an authority on the diseases of

childhood, has expressed the same view.

3

^*

8

It is a familiarand indisputable fact that codliver oil has a specific effect bothin the prevention and in the cure of rickets.IO35> 1057, I369* e tcB ut it is probable tha t the value of codliver oil m aydepend upon factors of an unknow n natu re , factors wh ichhave no connection with the A content of the oil. B or de rin gon the absurd is a statement by Hamshire and Hawker 9J4 tothe effect that rickets can be cured by a proprietary prepara-t ion "rich in vi tamins," known as "Universi ty Cream/ '

and consisting of beef suet, olive oil or earth-nut oil, syrup,benzoic acid, and decoction of Irish moss.

In 1920, the British Medical Association held " A Discus-sion on the present Position of Vitamins in clinical Medi-cine," I05S which served to clear up the problem a good deal.Whilst Hopkins expressed the opinion that the fat-solublefactor, though not (by its absence) the sole cause of rickets,was certainly an important etiological factor, and whilstHess looked upon Mellanby's discovery as very important,

Hess himself insisted th a t a num ber of other f acto rs bo thorganic and inorganic must play a part in the pathogenesisof this disease. M any m istakes ha d arisen from con fou nd ingslight cases of scurvy and other affections with incipientrickets. Still insisted upo n th e indispen sability of t h e fat-soluble complettin, bu t reported tha t milk which h a d beensterilised by the addition of hydrogen peroxide and wanning—being thereby freed from A—induced in children notrickets bu t scurvy . M ann likewise regard ed rickets a s th e

outcom e of a complex of causes, the chief of which w a s ade ar th of fat in th e diet. (Why th en do infants fed o n full




m ilk become rickety ?) Pr itc ha rd spoke of num erous factorsas contributing to th e causation of ric ke ts : defect or excessof one or oth er con stitu ent of th e d ie t; lack of fresh air or

bodily ex ercise ; chronic infections, especially of the g astro -intes tinal tract . All of these combined to increase th e needof the organism for calcium, so that the supply to the grow-ing cartilages was insufficient.

To anyone thoroughly well acquainted with the condi-tions under which rickets arises, these views are obviouslyfull of con tradiction s. Firs t of all it has repe atedly beenshown that human nurselings often become affected withricke ts even thou gh the ir food contains ple nty of A. Ag ain,

it ha s long been kn own th a t in cases of incipient rickets,the presence of a superabundance of calcium in the fooddoes no good unless codliver oil be simultaneously admi-nistered. Finally, even thou gh the diet is persistently poorin calcium, codliver oil can cure rickets, although the cureis certainly expedited by the simultaneous administration ofcalcium salts, and especially of soluble tricalcium phosphate.All these circumstances have been expounded in masterlyfashion in th e writings of H erb st and of Schloss. In especial,

the last-named author, whose premature death during thewar is profoundly to be regretted, has given an extraordi-na rily clear an d vivid picture of the disease. H e describesrickets as a constitutional affection of the osteogenic tissue,whereby not merely is the growth of the bones hindered,but, further, the deposit of calcium salts in the osteogenictissue is interfered with by a reduction in the affinity ofth is tissue for calcium salts . Th e specific effect of cod-liver oil consists in a stim ulatio n of th e affinity un til it

attains a normal or even a supernormal level, so that theosteogenic tissue is rendered competent to assimilate withthe utmost energy the available calcium, even though thisbe presented in very small quantities.

The se epoch-making writings of H erb st and Schloss,which for the most part appeared during the war, have notreceived sufficient attention from British medical authorities,who are rath er inclined toward s conservatism. B ut whilethe failure of the British in this respect is excusable, I findit impossible to excuse the German faculty for its neglect



2 3 8 VITAMINS

of these remarkable contributions of Schloss and Herbst.It seems to me characteristic of the mentality of my country-

men that, while uncritically accepting foreign opinions, theyshould ignore th e best prod uction s of Germ an science. I twould seem as if there were justice in the contention thatthere is an ebb in German science, and that the leadershiphas now passed to the Am ericans. A tragical outcome ofthe war, and perhaps for the German nation the worst ofall i ts outcomes!

To summarise the present position of our knowledge, itis certain that some sort of inadequacy in the diet must be

a predisposing cause of rickets and a co ntrib uto ry factor i nmaintaining the disease. On the other hand, it is prov edthat neither a liberal supply of A, nor a superabundance ofcalcium salts, nor both combined, can avail prophylacticallyor therapeutically unless codliver oil (which must not betoo highly refined) be used as th e vehicle for A. I t w ouldseem, therefore, th a t t he richness of codliver oil in A is amere accessory to the antirachitic action of this specific.

The effect of codliver oil in rickets m ay be fortified by t h erichness of the oil in A, but must have other essential causes.In fine, th e only certain proph ylac tic is breast-feeding b y amother able to supply good milk.

1 0 . A IN RELATION TO PELLAGRA.

No less uncritical than the contention that a lack of Ain the diet is the main cause of rickets, is the assumption of

McCollum and his collaborators^

1

that A deficiency is acause of pellagra. In C hapter Nine we shall show th at t h i sassumption is untenable.

I I . A IN RELATION TO MALNUTRITIONAL OEDEMA.

Equ ally unsound is th e contention of H opkins tha t Adeficiency is important as an etiological factor in the produc-tion of m alnu tritiona l oedem a. Chick "37 is also inclined t oregard a lack of A in the diet as one of the causes of mal-

nutritional oedema; and according to McCarrisonIJ4<> thenormal action of A is to keep down the adrenalin content.W hen th e fat-soluble facto r is deficient in th e diet, t h eadrenals hyp ertroph y, and there ensues an excessive pr od u c-




tio n of adre nalin, leading to oedema. W e discussed thi s the oryon p . 145, an d showed th ere th at it involved an inve rted viewof the facts, and that McCarrison had withdrawn his con-

t e n t i o n .1 ^ N everth eless, it is possible th a t a lack of A inthe diet may be a contributory cause of malnutritionaloedema. To this m att er we shall return .

12. ACT ION UPON THE ENDOCRINE GLAN DS.

Though it seems probable that as regards the osteopathies,as regards the causation of osteomalacia and rickets, theimportance of the fat-soluble complettin has been consider-ably overestimated, its influence upon body-weight and

gro w th has been definitely proved . Th is influence is fullyconsidered in Chapter Five, and all that is now requisite isto present a few important facts which are essential to thebetter understanding of the effects of A in the organism.We have seen that in growing animals and human beings,when there is a deficiency of A in the diet an arrest of growthen su es ; th en comes a decline in body-weight, gradual atfirst, and subsequ ently ra p id ; there is profound debility,which often proves fatal unless a speedier death should have

resulted from some intercurrent disease due to the lessenedresistance to infection and other noxious influences. Aconspicuous effect of A deficiency is a general atrophy ofthe endocrine glands, the only exception being the adrenals,which hypertrophy just as they do when there is a deficiencyof Funk's vitamin.876 Th e researches of Verzdr an d Bogel IJ7°have shown that, like B and D, A is absolutely non-toxicalike in cold-blooded animals and in mammals, and that indogs affected with diabetes from operations on the pancreas

neither the size of the pupils nor the excretion of sugar isaffected by their administration. But A differs from Band D in that it has no effect upon the secretion of theglan ds. Consequently the atroph y of the endocrine glandsin A deficiency must be due to an interference with theno rm al nu trition of these organs. The reduction in theirsecretion is merely an indirect consequence of the atrophy.

Verzdr and Bogel report, in addition, the interesting factthat A is a vasodilator, that it has an action antagonisticto t h a t of adren alin. All the more striking is it , then , th a t



240 VITAMINS

the adrenals should undergo hypertrophy when there is alack of A, for there would not seem to be any direct occasion

for a surplus produ ction of adren alin. Th e lack of A mu stenhance the effect of the adrenalin, and the hypertrophy ofthe adrenals must be regarded as a direct consequence ofthe A deficiency—but the way in which this effect is producedis still to seek.

According to Drummond, the deposit of fat occurs inanimals quite normally when A is lacking, and the milk oflactating animals remains perfectly normal in respect of fatcontent 87$; but a sufficiency of milk for the growth and

the normal development of the offspring can only be secretedby the mother when her food contains an adequate supplyof A. The lacteal glands cannot themselves manufactureA ; but, just as they are able to call upon th e m atern alorganism, even at the cost of its own health, to supply allthe other necessary constituents of normal milk, so are theyin a position, when there is a lack of A in the diet, to com-mandeer whatever quantities of A may be circulating in them aternal blood and to secrete the m in th e m ilk. According

to McCollum and Simmonds,10*6 only when the lack of A inthe maternal diet has been long continued does there arise adeficiency of A in the milk, and t h e effects of th is ar epromptly manifested in the sucklings by an arrest of growth,by debility, and by a proneness to xerophthalmia.

The facts just recorded indicate clearly that the fat-soluble complettin A cannot be synthetised in the animalbody, and that the animal organism's need for this substance

can be satisfied in no other way than by its provision ready-made in the food.234, 56l>

10 * t, XI7° The ulti m ate source ofthe fat-soluble complettin is, therefore, the vegetable kingdom.The main supply would appear to be derived from th egreen and growing parts tof plants, but in exceptionalinstances it is found in the stored-up fat.

The various yeasts and microorganisms are able to syn-thetise A for their own needs, and are therefore independentof supplies from without. Very interesting, therefore, is

the statement of Willaman IO43 (if correc t), th a t ce rta in fungi,and notably Sclerotinia cinerea, appear to need a supply ofA, being otherwise incom petent to form spores. W e m us t




assume that, just as in the case of animals (which are allparasitic upon the plant world), the parasitic mode of lifeof these fungi has led to a degeneration of the parasites in

this respect, so that they are no longer competent to satisfytheir need for A by independent production, and are com-pelled to draw upon the stores of the host.

In conclusion let me emphasise the fact that the effectof A is of course subject to the law of the minimum to thisextent, that when some other essential constituent of thediet is wholly lacking or is supplied in inadequate quantities,even the mo st liberal provision of A can have no effect. As

regards proteins, fats, and carbohydrates, and as regardsthe other complettins, the fact will be obvious to everyone.But people are so apt to overlook the importance of inor-ganic salts that I find it necessary to insist once more thatan adequate supply of these substances (adequate bothqualitatively and quantitatively) is an indispensable prere-qu isite to th e effective ac tion of A. W e ha ve alread y seen 6 8a

that on a cereal diet a supplement of A remains withouteffect unless the inorganic content of the diet be likewise

supplemented by the addition of sodium and calcium untilth er e is an excess of bases. In like m anne r, McCoUum a ndhis collaborators have shown I026 that, even when there isplenty of A in the diet, the maternal organism cannotsecrete sufficient milk, and therefore that the progeny cannotthrive, unless the mother's food likewise contain an adequateam ou nt of inorga nic salts in due prop ortions. Aulde 12S9 hasalso shown th a t a lack of calcium, when c om plettins are sup -plied, induces the same changes in the glands as those seen

when the diet contains plenty of calcium but is deficient incom plettins. Similarly, although there be ab un da nt A inthe diet, if calcium be deficient there will arise affections ofth e eye such as are witnessed when A is deficient; and incases of xerophthalmia, the administration of calcium inaddition to A will cure more quickly than will the admini-stra tion of A alone. Th e only possible inte rpr eta tion ofthese facts is that the complettins cannot do their work inthe absence of the necessary inorganic salts.

16



CHAPTER SEVEN

THE ANTISCORBUTIC COMPLETTIN C

i . HISTORICAL.

ALTHOUGH the nature of scurvy was not elucidated untilduring the last decade, this disease is one of the oldestscourges affecting m ankin d in nor thern latitu de s. An ex am i-natio n of skeletons datin g from n eolithic times, from th ebronze age, and from the iron age, has shown that in Swedenduring those times scurvy must have been devastating inits prevalence, whereas rickets seems to have been almostunknown. During the long winters of those northern r eg ion s,

when smoked or dried meat and fish constituted the staplediet, it was inevitable th at scurvy should be pre vale nt. A tthe present day, the Eskimos of North America live underconditions similar to those which prevailed in Scandinaviaduring the stone age—at any rate, during the paleolithic era,the greater pa rt of Sweden was covered by an ice-s hee t.Now, in summer the Eskimos, who live almost exclusivelyon flesh and fat, often suffer from a mild form of th ehaemorrhagic diathesis, being affected w ith bleeding from

the gums, nosebleed, haemorrhages from the other mucousmembranes, and severe extravasations of blood in the sub-cutaneous tissues upon comparatively slight provocation,while in winter, under the combined influence of famineand unsuitable diet, typical scurvy is apt to arise, sometimescarrying off entire tribe s. Am ong th e indigens of N o r th -W estern Asia, who are at a n even lower level of cu lture th a nthe Eskimos, and among the Ainos of Northern Japan,similar conditions prev ail. The rise of large ur ba n co m -

munities in Northern and Central Eu rope, populations h em m edin by the walls and moats of the fortifications, gave occasion

2 4 *



T H E ANTISCORBUTIC COMPLETTIN C 243

for long-continued epidemics of scurvy . Th e town-dwellerswere dependent for their food-supply upon the peasants ofthe immediate neighbourh ood; and when there was any

arrest of the provision from this source, scurvy promptlymade its appea rance in th e cities. This was th e rule as lat eas the beginning of the nineteenth ce ntury. An exam inationof the death registers of the old cities shows that scurvytook its place beside consumption and apoplexy as one ofthe most common causes of death.

When sea voyages grew longer, so that ships were monthswithout communication with the land, scurvy became afrequent and dreaded guest on board. The whalers, in

especial, who sometimes spent years in the far north underthe most unfavourable conditions, working very hard on anunsuitable diet, suffered grea tly from th e disease. So didthe men of the navies, who were closely herded together,and were fed almost exclusively upon badly preserved food.It was natural, therefore, that upon ships the specific valueof the various sorts of lime and lemon as preventives ofscurvy should first hav e become kn ow n; an d as early a sthe sixteenth century, the antiscorbutic effect of fresh vege-tables was familiar. B ut it was no t un til the yea r 1796 th a t

the provision of lemons as a means for the prevention ofscurvy was made compulsory in the British navy.

We see, then, that it was no chance matter that theimpulse to the scientific study of this disease should haveoriginated in the north, and that the pioneer investigationsshould have been made in a land whose population has forthousands of years furnished so large a proportion of sea-faring men. In the year 1905, the Swedish physicianEkelof 47 expressed the opinion that the disastrous effect of

preserved nutrients must depend upon the generation ofautolytic poisons within them . A little later, a similar ideawas promulgated in Germany by M. Schubert.5 1 Shortlybefore this, writing in the Swedish medical journal " Hygiea/'the Norwegian Schmidt-Nielsens© had amended the theorywith the suggestion that what happened during preservationwas not the formation of toxins, but the destruction ofimportant substances—enzymes, perhaps, or antibodies suchas were then becoming known in connection with the theory



244 VITAMINS

of imm unity. W ithin the next year or two came th e publi-cation by two Norwegians of the most important studies

incorporating the results of modern research into the natureof scurvy. In an exten ded series of expe rim ental investi-gations, Hoist and Frolich have attempted, with the aid ofmodern physiological and chemical methods, to throw lightupon the etiology of scurvy.6** 63> *4,

6$> 10X> w l86> 20*> e tc -Fir st they were able to show th a t bre ad, cereals, or dried

potatoes, gave rise to scurvy in gu inea pigs ; so did driedcabbage, dried carrots, and dried dandelion. On th e otherhand, fresh fruits and vegetables, such as apples, potatoes,

cabbage, carrots, dandelion, and lemon juice, can not onlycure scurvy, but when added to a scorbutogenic diet canprev ent th e onset of th e disease. Pe as, lentils, and alm ond s,and also maize, give rise to scurv y in guineapigs. W hennutrients which, as an exclusive diet, induce scurvy are givenin conjunction, the disease still arises, and this shows thatwe are not concerned here wit h a deficiency disease resemb lingthat which occurs when an inadequate protein is given,seeing that several inadequate proteins respectively derived

from different classes of foodstuffs can compensate oneanother's deficiencies.102* l87» *°3 The ad dition of m ilk to th ediet will prevent the onset of sc ur vy ; b u t this prop hylacticpower is more or less completely lost if the milk be boiled,condensed, or dried. In like m ann er, the prolonged boilingof such nutrients as cabbage, carrots, or dandelion, greatlyimpairs their antiscorbutic value.

The two Norwegian scientists inferred from their studiesthat quite a number of natural nutrients must contain anantiscorbutic ingredient. Th ere are other nu trien ts in whichthis substance is present in small quantities only, or fromwhich it is entirely ab se n t; and when such substances formthe staple diet, scurv y arises. Th e protec tive principle isthermolabile, and is rendered inactive or destroyed byprolonged boiling or by drying.

Another Norwegian, V. Fxirst,10** l87, 203, etc. confirm edand expanded these conclusions in a long series of investiga-

tions. Notably, as early as 1910, Fiirst made the importantdiscovery that oats, peas, and lentils, which in the ordinarycondition are scorbutogenic for guineapigs, become during



T H E ANTISCORBUTIC COM PLETTIN C 245

germination so rich in the antiscorbutic complettin that theiraddition to a scorbutogenic diet can cure sc u rv y; and th atas exclusive diet these germinated grains or pulses are not

scorbutogenic. H e found, further, th at in th e germ inate dseeds, likewise, the efficacy of the antiscorbutic complettinwas gravely impaired or completely destroyed by drying.Like Hoist and Frolich, Fiirst drew the inference that scurvymust depend upon the absence of a natural prophylactic fromthe diet. Since this substan ce is presen t in milk, which isa nutrien t rich in vitamin, and since vitam in is rat he r sensitiveto heat, Funk assumed that scurvy must be akin to beriberi.*°5Numerous subsequent investigations, conducted by various

authorities, have shown that the occurrence of scurvy mustactually be due to the absence of some protective principle.(Cf. in especial, 391* 7*4> ™M.)

Furs t l87,203 had been able to exclude acidosis and infectionas possible causes of scu rvy . McCollum and Pi tz , howe ver,now came forward with a new theory, according to whichscurvy was indirectly, though not directly, due to micro-organisms. Th ey held th at t he causation of th e disease didnot depend upon the lack of an accessory food factor, but

upon prolonged retention of the faeces in the bowel, putre-factive processes, and consequent toxaemia.^1* 65* Pitz 693quotes an experiment by Lusk, who found that whole graindid not bring about scurvy in guineapig s; b u t McCollumfound that the addition of milk to a diet of whole grain inducedconstipation, and that the putrefactive processes which thenensued in the intes tine gave rise to s curv y. Figueira,IO46

experimenting on guineapigs and dogs, came to the sameconclusion.

In support of this hypothesis, stress is laid on the assertionthat laxatives are said to prevent the onset of scurvy.^1* 65*> ^3The same effect is supposed to be secured by a modificationof the intestinal flora, leading to a replacement of putrefactiveprocesses by innocent fermentations ; in this way considerabledoses of lactose are said to prevent an d cure scurvy.*93 Pitz,786

however, makes a reservation to the effect that althoughlaxatives and lactose can retard the outbreak of scurvy foras long as twenty weeks, they do not furnish complete

protection.



246 VITAMINS

Other authorities have been unable to confirm these data.Moreover, according to Harden and Zilva, large doses of thealkaline citrates are ineffective,794 although they destroy theorganisms of putrefaction and have a marked laxativeeffect; and according to the same inves tigators, the freeadministration of sugar, which has a similar action, is value-less.795 Accord ing to Hess and Unger,75<> la xative oils are ofno use as preventives of scurvy. H ar t, Steenbock, an d Smith?01

were unable to prevent the onset of scurvy by modifying theintestinal flora through the administration of chemicallypu re lactose, or such laxatives as mine ral oils or phenol-

ph tha lein. M ouriquand and MichelIO2

3 likewise declare thatlaxatives are useless for the prevention and cure of scurvy.The same authorities found that in scorbutic guineapigs theintestine was often practically empty, and they concludedtherefore that stagnation of the faeces and intestinal putre-faction could no t be regarded as th e causes of scu rvy . Onth e other hand, K arr and Lewis 638have shown th a t in scorbuticguineapigs, even when constipation occurs, there is no increasein microbial ac tivity within the intestine. Cohen an d Mendel 749consider that retention of the faeces has no etiological relation-ship to scurvy, although naturally constipation, like anyother complication, can aggravate the symptoms of thepr im ary disease. Ro hm ann 473 would no t adm it the existenceof an antiscorbutic accessory food factor, and referred theorig ination of scurvy to pro tein insufficiency. B u t this viewproved untenable when it had been shown that certainvegetable extracts which were absolutely free from nitrogen

were competent to cure or prevent scurvy.It is remarkable to find that McCollum, collaborating

with Simmonds and Parso ns,^1 has insisted that in the produc-tion of scurvy other causes must be operative in additionto the lack of A or B, and that Funk's vitamin has nothingto do with this disease. Aron, too, insists th a t t he c urativeeffect of fresh fruits and vegetables in infantile scurvy dependsupon the presence of water-soluble extractives.78* Willcox ioa5

came to the same conclusion from his study of scurvy amongthe British troops in Mesopotamia during the recent war.Bierich,954 again, regards scurvy as dependent upon a denatu-ration of the food whereby it is rendered qualitatively inade-



TH E ANTISCORBU TIC COM PLETTIN C 247

qu ate . Qu ite isolated sta nd s the report of Fu nk 5*7 to th eeffect th at an tiscorb utics are valueless in guineap igs. Th eanimals were being fed on oats, and Funk's experience of thevaluelessness of antiscorbutics is in such flat contradictionwith the experience of all other investigators that we areforced to assume the presence of some grave error of diet asa con tributo ry factor—p erhaps a lack of calcium. I t is, ofcourse, hard to believe that so noted and experienced aninvestigator can have made such a mistake, but this is theimpression left upon my mind by the secondhand referenceto which I have alone had access.

However, all the mor e recent researches point to the conclusionthat the cause of scurvy is a lack of complettin in the diet, andDr ummondÛ has christened the complettin specifically activein connexion with scurvy " water-soluble G ."

2. SCURVY EPIDEMICS DURING RECENT YEARS.

Prior to 1914, people had come to regard scurvy as adisease belonging to obsolete stages of social evolution, asone of which civilisation had made an end. B u t th e war of

1914 to 1918, and the subsequent years of alleged peace, havefurnished plenty of opportunities for the study of scurvy onth e Euro pean continent, and notab ly in th e armies. A fore-taste was provided in the last Balkan war, when scurvy wasrife in the Bulgarian army, although preserved vegetablesh ad been supplied as prophylactics. I hav e repea tedly ha doccasion to insist that these preserved vegetables wereprob ably the cause of th e disease. Fo r the water-solubleantiscorbutic complettin, just like the excess of bases, is

removed by the " bleaching " process which (despite all thathas been said against it by scientific authorities) is still invogue for th e factory preparation of these preserves. Th usthe vegetables which were specially intended to preventscurvy, must have favoured the incidence of the disease.

Willcox I0*5 ha s pub lished a detailed accoun t of th e ep idemicof scurvy am ong the British troops in M esopotamia. Inorder to prevent beriberi among the Indian soldiers, insteadof rice they w ere given " at a, " a barley flour containing a

good deal of "bran and an abundance of vitamin, but poor inC. T he men had no fresh m eat, no vegetables, and no fruit,



248 VITAMINS

and the result of this diet was a severe outbreak of scurvy.The onset of the disease was favoured by the circumstance

that the men had already been weakened by the long seavoyage, were under-nourished, anaemic, and suffering (manyof them) from dental caries when they arrived at the theatreof war. Doubtless, too, their powers of resistance wereweakened by the terrible climate, the uncertainty of theirfate, and the home-sickness which m ust h ave been accentua tedby the contrast between the Mesopotamian deserts and theirnativ e land. Willcox considers th at th e m ain factors of thecure were the supply of fresh vegetables and fruit and fresh

m e a t; and he states th at a salad mad e with ma lt vinegarof raw, thinly sliced potatoes and raw onions was especiallyefficacious. H e insists th a t th e lack of com ple ttin in th ediet must have been the main cause of the disease.

It is well known that, during the war, scurvy celebratedpositive orgies in Northern Russia, and the building of theMurmansk railway will be ever memorable in this respect.A British doctor, J. D. Comrie,1118 has given a d etailed d escrip-

tion of the affair, and his account may be summarised asfollows. Among the R ussian troops, scurvy w as co mp ara-tively infrequent, owing to the abundant supply of potatoes,pickled cabbage, fresh me at, an d fresh fish; an d among theBritish troops which, in accordance with the suggestions ofChick and Hume, were given germinated beans or peas asa proph ylactic, th e disease was exceedingly ra re . I t was ,however, terribly severe among the prisoners of war, whowere put upon extremely strenuous work and who lived under

the most unfavourable and insan itary conditions. Fro m th edescriptions of German prisoners of war who escaped fromMurmansk, we know that the Russians had no time orsympathy to waste on prisoners who were affected withscurvy. Anyone who became unable to work was left toperish like a dog, unless a Russian soldier m igh t b e com passion-ate enough to put him out of his misery with a blow froman axe or with a bayonet th rus t. The six hun dred cases

Comrie describes as having been treated in the hospitals ofMurmansk and Archangelsk were no doubt drawn from amongthe prisoners of war who were lucky enough to be workingin or near these towns. Th e diet is said to ha ve been fairly



TH E ANTISCOR BUTIC COM PLETTIN C 249

varied, consisting of flour or biscuit, rice, oats, peas or beans,frozen meat or tinned meat, salted herrings, bacon, salt pork,

tea, sugar, salt, and preserved lime juice—the last, we maypresume, only in th e tow ns. Comrie tells us th a t the ra tion swere meagre, and that the diet was extremely poor in carbo-hydrates ; and we know from other sources that in actualitythe diet was less varied than on paper, and that the qualityof the nu trien ts left m uch to be desired. B ut even if thesefoodstuffs had been unimpeachable in quality, even if theyhad been supplied according to schedule and in abundance,they would still have induced scurvy, for the diet named

contains very little C, and the preserved lime juice of commerceis of course qu ite inactive. In Murm ansk, therefore, th elack of C m ust hav e been the m ain cause of s curvy .

Outbreaks of the disease, however, were not confined tothese remote corners where the supply of food satisfactoryboth as to qua lity and qu an tit y was a difficult m at te r ; scurvymade itself known in even W estern Eu rop e. Th e British hadexperience of it from time to time when the supply of potatoes

was tending to run short.Wiltshire J3O3 rep ort s u pon an epidemic of scu rvy in 1917among th e Serbian soldiers on th e Salonica front. In thisinstance, the scorbutogenic diet consisted of bread and meat,the latter being mainly tinned meat or frozen meat cookedby boiling. Sm all qu an titie s of th e lime juice of comm ercedid not preve nt the occurrence of scurvy. W iltshire me ntionscases in which scurvy occurred although " an abundance " ofboiled potato es, onions, and spinach ha d been e a te n ; herewe may suppose, either that the boiling had been undulyprolonged, or else that the water of the first boiling had beenthrown away. Special researches m ade by this investiga torshowed that germinated beans, which were used after a timeboth prophylactically and therapeutically, were far moreeffective th an fresh lemon juice. Eve n severe cases, whichresisted treatment with lemon juice, were speedily cured bygerminated beans . H ere, then, manifestly a lack of C in

the diet was the decisive etiological factor.Chick,I237 who studied the illness among children in En gland

and in Vienna, found that the main defect of wartime feedingwas everywhere a poverty in C, to which a lack of A, B, and






in No rthern Sweden. The diet in this area consisted m ainlyof very coarse, bad bread, with a small quantity of potatoes

and salt bacon, the beverage being a coffee substitute withoutsugar or milk.

3. OCCURRENCE OF THE ANTISCORBUTIC

WATER-SOLUBLE C.

a. Occurrence.

Th e com plettin C is found in special abu nda nce in freshvegetables 751,8<>0,Io66 and fruits.10 6* Th e variou s fruits of th e

genus citrus (lemons, limes, oranges, etc.) have long beenrenowned as antisc orb utics. Th e richness of these fruits inC app ears to va ry directly w ith their sweetness. McClendon II29has even maintained that natural nutrients in general arericher in C in propo rtion to their sweetness. B ut this asser-tion m ust be accepted with re se rv e; and certainly honey,29*the sweetest of all na tu ra l produ cts, contains no C. Th elemon in common use, and its juice, though when fresh both

are very active,

6

5,

Io66

is less rich in C than the lime,

I]C

77 whilethe orange and its sweet juice are richest.491, 577, Io66 T heinner layers of orange peel are likewise rich in C, and as asupplement to an otherwise scorbutogenic diet can act as avaluable prophylactic and curative agent even after monthsof drying.751 The juices of other fruits are curative inscurv y 4", 1066 - some of th em , like grape ju ice , a re effectiveprophylactics.1066 Apples do not contain much C, but arecurative; cucumbers,1066 tomatoes,838, Io66 a n d b a n a n a s ,^

are bo th prophy lactic an d curativ e. According to Weill andMouriquand,756 vegetables an d fruits contain m ore C in pro-portion as they are gre en er; when the y ripen, their richnessdiminishes. In conformity with this state m ent , we find t ha tripe hay, according to Hess and Unger,75° contains very littleC, and straw even less.

White cabbage in small quantities as supplement to anotherwise scorbutogenic diet is both prophylactic I71» l8 6 , 577.

754, 1053 and curative,

6

5,

I 0

5,

8 o 6

but is less rich in C thanspinach.83J Fresh green cabbage is as rich as oranges in theantiscorbutic complettin.II]C5 I have already mentioned th atdandelion can prevent the onset of scurvy l 8 6 ; and other






indeed is the report of Hess,49* that ripe cotton seeds canpre ve nt scurvy. For we know t ha t w h e a t , ^ barley,749, 885

o a t s ,

1

^ , 5*7,577, 749, 750,841, 885 and s o y beans,749, 831 c e r e a l s ing e n e r a l / 5 , 816,693 se e^s ^ g e n e r a l , 1 ^ , 203 b re a d , 6 4, 65, 186, ios5

and the brans of the cereals,885,969 are so poor in C that theyha ve always proved inadequ ate. W e hav e learned th a t haycontains too little C. It s poorness in this respect m ay eitherbe due to storage ; or, more probably, to th e ripening process,for Rossi 741 states that dried green grass, as a supplement toan oats diet, can prevent scurvy in guineapigs.

Opinions differ concerning the value of cow's milk as an

antiscorbutic. According to Fr6lich,IO7 Hopkins,26 7 Barnesand Hum e, 969 and Willcox,106 * fairly small quantities of milksuffice to w ard off sc u rv y ; bu t according to Cohen andMendel,749 Osborne and Mendel,7379, 831, 1131 Chick, H um e, andSkelton,689 and Wollman,89* fresh milk contains but little C,its richness being stated by Chick, Hume, and Skelton to beless than one -hundre dth of th a t of orange juice . Heim 533witnessed the onset of scurvy in adult guineapigs on an

exclusive milk diet. Pi tz *93 feeding guineapigs on oats, wasnot able to prevent the outbreak of scurvy by supplementingthe oats with a fairly abundant ration of milk*

6. Natural Var iations in G Content.

Apart from the varying resistance of the experimentalanimals, the contradictions in the before-mentioned reportsare readily explained by the consideration that the C contentof the different fodders and other nutrients may vary con-

siderably at different tim es. In such substances as ha y,which is among the nutrients that stand on the borderlinebetween adequacy and inadequacy, the variations may makethe nutrient inadequate at one time whereas at another timeit m ay contain a fairly liberal supply of C. More especiallydoes this consideration apply to milk. Th e animal organismis just as incompetent to synthetise the antiscorbutic com-plettin as to manufacture the other complettins for itself;

it is entirely dep endent upon th e supply of C in th e food.1026

.I2

99According as the food contains more C or less, the animalorganism will possess a larger or a smaller am ou nt of C. I tis true that the mainmary glands have the power in the case



254 VITAMINS

of C that they have in the case of the other three complettinsand in the case of the different proteins and inorganic salts.

W hen C is sparsely supplied in the food, t he q ua ntitie s th atare circulating in the maternal organism are commandeeredfor the m ilk. B u t such a process has inexorable lim its, andwe have seen that in the case of the growth-complettin B,and still more in that of the fat-soluble growth-complettin,when they are persistently lacking in the diet of a lactatinganimal, the milk, though otherwise normal in composition,m ay be deficient in these com plettins. M anifestly th e com-plettins are of such vital importance to the maternal

organism, that the commandeering process by the mammaryglands cannot go beyond a certain point. As regards inorganicsalts, the self-sacrifice of the maternal organism may proceedto such a pitch that grave diseases (osteoporosis, for instance)m ay ensue. In th e case of the three m ain classes of nu trien ts—proteins, fats, and carbohydrates—the maternal self-abnega-tion may result in severe signs of malnutrition appearing inthe mother at a time when the milk, though certainly restricted

in quantity, still contains the normal proportions of the threem ain nutrients. B ut as regards the complettins, m atte rs dono t go so far as this. W hen studying beriberi we learnedthat sucklings may become affected with beriberi at a tinewhen the mother still appears healthy, for her milk isdeficient in vita m in. Th e secretion of m ilk con tainin g nogrowth-complettin would be an absurdity, and when thesupply of this complettin runs short, the quantity of thesecretion is re du ce d; bu t the proportion of A in th e milk

may fall off to such an extent that growth is inadequate andthe offspring become rachitic or are affected with xerophthal-m ia. I t would seem th a t th e C conte nt of th e m ilk can beeven more readily reduced. To express th e m at ter in an otherw ay, C is so im po rtan t t o th e life of th e m other, an d conse-quently to the life of the offspring, that the maternal needhas the first claim. T hat is why acco rding to Ingie r 387,405when gravid guineapigs are fed on a diet deficient in C, the

foetuses become affected within ten to twelve days with typicalinfantile scurvy. W hen th e gravid guineapigs ha ve beenprope rly fed un til near th e tim e of delivery, a suddeii tran sitionto a scorbutogenic diet does n o t affect the foetuses, which




are normal at bi r t h ; b ut the milk is inade qua te, and th e

offspring speedily becom e affected w ith scu rvy . P regna n tanimals put upon a scorbutogenic diet fall ill with scurvymore rapidly than non-gravid animals, and frequently dieof the disease before delivery.

These considerations explain the facts observed byFigueiraIO46 and by Dalyell and Still,IO55 who noted thatinfants at the breast may become affected with scurvy althoughthe mother appears perfectly healthy.

As regards the C content of cow's milk in particular,Barnes and Hume 9*9were the first to point out that the varia-tions in the complettin content are subject to seasonal changes.The C con tent is highest from May to Ju ly , an d lowest duringthe winter m on ths. H a rt , Steenbock, an d EHis,x*33 Hess,IO55and Dutcher and his collaborators, m* likewise refer to thisdependence of the richness of milk in C upon the seasons,

and they regard t he vary ing am ount of C in the fodder asthe essential cause of these changes. In spring an d sum m er,when plants are in the most vigorous phase of their develop-m ent, the y contain comparatively large qua ntities of C ; onthe other hand, the ripening of hay is attended by a gradualdecline in the amount of C it contains, which may be reducedto an inadequate proportion.

I t is owing to this scan ty supply of C in th e m ilk th atbottle-fed infants sometimes become affected with scurvy.Of course the customary practice of diluting cow's milk forth e hand-feeding of infants lowers th e percentage of C in th efood to a dangerous e xte nt, seeing th a t th e C con ten t of cow 'smilk is already low in many cases.737

Eggs contrast with milk as the first nutrient of a growing

organism, in that they appear to contain very little C,8

3*and certa inly canno t cure scurvy.75<> In th is pover ty , theyresemble seeds.

Fresh yeast S&, 737 is far more active th an m il k ; b u t th eautolys is of yeas t destro ys th e com ple ttin C,49* tho ug h ithas no effect upon vitamin and the growth-complettin.

c. Effect of Germination upon the C Content of Seeds,



256 VITAMINS

influence, develop large quantities of this complettin duringgerm ination . Consequently, an exclusive diet of ge rm ina ted

seeds is no t scorbutogen ic; and a supplem ent of ge rm inatedseeds to a scorbutogenic diet has prophylactic and curativeeffects.102* l87> 203, 267, 735, 749, 841, 918, 972, 1057, 1066, 1118 i n con-formity with this we find that malt extracts, and especiallythe fresh watery extract of green malt, have antiscorbuticqualities.533 Th e antiscorb utic substa nce in ge rm ina ted seedsis not in the cotyledons, and still less in the primary rootlets ;it is mainly found in the leaves, and th e process of germ inationpe r se does not increase th e C content of th e seed. T he an ti-

scorbutic powers of germinated seeds is not fully developedun til after the lapse of thre e days or more, wh en t h e form ationof the first leaves has begun.734 For thi s reason , th e ac tu algerm is inadequate in respect of C content, 491 whereas theleaves of the germinated seed are more effective than theentir e germinated plan t. If we wish to use th e aggre gategerminated seeds as a prophylactic nutrient, it is best to waituntil the leaves have grown to a length of from half to three-quarters of an inch.^ 1 When germinated seeds have been

dried, they no longer contain the antiscorbutic co m ple ttin. 93, ifi

7

4. PRO PER TIES OF THE COM PLETTIN C.

It follows from the foregoing that the complettin C mustbe soluble in w ater. According to Hess and U nger,75r andaccording to Harden and Zilva,794 it is soluble in alcohol thatis not too strong, and is therefore retained in the alcoholicsolution when the fruit acids are precipitated from fruit juicesby means of calcium carbonate and alcohol. Lik e the com -

plettins previously considered, C has a fairly high power ofresisting even strong mineral acids,536 and a moderately acidreaction of the medium definitely favours the durability ofth e complettin 756; bu t C is rath er sensitive to a lkalies. 53However, as in the case of the growth-complettin B, thedestructive effect of alkali is not immediately manifest, andcomplete destruction is not achieved for a considerable time.899T he complettin C is not entangled in prec ipitate s an d car rieddown with th em ; and it cannot be removed from orang ejuice, for instance, by alumina or by a Ch am berland filter.6 88

In the preparation of Osborne and Mendel's protein-free milk,




C is retained by the milk, which does not lose any of its anti-scorbutic power.737 Lik e th e fat-soluble cornp lettin A, thewater-soluble com plettin C is sensitive to oxidising agents. 1O55TMs doubtless is the main reason why the storage of driednutrients originally rich in C leads, even when the dryingprocess has been carried out with the utmost care, to a ratherrapid disappearance of th e C content. From a further stud yof this matter we learn that dried vegetables suffer less fromstorage as regards their C content in propo rtion to th e dry nessof the air;

I3»4 so th a t th e storage is best effected in th e presenceof phosphorus pentox ide. I t is remarkab le th a t Hoist and

Frolich :3°4 have failed to draw the obvious conclusion asregards the mechanism of this reaction, which ha s an im po rtan tbearing on our knowledge of the complettin : in the presenceof air, the dried green vegetable substance has a catalyticaction upon the aqueous vapour the air contains, leading totie formation of hydrogen peroxide, and this latter, whichexerts an oxidising influence upon the complettin, destroysits characteristic antiscorbutic quality.

Reports vary concerning the thermostability of the anti-scorbutic com plettin. Hoist an d Frolich inform us th a t th eboiling of cabbage, carrots, dandelion, and potatoes, reducestheir prophylactic power l8*; and according to th e sam eauthorities 305 and also according to Plirnmer,I]c59 expressedcabbage juice is rendered inac tive b y boiling. Fro lich I07, 204found that raw milk in small doses did not prevent guineapigsfrom becoming affected with scurvy, but was able to curethe disease ; this curative influence is greatly reduced when

the milk has been heated to 98 0 C, and completely disappearsafter ten minutes' boiling at 100 ° C. I think , however, th a tthe last statement must be an exaggeration, for the experi-ments of Nobel *3*6 have shown that, even after one hour'sboiling, milk contains considerable amounts of C, so that adouble or treble qu an tity will cure infantile scurv y. Accordingto Barnes and Hume,^ milk still retains after boiling thepower of protecting children against scurvy, provided only

th a t th e boiling has not been long continued a nd th a t afterboiling the milk has been rapidly cooled.According to Delf,8°6 the antiscorbutic power of white

cabbage is injured by h ea tin g ; and she tells us IIJ5 that the



258 VITAMINS

juice of green cabbage has its efficacy as an antiscorbuticnotably reduced by twenty minutes' boiling, while by anhour's boiling about five-sixths of the antiscorbutic complettinare destroyed. In turn ips, the C is mo re resis tant toboiling,IXI5 which seems easy to explain by the considerationthat the heat cannot so readily make its way into the interiorof th e masses. Th e antiscorbutic qualities of g erm inatingseeds are largely destroyed by boiling.9 l8 Exposure for fromone to three hours to a temperature of 120 0 C. destroys theantisco rbutic faculty of all nu trie nts . Th ere is gen eral agree-ment that prolonged heating at a moderate temperature is

far more noxious than brief exposure to a high temperature.1 0 66

This makes it obvious why the pasteurisation of milkgreatly reduces the C content of this nutrient^ 1 1 and whyinfants and children fed on pasteurised milk are so apt tosuffer from scurvy.800* m 2 Of course in th e process of cond ensa-tion, the antiscorbutic qualities of milk are gravely impaired.9 01

In young monkeys, a diet of condensed milk induces infantilescurvy *", *49; and in a du lt mo nkeys,211 and also in guinea-pigs 885 it induces typical scurvy. Since the co m plettin C is

sensitive to alkalies, we can readily understand that it iscompletely destroyed when milk is sterilised after the additionof sodium citrate, which has an alkaline reaction.I389 Gener-ally speaking, the sterilisation of nutrients impairs theirantiscorbutic power, being more injurious in proportion tothe height of the temperature. 74*> 1025 Tinned meat andtinned m ilk are therefore inva riably scorbntogenic "9 4; b u tvegetables with an acid reaction may still retain considerable

antiscorbutic powers after cautious sterilisation.

8

99> "94Since prolonged heating is in any case injurious, it isobvious that the drying of nutrients at a raised temperaturemu st be extremely disadvantageous. H oist an d Fr oli ch 1 8 6

report that the drying of cabbage, carrots, and dandeliongreatly impairs their an tiscorbutic qualities ; such efficacy asis retaine d by dried cabbage 749 is still preserve d after briefheating at ioo° C , b ut is completely destroyed at n o ° C.*5

Dried potatoes are likewise inadequate.65 Givens and

McClugage "4 8 have made a thorough study of the efiect ofdrying potatoes. They found th at finely minced raw p ota toe scould be boiled for fifteen minutes without ill-effect, but that



TH E ANTISCORBUTIC COM PLETTIN C 259

their antiscorbutic efficacy was considerably impaired byone hour's boiling. The boiling is be tte r borne when thewater contains 0-5 % of citric acid. Potatoes dried in vacuoat a temperature ranging from 45 ° to 60 ° C. lost much of theirefficacy ; and the greater par t of the complettin was destroyedby drying in an air current for from six to eight hours at atemperature ranging from 350 to 400 C .; subsequent briefboiling reduced the com plettin conten t still further. Equallybad was the effect of drying for from four to six hours in anair current at a temperature ranging from 55° to 6o° C .;drying for from two to three hours at a temperature ranging

from 750

to 8o° C. destroyed almost all the complettin C.Preliminary treatment of the potatoes with 2 % acetic acid or0-2 % hydrochloric acid for from eighteen to twenty hoursbefore drying, had no influence. Four m inutes' steaming ofthe minced potatoes before drying at a temperature rangingfrom 550 to 6o° C. destroyed m ost of the complettin, and asubsequent brief boiling destroyed what was left. Potatoesbaked in their skins for from forty-five to fifty-five minutes ata temperature of 2040 C , then skinned, and dried at a tempera-

ture ranging from 450

to 50°C , could still prevent scurvy ;the skins of the baked potatoes no longer contained anycomplettin. These authorities infer that the destructiveeffect of the drying must be partly due to the influence of aferment, seeing that less C is destroyed in proportion as theheating process is a rapid one. Here it is impossible to followthem, for were their reasoning correct, the preliminary treat-ment with steam should have given the best results, whereasthis proved extremely destructive to the antiscorbutic powers

of the po tatoes. Though it was found th at baked potatoeswere still comparatively efficient as an antiscorbutic, wemust not assume that this was because the heat was greater,and that the alleged ferment was thereby more rapidlydestroyed, for the substance of potatoes has a low conductivityto heat, and within the time allowed for the baking thetemperature in the interior of the tube rs cannot have risen veryhigh. Still, the re may be something in Givens and McClugage's

theory after all, for Delf and Skelton

8o

7 state t hat cabbage doesnot forfeit its antiscorbutic virtues so completely on dryingwhen, as a preliminary, it hats been dipped in boiling water.



260 VITAMINS

According to Givens and Cohen,754 in cabbage and potatoesC bears a quick but careful drying so well that the dried

pro du ct is still effective as an antisc orb utic ; bu t prolongeddrying, especially at a considerable heat, completely destroysth e com plettin. From tom atoes, according to Givens andMcClugage,838 a dried product that is still effectively anti-scorbutic can be prepared.

Owing to the acidity of lemon juice, the C in th is juicewill bear an hou r's heating at ioo° C. I0 5; and in the case oforange juice II09 and lime juice,XI77 cautious evaporation toth e consistency of a syrup does not impair the activity. B asse t-

Smith I249 was able to prepare a very active dried productby boiling fresh lemon juice for five minutes, cooling, andcondensing in vacuo at an ordinary temperature to a specificweight of i • 3 ; he th us secured a stron gly acid viscous fluidwhich could be made into tablets with lactose, or some similarvehicle. Hawk, Fishback, and Bergeim IO

58 were able to

secure an active dried produ ct from orange juice by ev ap ora tingit to dryness in vacuo at an ordinary tem per atur e. Ac cordingto H arde n and Zilva,794, etc. the precip itatio n of th e fru itacids with calcium carbonate and alcohol does not impairthe antiscorbutic efficacy of lemon juice, but the juice nowrendered neutral is injured by subsequent preservation forfourteen days at an ordinary tempe rature, and is injured stillmore by evaporation in vacuo at a temperature ranging from300 to 400 C. The untre ated juice bears such co nce ntra tionvery well, and so does the juice after precipitation of theacids if it be at once weakly acidulated with citric acid.

Delf,JI I5 who has made an exhaustive study of this ques-tion, finds that orange juice in its natural state of aciditycan well bear heating for an hour at a temperature rangingfrom 700 to ioo° C , and th at even after th e juice ha s b ee nheated for an hour at 1300 C. it is merely necessary to doubleth e prophylactic dose. In orange juice th e th erm ost ab ilityof the complettin is therefore twice as great as in expressedtu rn ip juice. Bu t even when the acidity of th e orange jui cehas been reduced to correspond with the low acidity of theexpressed turnip juice, the thermostability of the C in theformer is still retained, and it is therefore not due to thestro ng ly acid reaction of the juice. Orange juice t h a t h a d



TH E ANTISCORBUTIC COM PLETTIN C 261

been heated in sealed tins for from twenty to thirty minutesa t a tem pe ratu re ran ging from 8o° to ioo ° C. w as found tobe still fully effective as an antiscorbutic after five months.

Nevertheless, i t seems undesirable to trust to the anti-scorbutic efficacy of stored products. The antiscorbuticpower of expressed cabbage juice,I05 lemon juice,794, *>66 andorange juice rs 1 seems to disappear in consequence of prolonged

storage. Pe rhap s th e cause of this degra datio n is no t somuch a primary instabili ty of the complettin as i ts sensitive-ness to th e oxidising influence of th e atm osph ere . Th is, wemay presume, explains Delf and Skelton's observation,8o7that the storage of dried cabbage for from two to three weeksreduced i ts C conten t by abo ut nine-tenths, an d th at threem on ths ' storage ^completely destroy ed it s antisco rbu tic

efficacy.The complettin seems to be peculiarly unstable in germin-

ated seeds. I ha ve m ore th a n once m entione d th a t in theseC is destroyed by brief bo iling. D ry ing also des troys it com-pletely. 02

»Il66> J345 The soaking of other dried vegetables

appears to be very injurious to the C they contain.I]C99

Barnes and Hume state that the drying of milk reducesits antiscorbutic efficacy to about two-fifths of the original.But the extent to which this reduction takes place varieswith the method of desiccation, for Hess and Unger &99 reportthat milk transformed into an absolutely dry powder withina few seconds a t a tem per atu re of 116 0 C. by the Jus t -Hatm akerprocess was still fully efficient. In Ge rm any, similar result s

have been secured by the use of the Zetror apparatus of theBenno-Schilde Company. Especially valuable, from thispoint of view, is the Krause method of producing dried milk,which from the descriptions would seem to be identical withthe American.

According to Hess and Unger^s1 the most actively anti-scorbutic veg etab les lose their efficacy on dry ing . Erich





TH E ANTISCORBUTIC COMPLETTIN C 263

free access of moisture and a i r ; it is also rendered inactiveby direct oxidation, as for example by the action of hydrogen

peroxide. This fact, too , justifies certain conclusions as toits composition. One possibility is th a t it contains readilyoxidisable molecular groupings like those of the ketones orthe aldehydes. Another possibility is th a t of duplex combina-tions, which are sometimes readily oxidisable. Especiallysensitive in this respect are, once more, the conjugated duplexcompounds, which undergo transformation into dioxy-compounds under the influence of mere traces of hydrogen per-oxide, thus : R . CH : CH . CH : CH . R ' + HO . OH ==

R. CH 2 . CH(OH): CH(OH). CH 2 . R'.It is characteristic of such conjugated compounds that

when stored for a long time in the presence of moisture andair, and rapidly when the temperature is fairly high, theytake to themselves traces of hydrogen peroxide formed inthe aqueous vapour, and thus by degrees are transformedinto an entirely new substance . The process is favouredwhen the body under consideration can itself play the part

of a catalase (as so often happens with the terpene deriva-tives), or when other oxygen conveyers are found in themixture. This state of affairs obtains in plants, and in themajority of fresh animal tissues ; in both cases there is presentmore or less ca ta las e; furthermore, animal tissues containhaemoglobin, and vegetable tissues contain chlorophyll, bothof which are oxygen conveyers.

We have already seen that by rapid heating at a hightemperature and subsequent drying at a low temperature,

the keeping qualities of the product are favourably affected ;and we have drawn the conclusion th at an enzyme mayperhaps contribute to the decomposition of the complettinin the dried preparation. We have learned th at prolongedheating at a comparatively low temperature ranging from300 to 400 C. is more injurious to the integrity of C than boilingit for as long as an hour. We know, moreover, that the sub-stance is extremely sensitive to the action of the oxygen ofthe air, but that this sensitiveness is much less marked whenthe air is perfectly dry.I3°4 From all these considerations weare inclined to draw the conclusion that the complettin 0 isprobably a conjugated duplex compound. Fur thermore, the



264 VITAMINS

idea is supported by the fact that the substance is renderedinactive by temp eratures over n o 0 C, for at high temperatures

many dien compounds are converted into monin compounds.( - C H = C H - C H = C H 2 - becomes - CH 2 - C = C —CH 2 - - ) . The behaviour of the substance when exposed toultra vio let ligh t confirms th e idea. W hen ultra vio let lightacts on damp air-containing substances, hydrogen peroxideis formed, and this is fairly stable in weakly acid solutions,wh ereas it is extrem ely unstable in alkaline solutions. Zilva 9^tells us that ultraviolet light in weakly acid or in neutral

solutions has very little influence upon the antiscorbuticcomplettin, but speedily renders the complettin inactivewhen the solution is weakly alkaline.

Of course these hypotheses do not exclude the possibilitythat the substance may also contain other unsaturated groupswhich may lose their activity in some other fashion throughthe operation of heat.

Beyond this, we have nothing positive to say regardingthe nature of the antiscorbutic complettin. Delf

8o6 hassuggested that we may have to do with a special enzyme,seeing that it is sensitive to temperatures which denature thepro teins . B ut ou tside the living body, it is jus t as sensitiveto the much lesser heat which is the optimal temperature forwarm-blooded animals, and we are therefore led to infer thatthe process whereby it is rendered inactive when heated mustbe of a different na tu re . Fiir st l87, 203 declared a good m anyyears ago that this complettin could not be indentical with

any of the familiar forms of proteins, fats, carbohydrates,salts, or enzymes.

Funk2O5 seems to have been inclined at the outset tobelieve th at C w as identical with his vitam in, and Freise 391

regarded it as at least akin to the vitam ins. Th is the ory w asto some extent supported by the frequency with which beriberiis complicated with scurvy, Il 6 5 and also by the fact that inpreparing the vitamins small quantities of C are precipitated

w ith these. Subseq uent investigation has, however, shownbeyond a doubt that we have no justification for assumingthe identity of the two classes of complettins, for they differextensively in respect both of chemical properties and ofphysiological effects.




The non-identity of C w ith th e fat-soluble com plettin Ahas been established by a large number of investigations.491* 75°»751. 754, 805, 831, 1194 So h a s i t s n o n - id e n t i ty w i th B.491* IIl6 »1153, 1194

At this juncture, therefore, we can say nothing definiteas to the nature of the antiscorbutic complettin.

6. THE PHYSIOLOGICAL CONSEQUENCES OF

C D E F I C I E N C Y .

a. Clinical Picture.

Thu s when the re is a lack of C in the diet, a chara cteristicillness arises, th e disease know n as scurv y. In m inor cases,those running a subacute or chronic course, scurvy is oftenconfounded with other disord ers; for example, m an y slightcases of infantile scurvy are mistaken for rickets. Thesymptoms of the initial stage are anaemic and cachecticmanifestations, such as loss of weight, fatigue, drowsiness,disinclination and incapacity for work, mental depression,peevishness, etc. The em aciation m akes rap id progress, an d

at the same time th e skin becomes pale, flaccid, and rem arka blydry . The re are pains in th e joints, especially in those of th elower extrem ities. In this stage the disease m ay re m ainarrested for a considerable pe rio d; an d since in childrenduring the phase of growth there occur in scurvy disturbancesin the normal process of bone formation, it is not surprisingthat the illness should be confounded with incipient rickets.But even in this early stage there are pathognomonic symp-toms in the form of haemorrhagic manifestations, which insubacute and chronic cases of scurvy strongly resemble thoseof purpura.

In typical attacks, after about a fortnight the signs ofthe haemorrhagic diathesis become conspicuous, there beingin mo st cases a characteristic affection of th e gums. Thesebecome bluish at the edges, and are greatly swollen, so as toproject around and between the teeth . Th e tumefied gum sare extremely sensitive, bleed at the slightest touch, and

soon begin to ulcerate. As th e swelling increases, th e gumsbecome necrotic, and assume a whitish or a brownish-blacktint here and there, the ulcers being coated with evil-smelling



266 VITAMINS

greyish-white masses. The teeth are loosened and decayed;mastication is impossible; the breath is horribly foetid.

Whereas in purpura, the haemorrhages begin in tin? subcuta-neous tissue, and only extends by degrees to the gums andthe rest of the buccal mucous membrane, in scurvy they areconcentrated around the teeth and around neglected roots,so that the observer has the impression that the trouble startsfrom the teeth. Apart from th e affection of the gums, thesigns in the mouth are merely those of slight stomatitis withmoderate swelling and a little bleeding. In severe cases thereensue, to the accompaniment of moderate febrile manifesta-

tions, other haemorrhagic symptoms, such as purpuric patcheson the skin, intermixed with lichenoid or herpctiform eruptions,large ecchymoses, and also non-haemorrhagic bullae. Incontradistinction to purpura, the eruptions in scurvy have astrong tendency towards ulceration, the ulcers being largeand sluggish ; sometimes they are very deep, and when theyare situated in the flexures of the joints they are apt to leadto contractures should the patient recover and cicatrisationoccur. Haemorrhages may occur in various other pa rt s ;when they are superficial, they are prone to suppurate, areextremely painful, and are often attended with considerableirregular pyrexia. Should there be any prt:existent scars inthe bones (the seats of old fractures) these are apt to soften.In many cases, the articular ends of the hamm and thecartilages of the joints become diseased and the synovialmem branes grow dry, and these changes may lead to permanentstiffness of the jo in ts. The bone affections may even result

in the complete separation of epiphyses. Sometimes, gener-ally as an early symptom, there may be severe haemorrhagesfrom the mucous membranes like those that occur in haemo-philia ; among these, epistaxis is the most common.


The haemorrhagic symptoms are not difficult to explainon the supposition of a change in the walls of the capillaries,

perhaps accompanied (as in haemophilia) by a disturbance ofthe process of coagulation of the blood. On the other hand,there is as yet no explanation of the characteristic affectionsof the bones, which enable us after the lapse of thousands of



TH E ANT ISCORB UTIC COMPLETTIN C 267

ye ars to ascertain from an examination of the skeleton th atth e person to wh om i t belonged had died of scurvy, or else

h ad recovered from a se ve re attack of the disease. Th ere areno othe r organic ch an ge s of a specific na tur e. The atr op hyof the glands and the general emaciation, do not differ in anyway from what we see in other grave disorders of nutrition;an d we m ay assume t h a t they arise because a scorbutogenicdiet is usually poor in B as well as in C, so that they are notin any wa y peculiar t o C deficiency. Fu rtherm ore, thoug hoedem a is comm on in s cu rv y , it is common in all th e deficiency

diseases, and is therefore nowise characteristic of a lack ofthe antiscorbutic complett in.

Owing to the atrophy of the glands, there is an arrest ofth e digestive se cr eti on s. In severe cases, ther e is completeachylia, and the salivary secretion is greatly diminished,having usually a strongly acid reaction. 6 ^ These secretorydisturbances naturally favour the onset of gastro-intestinaldisorders as com plicatio ns. On the other hand , everythingwhich makes a special claim on the bodily activities, predis-

poses to the disease, and this statement especially applies tointestinal disorders,1 0 6 6 a deficiency of the food in calories,febrile disorders,10 0? a n d vigorous growth.Io87> "78 As in thecase of the other deficiency diseases, the adrenals are excep-tions to the general rule of glandular atrophy, for they undergohyp ertrop hy, while als o exhibiting a partial fatty degeneration,especially of the cortical layers.n77, ™ > *

Except for the reduction in the number of erythrocytes

which is ch ara cte risti c of the haemorrhagic diathesis and especi-ally of its haemophiliac forms, changes in the blood are notconspicuou s. Th ere is , indeed, almost invariably a declinein haemoglobin richness,I242 such as is usua l in anaem ic state s ;an d there is an inc re as e in the urea.577 Although the resistanceof the organism to infections is so greatly reduced, the Cdeficiency does not lead to any changes in the serologicalco nst an ts of th e b lo o d . 9*7, » »

As regards metabolism, the nitrogenous balance is usually

negative, and, in acute cases at least, there is retention ofphosphorus and calcium—but these manifestations are notespecially ch ar ac te ri st ic of C deficiency. All th e pa tien ts,at any rate in the early stages, and as long as the mental



268 VITAMINS

debility has not become excessive, exhibit a vigorous cravingfor fresh nutrients, whether meat, milk, fruit, or vegetables.I009

McClendonXI2

9 is certainly right when he insists that in astate of nature this craving must be one of great survivalvalue for m en and anim als. Am ong th e Am erican soldiers inthe trenches, when their rations were restricted to chocolate,eggs, dried milk, and sugar, worked up into a sort of biscuit,he noted that this craving became overpowering within twoor three days, and led them to refuse their rations.

The need for the antiscorbutic complettin varies greatly

in different species of anim als. Pra irie dogs

X

3o° and rats havea very low requirement, and can live for long periods on adiet containing no C; on the other ha nd , some of the otherrodents (rabbits and guineapigs, for instance) are extremelysensitive to a lack of C in the diet. Ch aracteristic in thisrespect is the fact recorded by Harden and Zilva II05 that fora guineapig weighing a few hundred grammes the sameproph ylactic dose of C is requisite as for a m onke y weighingtwo or three kilogrammes. Fu rtherm ore it would seem th at

young animals of the same species vary in their requirements,and this has led some authorities to formulate the hypothesisthat at birth animals must bring with them from their mothervarying stores of C, th e difference between one litt er and ano therdepending upon the supply of C to the m othe r during pregnancy.

c. R eciprocal Relationships between G and inorgani cSubstances,

Our account of this matter would be incomplete unlesswe drew attention to the fact that the full ef&cacy of C cannotbe developed unless the diet contains inorganic salts in suit-able proportions. H oist and Frolich 65 state that calcium saltsare useless in scurvy unless C be also supplied, but that a lackof calcium interferes with the rapid and effective action of C.

There can be no doubt th at the onset of scurvy is facilitatedby the circumstance that most of the nutrients which proveto be scorbutogenic are deficient in inorganic bases as wellas in C. W hen Fii rst 1 0 2 says that nutrients whose ash isalkaline can also give rise to scurvy, an error underlies thisassumption that the inorganic bases are of no value in nutri-tion. All th e ash analyses quo ted by Fiirs t are fallacious,



T H E ANTISCORBU TIC COMPLETTIN C 269

for recent investigations have shown that the nutrients (peas,lentils, and almonds) to which he refers, contain an excess of

acids, this excess be ing especially m arked in the pulses. Onth e o ther hand , we ha ve a r ep ort from F un k 5*7 to th e effectthat in certain cases of scurvy the administration of sodiumbica rbon ate ha s pro ve d useful. Some of the features of thepathological anatomy of this disease, especially the bonedisorders and the oedema, indicate that acidosis must playa part in i ts production.

Florence IX5

6 has published a speculative paper in which

he contends that a lack of sulphur may perhaps play a partin the causation of scurvy an d infantile scurvy. A lthoughthis writer has not done any experimental work in order tocorroborate his theory, there may be some truth in it , formany of the scorbutogenic nutrients, and the cereals inespecial, contain ina de qu ate qu antities of cy ste in; others,such as meat, part with some of their sulphur when stronglyheated, and thu s becom e inad eq ua te in this respect. Perh aps

such a lack may in part explain the malnutrition.

d. Form s of Purpura in relation to C Deficiency.

The various forms of purpura, and especially purpurasimplex, are to-day regarded by physiologists as the outcomeof chronic m aln ut ritio n due to C deficiency. This theo ry isconfirmed by the fact that the most successful treatment ofpu rpu ra simplex is dietetic. Although serum, gelatine, and

calcium salts, are sometimes given by injection in the hopeof increasing the coagulability of the blood, the value ofthese remedies is m uc h d ispute d. As regards diet, lemonsand other raw fruits, salads, and green vegetables, are foundto be the most useful nu trie nts . In purp ura simplex a curecan be effected by these means without confining the patientto bed, but absolute rest in bed is essential in the graver formsof purpura haemorrhagica if extensive extravasations are to

be avoided.

6. MODE OF ACTION OF THE ANTISCORBUTIC

COMPLETTIN.

No definite opinion can as yet be uttered regarding themode of action of C in the anim al organism. I n scurvy, as



270 VITAMINS

in most of the* deficiency di-M-asrs, the re is pr ob ab ly a com plexof cau ses at work ; f«»r instance., th e p ecu liar " fragility " ofthe tissues upon wliicrli the liability to haemorrhages depends

is probably favoured by aritlusis. But the latt er cannot bethe ma in cause of the disease, for, a s w«* hav e rep eate dly hadoccasion to note, scurvy may arisu when the diet is rich inbases.

The bone diseases characteristic* of srtirvy bear a certainresemblance to those whith ocrnr as a M'ljnrJ of A deficiency.The similarity is, howev er, very Miprrficiai; and th e twocomplcttins, A and C t are sharply dintingui hvt\ on«- from theothe r, esjwrdally by their behaviour to wa rds alkalies. Wem ight rat he r be inclined to look u p m acidoîs ;i.s the catise of

the bone disorders, but we have seen that acidusis cannot beregarded as the main factor of snirvy.

The negative nitrogenous balance, tlie uktrrs, etc., mightbe ascribr*d to a deficiency f*f the growth rnmplettin B. butwe have already learned that thin cample!tin k not alwayslacking in seorlmtogerik diet1-*.

We have, then* tn do with a rharaeteristic syndromedependent uj>on a tlffic-iency r*f an unknown sutistttncc orclass of sulistanrej* to which we Rivtr t\w tt,mu* of the tompicttinC, Bu t it rem ains diibioiin wh ether all th r phen om ena of

scurvy can as yet be cuin|iriM?d under a unified outlook.



CHAPTER EIGHT

MALNUTRITIONAL OEDEMA

i. CLINICAL PICTURE.

I N the accounts of the deficiency diseases previously considered,oedema has frequently been noted as a complication, and wehave seen that in certain circumstances it may attain suchproportions as to dominate the clinical picture. This happens,for instance, in the case of wet beriberi. I have, however,been careful to point out that the oedema was no more thanaccessory, and was not an essential feature of the disease.

There are, however, many facts to indicate that oedema mayoccur from defective nutrition as a primary disorder. InFrance, and still more in Central Europe, during the warmalnutritional oedema came to be recognised as one of theconsequences of wartime feeding, and has now to be describedas an independent clinical entity. We shall find that experi-ence gained in the study of the other acomplettinoses will beof considerable value in this connexion; and, on the otherhand, that an accurate study of malnutritional oedema willthrow light on the etiology of the other acomplettinoses.

Apart from local oedema, due to local causes or to suchnervous disorders as hysteria, it has been customary to recog-nise three varieties of oedema, dropsy, or anasarca, whichoften pass into one another, though in isolated cases they mayappear to constitute distinct types. Firs t of all there is renaloedema, due to the blocking of the uriniferous tubules inconsequence of ^generative changes in the kidney tissues,

or in exceptional cases to grosser mechanical obstructionssuch as those caused by renal calculi. Secondly we have thepassive oedema that arises from an insufficiency of the arterialwalls, perhaps from organic changes in these (hyaline

27 X



2 J 2 V I T A M I N S

degenera t ion ) , o r i t may be caused by an abnormal f a l l i n

bl oo d- pr es su re . N au H ifi ji 's p as si ve t t-clt*zia;i m a y he du e to

a met ha ui ra i i r la x . i t io n of th r w al l* of the b loodvessels ,es pe cia lly w ln-ii th e y art* no t sulto j«-nt ly .m i n i b y the* su rro un d-

ing n*uvrh-\ as happru ' - . to UIOM* wlm sit or stand for excessively

lon jj period** wh» ii a t w o rk in f a r to n e - s ?>h<*ps, c#r c4fkt?s.

W h en pa ssi ve eoiiir*-.! inn 1M S la ^t rd a ln n^ tini*\ i t m ay react

tijHin th e h e a rt , whirl* l ias m ^ jr w ui k thn r* t uj*un i t in the

a t t t i u p t t«> <Irivt* th«* M«««! thiou j^h th«* n- la xr ii an d di lat ed

v r s s r l s . T h u s w r f*t*t a tr a n s it m » to th** th ir d f«*nn, wh ich is

k no w n a* carcliar. t***drina, In tar d ia * wwU*uui , \ \u* hear t

has fai led, i t may hr int thr i tM«.«*n just mentionrd, i t maybi* innn i n b o r n w r a k n e v * t* t f r o m r o n ^ i u t a l r i r a cq u i r ed

t irgai i ie defrr . ts , ti t it in a v be a% a fM inj4ir,i!iun nr M;«JIII"1 of

o th e r illiie.sM*s, to x a t ' i m a s etr*. H ov vrv rr ori |*in;tt tfd, cardiac

oe de m a is th r outt ;orm* <4 a f .ulur r of rsrr i j la f ion .

O w ing to th e arr es t **f th e blood - ' - ' t i ram *n p u î v i ; oedem a

or card iae ordenia* and *i \v i ru : to th r ju r . u ui*Tea.M* in th e

content t»f the bli«wjvrv (r!' . in rnial t*rileina, the v;t.M:ular

w al l^ ,snffrr# a n d th«-y al lo w v r u i n t o tr;ifi:.?$d*

#

i n t o f h rwu tif-'.i ir\ . i h iH i-x tj .tva .s it r* ! JJind ;*o;timul-ai<•:•>; r

in tin* «o nip ar .ttiv r-) y m«*n Mih«-ut;m«'otis trvM»r^, w h it h m ay

l ie t in ts swol len bryond u-*' i*£Mti**n. b u t m patt. it infiltrfittrs

t h e ti.NMi«*H of t h r t i iU*' t u it* ;u ri, In a d v a n t r d cw*, i t atxumti*

late?4 a!v-o in t h r vat iotr* bofty< . ivi t i*^ th e jo in ts, the peri-

t^neal ravi ty . the |*lrur>d *»tvi t i r-^ the {îtt:;irdi;d r a v i t y , e t c

AH the Vatlrt|«'-i of U n U ' i U t t Wir h.iVe «: ol)'-.tcl*-|i-irt in

With the delujenrv dls*';i'-.*-'% brlon^ to the tl4,'-H r»( the

ordi» ni; t^. In t-jcr«-j»!u#nal nMMirr% nnh\ as tn H«rvrrr canesof b er ilw ti or M it rv y, tin* j»a*,*4Vr i4«}t-rna m a y ^» tnr w ha t

sufldefitly |*a.^s nv«-r into r.iitlia*; *m h m n$ th u bring a Mgn

t h a t t h e h«Mft h,i% l.irrcfriir ir.xh4U%tf*fi. I h e ;ijija**ir;inCi' of

curdiar , uw lem;i an t h r fu lm uia nt fofin «4 brt i in-r t th ri6 (or «

Juntiftri a very gravr j>ro^tiMHisf for d*#ath inîy mcxtt $tl my

mimimi from heart Li i lurr , Hut nialni i fr i t joj tal cwdwna*

known in (k^niiany a/* M H t m ^ r r A d r m M ((unttnf drnpisy) is

of a w r y different tyj^% for here t h r urrlr tna tak r* the form ofsm mckpendirnt diMM.scr. l*ir»t4 then, we nnmt study theclinical iymptciin.*« and tin? patlmlMgiral rhange<i which entitleu# to luok u|K>n tin dim^m ^ an uidcpcndcut enti ty.



M ALN UTRITIONAL OEDEMA 273

Numerous reports are available for this purpose, based for

the most part on the work of German investigators.According to Jansen,6 84, 1061 ^ d to B u rg e r, ^ , "17 ap ar t

from the dropsical effusion in the subcutaneous tissues andin the various organs and cavities of the body, the mostprom inent sym ptom s are bradycardia, anaem ia, and h ydraem ia,polyuria and nycturia, a lowering of blood-pressure to 65 mm.or less, hem eralopia, an d a lowered tem pe ratu re. Sch itten-

helm and Schlecht9°9 draw special attention to the markedslowing of th e pulse du ring repose. In m ost cases, too, the reis extreme emaciation.9°a

2. PATHOLOGICAL ANATOMY.

The most notable features on post-mortem examinationare the almost complete disappearance of the fatty tissue,even in the case of the viscera,9°9 and the atrophy of theparenchymatous organs. O37, »>6if 1340 i n especial the heartand the liver are very small, and sometimes show signs ofbrow n atro ph y. The liver and the muscles are as a rulelacking in glycogen. Jansen stresses the atrophy of thethy roid . T he activities of the pitu itary body and th e adrenalsare arrested IO37» I

3l 6 ; the adrenals are usually hypertrophied.

McCarrison actually declares that in oedema he has found the

adrenals thrice the usual size, but he is probably referring tocases of beriberi.I3I5

The most notable characteristic of the blood is hydraemia.In consequence of th is, th e refractive index is gre atlyreduced i

l6>

I2 J7 and the specific weight is also much lowered.Th e dried residue m ay be as little as 20 % or even 15 % of theaggregate blood.IZ I7 As a rule, the w ater is abo ut 10 % above

normal, and therefore the protein concentration is reducedboth relatively and absolutely.716 On the other hand, theresidual nitrogen may be normal, or may be increased byas m uch as 30 %.7l6> 9"> *°61, ia l7 Feigl 7X* found in patientsstrictly dieted in institutions that there was hypoglycaemiato an average extent of 40 % , bu t th a t w hen th e p atie ntswere able to feed as they pleased the ratio of sugar in the



274 VITAMINS

case Jansen found th a t then* was only n-u\%. Tin* fattyacids in the blood ant considrrablv mint***!,?1* ami *••*> r* th e

aggregate fat.1*1? According to Ja iw u," '* 1 th«« uir;i t**ntrtitis no rm al. The lipoid phijsphcjrits is u'«lu«'r«1.5tM- J*J? but th«acid phosph oru s is incmiM-d. 111?: l i . iviwmhAtin mhnrv* ofthe blood varies greatly, and ,so i luvs th«* I4*««i *•t*unt both <4the crythrocytes and of ihv Ivncncytv><. Hi* .irrtoiiv nmtt-ntof the blood is always somewhat itim-aMM-l.^'1

According to Feigl,7If> thtrr is in timst * 4 * * art tticrtsi.scin the krcatin richness of tht» Wuorl. at any taiv in thr «MiIy

stages of the disease, but a t!tTlin«

f

in th«- kt*

v

. itunn ruhn*-^.In con form ity w ith tliis In* finrlî H» .1 fulr , ;%ui n u r i t * lam m onia richness. Relatively, tl w U <- * - cU^h'sti'Sin in tl#t*blood is usually increasrd, thta^h ihn*- nw v b«- ,1 «!«•«Irti*- inth e ab solu te q u an t ity . (*ho!t:*t<*rui «^t«-r i** Jt*$m*l in abnor-mally small quantitiirs. l lwn* is ^mwUtuvi aincrease in the anumnts of %udnun <• hlîid*-, r.isu lp h a te s ; but there m ay also }»•? a f,iJl$ni.: *>li 111 fl**-of calcium. Iron, and esjHriaUy t^hmuh ai*r v*

nota bly diminihhecl. {Tlitvse rrjw4i^ ar«* t n lr*4adequate to the cnntemjHirary i4,»in«l4i#.i'» «4analysis!]

Very little infcirniation has hr«ii jtubhOi^l fr^»ir<l!iif{ tinecomposition of the urine irj cani-s oj jiwliinuifi^n.*! r^4r$iia.All investigators are a^rei<*| that ih** »uif|ity »4 th»- um$r t.»extrem ely v ar iab le, In a rr si-a rth *4 m y *»wr». I hmi4 *igreat increase in the ausmnnia hrhm*v» «-4 thr urtnr {tfi^

ammoniacal nitrogen anintirttinK t« ^;p

,, «4 th«* futw ith a re duc tio n in t he tir«*u nrhfu'si*, A htl!«* mr tpresent. Feigl v*>also {fointr* ou t tlia t th r tir tu r ycontains kreatin.

Corresponding with Xlw atrophy of thr i;l;iiirl^ ilirrr $•* Agre at falling-off in the ac tiv it y <*f thrw? ci rân ^ nti«i $« *-Mmm uilong du ra tio n th er e m ay be nrhylia,*** Tht> t*x|44infi li pfrequent occurrence of g;tHtro4ntrstinal thwulzt*cat ions.^* wi7* » ^ J*f7

3. PK

Generally speaking, the pragntmiJt iii (avriiifAMc, % m U mcardiuc oodema should develop, whkh b (ollvwctl by dc**lti



MALNUTRITIONAL OEDEMA 275

from heart failure. The first essential of trea tm ent is restin bed. Next in importance comes a change of diet, bu t

views as to what should be the nature of this change varyfundamentally, the variations depending on the differences ofopinion presently to be discussed concerning the dieteticfactors of the disease. Some insist th at the supply of proteinsshould be improved ; others emphasise the importance of abetter supply of fats or carbohydrates or both. Some thinkthat to increase the vitamin in the diet is of no av ai l; othersstress the need for the provision of a sufficiency of B ; andso on.

4. METABOLISM.

a. Nitrogenous Metabolism.

Passing to consider the; details of metabolism in thisillness, we find Nixon l5

58 reporting that the nitrogenous

balance is maintained. Janscn loCl and Burger »*7 found anegative nitrogenous balance in cases where the supply offats and carbohydrates was inadequate, and Burger claims

to have noted a moderate decline in the protein turnover.This last may perhaps be connected with the fact observedby Schittcnhdm and Schlctcht?12 that in persons sufferingfrom nainutritional oedema the organism manifests an intensenitrogen hunger, and that for this reason the utilisation of theproteins in the food is comparatively effective. No notableabnormalities have been noted in the fat or the carbohydratemetabolism. Observers have been unanimous in recordinga markedly negative calcium balance ; and Burger also refersto the phosphorus balance as negative.

b. Sodium-Chloride Metabolism.

An in all varieties of oedema, interest has been mainlyconcentrated upon the sodium-chloride metabolism. But inthift connexion the medical publications referring to the matterhave repeatedly displayed lamentable ignorance of long-familiar facts concerning the way in which the various ions

act on the urinary apparatus. For more than th irty yearswe have known that the sodium ion has a paralysing effectupon the activities both of the kidneys and of the ureters*



VITAMINS

a n d attordinf* t o t h r mo n - a^rut (though n*4 -r* V«TV n r r n t )

re se ar ch es of A m er ic an ph ys iol og ists , thi* is r« |i ii iUy tni«- «»f

th e ch lo ri nr km . Kos<?# mo re o v e r , h a s p ro wd b y t -x p rh *

m e n t #*i« 7° th a t w he n th e o rg an is m is JWHIF in :-«««liuin rhl«»nd*\

do sag e w ith th is sa l t redu ce s th e vx crct i nn of tm n«\ Tht*

di sc ov er ie s of M ag nu s- L ev y ***** havtr thr t«'f nrr «!r4i«* iiî iti**r**

than ronf tnn fa r t s tha t lu iv r* IOUR l»**-n rs t,» !4 j'Ji rd , In m y

own wr i t ing I havr a lways in^ i^f r* l tha t th« ' r%<t^ i i* m * 4

socisufti thlr*rid<* is a sk*\v lnisiu«^s # and tha t in j^rrs^n4* u*ho

have* h**f*n acTU^tomrci to amount* an ahundam-r «4 f«.4nm<»u

^ i l t r r n a n th s o r y«*ar **f r|»'j»rivatj<in rnnvf «-}4jf.*- VrJ . , | r ih r

stores cif smlitt tn chlurid* ' in th^ U * \ y a i r *lfj»J«-tfd. If tihiy

th er e fo re be* tak<*n an a m a t t e r «4 «u iif .r th a t w h r n ^*-d*-m.-t

st*tH in in a p er so n w h n v r di *i r*»nt.imH a h J^ x.i l ^t?pj*ly *•!

conn mem sa l t , thfR* will ahvay -* !».* a r«*trnti<>n «*f th r* ' .ait-

s t a n r tt in tht* b o d y A s a ina tft- r of f*xj«*ii«*tKT, all «»!>" rvrf*

arc? a g r a t l t h a t in m al n ut fi ti *i n al rK^JfiiM tjj*-t«- r-- »* j**if|jti*»n

of sm ii ti in rhlfirid** b y tin* b o d y , a n d tl i.i t w brt s lit*- **»-<}r'in4

th«*nr is a p ru fu sr i*xrr rtk*n «4 th«- '-"ilt. l'u f|. ;r r

t h a t wh**n th e rn -rlnn a wa.% ^»-it»ur in , i h r t r UMH

m a r k e d c r a v in g fo r M edium *-fil 4id*% alth«*uf.*h ,r< itnuh ;r*

12 g r a m m e s u v r r bi-irn* ron%un^"'d d-uJy. "lii** r^j*l,iii.ifi«»nd o u b t l e s s k t h a t d n r iu i : th»- o m H r.»f iT3.iliiii!fitioii;iJ *r#r*lriii^#

an during that of all th<* maladif^ d r j ^ n d ^ i i t \^m nn ill*

b a l a n r t t l d i r t , tht-r^ {(r ad na liy »iti *.% a !*•« »>l rtjijwtit**,

and som et i fn ts a }w 4t iv r loa th ing f >r f ^ ^ l . ih** j*4i?rnl

th en a t te m p ts t o st i i i ni la tr apjwti!«* by o v n '^, iv?iii?i |* fh«?

F o r t h e rr\f# i t would «;wm Out %

li.sin i^ normal during m»i1ntttritii»n fiJ f-*ntjrm.t ;

'hn and hrh1* '*ht '% ob^rv-i t i^n^* 1 t l w tof the s i l t h '-.omewhat r«-tard«.'fJ in tht** d

t o confi rm t h r f;i^t. Kna«-k a n d N r , $

a.ncl KottiHtrtn $ t t | s .it** a ^ m - d th a t th** iso ta trr l a «Im mt.n tration

nf w at er dm«-i no t p ro m o tf t in- tttmihn of w,it^r, ittid tlmi

the iwlatarJ ndminj^tr ; i t^«n nf wJmtf* rhl«ri*l** *W:% not

f! th e re ten t io n of vxt iu m t h l o n d r ; r»nly w hr n «t«}itt in

ta g iven in w at r r y v4 tn$on , * k w% th<^rr ocnir a rrtun*

l ion o f bo th wate r m 4 sodium r-hl«>ri*lr.



MA LNUTRITIONAL OEDEMA 277

5 . D I E TE TI C FA C TO R S O F TH E D I SEA SE .

a) The pathogenic Diet.

Opinions are diametrically opposed concerning the natureof the pathogenic diet . There is har dly an assertion in respectof this which is no t disp uted by some rival au th or ity . It isobvious th at the person al bias of the variou s writers has playeda considerable part in dictating their respective assertions;what one describes as an abundance is referred to by anotheras a quite inad eq ua te quan tity. Most observers are agreedin stating that the calorie content of the pathogenic diet istoo low 684, 9°*. ™ i* ™58; b ut according to Schittenhelm andSchlecht,9« th is ha s no t always been the case. W e are often

told tha t t he su pply of pro tein h as been to o small,9°^ 91

*. "96

>»*5, 1258 the daily am ou nt rang ing in th ese insta nce s from41 to 74 gram m es. Acco rding to Liebers,IO79 however, theprotein co nte nt of th e diet was sufficient: in pea cetim e th eamo unt of protein in th e ho spital diet ha s been 77 • 33 gramm es ;in 1916, i t fell to 50-53 gr am m es ; in 1917, i t was 6 0-26grammes; and in 1918, i t was 71*05 grammes.

Many authorit ies incline to regard a n excess of carb ohy dratesin the diet as injurious 9°*> I3 I7 ; bu t Janse n 684 reports a cureby a l iberal sup ply of carbo hydra tes. Others consider th a t

the fats in the food were deficient.91*, Io64 According toBurger,la l7 i t was not always possible to demonstrate thatthe supply of inorganic salts was inadequate.

German writers in general are agreed in insist ing thatthere seemed to be no lack of complettins in the diet 639> 9°2»912, IO64J 1235, **5»; w he rea s th e B ritis h au tho ritie s refer to th elack of accessory food factors IO37, ™ s6 ; and according toBurger la i7 the complett in content of the food was primarilylow, an d th e deficiency w as often exag gerate d b y fau ltymethods of preparat ion. K oh m an I o 8 6 and Nixon "5 8 stressthe disproportion between the richness of the food in waterand i ts lack of solid con sti tuents. Ko hm an, working aloneand also in collaboration with Denton,784 saw dropsy arisein cases in which carrots were being consumed in conjunctionwith an abun danc e of fat or starch, bu t in which a cure resu ltedon the adm inistration of casein and calcium s alts. Thereports of H. de Waele IX 96 and Burger 9°* contain typical



278 VITAMINS

instanc es of diets leading to m aln utritio na l oedem a. Acc ordingto <le W ad e , in a F rrn ch ahnshousi* tin* di rt comist« d of

soup and bread, or soup and potatoes, with br.in.^ an«l fattwice a we rk. In Burger 's rases, the pa thn am e: diet wascomposed of bread, vegetables, and a small quantity uipotatoes, with a little lard, and small amounts of pi* kkxlor sal ted meat .

There is general agreement that strenuous physical lut 'curpred isposes to th e dise ase . Burgerv*>2 (see also i iV ») ui*iivnthat among persons consuming the same amount of raluiir .s ,tho se who did t h e ha rdes t w ork were the first to fall ill ; andthat when the supply of calories varied, the persons whosediet was most deficient in this respect were the first to br rumeaffected with the disease. AH in the ca.st« of scurvy, pn drtion arises from anything which increases the bodily(hard work, very cold weather,% febrile disorders), and fromany thing w hich tend s to hinder absorption (gantiy intr 4i ia ldisorders).

h. Wartime Feeding,Sporadic cases had occurred earlier hut malnutrit ion*!

oedenia first assumed an itpidennc pR'valentt* m Gt'iiuaityduring the summer of 1.917,

im$ when tin? t l iH ui th« |w*»pk

was cha racte rised by a lack of fats, h igh-g rade pf trie ins, j**t.vtoes, and fresh vegetables, except for kohlrabi, wht«:h wmab un da nt. Du ring the subseque nt y ea rs, tin? Kt-mtAi di rt,and especially thu diet in institutions, was still grrafly l*ii,kif?g

in fat, high-grade proteins, {xitatocs, and i w > h vrgrlablcai,whereas cereals (which had to a considerable: e x trn t U-rndegraded in value—see abovu p, zit), kohlrabi^ M U I verypoor soup-powders or ^mp-tablets, and dried vqgrtablr*,predom inated. To com plete the picture it h n^cimâty tomention that as a rule, and doubtless invariably in itiMitistioiw,the boiling of the kohlrabi was exce&sive, and that the waterof the first boiling was thrown away ; alao that in the factorypreparation of dried vegetable*, the fresh vegutabitr* had

been treated with steam before drying.1*** W e mit^t tmtwmUtr ,moreover, that the abundant consumption of kohlrabi tnducvdin many instances neverc intestinal irri tation, whereby theutilisation of the food was greatly




c. Prison Dropsy.

So-called famine dropsy or malnutritional oedema is by

no means a new disease. As long ago as 1907, Hoist 65pointed out that, in the beginning of the nineteenth century,dropsy was exceedingly common in the jails of Europe andNorth America (see also *554), so that , among the causes ofdeath in pr iso n, dropsy sometimes took the first place. Big-land,10*? who studied malnutritional oedema among prisonersof war in Egy pt, was able to compare the disease with th efamine dropsy he had seen in India, where it has long beenknown that dropsy is a common sequel of the frequentlyrecurring famines.

d. Ship Beriberi.

Hoist and Frdlich,65 who have studied the old reportsconcerning prison dropsy, consider it to have been identicalwith th e so-called ship beriberi. Rumpel and Knack 571have co m e to th e same conclusion. Nocht,43 who is thegreatest authority on ship beriberi, gives a description of it

which assimilates it in every respect to famine dropsy. Italways runs a chronic course, and even in the comparativelyrapid ca se s it lasts for several weeks at least. The initialsymptoms are nausea, lost of appetite, constipation, andgeneral d eb il ity ; then comes the characteristic oedema,beg inning in the feet and ankles, and slowly but surely spreadingupwards. Ultimately, owing to the extensive swelling andthe consequent palpitation and dyspnoea, the patients areforced to take to their beds, and die from heart failure.

Associated symptoms in many cases are severe gastric dis-comfort, gastra lgia, and even hacmatcmcsis. Among nervoussymptom*;, hemeralopia is common, and there may be alsoslight paraesthcsias in the feet and legs. True paralysis isnire, and when it orrurs may perhaps be due to a complicationwith g enuine beriberi ; just as an eruption of vesicles in themouth, and the tendency to moderate haemorrhages, some-times svi'.n in ship beriberi and famine dropsy, suggest atornplirtttion with scurvy. The only point in which ship

brrihrri resembles true beriberi is the,"occurrence of paraes-thesiftf in the former as well as the la tt e r/ b u t these are by



28o VITAMINS

no means characteristic*. Kveryone who lias to sit still fora long time is familiar with the onset of such paraesthesias,which may become intolerable even in healthy persons.

This description of ship beriberi seems a mere plagiarismfrom the description of famine dropsy. There can be nodoubt that prison dropsy, ship beriberi, and the malnutritionaloedema of the war years and of the Indian famines, are oneand the same disease. The treatm ent which is found mostuseful for ship beriberi confirms this supposition, for herelikewise rest in bed is the first essential and change of dietthe second. Ju st like the pat ients suffering from m alnutr i-tional oedema, those affected with ship beriberi recover withmarvellous rapidity, so that they can be discharged fromhospital in a week or two, and in slight cases can even resumetheir work on the ship after four or live days. In 190B, a tthe first congress of the German Society for Tropical Hygiene,Nocht 74 pointed out th at even in Germany atta cks of illnessresembling ship beriberi were by no means rare, and mustbe due to defective nutrition.

A. W. McCann '55* gives a g raphic description of the fateof the German accessory cruiser " Kronprinz Wilhclm/*which, after a raiding voyage which had been successful for

two hundred and fifty-five day s, had to surrender to intern -ment in the United States because the spread of ship beriberiamong the crew had made it impossible to manoeuvre thevessel any longer. But Met ann is mistaken when he supposesthat wholemeal could have prevented the trouble, for thenscurvy would have taken the place of malnutritional oedema*This warship was conquered by the food-preserving industry !

The diet which induces ship beriberi is closely akin tothat which causes malnutritional oedema. It consists of

flour and bread, peas or beans, dried potatoes, tinned orsalted meat, and preserved vegetables* In German experiencethe disease usually makes its appearance on shipboard whenthe store of fresh potatoes has been exhausted, and the crewhas had to be fed on dried potatoes for a time. Hoist an dFr6lich*5 and Schaumann,1** who record this observation,state also tha t the* continued d iet of preserved foods soonbecomes so distasteful, that many of the crew restrict theirconsumption to a few articles (especially bacon, bread, meat,




and preserved vegetables), so that a diet already ill-balancedis thereby yet more restricted. The same phenomenon hasbeen noted in many cases of malnutritional oedema in Ger-many. Moreover, every doctor will be able to recall fromhis personal experience the cases of a number of neurasthenicpatients who lived on some such extremely restricted diet

in the conviction that they could not tolerate other foods.Arneulle Xi28 maintained as recently as 1920 that malnutri-tional oedema in Germany occurred only among the prisonersof war. This gross misstatement must, of course, be ascribedto the war psychosis, by which, unfortunately, other notedscientists have also been afflicted.

6. CONTRIBUTORY CAUSES OF MALNUTRITIONAL

OEDEMA.

a. Microorganisms.

From time to time it has been contended that malnutri-tional oedema must be due to microbic infection, but thedietetic causation of the disease is so obvious that suchtheories have never secured wide acceptance.

Jiirgens 5°*considers that malnutritional oedema is directlyor indirectly due to infection. He holds tha t th e ill-balanced diet gives rise to gastro-intestinal disorders, and

that microorganisms may then invade the tissues, or mayproduce toxins which are absorbed from the alimentary tractand thus injure the tissues so as to give rise to oedema.

Writing in 1917, Nocht,637 in view of the then state of thecomplettin doctrine, left the question open whether shipberiberi was the outcome of a special form of malnutrition,or of an intoxication by damaged nutrients or by otherpoisons, or of some form of auto intox ication.^ W uth 88°considers that the cause must be a true toxin, quite distinct

from haemotoxin, and characterised by marked lecithinophiiia.Smith 479 in like manner assumes autointoxication to be thedirect cause of glaucoma, a local oedema.

b. Inadequate Supply of Energy.

Most authorities on diet are prone to regard a deficientsupply of calories, and the consequent disintegration of the



282 VITAMINS

bodily tissues, as the main cause of malnutritional oedema.684»902, 1217 We hav e seen, however, tha t m alnutritio na l oedemamay arise in persons whose diet has a fully adequate calorie

content, and we are therefore forced to conclude that caloriedeficiency can at most be an accessory factor, one which maypredispose to the disease and may reinforce the noxiousinfluence of th e main factor. A gen eral deficiency of nu tritionhas been assigned as the cause.639> 91*, 9*3 B u t b y pari ty ofreasoning this can be no more than an accessory factor.Absolute starva tion does no t cause oedema. Some authoritiesrefer to protein insufficiency io86 or inadequacy 784, 90* as th emain cause, bu t othe rs contest th is view.IO78, "96 One au tho rityconsiders that an insufficient supply of carbohydrates is themain dietetic defect,1061 whilst o thers speak of an excess ofcarbohydrates as responsible.90* Burger, I2I7 who believes aninsufficiency of calories to be the main cause, thinks also thatan ill-balanced diet containing an excess of carbohydratesmay favour the onset of malnutritional oedema by its tendencyto promo te th e retention of wa ter. [The carb oh ydra tes arenot stored up in the body, and therefore cannot promote the

retention of w ater in the tissue s; on the con trary, it hasoften been possible to detect the presence of hypoglycaemiain this disease.] W hereas Maase and Zondek Io64 regard alack of fat as the essential cause of the disease, Jansen Io6r

reports that although the supply of fat was sometimes insuffi-cient, it was in general ad equ ate. Bigland IO37 speaks ingeneral terms of an insufficient and ill-balanced diet, withoutsaying precisely in w hat way the food was defective. Kn ackand Neumann 639 lay the blame up on th e excessive ingestion

ofjfluids by persons tak ing an ill-balanced die t. Kohm an Io86

and Nixon I25

8 advocate the same theory, without troublingto reflect how innumerable are the persons who consumevast quantities of water or other fluids without being troubledwith oedema, provided only that the kidneys are healthy.Denton and Kohman 784 are inclined t o regard a lack of calciumin the diet as a possible contributory cause.

c. Complettin Deficiency.Most investigators, as I have already said, incline to

exclude a deficiency of accessory food factors as a cause of



MA LNUT RITIONAL OEDEMA 283

malnutritional oedema.639,9°*, 9^, Io64, i«5. 1258 i t w ou ld seem ,however, that a lack of real knowledge of the accessory foodfactors has led many of these authorities astray, for it isplain that in a number of instances they are thinking only ofFunk's vitamin. Sometimes a contention has been putforward which is in manifest conflict with the data reported

by th e assert or himself. For example, Burger 9°* rejects thetheory that a lack of " vitamins " can have caused the diseasewhen the diet consisted of bread, pickled meat, salted meat,lard, kohlrabi (which had obviously been boiled in the usualmanner), and a little potato—this being a regimen practicallydevoid of all accessory food factors ! K oh m an Io86 will nothear of a lack of A as a cause, finding that to supplementthe diet with an abundan ce of bu tter mak es m atte rs worse,whereas an abundant supplement of B does not increase the

dropsy. McCarrison,I34<> on the other hand, insists that buttercontains a substance which has an antidropsical effect, andfinds that the richness of butter in this substance runs parallelw ith its richness in A. Elsewh ere McCarrison IO

56 s ta tes tha t

the lack of B in th e diet is m om ent ou s; it almost alwaysleads to ga stro inte stin al disorders, to dysentery and diarrhoea,which culm inate in oedema. In ano ther pub lication, Bu rgerpoints out that in the diet which induces malnutritionaloedema the quantity of complettin is usually very small,and may be further reduced by various method s of p repa ration(excessive or unduly prolonged heating, the pouring away ofthe wa ter in which the food has been bo ile d) ; conseq uently,we must not reject the possibility that an insufficiency of" vitamin s " in th e food m ay be an etiological factor. W henSchlesinger Il6 5 refers to neuritis as a complication, and whenNocht refers to scurvy as a complication, it is obvious thatthere must have been a lack of complettins to produce these

intercurrent disorders, and that such a lack may thereforehave had something to do with inducing the malnutritionaloedema as well. Za m brz yc ki I I 6 2 regards malnutr i t ionaloedema, scurvy, and beriberi as nutritive disorders whichhave a kindred etiology. H e says th at th e same sym ptom sare common to all three diseases, the difference being theextent to which this or th at symp tom predom inates . Inberiberi the pareses are mo st conspicuo us; in scurvy, th e



284 VITAMINS

sym ptom s of the haemorrhagic diatheses give the specificcharacter to the disease; and the most notable feature ofmalnutritional oedema is, of course, the anasarca.

d. Malnutr itional Oedem a akin to Mehln ahrschaden.

Many authorities draw attention to the resemblancesbetween malnutritional oedema and Mehlnahrschaden; amongthem I may mention Burger,9°* Schittenhelm and Schlecht,ând Maver.la*5 This is in conformity with the foregoing,inasmuch as a lack of complettins plays its part in the causationof Mehlnahrschaden. Funk 3 8 has definitely classed Mehl-nahrschaden among the avitaminoses, using the latter term

in the wider significance in which it is still current to-day (asequivalent to acomplettinoses). But in the review of Funk 'swork in t he " Zentralblatt fur Biochemie und Biophysik "(1914, 16, 758), the reviewer, who is a medical practitioner,is strongly opposed to the idea that Mehlnahrschaden,Milchnahrschaden, rickets, and spasmophilia are to be regardedas deficiency diseases.

There are certain respects in which Mehlnahrschaden isdefinitely distinguished from malnutritional oedema. Firstof all, whereas in malnutritional oedema there is a great

relaxation of muscular tone, in Mehlnahrschaden the musclesare from th e first hard and hypertonic. Furtherm ore, inMehlnahrschaden there is marked nervous irritability whichmanifests itself in the proneness to muscular spasm, andperhaps assimilates the disease to spasmophilia rather thanto malnutritional oedema. For in malnutritional oedemathere are no nervous symptoms except for the occasionalparaesthesias, and even these are probably a secondary out-come of the mechanical pressure exercised by the swollen

tissues on th e nerves. I t is no more than a chance resemblancethat, in the long run, atrophy and oedema may becomeassociated in both diseases.

7. CAUSES OF DROPSY.

a. Chemical Causes.

Obviously, by the routes hitherto followed there is nohope of reaching a clear conception of the etiology of the



MA LNUT RITIONA L OEDEMA 285

disease. W e shall do be tte r to set out from a study of themorbid anatomy, and to enquire how, in the given cases, theoedematogenic diet can hav e induced this. W ha t we hav eto consider is not any mechanical lesion of the capillaries,for that would lead to a haemorrhagic and not to a merelyserous infiltration of th e tissues. W e are concerne d w ith a

chemical lesion of the capillary walls, and with an interferencewith the flow of blood throu gh the venous system. Such a ninterference, for instance, as results from a great lowering ofblood-pressure, causing passive congestion. W e ha ve also tothink of a true hydraemia, a decline in the internal pressureof the serum, dependent upon its excessive dilution, leadingto a so-called dyscrasic oedema of a general character—toanasarca.

b. Oholesterin Impoverishment.A chemical injury of the capillary walls, just as in the

case of the walls of the larger bloodvessels, may arise in eitherof tw o chief w ays . T he first of these is b y a d isap pea ran ceof the lipoids from the cellular walls, which makes them morepermeable by w atery solutions. Such changes ensue when,in especial, any of the cholesterin compounds are lacking inthe cells of the capillary wall, either because there is a general

impoverishment of the blood in respect of these compounds,or else because the solubility of the co m pounds in blood-serumis increased.

Such a disappearance of the cholesterin esters is especiallynoted in diseases in which, in conjunction with a hindranceto the new formation of such esters, there is a hypertrophyof certain organs very rich in these compounds—notably theadren als. I n th e deficiency diseases in general, an d in m aln ut ri-t ional oedema in particular, there is such a hy pe rtro ph y ofthe adrenals. More particularly we know that in mal-nutr i t ional oedema this hypertrophy is a t tended by a fat tydegeneration of the adrenals, which means that these organsare overloaded w ith cholesterin esters. T ha t chang e alone,however, cannot give rise to impoverishment of the blood.There must simultaneously be some interference with a newformation of th e cholesterin esters in th e blood. B u t wehave no evidence of anything of the kind in malnutritional

oedema, for th e oedem atogenic diet ha s usually con tained



286 VITAMINS

an ample supply both of free cholesterins and of cholesterinesters. Moreover, Albrecht and Weltmann (" Wiener klinischeW ochenschrift," 1911, No. 14) hav e proved th at in m ost

cases, when the cholesterin content of the blood declines—as it will tend to decline from time to time when this substanceis deficient in the food—the adrenals readily surrender partof their store of cholesterin esters.

A second way of inducing cholesterin impoverishment ofthe capillary walls might be that there should be an accumula-tion of lipoid-solvent m aterials in th e blo od ; b u t in th atcase there would not be a deficiency of cholesterin compoundsin the blood itself, such as we find in malnutritional oedema ;

there would rather be an excess of cholesterins, such as isknown to occur in dogs du ring ether anaesth esia. (Cf. Bang.5<>8)It follows, therefore, that the before-mentioned occurrenceof acetone in the blood can have nothing to do with thequestion we are considering, although acetone is a lipoid-solvent.

Much more important is another consideration, a factwhich has again and again been dem onstrated . T h e ra tiobetween cholesterin compounds and neutral fat in the bloodis remarkab ly con stant. If for any reason th e richn ess ofthe blood in neutral fats should decline, there is also noteda decline in the amount of cholesterin bodies in the blood;and when the proportion of the one class of substances in theblood increases, the proportion of the other class increasesalso. This might explain why the blood is poor in cholesterinwhen the diet contains too little fat. B u t since, as far asmalnutritional oedema is concerned, the oedematogenic diethas often been shown to contain an abundance of fat, wecannot look upon this cause, either, as accounting, in general,for the cholesterin impoverishment of the blood, and thusindirectly for the origin of the oedema.

There is, however, a persistent factor in th e clinical pict ur e,one which might lead to a lack of fat, and consequently toa lack of cholesterin, in th e blood. W e ha ve a lread y seenthat in malnutritional oedema the digestive glands do theirwork badly, so that sometimes there may be more or lesscomplete achylia. This will m ak e it impossible for th e abso rp-tion of fat and cholesterins from the intestine to be effective,




and thus the known impoverishment of the blood in fat andcholesterin compounds is easily explicable as a result of thedisorder of digestion. But since the blood still retains itspower of dissolving the cholesterin compounds, it will dissolvethem out of the vascular walls (and they will then be with-drawn from the blood for storage in the morbidly hypertro-

phied adrenals). This mechanism may account for the onsetof general oedema.

But the factor we have just been considering can onlycome into operation in the later stages of the disease. Whensuch an impoverishment in cholesterin bodies gets to workas a cause of oedema, it must promptly induce universalanasarca. We have learned, however, th at the oedema comeson gradually, beginning in the feet and ankles, and extending

upwards by degrees. Not until the final stages does universalanasarca ensue.

c. Anomalies of inorganic Metabolism

A second way in which a chemical lesion of the capillarywalls may arise is through the instrumentality of the meta-bolism of the inorganic salts. Here we have three possibilitiesto consider. Firs t the blood may be relatively or absolutelyoverloaded with sodium ions ; and secondly it m ay be impover-

ished in respect of calcium ions, for this impoverishmentwould have a similar effect. In both cases there may ehsuea transudation of serum from the blood into the tissues;whereas, conversely, when the blood is comparatively poorin sodium ions, or fully supplied with calcium ions, serum willtend to pass out of the tissues through the vascular wallsinto the capillaries. To understand this we have to rememberthat, even under perfectly normal physiological conditions,

fluid is continually passing from the blood into the tissuesand from the tissues into th e blood. This transudation,however, is not a filtration; nor is it, mainly at any ra te,the result of osmosis. I t is due to secretory activities on thepart of the vascular endotheliurn, which, both from the bloodand from the tissues, incorporates substances in solution,and then selectively passes them on to one side or the other.This endothelial activity is paralysed by an excess of sodiumions, and on the other hand it is stimulated by a sufficiency



2 88 VITAMINS

of calcium ions. Oedema can be induc ed by a n ex cessivesupply of sodium io n s; and , conversely, abs orp tion from

dropsical tissues can be promoted by the supply of calciumions. (I should m ention th a t the absorption of dropsicaleffusion from the body cavities is not furthered by the supplyof calcium, which has an unfavourable effect here).

But there is a third way in which variations in the meta-bolism of inorganic salts may injuriously affect the vascularsystem. W e know th a t th e effect of acids on th e walls ofthe bloodvessels is to induce swelling and hyaline degeneration.Ev en free carbonic acid m ay have this actio n. Now , th e

oedematogenic diet always contains an excess of inorganicacids, so that there must be acidosis in malnutritional oedema.Moreover, the increase of ammonia and acetone in the bloodand the urine of these patients is a definite indication ofacidosis.

d. Effect of Hydraemia.

W e hav e, the n, found an effective c ause for th e occurrenc eof dropsy in malnutri t ional oedema, but we have to make thesame reserve that we made in the case of cholesterin impover-

ishmen t. This disturbance of the metabolism of inorgan icsalts would necessarily lead to general anasarca, such as doesin fact arise during the final stages of th e disease. I t follows,therefore, that cholesterin impoverishment and disorder ofinorganic metabolism can be no more than contributorycauses. W ha t we are still in search of is som e pred ispo singcause, which can account for the localisation of the initialoedema. B ut before we pursu e this ques tion, we hav e t oconsider a third factor, which may very well explain theonset of the oedema, but itself in turn requires to be explained.I refer to the condition of hydraernia which is actually provedto exist—the general impoverishment of the blood as regardssolid constituents, and the undue richness of the blood inwater. Excessive wateriness of the blood m us t of coursetend to result, by osmosis, in the passage of fluid into thetissues, especially if there should be a lowering of the osmoticpressure of the blood. Th is lat ter change is no t, how ever,

associated; for in malnutri t ional oedema, thanks to theaccumulation of sodium chloride in the blood, the osmoticpressure is kept at its normal level—and in all the cases he




has investigated, Feigl 116 has found the cryoscopic conditionsnormal. Of course this means no more th an tha t the relativesodium-chloride content of the dropsical effusion is normal.The impoverishment of the blood in respect of certain otheringredients involves a reduction of the partial pressure ofthese substances, which must lead to an impairment of the

proper relationship between the blood and the tissue fluid.In consequence of this, a transudation of serum will ensueuntil the partial pressure of these substances in the tissueshas become identical with that in the blood.

This explanation may seem most acceptable, but in realityit merely thrusts back the problem a stage further, for wehave to ask, W hat is the cause of the hydraemia ? Althoughmany authorities tell us that the wateriness of the regimen isthe cause, this is absu rd. Provided my organism is healthy,

it makes no difference if I consume a lot of watery nutriment,or even drink large quantitie s of pure water. The body hasits own way of dealing with an excess of water. The cardinalpoint of which we are in search is the explanation of thefailure of this regulative mechanism.

e. Cardiac Asthenia.

The regulative capacity of the organism in this respectcan, first of all, be reduced by cardiac asthen ia. But thoughall authorities refer to the existence of bradycardia in theacute stage of the disease, this is by no means synonymouswith cardiac asthenia, and is probably a consequence ratherthan a cause of the increase in the quantity of the blood andof the fall of the blood-pressure. Furtherm ore, although thelowering of the blood-pressure may lead to a reduction inrenal excretion, it can hardly account for the hydraemia.We must, therefore, direct our attention in the first place tothe organs preeminently responsible for excretion, namelythe kidneys ; we must enquire whether, in th e pathogenicdiet, there are any factors competent to interfere with theprocess of renal excretion.

/ . Behaviour of the Kidneys.

In this connexion, once more, we have three symptomsalready known to us to reckon with—symptoms which are

19





MA LNU TRITIONA L OEDEMA 291

tend to paralyse the sphincter vesicae. Consequently, anurgent desire to make water is felt even when there is but aver y small qu an tity of fluid in the bladder. I t is a fact that

these patients all complain of a frequent desire to pass water,although they pass only small quantities at a time (from 50to 150 c c ) . Nevertheless, as Rose's researches and mine haveshown, despite the paralysing effect of the sodium ion onrenal activity, the consumption of large quantities of sodiumin the form of table salt (more than 12 grammes) inducesm arked diuresis. To understand this phenomenon, we mustremember that in the excretory function of the kidneys twodistin ct factors are at work. The genuinely regulative func-

tio n of these organs depends upon a selective excre tion; thekidn eys are excreto ry g lands, and it is, primarily, this excretoryac tiv ity which is affected b y small quantitie s of ions. But inaddition, the kidney tissue, like that of all other organs, issubject to th e laws of osmotic pre ssu re; there m ust be anosmotic equilibrium between excretion by the kidneys andth e constitu tion of th e blood. I t is to this osmotic elementin the renal function that we must refer the increase in theurinary excretion when large quantities of common salt are

consumed. The bodily tissues are adapted for a specificosmotic pressure, and as soon as this pressure is exceeded,the ion whose partial pressure is excessive is automaticallyexcreted by the kidne ys. But since, in this process, thegenuinely active function of the kidneys plays no part, itfollows that, as far as the excretion of other substances isconcerned, excretion takes place only in proportion as theblood passing through the kidneys is able to provide theactively excreting tissues of these oigans with a sufficiency

of the stimulating and regulating ions.We have already learned that the excretion of sodium

chloride in the urine is always a tardy process, and the factsju st m entioned explain the retardation. They also enableus to understand that a sufficient excess of water and sodiumchloride may ultimately lead to polyuria although at thesam e time th e blood ha s become hydraemic. The secretoryactivity of the kidneys has been to a considerable extentparalysed, and nevertheless the excessive supply of sodium

chloride has raised the osmotic pressure of this salt so high



292 VITAMINS

as to prom ote diuresis. If th e accu m ulation of w ater an dsodium chloride in the body be considerable, the diuresis may

be excessive, and may be none the less inadequate to freethe blood from its excess of water.

h. The Reduction of Blood-Pressure.

A third factor has now to be considered, one competentunaided to induce oedema. In my account of th e polyneu riticdisorders I referred to McCarrison's hypothesis that thehypertrophy of the adrenals led to an increased formation ofadrenalin, and that the resulting constriction of the capillariescaused an exudation of serum into th e tissues. I q uo tedBarr, however, in support of the contention that adrenalinacts on the larger bloodvessels rather than on the arterioles,so that a surplus production of adrenalin must favour thecirculation and must tend to counteract the occurrence ofoedema. B ut in beriberi, notw ithstanding the hyp ertro ph yof the adrenals, the blood-pressure is low, and thi s leads to

so great a flow of blood through the arteries that the outflowfrom the capillaries is insufficient. In view of these considera-tions, McCarrison ha s formally withdra wn his hy poth esis. Inmalnutritional oedema, the fall in blood-pressure, the relaxationof the great vessels, is even more marked than in beriberi,so that on this count alone we should expect the onset ofoedema.

i. The Effect of B Deficiency.

B ut w hat is th e cause of th e fall in blood-pressure ? The reare two factors, which work han d in ha nd . W hen stud yin gthe determinants of growth we found that vegetable extractsrich in B could induce a lowering of blood -pressure. B utthis factor is no t in qu estion here, for in m alnu tritiona l oedem athe re is a lack of B in th e diet, no t an excess. How ever, t h edeficiency of B may be the indirect cause, for it may act byimpairing the secretory activities of the endocrine glands.

In the case of the polyneuritic disorders we saw that thisapplies to the production of adrenalin, for although the adrenalsare hypertrophied in these disorders, they do not supply anormal quantity of adrenalin.




k. The L ack of Potassium and Calcium ,

The lack of B, however, cannot make itself felt quickly.There must be a considerable period of incubation before theinsufficiencies arising from this lack can induce oedema.But simultaneously with the B deficiency there is at work

a second factor competent to bring about a relaxation of thebloodvessels. I have already shown th at an excess of sodiumand chlorine ions in conjunction with a deficiency of potassiumand calcium tends to paralyse the vital secretory activitiesof the endothelial cells lining the bloodvessels, with the resultthat the interchange between the blood and the tissues ispredominantly effected by differences in osmotic pressureinstead of by the active intervention of the vascular endothe-lium. Bu t the richness of the blood in these various ions hasanother direct influence upon the bloodvessels, upon thearterial walls this time. Ju st as in the case of the sphinctervescicae, the intestinal musculature, and the ureter, an excessof sodium and chlorine ions has a paralysing influence uponthe involuntary muscular fibres in the arterial walls. Thisaction is reinforced by the lack of the corrective influenceof the calcium and potassium ions. Consequently, the excessof sodium chloride and the deficiency of calcium and potassium

in the blood must lead to a relaxation of the arterial muscula-ture, and this will obviously induce a fall in blood-pressure.

8. SUMMARY.

Let us now summ arise the foregoing considerations. Wemay regard as the primary cause of the oedema the declinein the secretory activity of the kidneys owing to the lack ofcalcium and potassium . Consequently the blood becomeshydraemic. The transudation of the hydraemic serum intothe tissues is brought about by a paralysis of the regulativeactivity of the vascular endothelium owing to the calciumand potassium activ ity ; also by the hydraem ia ; also bythe relaxation of the bloodvessels consequent on the lack ofcalcium and potassium, which leads to passive congestion,and by other chemical changes in the blood and the vascularwalls. Th e passive oedema must make its appearance firstwhere the driving power of the heart has the greatest difficulties



294 VITAMINS

in making itself felt—in the lower, extremities, and notablyin th e joints, where th e circulatio n is especially sluggish. The

tendency to oedema is reinforced by the failure of the adrenalsto provide a sufficiency of adrenalin.

All these factors are brought into play for much the samereason. The lack of B in th e diet, which leads to a declinein glandular activity, is responsible for the failure of theadrenals and for the consequent loss of arterial tone. Th edeficiency of lipoids in the vascular walls and the blood isreferable to the defective absorption of lipoids from the intes-tina l tra ct, and this , too , is an outcom e of B deficiency. Afurther change in the vascular walls and in the blood is dueto the excessive consumption of table salt, and to the lack ofcalcium and perhap s of potassium ions. T he degeneration ofth e walls of th e bloodvessels is acc entu ated b y th e acidosisconsequent on the diet. Fu rthe rm ore , th e acidosis an d th eother effects of inorganic metabolism have a directly paralysinginfluence upon the arterial musculature, and also upon thesecretory activity of th e ki dn ey s; while th e large qua ntitie s

of sodium chloride, raising the osmotic pressure of this salt,induces a morbid diuresis, which nevertheless does not sufficeto clear the surplus water out of the system.

A study of the actual diet should, therefore, enable us toascertain the factors leading to oedema. Th ere m us t be alack of B, a lack of calcium, and perhaps a lack of potassium,in conjunction with an excess of sodium chloride, togetherwith an abu nda nt consumption of fluid. I t is possible th a ta lack of A ma y be con trib uto ry, for according to McCarrison I24°this com plettin is able to hinder th e onset of oedema. B u tMcCarrison's observation has not yet been confirmed.

O. Bossert 10I4 repo rts a very interesting case bearingupon these theories. In children affected w ith spasm ophiliaupon a gruel diet, a raw egg was added to make the diet betterbalanced. Th e consequence wa s the onset of oedema, m ainl yin the feet and legs, but also to some extent in the face, andoccasionally carpopedal spasm s were note d. Th e sym ptom s

promptly disappeared when the eggs were discontinued.While the oedema was present, Bossert found that there wasmarked retention of nitrogen and inorganic sa lt s; w ith th ewithdrawal of the eggs, and concurrently with th e disappear-



MA LNUTRITIONAL OEDEMA 295

ance of the oedema, the retained substances were excreted.Bossert considers that local changes in the tissues with arelative lack of calcium in the interstitial fluid of the tissues,leading to an accumulation of chlorine and alkali in this fluid,must have been the cause of the trouble. Now the calciumimpoverishment preexisted, and since there is an abundance

of calcium in yolk of egg, the giving of the eggs ought to havehad a good effect as far as this matter was concerned. But,together w ith the calcium, there was introduced by the additionto the diet a marked excess of sulphuric acid and still moreof phosphoric acid, so that despite the absolute enrichmentwith calcium there must have been an increase in the relativeimpoverishment as far as this ion was concerned. Furthe r-more, the acidosis already due to the gruel diet must havebeen accentuated. In these cases, however, there was a

factor at work which is not operative in ordinary malnutri-tional oedema. Eggs are very rich in lecithins ; during thedecomposition of lecithins in the processes of digestion or inthe blood, cholin is liberated, and this natural antagonist ofadrenalin must give rise to a lowering of blood-pressure.Even though the conditions for the onset of oedema alreadyexisted, they did not become fully operative until a conditionof passive congestion was brought about by the action ofthe cholin. A contributory , and perhaps decisive, influencewas exercised by the deficiency of nervous tone in thesespasmophiliac children, and this perhaps explains why thesymptoms were noted in spasmophiliac patients only.

Pending fuller knowledge, we may therefore regard a lackof B, of calcium, and sometimes of potassium and A as well, inconjunction with an excess of sodium chloride, inorganic acids,and water, as the determinants of malnutritional oedema.

ADDENDUM TO CHAPTER EIGH T : KIN DR ED NUTRITIVE

DISORDERS.

a. Mehlnahrschaden.

We have already learned th at various authorities 902-* 9J3, ***5consider that there is a kinship between the Mehlnahrschadenof infants-in-arms and malnutritional oedema. I t will thereforebe expedient to undertake a more detailed examination of thefactors that may contribute to the onset of Mehlnahrschaden.



296 VITAMINS

It has been shown that at the very outset this disease is

distinguished from mainutritional oedema inasmuch, as inthe latter the muscles are relaxed and toneless, whereas inif ehlnahrschaden they are hard and hypertonic. Fu rtherm ore,in mainutritional oedema there are no nervous symptoms(unless polyneuritis be present as a complication), whereas inMehlnahrschaden there is a nervous hy perirritability whichmay lead to tetanoid spasms. Again at an early sta ge ofMehlnahrschaden, the little patients suffer from moderate

meteorism. By degrees, the nu tritive condition grows worse,until ultimately a markedly atrophic state arises. In. thelast stages, there may be oedema. To complete the picture,it is necessary to add that acute gastro-intestinal disorderis a frequent complication. There is also a no tab le increasein the susceptibility to every kind of infection.

The diet in these cases has consisted mainly of gruel,mush, or porridge of some kind, to which sugar and fat areoften added to prom ote energy. The errors of such a dietfrom the standpoint of modern dietetics are obvious. Wehave learned that all the cereals have certain defects whichmay be looked upon as characteristic of these nu trients. Asregards inorganic salts, they are deficient in sodium and cal-cium ; they are also poorly supplied w ith organically com binedsulphur and with bases generally ; but they contain a super-

abundance of inorganic acid-formers and of po tass ium . Thecereals are also poor in B, A, and C, the poverty being moremarked in proportion to the fineness of the flour. Fin ally ,the proteins of the cereals are always inad eq uate; th ey arelacking to some extent in the ringed amino-acids, and areespecially poor in lysin and cystin. These defects afford aready explanation of the causation of the disease. Thedeficiency of A and B impairs the activity of the digestive

glands, so that th e utilisation of a diet th at is already inadeq ua teis rendered incomplete, and a t the same tim e th e door is openedfor all kinds of intestinal infections and fermentations. Theexcess of potassium, when there is a deficiency of sodium asan antagoniser and of calcium as a corrective, leads to muscularhypertension, to contractu res; and a t the same time inducesa nervous hyperexcitability which manifests itself in tetanoid



MA LNUTR ITIONA L OEDEMA 297

well compensated by the addition of bu tter . W hen thissupplement is lacking (as in Denmark, where the butter isdestined for export) xerophthalmia often occurs as a complica-tion. This is supposed to be th e chief cause of blindnessamong Danish children.940

The lack of complettins and of important inorganic

nutrients, the acidosis, and in especial the lack of an adequateprotein, must gradually induce general atrophy, as the out-come of which the glands will be paralysed and atrophied,and more particularly the production of adrenalin will bereduced.ia4<> In th e long run th ere will ensue a fall in blood-pressure, and this, in conjunction with the onset of cardiacasthenia due to the malnutrition and the lack of calcium,will give rise to oedema.

J. Milchnahrschaden.Aron 388 protes ts against confounding Mehlnahrschaden

with Milchnahrschaden, probably with justice . Milchnahr-schaden, which is a rarer disease than Mehlnahrschaden, is aresult of the hand feeding of infants with milk, especiallycow's milk. Ordinarily , in this form of artificial feeding, themilk is greatly diluted and is also pasteurised or at leastscalded. The first sym ptom of the disorder is th a t sleep is

greatly dis tur be d; th e infant is overtired, and manifestsits discomfort by repeated fits of crying. The skin becomespale and turgid, an d is morbidly sensitive to injury. Th etonicity of the tissues and the blood-pressure de clin e; thestools contain large quantities of fatty so ap s; and there ismarked meteorism. For a time there is an arrest of weight,and then the weight actually falls until extreme atrophy hasbeen established . Marked intolerance of fat is displayed,especially when cream is added to the milk in the hope of

improving the nutritive condition.Nervous symptoms have not been noted, but the disease

may sometimes be complicated with infantile scurvy.

c. Fat as a noxious Factor in Infant Feeding.The fatty acids of the milk have hitherto been regarded

as responsible for Milchnahrschaden. I t ha s been supposedthat, as the outcome of some gastro-intestinal disturbance,



298 VITAMINS

the unabsorbed fatty acids have been eliminated in the stoolsas sodium, potassium, or calcium soaps, this leading to animpoverishment of the body in respect of bases.

Czerny considers that the volatile fatty acids in the milkfat are especially to blame, and therefore he and Kleinschmidtrecommend the well-known butter-and-flour preparation,made by heating butter with flour so that the volatile fatty

acids are driven off. R eic he ,1^ however, reports that childrendo not thrive permanently on this butter-flour diet, and thatultimately the increase of weight is arrested.

WTiile we may admit that a failure in the absorption offat may actually lead to the onset of acidosis, the symptomcomplex of Milchnahrschaden cannot be thus explained. But

the knowledge we have now acquired concerning the physi-ology of nutrition should enable us without much difficultyto ascertain the true pathogenic factors in this instance also.In contradistinction to Mehlnahrschaden, the dominantfeature is here an impoverishment in potassium, and, thanksto the dilution of the milk, also in sodium and calcium, andin bases and inorganic nutrients generally. The deficiency

suffices to induce acidosis, and that condition can certainlybe aggravated by the losses due to the fatty discharge in thestools. But the acidosis does not suffice to explain thesymptoms, even though the impoverishment in respect ofinorganic nutrients must certainly tend to reduce the vigourof the vital reactions.

The pallor, the turgidity of the skin, the digestive dis-orders, the loss of tonicity of the tissues, the sensitiveness ofthe skin to injury, the weakness of the digestion, and theincreased susceptibility to infections, comprise a syndromewe have already noted when discussing the conditions ofgrowth, and we have recognised it to be an outcome of B



CHAPTER NINE

PELLAGRA

r . CLINICAL PICTURE.

THOSE who speak to-day of the avitaminoses, or, as I preferto call them , of th e acomplettinoses, have usually th ree diseases

in mind : scurvy, beriberi, and pellagra. A full accounthas been given of beriberi and scurvy, and it remains onlyto unde rtake a critical discussion of pellagra. The primaryrequisite in this connexion is a precise knowledge of thesymptom complex that passes by that name. The firstspecific feature is the chronicity of its course. A t the outse tthere are slight atta ck s, chiefly in spring and au tu m n; andduring the intervals between these the manifestations recedeand may completely disappear. In the attacks, the patientexhibits a peculiar awkwardness of movement, which makeshis gait typically cum brous. He complains of headache,dizziness, sleeplessness, weakness, paraesthesias, and neuralgias.He is listless, depressed, and irritable. Gradually, loss ofappetite sets in, sometimes culminating in a positive loathingfor his ordinary food, but occasionally alternating withbulimia. Th e tongue is apt to be thickly coated, or in a s tat eof inflammatory desquamation ; there are salivation, heart-

burn, often intense thirst and gastralg ia; in many cases,diarrhoea completes the picture of severe gastro-rntestinaldisorder. The attacks commonly recur year after year,"becoming worse perhaps, but not exhibiting any other change.By degrees, however, upon this basis, there is superimposedthe group of serious nervous disturbances typical of advancedpellagra. Concurrently with their onset, in th e spring orautumn an eruption usually appears. Th e digestive troublesbecome more obstinate, stubborn constipation sometimes

299



300 VITAMINS

alternating with diarrhoea. Em aciation sets in, and the

aspect is now cachectic. Nephritis is common, and theurine (which is often alkaline from secondary infection of thebladder) contains album in. W hen there is m arked gastro-intestinal disorder, indican uria is no t uncom mon. Anaemia,with moderate lymphocytosis, develops as a secondary symp-tom . Most charac teristic of all are pa raly tic manifestations,often associated with nerve atrophy and with tonic or clonic

spasm. The knee-jerks are usually exaggerated, bu t in somecases are a b se n t; Romberg's sym ptom is generally present.The gait is th a t of spastic paraplegia. Vertigo, trem or, andtwitching are com m on ; and the spasms m ay pass on intoepileptiform convulsions. Other typ ical sym ptom s are photo-phobia, retinitis, and at times disorder of the auditory nerve.Severe neuralgias and obstinate paraesthesias of the mostmultiform character contribute to the development of themental disturbance which often arises at this stage, and mayultimately drive the pa tien t to suicide. Th e m enta l sym ptomsmay take the form of melancholia, mania, cyclic insanity,paranoid and obsessive ideas, etc. The apathy and theamnesia may affect the intelligence so profoundly that themental state comes to simulate that of paralytic dementia.

The parts affected by the exanthem are especially thoseexposed to light, and no tab ly to direct sun light. Th ere is aremarkably symmetrical erythema, which may be light-red,dark-red, or bluish in tin t. Th e affected areas are th e seatsof a burning sensation, which is apt to be almost unbearablea t n ig h t; and vesicles or pustules often form u pon the skin

of these regions. Th is vesicular de rm atitis gradually leadsto the formation of crusts, or sometimes to the onset of typicaleczema. After a number of such attacks of dermatitis,hyperkeratosis sets in, subsequently leading to markeddesquamation, after which the skin is left in a dry, raw, parch-m enty, and deeply pigmented sta te . U ltimately, the skinbecomes shrunken, wrinkled, and atrop hic. Striking as th e



PELLAGRA 301

I have already referred to the fact that the course ofpellagra is chronic. In the worst cases, it is tru e tha t w ithina few months or years death may occur from cachexia, orin consequence of the mental or nervous disturban ces. As arule, however, the illness lasts for decades, and in exceptionalinstances throughout a life of normal duration.

There is, however, an acute form, the so-called typhuspellagrosus, characterised by pyrexia and a typhoid state,and by an accentuation of all the usual sym ptom s. Theintelligence is clouded at an early stage, and before longdelirium occurs. In con tradistinction to the chronic form ofthe disease, in the acute form there is a hypertonicity of thewhole muscular system, sometimes so marked as to causeopisthotonus. As in severe attacks of typhoid and typ hus,

the patients are completely helpless, and pass the faeces andurine involuntarily. Death ensues within a week or two , tothe accompaniment of grave complications, such as pneu-monia, encephalitis, extensive bed-sores, etc . Notw ithstandingthe onset of this typhoid state , no typical m icroorganisms havebeen found in the stools or in the blood in this form of thedisease; it is doubtless due only to severe complications inthe form of gastro-intestinal disturbances. The amoebaeof amoebic dysentery, various microorganisms, nematodeworms, etc., have been found in great variety in these cases.We may therefore presume that the typhoid state is the out-come of the association of the severe gastro-intestinal disorderand the malnutrition with the nervous symptoms characteristicof pellagra.

In the early stages of pellagra, a complete change of dietoffers the best hope of cure, though by no means a certainhope. W ithout such a change, and in advanced cases, the

prognosis is exceedingly grave.

2. PATHOLOGICAL ANATOMY.

The first morbid changes take the form of congestion ofthe whole intestinal tract, passing on into grave atrophy,and often atten ded by ulceration of the large intestin e. The reare also degeneration and atrophy of the muscles, the heart,the liver, the spleen, the kidneys, and the endocrine glands.

Whereas in the other deficiency diseases, the adrenals are



3o2 VITAMINS

hvpi r:r ûied, in pellagra these glands are markedly a trophie d ,

and may be reduced to one-tenth of their normal size.lr

37,ns-, 21;: Degeneration is especially frequent in the medullaof the adrenals and in the Langerhans' islands of th espleen.

In the later stages, when the nervous and mental symptomshave developed, we find extensive and diversified changesin the nervous system. Most conspicuous are th e sign s of

inflammation in the meninges of the brain and the spinalcord. There is degeneration of th e large ganglion cells in th ecerebral cortex, of the posterior horns of the spinal cord, andof the ganglia of the posterior roo ts ; less often th e re isdegeneration in the cells of Clarke's columns and in those ofthe anterior horns. There are also symm etrical degene rativeor sclerotic changes in the posterior tracts (especially in th ecolumns of Goll), the pyramidal tracts, the lateral tracts, andabove all in the posterior roo ts. According to Roaf,IoS6 th ecells of the ganglia of the sympathetic always exhibit a condi-tion of plasxnolysis, attended with atrophy of the medullatednerve fibres "9»—changes which have a great resemblance tothose met with in Addison's disease. (Cf. also rl37, «7*.)

As previously mentioned, the glands participa te in th egeneral atrophy, and this statement applies especially to t h e

endocrine glands.JI37, 1I93 But the first of all the organs tobe involved in the atrophic process would seem to b e t h edigestive glands—the salivary glands alone excepted. A t t h every outset of the disease there is a falling-ofi in the amountof gastric juice, in the peptolytic power of the secretion, andin its hj'drochloric-acid richness. In severe cases, there m a ybe no acid at a ll. This failure of secretion spreads by de gree s

to the whole digestive tract, so that in bad cases there iscomplete adhylia.z7°. 3**. Il87 The inevitable result is a g r a v edisorder of digestion and absorption, this trouble beingaccentuated by the atrophy of the mucous membranes.~8

5*3", 337 As a result, even in the early stages, the n it ro genou sbalance tends towards the negative,316 * 3*8 and before longbecomes definitely negative.Il87 Except for the interference

l 8



PELLAGRA 303

carbohydrates, but his conception of the normal tolerance isso high (1*5 to 2-5 grammes of glucose per kilogramme ofbody-weight) that we are hardly entitled to speak of a realreduction in the carbohydrate tolerance.

The digestive disorders, and especially the lack of hydro-chloric acid in the stomach, cannot fail to react unfavourablyupon the nature of the intestinal flora, and at an early stagefermentations and putrefactions of all kinds set in. Owing tothe failure of the natural powers of resistance of the alimentarytract, every conceivable kind of affection of the stomach andbowel may ensue, ranging from simple heartburn to typhoid.

Of course these disorders impair yet further the chances of thepatient's being satisfactorily nourished.s73. 285, 337,1066, 1176, 11*7There is also grave disturbance in the balance of nutrition

as regards inorganic salts. Eve n allowing for the fact th atabsorption is so much impaired, there is a negative balancein the case of all the inorganic nutrients as soon as the diseasebecomes acute.s85

The excretion of nitrogen, phosphorus, magnesium, cal-cium, and potassium in the urine is greatly diminished,x85385, 30* the reduction affecting the ph osp hate s more than theurea, the alkalies more than the calcium, and the calciummore than the magnesium . W hen there is a sufficient supplyof sodium chloride, the excretion of sodium and of chlorinemay be normal or even increased. 84 The quantity of amm oniais always increased, both relatively and absolutely 8> l84, ia»6;and as a further sign of acidosis there is an increased excretionof acetone,8 and also of kreatinin in conjunction with well-

marked kreatinuria.318 Th ere is no uxobilin in the urine

3 I

4 ;but, owing to the great disturbance of intestinal digestion,there is an increased excretion of indican in the urine, oftenleading to marked indicanuria.442, Io66 Galmozzi records theremarkable observation that the sulphur in the urine in theform of ester compounds is diminished, a fact which perhapsdepends upon the invariable poverty of the pellagrogenic dietin sulphur

At the outset of the disease there is a moderate fall in

blood-pressure (to 119 mm. of mercury) ; bu t t he relax ationof the vascular tone rapidly increases pari passu with thegeneral loss of muscular tone , an d when th e disease is thoroughly



304 VITAMINS

established th e b lood-pressure ra ng es from 92 m m , to aslow as 78 mm.Il87

In the acute stage we find an excess of lymphocytes inth e blood, with n eu tra l leucop enia a nd a faUing-off in th enumber of eosinophil cells,I44 phenomena met with in allessential anaem ias. Re ports are very variable as regards theserological conditions, and it will be best to defer the discussionof this matter until we come to consider the probable causesof the disease.

3 . THE PELLAGROGENIC DIET.

The occurrence of pellagra was first recorded in connexionwith an ill-balanced diet consisting chiefly of m aize. I t hasbeen supposed that the appearance of the disease in Europedates from the time when the cultivation of maize becamewidespread in Northern Italy, but there is no proof of thisassertion.312 For a long time it was believed that the patho-genic cause must be connected with maize, though it wasuncertain whether the influence was a specific property of

the maize or was the outcome of a decomposition of the grain.The importance of maize as pathogenic agent was confirmedby the terrible spread of the illness in Rumania, where theannual toll of deaths from this cause became enormous, andwhere according to U rbean u 8 the rura l population lived almostexclusively on maize (for the amount of other food consumedper head in the course of a year would hardly exceed twokilogramm es.) U rbea nu was able to prov e th a t an ill-balancedmaize diet induced pellagra-like diseases in fowls, and thisobserv ation was confirmed b y Clementi.5*9 I t was foundth at other animals became pellagrous on a maize diet. As faras pigs are concerned, the effects of the inadequacy of maizein respect of the inorganic nutrients predominate in theclinical picture, so that pellagroid symptoms are not conspicu-ous 347; b u t dogs,4o6 gu in eap ig s ,^ . 352* 3&> mice , and ra ts ,become affected with pellagra on an ill-balanced maize diet.(Hoist,1?1 who experimented on guineapigs, regarded the

disease induced by a maize diet in these animals as poly-neuritic.)

The method of milling seems to have a certain influence.Suarez 489 repo rts th a t mice and pigeons, which on a maize



PELLAGRA 305

diet become pellagrous, are affected with polyneuritis if fedexclusively upon finely sifted maize flour or upon maizestarch (maizena), and that they can be cured by giving them

yeast.The effects of the maize are most pernicious when it is

boiled. In th e case of rabb its,»7 and in th at of w hite mice,^*the supplementing of a diet of boiled maize with an abundanceof milk does not prevent the onset of the disease, whereasordinary mice can thrive on a diet of boiled maize and milk.Mice fed on wheaten rolls and milk were not found to displayany pellagrous sym pto m s. (Cf. Horbacz ewski X3*.)

In the United States, however, pellagra was found tooccur, even in its gravest forms, in human beings whose diethad contained no m aize a t all, or only a little . M ost of thesepatients were able to command an adequate diet, but forone reason or another (generally they were neurasthenicswith a fixed idea that certain foods did not suit them) theylived upon an extremely restricted and therefore ill-balancedregimen. As typical of such defective regimens may bementioned the experimental diet prescribed by Goldberger

and Wheeler,IX

57 whose subjects were prisoners voluntarilysubm itting to the experiment. The diet consisted of wheatand maize in the form of fine flour, maize starch, polishedrice, and small qua ntities of vegetables an d fat. T he su bjectsof the experiment were put upon light work and received anallowance of " only " 2,500 to 3,500 calories daily, the dietcontaining 41 to 54 grammes of protein (mainly vegetable),91 to 134 grammes of fat, and 387 to 513 grammes of carbo-hy dra te. In all th e eleven subjects there occurred, in th e

course of 205 days, loss of weight and general debility.Abdominal pain and headache were freq ue nt; in thre e therewas diarrhoea, and in five there was an increase of the knee-jerks. In th e case of six of the subjects, typ ica l cutan eousmanifestations appeared towards the close of the fifth month,bu t the site of these wa s in mo st cases anom alous. In twoonly did the skin eruption begin on the hands and the napeof the ne ck ; in the other cases i t began on th e scro tum .

Chittenden and Underhill599 were able to induce typicalpellagra in dogs by feeding them on boiled bean flour, wheatenbisc uits, an d linseed or co ttonsee d oil. (Cf. also fy 1.)

20



3 o6 VITAMINS

4. VIEWS THAT HAVE HITHERTO PREVAILED CONCERNING

THE ETIOLOGY OF PELLAGRA.

a. Microorganisms as the Cause.

It was, of course, believed at one time that infectionmust be the cause of epidemics of pellagra^ 8 , 878 fout sinceit was never possible to discover a specific microbe, the opinionwas abandoned. H arris 3z6 claimed to have induced pellagrain monkeys with morbid material from a case of pellagraafter the m ater ial had been passed thr ou gh a Berkefeld filter;but subsequent observers, such as Lavinder, Francis, Grimm,

and Lorenz,397 Siler, Garrison, and McNeal,4« and Bigland,J137were unable to secure any evidence of infection by the inocula-tion of the pellagrous matter or by its administration bymouth. Bass l83 believed himself to have proved the infectiouscharacter of the disease because he observed that fowlsacquired pellagra when fed upon maize that had been con-tam inated with the faeces of pellagra p at ie n ts ; bu t oth erinvestigators were able to show that the alleged proof was

invalid, seeing that a maize diet will induce pellagra in fowlsin the absence of any such contamination.

Babes reports favourable results from the treatment ofpellagra with arsenic, and considers that these successessupport his view that the disease is dependent upon aprotozoal infection.668* 669 Collodi JI7* I I 8 contests the infer-ence, for he holds that the observed improvement could readilybe explained as the outcome of the familiar stimulating andinvigorating action of arsenic. A les sa nd rin i I a 6 considers that

a maize diet is me rely a predisposing cause. H e believesthat this diet gives rise to intestinal disorder which preparesthe ground for th e invasion of the intestine by ce rtain nem atod eworms belonging to the family of the filaridae, the larvae ofwhich are to be found in the drinking water of regions wherepellagra is preva lent. This observation ha s no t been confirmed,and the presence of filaridae in the intestine of pellagrouspatients was doubtless an intercurrent affection on all fours

with the accidental presence of different sorts of extraneousmicro-organisms.

The commission appointed by the United States Govern-ment to study the etiology of pellagra 3*8 was at first inclined



PELLAGRA 307

to regard the disease as a specific infection, and this viewseemed to be confirmed when it was found th at in Spartanburg,South Carolina, a town where pellagra is endemic, there was

a notable decline in the number of cases after considerableattention had been paid to sanitary conditions.5I4 Accordingto Roberts,I007 however, this view has now been generallyabandoned, and pellagra is supposed to depend upon somesort of deficiency in the diet. Vallardi,l69 Patta,I03 Car-letti,I79» l8° and more recently Boyd,ll87 are definitely opposedto th e idea tha t pellagra is of an infective na ture , and in especialthey reject the notion that a protozoon is the exciting cause.

The principal idea of the Italian school was that the

cause of pellagra must be some sort of deterioration of themaize used for food. In Germany, the view gained strengthfrom the statement of M. Otto that the growth on maize ofItalian cultures of Aspergillus fumigatus formed extremelytoxic substances, whereas the German stocks of the samefungus did not do so. The growth of Penicillium glaucumupon maize was also said to produce toxins, and in this caselikewise the Italian stocks of the mould were the most venomous.Tiraboschi,77 too, as a result of these researches and of hisown, considered that such differences in the virulence of themoulds explained why pellagra appeared in certain < localitiesand not in others. Tizzoni,1^, *7<> again, considered thatdamaged maize was the cause of pellagra, and claimed thatwhile he had been unable to produce pellagra by feedingmonkeys on maize, he had succeeded in causing the diseasein these animals by the subcutaneous injection of cultures oforganisms isolated from th e grain. The filtrate from suchcultures was said to produce precipitin reactions with theblood of pellagra patients ; bu t according to a late r publication

of this authority,^8 did so only after the bacteria in theculture had been broken up.

Camurril84 also assumes that moulds form a toxin inmaize. In th e organism of healthy human beings the influ-ence of this toxin is supposed to be counteracted b y anti-bodies, and the toxin can only take full effect in exhaustedor debilitated persons. * Â

According to Volpino, Mariani, Bordoni, and Alpago-Novella,l89» X9° bo th pellagra pa tients and healthy persons



3o8 VITAMINS

react very little or not at all to the administration of aqueousextracts of damaged maize by mouth. In twelve out of

thirteen pellagra patients, however, the injection of I o r 2 cc.of aqueous extract of damaged maize induced manifestationsof disorder of the central nervous system, also a rise oftemperature, and general, local, and cutaneous disturbances;whereas in healthy persons the same injection induced nothingmore tha n a non-specific rise of tem per ature . For h ea lth yhuman beings and animals, the specific substance was almostnon-toxic ; it resisted heating to 115° C , and w as soluble inwater. This " pellag roge nin" w as precipitable by alcohol,

thus contrasting with other toxins sometimes present indamaged maize, which are hardly soluble in water but arereadily soluble in alcohol and ether. B ut these inve stig ato rswere unable either with the precipitin reaction, or by themethod of deviation of the complement, or by passive anaphy-laxis, to demonstrate the existence of specific antibodies inthe reacting patients, and they therefore came to the conclusionthat the substance was not a true toxin but a poison of someother kind.

Carbon and Cazzamalli 3*7 claim t h a t by growing A spe r-gillus fumigatus, a Penicillium, Mucor racemosus, or Tricho-derma lignorum, on maize, they made the grain so toxic thatordinary mice fed on it became affected with skin troublesor other signs of a pellagrous illness, whereas the originalundamaged maize did not engender any illness in the mice.B ut this repo rt conflicts w ith th e well-established fa ct th a tundamaged maize certainly does cause pellagra in m ic e. To

the toxins produced b y the before-mentioned m oulds, w e cantherefore attribute at the most a predisposing influence.

b. The Effect of the colour ing Ma tter of Maize, know nas Zeochin.

But before long a substance was discovered in maizewhich certainly seemed to be responsible for the causation ofthe skin affections forming part of the pellagra syndrome;this was zeochin, the fluorescent colouring matter of yellow

maize. W e have already learned tha t H orbaczew ski w asable to produce pellagra in white mice by feeding them onyellow maize and milk, whereas the same diet did not produce



PELLAGRA 309

the illness in ordinary mice. He supposed tha t th e cause ofthe disease must be the alcohol-soluble colouring matter,which, like all the fluorescent colouring matters, must, he

thought, induce a special sensibility to direct sunlight, andindeed a hypersensibility to light in general. This view seemedto him to be confirmed by the observation that the yellowmaize was no longer pathogenic after it had been decolourised,whereas white mice fed on their ordinary diet became pella-grous when this diet was supplemented with the colouringmatter, which was, however, innocuous to grey mice andrabbits. At most in ordinary mice, injections of the solutionof the colouring matter caused local skin trouble when the

skin was exposed to the light. According to Suarez/89 thesubstance administered to rabbits in the same way has a similareffect upon these animals, but the feeding of it to ordinarymice has no effect a t all. These statements were confirmedby Raubitschek,^ who also reported that zeochin causedskin trouble only in albinos, and only under the influence oflight on the skin. Ummes,245 in like manner, regarded thefluorescent colouring m atter of yellow maize as the cause ofthe skin troubles . All the mice fed on maize soon succumbed,whether the maize was yellow or w hite ; bu t only when theyellow maize was given did the animal become affected witherythema. The other symptoms of pellagra were supposedto be due to an alcohol-soluble toxin present in maize.

Plausible as this explanation might seem, good reasonsfor doubting its validity were soon forthcoming. Firs t ofall, it is a familiar fact that albinos in general and white micein particular are much weaker and less resistant than pig-

mented animals of the same species. Ummes himself pointsout that white mice perish from starvation more quickly inthe light tha n in the dark. Furthermore, Rondoni l64 provedth at white light is, in general, noxious to white m ic e; alsothat a maize diet causes pellagra in mice even in the dark,the animals pining, and suffering from a patchy loss of fur.Rondoni was unable to ascertain that the onset of the diseasewas hastened by the influence of light. The careful investiga-tions of Hirschfelder 2S°showed with considerable probability

tha t the zeochin had nothing to do with the case ! THe ideahad, of course, been that the colouring matter was absorbed



3 io VITAMINS

into the blood, and that its fluorescence made the blood more

sensitive. Hirschfelder was able to show th a t alth ough th eblood-serum of pellagra pa tient s was certain ly fluorescent,the fluorescence was no greater th an th a t of th e norm al se ru mof healthy persons, and that the tint was precisely the samein the hea lthy an d in th e diseased. Moreover, U r b e a n u 8

had proved that white maize, which contains no colouringmatter, is much more strongly pellagrogenic than yellow

maize.It is as well to point out that the morbific influence of

maize seems to diminish w ith tim e. Be zzo la80 no ted tha tmaize kept in store for a year had even, after boiling, no illeffect on ra ts , whether the maize was good or dam aged. I t isdoubtful if this investigator's experiments were carried on fora sufficiently long tim e, bu t Nitzescu 406 claims to hav e defin itely

proved that new maize is more toxic to dogs than the storedgrain.c. The Effect of the M aize Toxin.

Like Um mes, and simultaneously, Ro ndon i *44 expres sedthe opinion that the specific manifestations of pellagra weredue to a toxin in m ai ze ; b u t he left undecided the qu es tio nwhether this toxin was originally present in the maize or was

not produced in it until the grain had been damaged byfermentation or putrefaction. H e inclined to th e latt er vi ew ,finding th a t an aqueous extract made from dam aged m a iz egave rise, even in healthy persons, to a slight reaction, takingthe form of a moderate rise in temperature, of dizziness, andof malaise. Since, further, Rondoni discovered th a t th isreaction was stronger in pellagra patients than in healthy

persons, it seemed to him that there could hardly be anydoubt as to its specificity. Nevertheless, thou gh Volpino a n dhis collaborators lB9> p° had maintained that the reaction wasviolent in pellagra patients (having the nature, they said, ofanaphylaxis), Rondoni was unable to confirm this ob ser va tion .He therefore felt it impossible to maintain that the unmis-takable hypersensibility to the maize protein was really of



PELLAGRA 311

position products of maize protein, but he found also that20 % of perfectly healthy persons were no less hypersensitive.Such a reaction can hardly be regarded as specific. I t was,moreover, impossible by the injection of the so-called pella-

grogenin to induce a passive anaphylaxis in guineapigs,though this would have been essential had the theory beensound. Lui and Baccelli*64 likewise reported that theprecipitin reaction was not to be trusted for an early diagnosis,seeing th at it was not invariable, though it was usually presentin the early stages and in the acute exacerbations of thedisease, whether intestinal disorder was present or no t. Bu tthe sera of perfectly healthy persons would also give a similarreaction at times.

Volpino reported, too, that his pellagrogenin did notinduce complement formation or a specific precipitin reactionin the serum of pellagra patients—although he believed thatby repea ted injections of a 10 % solution he ultimately pro-duced a certain degree of immunity, seeing that the animalsthus treated remained longer immune to the harmful conse-quences of a maize diet. When we recall, however, how muchthe period of incubation varies according to the internalcondition and the outward circumstances of pellagra patients,we shall not be inclined to regard this deduction as of much

value.Other observers considered that the injuriousness of themaize depends upon the digestive disorders it evokes. Theysaid that Behring's extensive researches into the pathologyof tuberculosis had shown that when there was intestinaldisorder it was possible for undecomposed albumin to passdirectly into the circulation. In maize feeding, they supposedthat the zein in particular was thus absorbed, and gave riseto hypersensitiveness. Especially they maintained that theblood of pellagra patients contained ferments which decom-

posed zein, ferments whose existence had been proved by theresearches of Nitzescu.359,399, 406, 442 But Babes and Jonescu 394were able to show that Abderhalden's reaction to the zein-decomposing ferments is not invariable in the blood of pellagrapatients, and that it is fairly common in the blood of healthypersons if some transient gastro-intestinal disorder happensto facilitate the absorption of undecomposed zein,



3 i2 VITAMINS

Gosio had asserted that the blood-serum of pellagrapatients contained a precipitin that acted on maize protein,but Rondoni J58 found that this reaction was not peculiar topellagra pa tien ts. Like Ab derhalde n's defensive-fermentreaction, it is exhibited by the serum of normal persons, justas in the case of all the other veg etable extr ac ts. Moreover,according to Carletti, l8 ° neither heteroprecipitms nor maize-precipitins are regularly found in the blood of pellagra patients.The occasional presence of such precipitins will certainly not

explain th e problem s of th e etiology of pellagra. Th e bloodof the patients is sometimes hypertoxic for other persons,but it is very doubtful whether there can be much connexionbetween this and the maize diet.

Similar was the trend of the researches of Lucatello andCarletti,16 1 who found that antigens from the spleen andadrenals of pellagra patients sometimes induced comple-ment formation, but that none of the antigens gave a posi-

tive reaction w ith th e serum in all cases. Th e atte m pts ofVolpino and Bordoni 463 to induce active immunity were ablein guineapigs to secure no more than a " postponement" ofdeath , and in hum an beings to bring abo ut " m oderateim provem ent." Volpino's claims th a t th e injection of maizeextract in pellagra patients can induce an active immunity,and that in like manner a long continuance of a maize diet

ultimately leads to the acquirement of immunity againstmaize protein, are in such flagrant conflict with generallyobserved facts, that there must obviously have been someerror of experiment or interpretation on Volpino's part.

There is no doubt that zein can make its way throughth e diseased m ucous m em brance 359, 394,406, 742 • b u t it hasbeen rendered equally certa in by Rond oni's experim ents 348that in pellagra we have no ground for supposing that a

hypersensibility to maize protein is the cause of the disease.Raubitschek *63 was also unab le to discover a ny inva riablechanges in the serological behaviour of the blood in pellagrapatients. We must, therefore, seek other causes for thedisease.

d. The Inadequacy of Maize Protein.

When the work of American investigators directed atten-







PELLAGRA 315

In Italy it was Bravetta11 0* who first observed theoccurrence of pellagra independently of a maize diet. He

found that many cases of pellagra originated in Italianlunatic asylums, although the diet was abundant, varied, andcontained a sufficiency of proteins and vitam ins. He noticed,however, that the patients who became affected with pellagrawere always weakly and cachectic; and we know th at inasylums, just as among neurasthenics who are not underrestraint, an almost maniacal aversion to certain articles ofdiet is common. In such cases the diet actually consumedmay be extremely ill-balanced, although plenty of good food

is there for the taking. We may assume with considerableprobability that this accounts for the cases observed byBravetta.

/ . Specific Importance of Protein Deficiency.

The earlier views regarding the importance of protein haveoften tended to interfere with the attainment of definiteknowledge of this matter . I t is doubtless owing to an exag-gerated valuation of protein that Bigland JI37 and Chick andHume IIoS have come to regard a deficiency of protein as themain cause of pellagra. Chick and Hume, giving a diet other-wise adequate, but in which the protein consisted of maizegluten, were unable to induce any pellagroid symptoms(erythema excepted) ; more especially, the experimentalanimals exhibited no sign of the typical nervous disorders.On the other hand, we have just learned that Bravetta notedthe onset of pellagra in persons whose diet was apparently

well provided with proteins. Goldberger, Wheeler, andSydenstricker,1101 studying the domestic economy in NorthAmerica in households where pellagra occurred and in thosewhere there was no pellagra, could not detect any definiterelationship between the incidence of the disease and eitherthe calorie content or the protein content of the diet.

The last-mentioned authorities noted, indeed, that beforethe outbreak of the disease the diet of the pellagra patientshad been poor in products of animal origin, especially in milkproducts and in eggs. On the other hand the illness occurredindifferently upon diets in which maize, wheat, and ripe pulseswere respectively predom inant. They therefore inferred that



316 VITAMINS

pro tein inadequa cy m ust be one of th e factors of pellagra.The before-mentioned experiments of Goldberger andWheeler IZ57 on criminals, and the investigations of Boyd Il87concerning the outbreak of pellagra among the Turkishprisoners of w ar at E l K an tara , hav e th e same bearing. Inthe El Kantara cases, rest and the supply of high-gradeprotein had excellent results.

g. Pellagra and Malnutritional Oedema.

BiglandIO

37 is inclined to regard pellagra a s du e to m alnutri-tion, and he assimilates the disease to malnutritional oedema.But Bigland's own observation,1^? and those of Enright,XI76upon the German prisoners of war in Egypt who becameaffected with pellagra, conflict with this theory, for both theseauthorities expressly declare that there was no malnutritionin the ordinary sense of the term . Conversely, Harris,1062

who studied the incidence of pellagra in Italy during the war,

tells us that although the nutritive conditions were wretched,there was a definite decline in the frequency of this disease.

h. Vitamin Deficiency.

Ruhl,439 McCollum, Simmonds, and Parsons,^ 1 andBravetta,1103 agree in declaring that, despite the importantpart played by the nervous symptoms, a lack of Funk's

vitamin cannot be the cause of pellagra, seeing that thepathogenic diets have always contained an ample supply ofth is substance. Th e difference betw een vi tam in deficiencyand pellagra is obvious in any case. In v itam in deficiency,the pareses are the outcome of degenerative changes in themuscles, or perhaps of degeneration in the distal ramificationsof the peripheral nerves. In pellagra, on th e other h an d,the degeneration affects the central nervous system.

i. Com plettin Deficiency.

I t is, however, often asserted th a t a lack of othe r com plettinsis the cause of pellagra. N ig ht in ga le^ 8 indeed, holds themistaken view that pellagra and zeism occur only as the out-come of a diet of hulled maize, and this leads him to supposeth a t a general com plettin deficiency is th e cause , McColluni,



PELLAGRA 317

Simmonds, and Parsons 69X correct this view by maintainingthat, whilst there is no lack of Funk's vitamin, a deficiencyof A or of B, or of both (in conjunction with other factors),m ust be of etiological imp ortance. In ano ther paper,878

indeed, the same authorities restrict the importance of com-plettin deficiency yet further, for they say that this deficiencymust act by lowering the resistance to infection, and thatthe main cause m ust b e an infective agent. Goldberger,Wheeler, and Sydenstricker,1101* "57 on the o ther han d, considerthat complettin deficiency is a direct cause, although otherfactors must cooperate for the production of the typical

pellagra syndrome. A similar view was expressed byHopkins Io66 in the oft-quoted discussion of British medicalauthorities regarding th e clinical imp ortance of th e com plettins(London, 1920).

h. The Effect of inorganic Nutrients,

We have seen that almost all the constituents of our diethave in turn been looked upon as more or less directlyresponsible for th e cau sation of pellagra. Th e only d ietetic

factor still to be considered is that of the inorganic nutrients,and we find that some authorities insist upon their importancein this connexion* T he first to pa y a tten tio n to inorganicmetabolism in pellagra, and the only experimentalist whohas made systematic researches in th at field, was th e Ru m anianphysician Urbeanu.8 He was, indeed, the first to approachthe problems of pellagra by the experim ental r o u t e ; and inhis latest p ub licatio n 5*5 he ha s b een able to record a largenumber of protracted experiments on animals, extending insome cases to the fifth or sixth generation. U rbe anu wasstruck by the fact that maize is very poor in inorganic nutri-ents ; that there is a general lack of bases, but also a lack ofphospho rus; and t h a t in this respect wh ite maize is worseequipped than yellow maize. His experiments on dogs,guineapigs, fowls, pigeons, and human beings, invariablyshowed that white maize was far more dangerous than yellow.Although he does not deny that the lack of phosphorus may

have some im por tanc e, he considers tha t th e general deficiencyof bases m ust be th e m ain cause of injury. L im itatio ns wereimposed upon his researches by the lack of opportunity for



318 VITAMINS

elaborate analyses, and he was therefore chiefly concernedwith ascertaining the quantities of potassium provided in

the food and dealt with by the metabolic processes—startingfrom the fact that in vegetable nutrients (and, indeed, inanimal nutrients as well) potassium is greatly predominantamong the bases of the ash. H e found, m oreover, th a t th enutrients which have a curative influence, especially potatoesand green vegetables, are extremely rich in potassium . Inhis writings, therefore, he refers almost exclusively to potas-sium among the inorganic nutrients, although he says thatpotassium is to be taken as representative of the inorganicnutrients in general.

Feeding fowls on an exclusive maize diet, he found thatthe mere addition of calcium carbonate sufficed to preventth e appearance of pellagrous sym ptom s. Calcium pho sph atewas less successful t h an calcium carb ona te ; generally sp eaking,as far as white maize was concerned, calcium carbonate hadto be given as well as th e ph osp hate . Th is is in conform itywith Nicolaidi's observation *85 th at, even in h ealthy persons,

on an ill-balanced maize diet the calcium and magnesiumbalance became negative, whereas the phosphorus balanceremained positive.

Although in one of their pa pers, Goldberger a nd W heeler "57leave the question open whether an inadequate supply ofinorganic nutrients may not be responsible for the etiologyof pellagra, in another publication I I01 they definitely committhemselves to th e opinion th a t this lack is of crucial impo rtan ce.

In conformity herewith, Centanni and Galassi2

93 found th a tguineapigs, which in general are extremely sensitive to theinjurious effect of maize feeding and of feeding with othergrains, throve upon a maize diet adequately supplementedwith green fodder.

We have already seen that all the cereals, including maize,hav e 3, low excess of bases and a poor calcium co nte nt. I twould be very remarkable should the law of the minimum

fail to be valid where a diet of this grain is concerned.

6

^//. The Effect of Silicic Acid.

Alessandrini and Scala,3«> 33&, 356 who also refer the causa-tion of pellagra to the peculiarities of inorganic metabolism,



PELLAGRA 319

have a favourite theory in this respect, which is doubtlessconnected with opinions that have been recorded concerningthe origin of goitre. Th ey sta te th a t in regions w here

pellagra is prevalent the drinking water is exceptionally richin colloidal silicic acid, and they say that they have proofthat this excess of silicic acid is the real cause of pellagra,maize feeding being no more th an a predisposing cause. T he ybelieve that the effect of the silicic acid is reinforced by theeffects of calcium chloride [!] and aluminium hydrate.Voegtlin,39& who has obviously been influenced by Alessandriniand Scala, contends that the aluminium found in many vege-tables is one of the factors of th e disease. R ec en tly, how eve r,Breest 127I has definitely established that whereas the ingestionof soluble silicic acid, and still more the ingestion of solublesilicates, may lead to a certain accumulation of silicic acidin the animal organism, colloidal silicic acid is not absorbed,and the animals ingesting it remain perfectly healthy if theirdiet is otherwise satisfactory. Seeing th a t Alessa ndrini an dScala found that the troubles they supposed to be due tosilicic acid were perfectly relieved by alkalies or by calcium

carbonate, we must suppose that the lesions met with intheir researches were local or general effects solely due to theinfluence of acidity. W ha t th ey tell us of th e m orb id an ato m yof the affections confirms this theory.

m. Mental Influences.

Finally, it is necessary to point out that in pellagra, asin all other nutritive disorders, the onset of the disease may

be greatly influenced by psychical causes.I00

7 Homesickness,anxiety, sorrow, anything that causes mental depression, maynotably accelerate the appearance of pellagra.

n. Complications.

The association of pellagra and scurvy is fairly common,1?*but an association of pellagra and beriberi has not hithertobeen noticed. I t must be remem bered th at th e period of

incubation of beriberi is brief and that the onset of the illnessis acute, whereas typical pellagra has an incubation periodlasting several years



320 VITAMINS

5. SUMMARY.

Anyone who wishes to ascertain the cause of a nutritive

disorder, must be acquainted with the factors that can effecta cure. A comparison of the remedial diet with th e pathog enicdiet affords the quickest way of learning what constituentsof the latter, whether by excess or by defect, must be heldaccountable for th e variou s sym ptom s of th e disease. Th efirst thing we have to note is that in pellagra, as in othernutritive disorders, the simple addition of butter to thefaulty diet tends to make matters worse rather than better. 1^ 8

En right "7* reports th at a diet of bread, m eat, and eggs is

beneficial; bu t it cannot be said th at h is results were particu-larly encouraging, although as he was dealing with prisonersof war most of his cases were of recen t origin. Of th e 65cases under his care, only 46 -1 % were cured, and 33 -8 %improved (with marked increase in weight) ; but in a freshlydeveloped nutritive disorder one might have expected muchbetter results.

Boyd,Il 87 whose experience was also made in Egypt, butamong Turkish prisoners of war, considers that, in addition

to rest, the supply of a high-grade protein is the m ost i m po rta ntremedial m easure. Th e provision of prote in of high biologicalvalue and the simultaneous suspension of work, led to asudden fall in the number of cases reported.

As soon as the inadequacy of the protein in the pathogenicdiet had been recognised, as a matter of course the improve-ment of the quality of the protein was seen to be.the firstessential for the remed ial diet. McCollum, Simm onds, an dParsons 878 report that milk and milk products form the bestsupplements to a faulty die t. Rob erts,I007 in l ike manner,demands that the diet shall contain lean meat, eggs, butter,and milk. Ap art from U rbeanu, Roberts seems to ha ve beenthe only authority to stress the great value, in addition, ofvegetables rich in bases (this implying the avoidance of ripepulses!). H e informs us th at in the United State s, wh ereduring the last twenty years there have been about half amillion cases of pellagra with a mortality of 10 %, the numberand the severity of the attacks has notably declined sincedefective nutrition has been recognised to be the main cause



PELLAGRA 321

of the disease. In former da ys, th e larges t pro po rtion of thedeaths registered as due to pellagra were in cases of typhuspellagrosu s; this acute form of th e disease is now r a r e ; onthe other hand there has been a notable increase in the propor-tion of slight cases. These lesser cases ar e ap t to be over-looked, especially when the re is no de rm atitis (" pellagrasine pel lagra") .

Nevertheless i t must not be forgotten that the inadequacyof the protein in the pathogenic diet can by no means accountfor all the features of the pellagra syn drom e. Inn um era bleexperiments upon feeding with an inadequate protein have

been made, especially by the Am erican school. Some of thes ehave been carried out for several generations of the experi-mental animals, and as long as the diet has been in otherrespects adequate, no disease resembling pellagra has everbeen induced. Th e results of pro tein ina de qu acy are : arre stof weight or loss of weight, refusal of food, cachexia, and deathfrom cardiac asthenia—unless, in the debili tated animal,some complication arises to ha sten th e end. A lthou gh th esymptoms named are well marked in pellagra, there are otherwell-marked and typical symptoms in that disease whichmust be due to a different cause. T he frequency of pe llag rawithout dermatitis in American experience makes it probable,seeing that a maize diet certainly plays less part in causingthe disease in the United States than in Italy, that zeochinmust be the chief factor of the skin trou ble. B u t th e derm a-titis (which, moreover, may be aggravated, if not directlyexcited, by an excess of common salt and of acids in the diet)

cannot be regarded as pathog nom onic of pellagra. Th e m ostcharacteristic symptoms are the nervous disorders, which areobviously due to changes in th e ce ntra l nervo us system . I tmust be admitted that we cannot as yet indicate any factorwhich has a peculiar selective influence such as is certainlyexercised in pellagra upon the spinal cord and the greatnerve trunks. H ere, then, is an additiona l poin t th a t requ ireselucidation.

Perhaps the work of XJrbeanu will prove of enormous

importance in this connexion. My own innum erable o bserva-tions of sick persons during the last twelve years haveconvinced me that a lack of bases in the diet impairs the

21



322 VITAMINS

efficiency of the ne rvous system , th e disorder be ing especially

manifested in the form of neurasthenia and of migraine.These observations are in conformity w ith those of Hirschstein,who claimed moreover that in a particular case of migrainehe obtained chemical proof that a deficiency of organicallycombined sulphur was a co ntrib uto ry cause. Th is lack oforganically combined su lphur is likewise characte ristic of th epellagrogenic diet, and it is certainly remarkable that proteins

rich in cystin should be found especially valuable as ingredientsof the remedial diet.Perhaps a lack of bases in general, and a deficiency of

calcium and potassium in particular, in conjunction with anexcess of acids and a lack of organically combined sulphur,might in course of time induce the nerve degenerations charac-teristic of pellagra, especially if the before-mentioned faultsin the diet were supplemented by the inadequacy of theprotein it contained, by deficiency in respect of A, B, and D,and may be at times also by deficiency in respect of C.



CHAPTER TEN

CONCLUSION

As we have seen in the foregoing chapters, the data of themodern doctrine of nutrition are still dispersed in thousandsof brief essays an d re po rts . Th e mere collection of th e writin gsmost essential to the understanding of the subject is a formid-able task. A furth er difficulty in securing a gra sp of th ematerial arises because in many cases an important factnever finds direct expression. Sometimes, being take n bythe specialist as a matter of course, it is ignored and has tobe read between t h e lines. O ther facts, again, like th a t ofthe importance of an excess of bases in the diet, have escapedthe notice even of the experts, and have to be discovered bya comparison of the details recorded in numerous investiga-tions. We have no right, therefore, to reproach laymen(and as far as this subject is concerned, medical practitionersand the students of the chemistry of nutrients must be includedamong the laity) because their views concerning the moderntheory of nutrition and the results of the experimental study

of the physiology of nutrition are so confused and obscure—if, indeed, they have any opinions at all upon thesetopics.

But even the expert finds it extremely difficult to takea survey of the whole field, and the difficulty is especiallyconspicuous in connexion with the planning and carrying outof experiments. T ha nk s to the persisten t endea vours of th eAmerican school, even here there has been a certain clarifica-tion during the last year, so that we may look forward to agreater uniform ity in future results. Sy stem atised m ethod shave beep, form ulated for th e stu dy of th e vario us c om plettins,and have shown themselves to be of practical use ; but their

. 3 23 ]



324 VITAMINS

application demands critical faculty, judgment, a knowledge

of the literature, and wide practical experience.i . DIFF ICUL TIES ATTENDANT ON MODERN EXPE RIM EN TS

CONCERNING NUTRITION.

What applies to the more refined methods of chemicalinvestigation, applies also to the experimental study ofnutrition. An investigator m ay ha ve given th e mo st detailedaccounts of his procedures, and one who endeavours to followin his footsteps may be most scrupulous in the attempt toobserve these prescriptions, and still the result may be unsatis-factory. Success can no t be guaran teed un til methodologicaldetails hav e become auto m atic from long practice. Ev en th emost proficient analyst will not have satisfactory resultson the first occasion that he attempts to apply a complicatedme thod. H e has to m ake a num ber of trial experiments

simply to secure familiarity with the technique.In biochemical experiments upon nutrition the difficulties

are, however, enormously greater than in ordinary chemicalinvestigations, where the substance under examination issecurely confined within th e walls of a glass vessel. Thematerial studied in the physiology of nutrition is the livingorganism with its infinitely manifold individual variations,

which may be decisively modified by quite inconspicuouscircumstances.I have repeatedly insisted that in such studies an experi-

ment lasting several months may still be too short to givetrustworthy results, and that the whole lifetime of the animalunder exam ination m ay no t suffice. In such cases our onlyresource is to continue the experiment for several generations.

If after five or six generations the development of the animalsis still perfectly normal, we may then assume that the condi-tions of our tri a l experim ents are in sufficiently close conformitywith the conditions under which the animals in questionlive in a sta te of na tu re . N ot un til then can we safelyproceed to ascertain the effect of withdrawing one of theconstituents of the diet or of increasing the quantity ofanother .



CONCLUSION 325

not dealing with chemical constants, but with living beings;and although to our eyes they may seem as much alike astwo prints from the same negative, they are really character-

ised by marked individual variations. If the num ber of theanimals subjected to experiment be small, there is always arisk that the whole research may be invalidated by thesechance variations. Not un til the number of the experimentalanimals is considerable, can the experimenter be certain ofavoiding such errors.

In this book there has been frequent occasion to mentionthe accidents that can interfere with experimental results.Let me remind the reader of the experiment on vitamin in

wh ich Jhbe anijTia Is 3 ie th p ir own_£aeces^.... Thifv w a «> ain nb.vioiisi v .



326 VITAMINS

apparatus designed by Robertson and Ray for investigationson mice, it will still be necessary, in these new surroundings,

to study the undisturbed life-history of a great number ofanimals before proceeding to th e actua l experim ent. Thepossibility of local variations must always be taken intoaccount.

2. TH E COMPLETTIN CONTENT OF FOO DST UFFS .

Anyone making experiments as to the effect of complettins,must, of course, know where they are present, and approxi-

m ately how much of them the various nu trients contain. Bu tthis question does not concern the laboratory experimentalistal on e; it is perhaps even more im por tant to anyone who hasto prescribe diets for others. I am, in fact, besieged withqueries on this subject, not only by doctors, but also byhousewives and by th e head s of institu tion s. I can hardlyemphasise the importance of the m att er be tter t ha n by quotinga passage from Sherman and Smith's latest work.J554 I should

mention that until recently Sherman was one of the mostzealous advocates of the protein-calorie doctrine!

" If we compare the human organism to an internalcombustion engine (the traditional simile of the steam engineis inapt), the organic nutrients constitute the fuel, theprotein and part of the inorganic nutrients form the materialsout of which the engine is made, the rest of the inorganicnutrients represent the lubricating oil, and the complettins

play t he pa rt of th e spark. . . . All these substanc es areessential to the working of the machine. . . . In accordancewith the law of the minimum, any one of them can functionas the determining factor of the whole process. . . . Inscientific experiments we may devote special attention to thesupply of protein or to the provision of a sufficiency of calories.On the other hand, when we are practically planning a di§tor considering the nutritive requirements of a family, we shall

do better to make it our first aim to ensure the supply of asufficiency of those nutrients which are known to us to bepreeminent as conveyors of the necessary inorganic salts andthe com plettins. N ot un til the n need we con tern ourselveswith the possibility that it may be necessary to supplementthe diet &L respect of protein or of energy by a further supply



CONCLUSION 327

of some suita ble nu tri en t. Consequently, th e person respon-sible for th e diet m us t, abov e all, see to it th a t the re shall be

a sufficiency of milk, vegetables, and fruit, thereafter, cerealsmeat, fats, and sweetstuffs may be added according to thetaste, the financial resources, and the digestive powers ofthe individual, an d ac cording to his needs in respect of energy.. . . He re is a good em pirical rule in reckon ing die tetica lrequirements. Spend at least as m uch upon vegetables andfruit, and at least as much upon milk, as you spend uponmeat, fish, cereals, an d swe etstuffs! " [R etra nsla ted fromthe German.]

In preparing the following table I have made use of allthe data known to me in the li terature of the subject. Th eemployment of the very latest results of research has ledto considerable differences between my table and similarones that have previously been published, but I think thatmy own is th e most trust w orth y issued to date . I describe

the content of a complettin as " enough " when the quantitysuffices, not merely to cure, but also to prevent a deficiencydisease. W hen the co nten t is so considerable th a t even verysmall quantities of the particular nutrient are effective, thiscontent is described as " m uc h." A m ounts th a t a re con-siderable, though not adequate, are denoted by the term" li t t le / ' Insignificant am oun ts are described as " tra ce ." Azero is used to indicate th a t no com plettin ca n be detected.

A query denotes that definite information is lacking (p. 328).

3 . NUTRITION IN COMPLETTIN EXPERIMENTS.

Numerous standard diets have been tabulated for use inthe study of th e various complettins. Seeing th a t again andagain new dietetic factors requiring special attention havecome to light, all the older prescriptions can unhesitatinglybe * discarded as obsolete. To -day , for research es concerning

th e biological value of the different prtiteins, the recommendationsof B. Sure ll6s>x* 6* are those most worthy of consideration.For rats, he used an experimental diet consisting of dextrinisedmaize sta rc h, O sborne's latest m ixt ur e of salts , clarifiedbutter fat, and as conveyer of the water-soluble complettinsan alcohoSc extract of defatted wheat germs, while maceratedag ar was adde d as roughage. B y present l ights, a fewfmprove-



328 VITAMINS

FLESH-MEAT, FISH, EGGS.

Muscular Tissue (freshmeat)

Tinned MeatMeat, frozen (not long

in store)Meat, frozen (long in

store)Meat, salt (not long

in store)Meat, salt (long in

store)

Brain . .Heart . .KidneyLiver . .SpleenMeat Ext r a c t .Fi sh , leanFish , fa tFish , roeEggs (fowl's) .

m a

Eg g (white of)Eg g yolk of)

Vitamins

littletrace

Httle

trace

Httle

a trace

enoughHttleenoughenoughHttletraceHttleHttleenoughHttletraceHttle

D

p

trace

Httle

?

p

p

?p?p?pp??Pp?

A

littletrace

Httle

trace

Httle

trace

HttlemuchenoughmuchHttletracetraceHttleHttleenoughtracemuch

B

littletrace

Httle

trace

little

trace

enoughHttleenoughenoughHttlelittleHttleHttleenough ?littletraceenough

C

littletrace

Httle?

trace

Httle

trace

Httle?Httle?Httle?Httle?

o ?trace

o ?little ?Httle?trace?tracetrace?

Bfeans, haricot (freshly-dried)

Beans , haricot (old) ..Beans , haricot (ger-

minated)French beans (fresh). .Bean s , soyBeans , katjang-idjo . .Peas (ripe)Peas (young green) . .Peas (germinated) . .

PULSES.

muchtrace

traceenoughmuchmuchenoughenough

much?

?enoughmuchmuchenoughenough

littletrace ?

trace?enoughtrace ?

penoughenough

enoughtrace

traceenoughmuch ?enough?enoughenoughmuch ?

trace?trace?

enoughenoughtrace

?little?enoughenough

CEREALS, SEEDS, FLOURS, BREAD.Rye (whole grain)

Ry e (fine flour)Rye (bread, whole-

meal)Wheat (whole gra in) . .Whât (endosperm) . .Wheat (germ)Wheat (bran)Wheat (wholemeal) . .

Wheat (bread, white,with water)Wheat (bread, white,

with milk)Wheat (bread, whole-

me a l , with water) . .

enough

trace

littleenoughtracemuchmuchenough

little

little

enough.

enough?

?enough.

?muchmuchenough

little

little

en6ugh

littletrace

littlelittletracelittlelittletrace

?

little

little

enough

trace

littleenoughtracemuchenoughenough

little

little

little

little ?trace

?tracetracetracetracetrace

trace

?

?



CONCLUSION

CEREALS, SEEDS, FLOURS, BREAD—continued.

329

Wheat ( b r e a d , w h o l e -m e a l , with milk) . .Barley (whole g r a i n ) . .Barley (groats)Oats (rolled) . .Malt (green)MilletRice (unpolished)Rice (polished)Maize ( y e l l ow , whole

grain)Maize ( w h i t e , whole

grain)Maize (fine fl o u r , m a i z -

ena)Cotton seedsCotton seeds (fine

meal)LinseedHemp seeds

Earth-nuts . .Hazel nutsHickory nutsChestnuts (Spanish)Cocoanut

Cocoanut (cake)Almonds (sweet)Para nutsPine kernels . .Walnuts

ApplesOrangesOranges (juice)BananasPearsCocumGrape-fruit . .

Raspberries . .LimesMangoesMulberriesMulberries (dwarf)PlumsTomatoesTomatoes (boiled)GrapesGrape juice . .Lemons (ripe)Lemons (green)

Vitamins

enoughenoughenoughenoughenough?enoughmuch

trace

enough

enough

traceenough

enough??

enough

enough

?enough?

enough

enough

p??

N U T S .

enouglittlelittlelittlelittlelittlelittle

trace

little

trace

tracelittle

tracelittlelittle

FRUITS.

enough?enoughlittlelittleenough?enough?enoughtrace

enough

enough?

traceenough

trace

enoughenoughenoughlittleenough

mu c h .littleenoughlittleenough

enoughenoughenough

?enough

muchpenough

?enough

littletrace ?trace?trace?little

tracelittletracelittletrace?

enoughenoughenoughenoughenough

muchlittleenoughlittlelittle

Httleenoughenoughenoughlittle

renough

Httle?

r?

Httlemuchmuchenoughlittleenoughmuch

?enoughenoughenough

?

renough

???

r??

muchmuchenough

?enoughmuch

littlelittletracelittletrace ?

?r >r

trace ??r??

muchmuch

?

Httle ?littlemuch

Httlemuchenoughenoughlittle

t

enoughrenough

•\i?

Httlemuchmuchenoughlittleenoughmuch

ptracetracetraceenough

o ?tracetrace

trace

trace

traceenough

trace

trace?

trace ?trace ?

littlemuchmuchmuchtrace ?Httleenough

muchHttlelittlelittlemuch

?muchmuchenoughenoughmuchmuch 2.



330

FRUITS—continued.

VITAMINS

Lemons (juice of com-merce)

Tamarinds (dried)

Vitamins

pp

D

p

A

p

B

p

C

enoughlittle

ROOTS AND TUBERS.Sweet potatoesPotatoes (raw)Potatoes (boiled

one hour) . .Potatoes (dried)Carrots (raw)Carrots (boiled)Carrots (juice)ParsnipsRadishesBeetrootsTurnipsKohlrabiMangel-wurzelsSwedes

fo r

littleenough

enoughenoughenoughlittlemuchenoughlittlelittleenoughenough

enoughenough

littleenough

enoughenoughenoughlittlemuchenough

?p

enoughenough

enoughenough

enoughlittle

littlelittleenoughenoughenoughlittletrace ?

?littleenough

enoughtrace ?

littleenough

enoughenough ?enoughlittlemuchenoughlittlelittleenoughenough

enoughenough

GREEN VEGETABLES, LEAVES, E T C .

ArtichokesLucerneGreen leaves . .CauliflowerDasheenEgg-plantGrass

Green cabbageCucumberH ayClover (fresh)..LettuceCressesTimothy grassDandelion leavesRhubarb (stalk)Pickled cabbage (Sauer-

kraut)

CelerySpinach (raw)Spinach (boiled)Spinach (dried)Pumpkin (squash) . .White cabbage (raw) .White cabbage (boiled)White cabbage (dried)Onions

littlemuchmuchenoughlittleenoughenough

enoughlittleenoughmuchenough

enoughenough

pmuchenoughenough

muchenoughenoughenough

pmuchmuchenough

?enoughenough

enough??

muchenough

enoughenough

pmuchenoughenough


enoughmuchmuchlittletrace

p

much

muchpenoughmuchenough

muchmuch

\

muchmuchmuchenoughenoughenoughlittletrace

littlemuchenoughenoughlittleenoughmuch

muchlittleenoughmuchenough

muchenough

littlemuchenoughenough


tracemuch

enoughlittleenoughlittlemuch

trace ?p

muchmuchenoughmuch

pmuchenoughlittlelittletraceenough

muchmuchtracemuchmuchlittleenoughenoughlittle

pmuchenoughtrace

muchenoughlittleenough



CONCLUSION

MILK AND MILK PRODUCTS—continued.

3 3 1

Cow's milk (scaldedonly)

Cow's milk (pasteur-ised)

Cow's milk (con-densed)

Cow's milk (driedslowly)

Cow's milk (dried in-stantaneously)

Cow's milk (skim-) . .Cow's milk (butter-) . .ButterCreamCheese (skim-milk) . .Cheese (full-milk) . .

Cottonseed oilEggfatEarth-nut oilFish oilCocoanut oil ..Codliver oil ..Linseed oilMaize oilAlmond oil ..Margarine (vegetable).Margarine (animal) . .Nut oilOleomargarine (olein).Olive oilOrange-peel oilPalm oilHorse fa tBeef fa tMutton fat . .

Pig fat (kidney fat) ..Pig fat (lard)SuetStearinWhale oil

YeastYeast (dried) . .Yeast (extract)

Vitamins

enough

little

enough ?

trace

enoughenough

enoughtraceenoughtracetrace

enough

little

enough?

7

enough

enoughenough

enough

much

much

much,

much

much.littlelittlemuchmuchlittleenough

YEAST PRODUCTS.

enough

little

enough?

trace

enoughenoughenoughtraceenough

?

SUGARS AND STARCHES.

FATS?0

0

0

0

0 ?0

0

0

0

0

0

0

0

trace ?0

0

0

0

00

0

0

trace ?

AND OILS.?0

0

0

0

0 ?0

0

0

0

0

0

0

0

trace?0

0

0

0

00

0

0

?

littlemuchtracemuchtracemuch

tracelittletracetracelittletracelittletraceenoughlittlelittlelittlelittle

enoughtracelittletraceenough

?0

0

0

0

0 ?0

0

0

0

0

0

0

0

trace?0

0

0

0

0

0

0

0

trace?

muchenoughmuch

muchenoughmuch

muchtracetrace

traceenoughmuch

variable

trace

trace

trace

variablevariablevariabletrace?variable

ooooo

oooooooo

trace ?oooo

ooooo

tracetracetrace

Sugar (refined)Honey..Honey (artificial)Starch

0

little0

trace

0

0 ?0

0 ?

0

0

0

0

0

0

0

0 ?

0

0

0

0



332 VITAMINS

ments might be suggested. Po tato starch would be preferableto maize starch, for the latter contains traces of colouring

matter which might prove injurious (especially to white miceand white rats ). Th e salt m ixture could be bettere d byincreasing the dose of calcium carbo nate to ab ou t 170 gr am m es ;the small quantity of manganese sulphate should be replacedby 10 grammes of manganese ci tr at e ; the magnesia shouldbe increased to 20 gra m m es; the phosphoric acid should bereduced to 60 gra m m es; and, finally, 5 gramm es of crystallinesodium silicate should be added to th e m ixtu re. I t stillremains to be decided wh ether this mixtu re will prove adeq uate

for several successive generations of the experimental animals.(See next paragrap h.) The use of wheat g erms instea d of theyeast extract that has hitherto been customary is not adesirable change, for we have seen that wheat germs arecom paratively poor in com plettins. Be tter tha n either wouldbe an extract of young clover not yet flowering or of youngspinach, precipitated with alcohol to get rid of the proteinsand then heated for a short time to 60° C. Of course all

these extracts contain ammo-acids, which must on no accountbe left out of the reckoning.

In experiments on the inorganic nutrients, the protein ofthe diet should be supplied in the form of carefully purifiedcasein and lactalbum in ; th e other c on stituen ts of the foodshould be pure potato starch, macerated agar, clarified meltedbutter fat, and the improved salt mixture just described.Special series of experiments should immediately be under-taken to ascertain whether the experimental animals canreally thrive for a number of generations without a triflingaddition of copper and zinc to the diet. I n exp eriments upon,the various forms of combination of phosphoric acid and ofsulphur, it must not be forgotten that the proteins and thebutter contain these substances, and that the amount ofthem in the m acerated agar is by no m eans negligible. Theexperimenter must also bear in mind that the most sedulouslypurified nutrients always contain quantities of ash wMch may

in certain circumstances be of decisive im por tanc e. L et meremind the reader of what was said in the third chapter anentthe phosphorus content of edestin, and also of my ownexperience that purified fats invariably contain organically



CONCLUSION 333

combined sulph ur. Hen ce it is perh aps be tte r to use achemically pure filter paper as roughage.

In experiments upon the action of the real vitamins(Funk's), difficulties arise which have been especially stressedby Sinionnet.^01 Hitherto these experiments have usuallybeen made with nu trien ts which in other respects were extrem elyinadequate, and it is doubtless for this reason that the morbidanatomy of beriberi and experimental polyneuritis is sodiversified. Sim onn et recom men ds th e following experi-men tal d ie t: m eat, thoroughly boiled and pressed, thenextracted twice with boiling alcohol and once with ether,

I I gramm es; Osborne's salt m ixture, 4 gra m m es; agarpowder, 5 gr am m es ; earth-nu t oil, 5 gra m m es; bu tte r fat ,10 grammes ; qu an tita tive filter paper, 5 grammes ; po tatostarch, 60 gram m es. After m ixing with 80 % of distilledwater, the mixture is given to pigeons by cramming, the dailyallowance am oun ting to half th e weight of th e bird s. Bo thB and C are lacking in this mixture as well as v ita m in ; bu tthe lack of B and C is of comparatively little importance,

for it has not tim e to m ak e itself felt owing to th e rapid develop-ment of th e consequences of vit am in deficiency. Th ere is,however, one grave defect in Simonnet's recommendations;they take no account of the difference in the respective effectsof vitamins an d th e water-soluble antin euritic D. Theproblem of the origin of the various forms of polyneuritiscannot be solved without the recognition of this difference.We have learned that the two classes of substances unques-tionably make their lack felt in different parts of the organism.

As yet we have no trustworthy method by which Funk'svitamin and water-soluble D can be wholly separated eachfrom the other, and in this department of the research thediscovery of such a method must be our immediate task.Next comes an add ition al poin t to be considered. I t h ashitherto been assumed that the lack of B in these experi-ments is of no moment, for the incubation period of polyneu-ritis is so sho rt th a t B deficiency can not ma ke itself felt. I t

is nevertheless possible that even in so brief a period the lackof B m ay ta k e effect, especially upon th e gland s. M oreover,we have already notedfthat C deficiency is probably the causeof the trifling haemorrhages sometimes met with in cases of



334 VITAMINS

polyneuritis. We must, therefore, endeavour to discoverways and means of freeing B an d C from vitam ins an d th e

water-soluble antineuritic D, so that a sufficiency of B andC may be added to the experimental diet.When studying the conditions of growth, the experimenter

will naturally regulate the experimental diet with an eye tothe special problem under examination, but he must takethe utmost care that in other respects the diet shall beadeq uate. A stud y of the fat-soluble com plettin is a fairlyeasy matter, for this complettin is readily destroyed byoxidising agen ts. B ut it m ust no t be forgotten t h a t th ecomplettin C, whose presence in the diet is absolutely indis-pensable in these cases, is likewise sensitive to oxidisingagents, and may therefore be destroyed by the methods usedfor th e rem oval of A. Similar and more formidable difficultiesarise in the study of the effects of B, for the means employedto free the diet from B are apt to destroy D and C as well.There is still a good deal to be cleared up in connexion withsuch matters, and much further work will be requisite before

it will be possible to provide a throughly satisfactory experi-mental diet suitable for each particular type of investigation.As an example of the technique of these investigations, Imay refer to Osborne and Mendel's latest publication,X33r

with the remark, however, that the diet there mentioned isdesigned solely with regard to the fat requirements of theexperimental animals, and contains a source of fallacy eventhere . Dried, pulverised m eat cannot be comp letely defa tted

by extraction with alcohol and ether, and in the prescribeddiet the meat powder of the daily ration will still containabout o*4 grammes of fat.

Byfield, Dan iels, and L oughlin "53 tabul at e an excellentfundamental diet which they suppose to be satisfactory evenin respect of the absence of the water-soluble complettins.Bu t they were investigating the problem as to w hether vita m inand B are identical, and obviously the diet they recommendis quite unsuitable for the purposes of this investigation,seeing that the deficiencies of vitamin, B, C, and D reinforceone another. Moreover, in experim ents on grow th-factors ,casein should no t be the only source of pro tein,f seeing th a tthis protein is not wholly adequate for the growing organism.



CONCLUSION 335

We must either give an approximately equal quantity oflactalbumin in addition, or else, following Osborne and

Mendel's example, use meat protein purified as thoroughlyas possible.An experimental diet for the study of the effects of

B-containing extracts is no t difficult to arran ge . I t shouldconsist of meat that has been pressed and thoroughly boiledand subsequently extracted with alcohol and ether, starchsimilarly extracted, salt mixture, and filter paper. Theallowance of fat must be kept for several hours at a tempera-ture ranging from 1200 to 1300 C. with air passing through

it all the time , to free it from A. As conveyer of the w ater-soluble complettins, a vegetable extract will be used, freedfrom A by ex trac tion w ith alcohol and eth er. Th e smallquantities of vitamin or of water-soluble complettins whichmay pass off in solution when the inspissated extract is beingextracted in vacuo are negligible provided a sufficient amountof the extract be added to the diet.

For the study of the effect of the antiscorbutic complettin

0, it is likewise comparatively easy to arrange a diet thatshall be ade qu ate in oth er respects. This diet will consistof pure proteins, dextrinised starch, a fat (preferably butterfat as conveyor of A ), filter pa pe r, and salt s. As convey ersof the other water-soluble complettins, we shall use anexpressed vegetable juice, spinach juice for instance, in whichthe C has been destroy ed by e vaporation to d ryness in vacuoat a temperature ranging from 6o° to 70 0 C.

The foregoing indications as to experimental diets have

no claim to completeness. The y are merely inten ded <o showthat, despite the elaborately developed technique, the diffi-culties to be reckoned with in these experiments are stillextensive; and to show, further, t h a t all the problems arestill in a sta te of flux. A great d eal m ore work will ha ve tobe done before we shall possess an unexceptionable techniqueeven for one br an ch of these investiga tions. I t is, therefo re,rather remarkable that Aron and Gralka I3 8 6 should declare

it to be the duty of investigators henceforward, not only todetermine (as heretofore) the amount of protein, fat, carbo-hydrates, and inorganic salts the nutrients contain, but toascertain also by experiments on animals the biological value



336 VITAMINS

of these nutrients as regards protein, fat, and complettins.Aron seems to have no idea of the amount of work that isalready imposed upon those who are studying" th e biocliemistryof nutrition, and he fails to realise the scantiness of theirresources. For such investigations as he recommends itwould be necessary to have a regular zoological garden witha highly trained staff. No private investigators have any thingof this sort at their disposal, nor as yet can official researchlaboratories comm and any thin g like it. One who read sAron and Gralka's paper cannot but feel ironical when henotes that even so distinguished an investigator as Aron

himself is obviously tinaco[iiainted with the most importantresearches of the last two years. In especial it m ust bementioned that the salt mixture recommended by Aron isquite inad equate . [Furthermore, he suggests plasnion as asource of protein, but in long-continued experiments thisprotein proves inadequate.

4. THE IMMEDIATE PROBLEMS OF COMPLETTIN- RESEARCH.

W hat are the imm ediate tasks of com plettin resea rch ?

They are as follows : further study of the biological value ofthe various proteins used as nu trie nts ; an exam ination asto how far there is a vital need for certain inorganic sub-stances universally present in natural food, hut present onlyin very small quantities ; the differentiation of Funk's vitaminsfrom the antineuritic complettin T> , and from the growth-factor B ; a stu dy of the function of the fat-soluble com plettinA in the organism of growing animals and adults respectively ;finally, the isolation of th e com plettins in a pur e sta te. Fu r-ther, it will be eminently desirable, in all these researches, toseek the aid of experts in pathological anatomy, so that wemay ascertain the precise effect upon the organs and tissuesresulting from a lack of the various com plettins. Th is know-ledge would be of the greates t value to thera peu tics. Fin ally,I must insist once mo re th a t the m ethods hit he rto em ployedfor the analytical determination of the inorganic constituentsof the diet, whether employed by biologists, medical practition-

ers, or biochemists, have been inadequate and misleading.The Experimental Stations Office in Washington, U.S.A., hasrecently endorsed this criticism. T he utm ost ac curacy isessential in such investigations.



CONCLUSION 337

5 . THE NEED FOR STATE AID IN EXPERIMENTS ON

N U T R I T I O N .

It is obvious that these problems can only be studied withsuccess in great institutes, with the aid of large laboratoriesand extensive zoological gardens, with that of a staff ofanalytical, biological, and anatomical experts, and a numberof well-trained subord inate assistants. These requisites arenot fulfilled at the extant institutes attached to the universities,for there the personnel of the staff changes so rapidly thatthe trustworthin ess of th e results is endange red. W ha t we

need is the foundation of large institutes with permanentstaffs whose m em bers ha ve an assured position. In th eUnited States such places may be provided by the munificenceof m illionaires; bu t in impoverished Euro pe , an d especiallyin Germany, we m us t look to th e S ta te for aid. In suchmatters, thrift is out of place. Every day demands itssacrifice of the public health through errors of diet, andthereby the whole body politic is enfeebled.

But it will not suffice that steps should at length be takento throw light up on th e biological processes of nu trit ion. Ofwhat avail would it be that scientific experts are fullyinformed concerning these matters, so long as the great massof the population is being ruined in health by irrationalfeeding? In addition to institutes for the biochem ical studyof nutrition, there must be institutes of nutritive hygiene whosetask it will be to ensure the practical application of the theoreticalacquisitions of biochem istry, to ensur e that the data of the new

science of nutrition shall be real ised in daily life. The con-sciousness of the masses m ust be per meated wi th a practicalknowledge of the new science of dietetics.

2 2



BIBLIOGRAPHY

(C = Chemisches C en tralb la tt; BZ == Zentra lbl. f. Biochem. u.

Biophys.; BPh = Ber. ges. Physiol. u. Pharm.)

1. RIESELL. In Hoppe-Seylers Med.-chem. Untersuchungen. 1868.2. SCHETELIG. Arch, pathol. Anat. 1877, 82.3. G. L U N I N . Zschr. physiol. Chem. 1881, 5, 31.4. E . LEHMANN. Berl. klin. Wschr. 1882, Nr. 21.5. T. BARLOW. Med.-chirurg. transact. 1883, 46, 159.6 . TEREG and ARNOLD. Arch. ges. Physiol. 1883, 32, 122.

7. KGNINGER. D. Arch. klin. Med. 1884, 34.8. A. URBEANU. Atiologie der Pellagra vom chemischen Sta nd-

pu nk t aus. Bukarest, 1884.9. K. TAKAKI. Sei-i-k-wai 1885, 4, August.

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261. J. M. LITTLE. Journ. Amer. Med. Assoc. 1912, 58, 2025;

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262. C.LOVELACE. Journ. M«d. Amer. Assoc. 1912, 58, 2134 I B ^1913, 14, 552-

263. H. RATJBITSCHEK. D. rned. Wsclir. 1912, 216 9; s z l9*3>

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267. E. G. HOPKINS and A. NEVILLE. Biochem. Journ. 1913» 7>9 6 ; BZ 1913, 14, 628.

268. C. F U N K . Biocliern. Journ. 1913, 7, 211; BZ 1913, I5> 235-269. E.A. COOPER. Biochem. Journ. 1913,7,268 ; B Z 1913. *5> 642.

270. L.NICHOLAS. Joizrn. oiHyg. 1913, 13,149 i BZI9*3>15f 768-

271. H. RICHTER. Zschr. ges. Neurol. 1913, 21, 172; BZ I9i4>J^>

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272. SAWAZAKI. Mitteil. med. Ges. Tokyo 19*3* 3 ; BZ 1913,IS 314.

273. C.FUNK. Journ. of physiol. 1913,46, 173; BZ 1913, 15 , 643.

274. O. HERBST. Zschr. Kinderheilk. 1913, 7, 161.275. C. FUNK. Brit. Med.Journ. 1913, I, 814.276. E. B. TALBOTT, W. J. DOBD and H. O. PETERSON. Transact.

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337. P. ALBERTONI and P. TULLIO. Real accad . s c ienze ist. di

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1269. H . ABELS. Wien. kl in . Wschr. 1920, 33, 899.1270. F . V E R Z A R and J. B O G E L . Biochem. Zschr. 1920, 108, 185;

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INDEX

A, fat-soluble, 22, 138, 159, 160, 184—187, 188, 189, 191, 194, 195, 200,207, 208, 210, 211, 219-241 (forDetails see Table of Contents,Chapter Six), 246, 249, 254, 265,270, 283, 294, 295, 296, 314, 317,

322, 334, 335, 336compounded with B, 222, 226AB DER HALDEN, 22, 30, 31, 34, 36, 41, 42,

44, 45, 46, 48, 49, 58, 59, 73, 139,146, 147, 148, 155, 159, 167, 193,195, 202, 352, 367, 372, 384, 385,389

ABDERHALDEN and BRAMMERTZ, 203,384ABDERHALDEN andEwALD, 74, 122, 139,

360AB DER HALDEN and G E L L H O R N , 379AB DER HALDEN and K O E H L E R , 194, 368ABDERHALDEN and L A M P E , H I , 1x8,121,

346

AB DER HALDEN and SCHAUMANN, 114,120, 137, 139, 155, 364

ABDERHALDEN andScHiFFMANN, 20 0,38 0ABDERHALDEN and SCHMIDT, 147, 381ABDERHALDEN and W E R T H E I M E R , 389Abderhalden's Reaction, 311, 312A B E L S , 369, 380Aberi Acid, 21, 111Absorption, Assimilation, and Digestion

distinguished, 92Accessory Food Factor, Term defined,

22, 23Accidents that invalidate experimental

Results, 325

Acetic Acid, see VinegarAcetonuria, 78, 80, 303Achlorhydria,213Achylia, 267, 274, 286, 302Achtzig Stoffwechselversuche uber die

therapeutische Beeinflussung der ra~chitischen Stoffwechselstorung, 353

Acid Ferm entation in Bowel, 77Acid-formers, Effect of Oxidation on

their biological Value, 94-99Acidosis, 41, 43, 44, 65, 66, 70-75, 76-

83, 84, 87-88, 90, 103, 104, 108,288, 294, 295, 296,297,298, 319,321, 322

defined, 80in malnutri t ional Oedema, 288, 294,205

in Osteomalacia,234in Pellagra, 303, 319in Scurvy, 245, 269, 270in Sprue, 216, 217, 218

391

Acids—Effect on C,259, 260, 264Effect on Walls of Bloodvessels, 288 »Excess of, seeAcidosis

Acids and Acid-formers, excess of, incertain Nutrients, 70 et seq., 180,

182, 2 ii , 216, 217 ; see alsoAcidosisACKROYD and H O P K I N S , 33, 355Acne, 76Acom plettinosis (terminology),24Activation and Activators, 156, 158Active T issues, 192Addison's Disease, 302Adenin, 117, 121Adenoids, 209A D K I N S , 48, 376ADLER , 366Administration of Alkalies as a Pre-

ventive ofAcidosis, 87-88

Adrenalin, 86, 121, 122, 145, 146, 152,153,154, 239, 240, 292, 294, 295, 297antagonised by Cholin, 295

Adrenals, 143, 144, 145, 146, 153, 201,204, 223, 238, 239, 240, 267, 273,285, 286, 287, 292, 294, 301, 302

Aetiologie der Beriber i, 341Aetiologie der Pellagra vom chemischen

Standpunkt aus, 338Agglutinin,199AGAR, 160, 327, 332AGULHON and LEGROTJX, 363Ainos, Scurvy among, 242Air, Exposure to—

effect on Fat-soluble A, 187Alanin, 29, 31, 32, 33, 49Alanyl-glycin,59ALBERT, 351ALBERTONI and TULLIO, 42, 313, 348ALBRECHT and WELTMANN, 286Albumiiruria, 300Albumose Poisoning, 75, 311Alcohol, 109, 195, 216Alcoholism,76ALESSANDRINI, 306ALESSANDRINI and SCALA, 318, 319, 341,

347, 348, 349Alkalies ; see also Bases—

their Administration as a Prevent iveof Acidosis, 87-88

the ir Effect on GrowtMactorJB) ,196their Effect onC, 256, 258, 204

Alkalosis, 78, 80Allan toin, 121ALLEN, B., see SHERMAN



392 VITAMINS

A L L E N , E., 364A L L E N , F. P., see E M M E TAlmond Oil, 22 1, 224, 331Almonds, 50, 191, 224, 244, 269, 329ALPAGO-NOVELLA, 307ALSBERG, 344Altstadt Hospital,250Aluminium Hydrate, 319A L W E N S , 369, 383AMAND, 339AMAR, 38, 40, 363Amboceptors, 166, X99Amenorrhoea,235America, see United StatesAmerican School, 323A M EU LLE, 281, 378Aininisaticn, 167Amino-acids, st& also Tissue BuildersAmino-acids, 121, 164 etseq.

Amino-acids, biological Value of, 29-36Ammonia, Formatioa of, 65, 73,74,75 >80, 81, 86,go

See also AcidosisAMUNDSEN, 252Anaemia, 265, 267, 273, 300Anaesthesia, 286Anaphylaxis, 308, 310, 311Anasarca, see OedemaANDERSON, E, V., D U TC H ER , EC K LES ,

and "WILBUR, 385ANDERSON, A. K., and F I N K E L S T E I N , 365A N D R EW S , 344Animals—

Experim ents on, Application of Results

to Human Beings,174parasitic onVegetable Kingdom, 240,241

A N R E P and DRTJMMOND, 385Antiberiberin, 22, 111Antibodies, 243, 307, 308Antigens, 312Antineuritic Principle, se e DAntiscorbutics, 243-262Apoplexy, 243Appetite, X43, 149, 200, 231, 276, 279,

299,321A P P LEM A N , 361Apples, 191, 209, 244, 251, 329APPLETON, 388

Aracnin, 49, 58, 59Araclds hypogaea, see Ear th -nu tArchangelsk, Scurvy in,248, 249Arginin, 29, 31,33,121A R N ETH S , 361A R N O LD , 96, 349; see also T E R E G and

ARNOLDARNSTEIN, see E P P I N G E RA R O N , 14, 68, 185, 189, 190, 191, 199,

212, 231, 235, 246, 297, 336, 341,352,363,372, 378, 380

A R O N and GRAUCA, 68, 335, 336,374, 384A R O N and H O C S O N , 103,155, 341, 342A R O N and SAMELSON, 379Arrest of Growth, see Growth

Arsenic—as Remedy for Pellagra,306is it essential ? 67 et seg.

Arthralgia, 265Artichoke leaves, 224

Artichokes, 330Artificial Feeding of Infants, see Breast-

feedingArum , 192,224ASAYAMA, 355

Aschamin,120A S C H O F F and K O C H , W., 368A S F O R D , 51, 341Ash, 64 et seq., 332 ; see also Salts

total, Balance, 103, 130Asparagin, 29, 121, 290Asparaginic A cid, 29Aspergillus fumigatus, 307, 308Assimilation (Utilisation) must not be

confused-with Digestion and A bsorp-tion, 92

Asthenia, see Debili tyAsthenia, cardiac, 289, 297, 321Ata ,247

A-tonicity, se e T o n eAtrophy—brown,273in Adeficiency, 239in B deficiency, 201in Cdeficiency, 267in m aln utr itio na l Oedema, 273, 284in Kehlnahrschaden, 296in M lchnahrschaden, 297in "Vitamin deficien cy, 143 , 154.muscular, 147, T-57, eiseq.Nerye, in Pellagra,300

A.tropin, 122, 144A/TWATER, 39, 40Auditory Nerve, Affections of, in Pel-

lagra, 300A U E R , 232, 364.A U L D E , 74, 241, 380Autoclave, 197, 229Autointoxication, 281Autolysis, 114, 120,121, 136, 186, 187,

Autolytic P oisons, 243Avitaininosis (Terminology), 23,24Azoospermia in Vitamin Deficiency, 143

B , water-soluble {see also Growth-factor),22, 136, 138, 139-142, I44-, 160,161, 187-201 , 216, 218, 222, 226,

227, 228, 230, 231, 235, 236, 239,246, 249, 256, 262, 265, 275, 283^292, 294, 295, 296, 298, 514., 317,322, 333,334, 335,336

confou nded "with A, 222, 226confounded-with D, 195-196historical, 187—191Occurrence, 191—194.physiological Effects, 198—201Properties , 195-198qu an tita tiv e Estim ation , 194—195

B A B E S , 306, 359B A B ES and J O N E S C U , 311, 350BAXCELLI, see XuiB A C H , 365

BACHMANN", 194, 369, 378Bacon, 249, 280

salt, 251Bacter ia l Flora of Intestine, see F l o r aB A G U O N I , 42, 43, 45, 313, 350, 352



INDEX 393B a l a n c e , n i t r o g e n o u s , etc. See N i t ro -

g enous , etc.B al kan War, Scurvy dur ing ,247Banana Prote in , 140, 176, 178B ananas , 50-51 , 54, 55, 66, 140, 182,

186,191 , 224, 251, 329B A N G , 32, 286, 354, 363JBANGNESS> see M C C L E N D O NBarcelona Nuts, 224.B A R G E R , 349Bar ley , 46-47, 138, 176,181, 186, 191,

223, 247, 253, 329B A R L O W , 338B A R N E S and H U M E , 233, 253, 255, 257,

261, 365, 369BA RR, 77, 91, 103,104, 145, 293B A R S I C K O W , 119, 34.7B A R T E N S T E I N , 339Bases, seealso Alkalies

Deficiency of, 53, 73, 199, 247, 268,

296, 298, 317,318, 321, 322Excess of, 56, 58, 64, 65, 66, 70-75,140, 180, 182, 183, 209, 217, 241,261, 262, 270,321, 323

in organic combinat ion, 90supply of, 58

B A S S , 306, 343 ; set also W E L L M A NB A S S E T - S M I T H , 260, 377, 379, 387BAUMANN" and H O W A R D , 345, 358B A Y L I S S , 78, 379Bean Flour, boiled, 305, 314B eans (see also Haricots, Katjang-idjo,

Leguminosae , Soy Beans), 48-49,55 ,133,175, 191,196, 223, 249, 280, 328

fresh, r 06 , 328

germinated ,248, 249, 328

green unripe, 252Beef—

corned, iorfat , 222, 225, 331lean, 138Suet ,236

BEESOIST, 380Beet, Sugar, 192, 224Beetroot , 192,224, 252,330B E G E R , see MORG-ENBEGUN, HERRMANNT, and M ^ N Z E R , 79,352B e h a ^ o u r o f theGlands, 142-146B E H R E , 379BEHRINTG, 311B E N E D I C T , F . G., 60, 370B E N E D I C T and R O T H , 73, 351B E N E D I C T , S, R., see SUG-IURAB E N I N D E , 371

Benno-Schi lde Company, 261Benzoic Acid, 236B E R G , 9, 10, 11, 12, 13, 14, 15, 18, 19,

28, 41, 48, 51 , 53, 58, 60, 61, 62,6 5, ?o, 7i, 73, 75, 76, 84, 85, 86,89 , 90, r 8 i , 34.0, 342, 345, 347, 348,357, 364, 388 ; see also BIRKNER,R O S E

BERG-MANN, 206, 365Beriberi , 77,*74, 245, 254, 264, 273, 283,

292, 299, 314, 347

acu te cardiac, 131a n d o t h e r f o r m s of Po l y neur i t i s , roo-T71 (for D eta i l s seeTable of Con-t en t s , C h ap t e r Four ) ,333

Beriberi (cont inued} —dry, 130Etiology, 100—109,124fulminant, 272latent,162

ship, 109,279—281wet, 130, 131, 271Berkefeld Filter, 306Betain, 121,122,123BEZSSONOFF, 383, 385BEZZOLA, 310, 340BIDAXJLT and COUTURIER, 119, 379BIERICH, 246, 368BlERRY,38, 365 369

BlERRY andPORTIER, 78, 361

B I E R R Y , PORTIER, and RANDOIN 1, 143,153, 3/7

BIESTER, seeDutchex, WheelerBlGLAND, 279, 282, 315, 316,371, 375Bilberries, 215

Biogenen Amine, etc., 370Biological Value—of Acid-formers, the Effect of Oxida-

tion on, 94-99of animal Proteins, 52-58of various Proteins, 29—61, 327of vegetable Proteins, 41-52 ; see also

Protein, Importance ofBiophor, 22B I R K N E R , 75BIRKNER and BERG-, 347Biscuit, 249, 252, 268, 305, 315BISHOP, see EVANSBleaching of Vegetables, 211, 247, 261,

262, 278

BLENCKE, 373BLIECK and BAJUDET, 369Blindness, 297BLOCH, 233, 357, 362, 383BLOCK, 211, 212, 380Blood—

(as Nutrient), 178-count, 274-pressure, 142, 144, 154, 272,273, 285,

289, 292, 295, 297, 303, 304Protein, 53, 178self-reguLating Power of, 81, 83-serum, 53,269, 310, 311, 312

BLOOMBERGH, see CHAMBERLAINBLUM, 379BLUNT and W A N G , 383B O A S , see MCCOLLUMBody—

Temperature, see TemperatureWeight, seeWeight

Body-fat, 185, 222, 223BOGEL, see VERZARBoiling—

effect on.A,219, 229effect on.B, 196effect on. C, 244, 249,257-262effect on Vitamin, 118 et seq.f 124, 125of Vegetables, effect on Base Content,

of Vegetables -with subsequent Rejec-t ioa of Water , 73, 125,171, 183,217, 249, 262, 278, 283

unduly prolonged, 249,250,^78, 283BOLDVREFT, 358



394 VITAMINS

B O N A R , se e PHEMISTERBone, Diseases of, se e OsteopathyB O N N E , se e K O C KB O R D O N I , se e VOLPINOBORTJTTA.N, 42, 36 3, 37O, 378BORY, 375BOSSERT, 76 , 294, 371BOSTOCK, 139, 347BOSWORTH an d BoWDITCH, 35 7Bottle-feeding, {see also Breast-feeding),

•r, 2 5 5

BOTTOMLEY, 355, 356B O U T W E I X , se e STEENBOCK:BOWDITCH, se e BOSWORTHB O W ER S , se e MCCLENDON-B O Y D , 41, 45, 48, 54, 58, 6 1, 307, 313,

316, 320, 377BRADDON, 339BRADDON and COO PER, 349, 350Brady cardia, 273, 289Brain—

as Food, 139, 193, 195, 196, 328changes in Polyneuritis, 142, 143

BRAMMERTZ, se e ABDERHALDEKTB ra n, 45, 51 , 59, 111, 113, 189, 191, 200,

223, 247, 253, 328. (See also RiceBran.)

B R A N D T, se e M I L L E RBRAVETTA, 315, 316, 374Brazil Nuts, 224.Bre ad, 196, 244, 249, 250, 25 1, 253, 278,

280, 283, 320, 328, 329baking of, 196white, 101,106, 124, 125, 328wholemeal, 328

Breast-feeding, Adv antag es of, 206, 207,231, 238

BREAUDAT, 103, 343B R EES T, 319, 380Brief Experiments, se e Duration

Br itish M edical Association, 236, 317British Navy, Antiscorbutics in, 243B R O W N , M. A , 172, 370B R O W N , W. L., 383BRUDZINTSKI and CHELKOWSKI, 351BRTJGSCH an d KRANS, 212BRUNTZ and SPILLMA,**, 51 , 363Bucco, 105, 378BUCKNER, N"OLLATJ, an d CA STL E, 351BUCKNER, NOIXATJ, W ILK IN S, and

CASTLE, 41, 46, 366B U E L L , se e STEENBOCKBuffer Salts, 79, 81Bulgarian Arm y, Scurvy in, 247Bulimia, 299

B U L L , 360B U LX EY , 232, 364, 367B C R G E R , 273, 275, 276, 277, 2 78, 282,

283, 284, 367, 378B ut te r, 185, 187, 209, 211 , 220, 221,22 2,

223, 224, 225, 229, 230, 233, 236,283, 297, 320, 327, 33i, 332, 333,335

superheated, 221, 229Buttermilk, 232, 233, 331Butternuts, 224Butter-and-Flour Preparation, 298B uty ric Oil, 185, 222, 227, 228, 230B Y F I E L D , 139; se e also D A N I E L S

B Y F I E L D , DANTIELS, and LOUG HLIN, 196,

334> 376

C, water-soluble (antiscorbutic) , 22,159160, 210, 2ix, 217, 227, 228, 235,242-270 (for Details se e Table ofCon tents, C hapter Se ven), 296, 322,333, 334, 335

Animals cannot synthet ise, 253

Cabbage, 118, 119, 192, *9

6

>

X

97, 224,225, 229, 244, 251, 330boiled, 2.57, 258, 330dried, 224, 229, 244, 258,259, 260,330pickled, 248, 330w hit e, 192, 224, 25 1, 257> 3 3°juice, 257, 258, 261

Cabbage Water as Source of nutritiveSalts, 90

Cachexia, 300, 301,321Cage Factor, 25C A J O R I , 50, 193, 380Calcium, 55, 87, 88, 91, 209, 218, 241,

274Ba lan ce, 93, 94, 103, 267, 275, 303, 318

Carbonate, 319Chloride, 319Deficiency of, 43, 69, 70 , 71, 72, 74,

140, r8o, 181, 182, 184, 205, 209,218, 234, 235, 237, 241, 247, 268,282, 294, 295, 296, 298, 318, 322

Demand for during Growth, 180,181Embryo may rob Mother of , 72Ions and Oedema, 287-288, 293-295Metabolism, 93, 287-288Requi rements , 62Xerophthalmia and , 241

Calcium Salts—injection of as R em edy for S curvy , 269their paradoxical Effect , 83-87

their st imulat ing Influence on endo-thelial Activity, 288, 290urinary Excret ion and, 290use in ma lnu t r i t ional Oedem a, 277utilisation of, 180utilisation in various forms of Admin-

istration, 92—94Calories (see also Energy)

deficient Supply, aggravates Scurvy,267

deficient Supply, in relation to mal-nutri t io nal Oedem a, 277, 281, 282

in pellagrogenic Diet, 305, 315CAMPBELL, H . 1 . , se e M E R , SH E R M A NCAMPBELL, M. E. D. , and CHICK, 363

CAMURRI, 307, 343Cancer, 201, 216Cancer Hospital Research Institute, 77Canning, 125Carbohydrate Diet—

in relation to Acidosis, 77, 78in re la t ion to malnu t r i t ional Oedema,

277, 282excess of, accelerates onset of Poly-

neuritis, 118Carbohydrates—

as Nitrogen Economisers, 39manufactured from Proteins, 37

C A R B O N S and CA.ZZAMA.LLI, 308, 348



INDEX 395Carbonic Acid, free, as cause of hyaline

Degeneration, 288Carbonic-Acid Tension in Alveoli, 79, 80Careace, 10, 14Careace fruste, 14

Carence, M aladies de, 10, 24Caries, denta l, 209, 248, 266CARLETTI, 307, 312, 343 ; seealso

LUCA/TELLOCARNEIRO, 347Carnivora, supp lem entary Vegetarianism

in , 58Carolina, Pellagra in, 307Carotin, 228Carpopedal Spasms, 76, 294. Set also

TetanyCARREL, 163, 164.Carrot Juice, 211Carrots , 50,51 , 55, 66, 92, 93, 94, 137,

176, 178, 182, 186, z8g, 192, 196,197, 21/ , 224, 225, 244, 252, 277,290, 330

boiled, 257, 33Odried, 244, 258Ext rac t of,252Juice, 330

C A R R U TH , sec W I T H E R SC A R V , 380

Casein, 34, 43, 45, 46, 48, 50, 57, 53,54, 55-56 , r.40,178, 186, 194, 197,221, 222, 230, 277, 332, 334

CASTILE, see B U C K N E RCatabolism,171Catalase, 147, 148, 158,159, 171, 263Cauliflower, 330Causes andPrevention of Beriberi ,339CAZZAMAIXI, see C A R B O N ECAZZANI, 358Celery,330C EN TA N N I arid G A LA S S I , 3Z3, 318, 347Cereals, 41-47, 176, 178,181, 183, 185,

186, 187, I91 ,2O9, 2IO, 211, 217,232, 241, 244, 252, 253, 269, 278,296, 327, 328, 329

unsuitable Food for growing Animals ,181, 296; see also iinder specificnames, as Wheat , Maize ,etc.

CESSNA, see N E L S O NCHACE and M Y E R S , 374

CHAMBERLAIN, 342, 352CHAMBERLAIN, BLOOMCBERGH, and KIL -

BOURNE, 102, 132, 342CHAMBERLAIN and V E D D E R , 102,120,342C H A M B ER LA IN , V ED D ER , and W I I L I A M S

3i6, 343Chamberland Fil ter, 256Charcoal as Roughage , 190Cheese, 222, 331Chemie der Zerecdien, 354Chestnuts , 191, 329Chicago experiences, 209C H I C K , 211, 238, 249, 372, 374, 379 ; see

also C A M PB E LL , D A L \ T I L L , H O P K I N S ,H U M E

C H IC K and D A LY EZ, L , 176, 373, 380C H I C K and D E L F , 367C H IC K and H U M E , 119, 248, 315, 357,

368, 374 ; see also H U M E and" IICK

368,CHIC

C H I C K , H U M E , and SKELTON-, 253, 340,360, 361, 368

CHICK and R H O D E S , 361Chicken Fat, 225Children, Feeding of, 172 ei seq.,zog-

2x2, 250Chinin, 121,122Chinolinic Acid,123CHITTEN-DEN and U N D ER H ILI , , 305, 314,

357Chlorine Ion—

effect on.Kidney, 290paralysing Influence of, 276, 290, 293-

295Chocolate, 252, 268Cholesterin, 204,221, 274

Impoverishment, 285-287, 288Cholin, 113, 121, 144, 145, 204, 295

the natural Antagonist of Adrenalin,

295CHRISOSTOMO, 350CHRISTMANN, 357CIACCIO, 371Cinchoraeronic Acid,123Cinchonidin, X21Cinchonin, 121, 122Citrates , 246Citric Add,seeLemonsCitrozinic Acid,123Citrus,251Civilisation,205CLAIR, 105, 373CLARK, A. B., see STEPHENSONCLARK, E., 203, 352, see V E D D E R

CLATPON, see LANJE-CLAYPONC LEM EN TI , 106, 304, 354Clover, 192, 200, 224, 252, 330, 332Cocoanut, 50, 329

Cake, 191,224, 329Oil, 185, 224, 225, 331

Cocum,329Cod,225Codliver Oil, 147, 185, 211, 221, 223,

225, 229, 233, 235, 236, 237, 331phosphorated,235

Co-enzymes, 147, 154, *55, *59, 166COHEN, see G I V E N SCOHEN and M E N D E L , 246, 253, 362Coffee, 250

Substi tute,251COLE, see MCCLEN-DONCOLLATZ, see D U T C H E RCOLLODI, 306, 341Colloids,198Coma, diabetic, 79, 88Commandeering by Foetus, see Milk,

secretion ofComplement Activity, 199

Deviation of the, 308Format ion,311

Complettin Content of Foodstuffs, 326-3 3 i

Experiments , Nutri t ion in, 327, 333-33 6

Complettin, term defined, 22COMRIE, 248, 249, 374Conarachin,49CONCEPTION, see GIBSON, GTJERREROConclusion, 323-337



396 VITAMINS

Condensation, of Milk, see MilkConditions of growth, 172-218Conditions requisite for Efficiency of

various kinds of Protein, 58-61Congestion, passive, 272, 285, 293, 295

Conglutin, 48,176CONKLIN, see MATTILL

Consequences of Insufficiency of Vita-mins (Funk's)—

(a) clinical, 126-128(b) pathological anatomy, 128-129(c) the Forms of the Disease, 130-

132Constipation, 245, 246, 279, 299 ; see

also RoughageConsumption, 243Contractures—

cicatricial, after Scurvy, 266spasmodic, see Tetany

Control experiments, 60, 72, 136, 201

Cooking Salt, see Sodium ChlorideCOOPER, 109, 1x7, 122, 129, 137, 346,

34-7, 348, 349, 386 ; see alsoBRADDON

COOPER and FUNTK, 343

COPEMANT, 2 0 1

Copper, 67 et seq., 332CORNALBA, 358Cornea, IJlceration of, see Keratoma-

laciaCorned Beef, see BeefCottonseed Oil, 186, 187, 224, 225,3°5>

314, 33iCouirs, 36rCOUTURIER, see BIDAULT

COWARD, see DRUMMOND, ZILVA

COWARD and DRUMMOND, 376, 388

COWGILL, 383, 387, 388

Cotton Seeds and Cottonseed Meal, 43,49, 50, 107, 176, 178, 182, 185, 191,

253,329Proteins of, 55, 182Toxicity of Meal, 67

COWGILL and MENDEL, 388

Cox, see LEWIS

CRAMER, 145, 374, 379

CRAMER, DR EW, and MOLTRAM, 387

CRAMER, and SCHIFF, 381

Cramming, 132, 143, 333Cranberries, 70Cream, 147, 222, 233, 297, 298, 331

University, 236Cress, 330CRONHEIME, 341

CROWELL, see STRONG, WIL LIAMS, R. R.

Cryoscopic conditions, 289Cucumbers, 251, 330CULLEN, see SLVKE

CURJEL, see GREIG-

Curry, 216CUTLER, see ROBERTSON

Cyclopoiesis, 31 , 34, 156,157, 167, 262Cynuric A.cid, 34Cystein, 29, 30, 31, 95,168 , 269Cystin, 29, 31, 34, 47, 49, 53, 54, 56, 57,

59, 95, 96, 168, 176, 177, 180, 296,322

CZERNTV 298

CZERNV and KLEINSCHJIIDT, 298

D , water-soluble (antineuritic), 136, 138,139—142, 159, 160, x6i, 162, 164,165, 166, 170,194, 197,200,204,218,228, 239, 262, 322, 333,334, 336

confounded with B, 195-196, 197

confounded with Fun k' s Vitamin, 333DAHLE, see DUTCHER.

DALYELL, 211, 231, 235, 379

DALYELL and CHICK, 388

DALYELL and STILL, 255

DAMIANOVICH, 388, 389; see alsoMATHEW

Dandelion, 244, 251, 257dried, 244, 258Leaves, 330

DANIELS, see BYFIELD

DANIELS, BY-FIELD and LOTJGHLIN, 366

DANIELS andLOUGHLIN, 49, 360, 375,381

DANIELS and MCCLURG, 118, 119, 365

DANIELS and NICH OLS, 49, 66, 359

DARLING, 350Dasheens, 330DAVEV, 384

D A V IS , D. J., 358, 361, 3^5,388D A V IS , M., and others, 373DAVIS, M., and OUTHOUSE, 387

DAWSON, see SULLIVAN

Debility, 200, 231, 239, 268, 279, 299,

305Deficiency Diseases, 24Deficiency in Diet of Par ents may affect

Offspring, 72, r74, 189, 204-207Degeneration, hyaline, 270, 271Degeneration, so-called, as an Outcome

of parental dietetic Errors, 174, 204-207

DEHIO, 370

DELF, 14, 189, 229, 257, 260, 264, 364,

374, 375 ; see also CHICKDELF and SKELTON, 230, 259, 261, 364

DELPRAT, see ROBERTSON*

Denaturation of Food, 220,246

DEN-TON and KOHMANN, 182, 277, 282,

363DESGREZ and BIERRY, 374

Dermatitis—in Pellagra, 299, 300, 305, 308,309,321in Scurvy, 266

Determinants of Growth, see Growth-

FactorDeviation of the Complement, 308DEVLOR, 339

DEZANI, 221, 350

DIABETES, 76, 77, 78, 79, 88, 239

Diarrhoea, 200, 283, 299, 300, 305Diathesis, haemorrhagic,

see HaemophiliaDICK, see MCCLENDON

DlCKENSOiN, 109, 351Diet, Analysis of its Constituents

essential, 91Diet—ill-balanced, 126, 132, 151, 159,

232,276, 281, 282, 304, 305,315monotonous, 221

pathogenic of malnutritional Oedema,277, 278

peUagrogerdc, see Pellagraremedial in Pellagra, 320-322rigid, 126



INDEX 397Dietet ic Errors in Parent, their Effect

m ay be first noticeable in Offspring,72, 173, 174,175, 204-207

Dietet ic Errors leading to Arrest of

Growth, 208Dietetic Experiments, their Difficulties,

324-325Dietetic Test, see TestDifferences between Polyneuritis and

Starvation States, 148-153DJLfferences between water-soluble B and

water-soluble DDifficulties att en da nt ondietetic Experi-

ments, 324-326Digestion, Absorption and Assimilation

distinguished,92Disaminisation, 169, 170Discussion on the present Position of

Vitamins in Clinical Medicine, 236,317Diuresis, 292, 294; seealso PolyuriaDizziness, 299, 3roD O D D , 346; see also T A L BO TDONALDSON-, H. H., 365DONALDSON, J. C, 365DOTSCH, 339DOUGLAS, see F U N KD O W N S and E D D Y , 389D R E I F U S , 77, 372D R E W , see CRAMERD R I E L , 143, 375Dripping,185

Dropsy,see

OedemaDrugs that cause basic Deficiency, 73DRUMMOND, 22, 44, 138, 185, 188, 189,

193, 198, 199, 200, 228, 229, 240,247, 354, 357, 360, 366, 376, 383,388 ; see also A N R E P , C O W A R D ,H A L L I B U R T O N , H O P K I N S , R O S E N -HEIM, ZlLVA

DRUWMOND and COWARD, 229, 376, 382,DRUMMOND and F U N K , 112, 350, 361DRUMMOND, COWARD, and W A T S O N , 388DRUWMO»ND, GOLDING, ZILVA, and

COWARD, 382DRUMMOND and W A T S O NDrying of Foodstuffs, Effect on B , rgj

Effect onC, 245,258-262Dryness of the Cornea, see XerophthalmiaDU B IN , see F U N KDUB IN- and L E W I , 372D U B O I S , 7S, 361Ductless Glands, see EndocrineD U F O U G - E R£ , 109, 379D U N H A M , 384DuRANr>, 356Durat ion of Exper iments , 18, 35, 36, 41,

65. 72,<A173, m ,*77D<JRCK, 128D U R H A M , 103, 155, 339DXJRLACII, 99, 346

B U T C H E R , 146, 14.8, 252, 368, 370, 387;see also A N D E RS O N , F I E RS O NBU T CH E R and COIXATZ, 148, 362, 363B U T C H E R , E C K I X S , D A H L E , M E A D , and

SCHAEFER, 255, 382B U T C H E R , H A R S H AW, and H A L X , 387B U T C H E R , K E N N E D Y , and E C K L E S , 373BuTCHER,PiERSoar,and BIESTER, 252,377

DUTCHER and W I L K I N S , 388D Y K E , 361Dysentery, 283

EARTH-NUT, 45, 49, 160, 191, 223, 329Oil, 236, 331, 333

ECHOLS, see T A N N E RECKLES, see A N D E RS O N , BU T CH E R,

P A L ME RECZEMA, 300; see also Dermati t isE D D Y , K. B., see D O W N SEDDY, W. H., 138,198, 356, 357,372,384EDDY, HEFT, STEVENSON, and JOHNSON,

386E D D Y and R O P E R , 357E D D Y and STEVENSON-, 139, *4** 37i, 378E D E L S T E I N , see LANGSTEINEDELSTEXN1 and LANGSTEIN, 54, 365

Edcstin, 43, 4-9, 56, 98,176, 332E D I E , see SIMPSON*ED IE , E VAN S, MOOR E, SIMPSON-, and

W E B S T E R , 103, 113, 344Effect of Oxidation on biological Value

of A.cid-formers, 94-99Effects of Punk's Vitamins, 136-139Egg Albumin, see OvalbuminEgg Fat, 331Egg Plant , 330Eggs, 52-53, 55,176, 192, 209, 223, 233,

255, 268 315,320, 328are rich in Punk's Vitamins,124raw, 294., 5595

their Toxici ty in Acidosis, 76White , see Whi teYolk, see Yolk

Egypt, Pel lagra in,316, 320Egypt, Prison Dropsy in, 279EHRLICH, 97, 338

ElJKMAN, IO2, 129,148, 338, 339, 343,348, 354,362

EIJKMAN and HOOGENTHUVGE, 355EIJKMAN and H U L S I I O F F - P O L , 363EinflU'SS des Abbfiihens aufden Nahrweri

unserer Gemiisekost, 342Ein-wiikung von Erdsalzen ttsw. auf

A usscneidung, and Zusammen-

setzung desHams, 343E I S L E R, 369E K E U J F , 105, 243, 339EL K A N T A RA , 316ELIAS, 76, 360ELLIS, N. R., see H A R TELLIS, N\ R., STEENBOCK and H A R T ,

385ELLIS, "W* G., 341Emacia t ion, 78, go,98, 102, 126, 132,

134, 135,136, 137,148,149,150, *&o.r6 i , 178, 199, 208, 2x3, 230, 231,239, 265, 267, 273, 297, 300, 305, 321

Embryo, seeGerm

E MME T , 90, 373, 386, 387E M M E T and A L L E N , 367E M M E T , G R I N D L E Y , J O S E P H , and

W I L X I A M S , R. H., 348E M M F X and JLUROS, $6, 141, 366, 367,

E M M E T and M C K I M , 116, I36,"359E M M E T and STOCKHOLM, 141,^194, 378



398 VITAMINS

Ems Water, 215Endocrine Glands, 35, 201-204, 235

239-241, 267, 292, 301, 302; seealsoGlands

Endosperm of Maize—it s low nutritive Value, 314

Endosperm, Growth-factor in, 140Endosperm, Value as Nutr ient , 42, 43,

45, 46, 223, 328Vitamin. Deficiency of, 124,125

Endothelium, secretory Activities of,287-288, 293 ei seq

Energetics of the Muscular System, 146-148

Energy, Diet as Source of, 179, 326, 327 ;see also Calories

ENGSTRAND, see MCCLENDONE N RI G H T , 316, 320, 371, 377Enzymes (see also Co-enzymes), 166, 171,

243, 263, 264Epilepsy and Epileptiiorm Convulsions,76

Epipayses, Separation of, 266Epistaxis, see NosebleedE F P I N G E R and A RN S T E I N , 345E P P I N CE R and U L L MA N N , 380E P S T E I N , 361

E r d s a l z a r m u t and E n t a r t u n g , 339Erganzungskorper, 22E RL A CH E R, 385

Errors of Diet , set Dietetic ErrorsEskimos, Scurvy among, 242E T I E N N E , 86, 345ETIEN-NE and F RI T S CH , 86, 340E U L E R and PETTERSSON, 384, 388Europe, Western, Scurvy in, 249E U S T I S , see W E L L MA NE U S T I S and SCOTT, 350E U T O N I N S , 22, 137E V A N S , H. M, and B I S H O P , 389E V A N S , W. H., see E D I EE W A L E , see ABDERHALDENE W I N G , see W E L X SExcelsin, 50, 176Experimental Stations Office, 62, 336Exper iments , "brief,see D u r a t i o aExperiments , Control , see ControlExper iments , Durat ion of, see Dura-

t i onExper iments on insufficient Nurnbei ofAnimal s , 190

Exuda t i on i n t o T i s sue s , see Inf i l trat ionE ve Tro u b l e s of R ou m a n i a n C h i l d r e n ,

386N, see EIJKMAN

F A B E R , 377, 381, 388

Faeces, Vitamin in, 163, 325FAHRION, 375

TALK, 369

FALTER and QUITTNER, 358

Famine Dropsy, see Oedema, malnu-tritionalF A N D A R D , see RA N D O I N - F A N D A RDF A RG I E R, 345Fat, Intolerance of, in Milchnahrschaden,

297Fat-soluble A, see A

Fats , 186, 187, 189, 327, 33i ; see alsoB o d y - f a t , and Storage - fa t , andspecific Fats

Fats as Nitrogen Economisers, 38, 39Fats as Tissue Builders, 37, 38Fats , hardened, 225Fats in Infant Feeding, 296-298Fats , Ingestion of, in Relation to

Acidosis, 77, 78in Relat ion to Malnutritional Oedema,

277, 282, 283, 286Fa ts manufactured from P roteins, 37, 40F E I G H , 273, 274, 289, 361Fermentat ion in Bowel, 104, 214, 215,

245, 246, 296, 3°3, 3*3Ferments , see Enzymes, Co-enzymesF E R R Y , 382 ; see also O S BO RN EF E U I L L E , 82, 364F I BRI N , 53

F I G U E I RA , r ip , 200, 245, 255, 372F I L D E S , 383Filter Paper, 160, 190, 333, 335FINDLAY, G. M., 340, 382, 384, 387FINDLAY, L., see P A T O NFINDLAY, L., P A T O N and S H A R P E , 385F I N E , see M Y E R SF I N G E RL I N G , 63, 97, 343

FlNKELSTJEIN, See ANDERSON

F I N K S , see J O H N SF I N K S and J O H N S , 386F I S CH E R, 29, 59F I S H , see H E S SFish (see also specific Fish, e.g. Pike,

Cod), 57, 139, 327, 328dried, 242fresh, 248Fa t, 223,328lean, 328Oil (see also Codliver Oil, etc.), 185,

n 223, 331Roe, 328smoked, 242

F I S H BA CK , see H A W KFlat-foot, 209F L A T H E R, 364FLEMING, 388F L E T C H E R , 143Flora, intestinal, 189, 198, 234, 245, 246,

303F L O RE N CE , 269, 376

Hour, 186,249, 280, 328, 329Flour, white, 101, 106, 183, 296

"wholemeal, 280Fluorescence, 309, 310Fodder, 234

<ky> i94» 226green, 194, 318lactat ion and, 194, 207

Fodder Pea, 48-49Fodder, seasonal Variat ions in, 225, 226,

253, 255Fodders , na tura l , 192F O R B E S , H A L V E RS O N , and SCHXJLZ, 70, 84,

Forc ed Feed ing , s e e C r am m i n gF or m s of Combina t i on of Inorgan i c

Subs tanc e s , 88 -90Frag i l i t y of the Tissues , 270FRANCHETTI, 374



INDEX 399FRANCIS, C. K,andTROWBRiDGE, 170,341F R A N C I S , E., see L A V I N D E RF R A N K , A., see F R E I S EF R A N K , L., and SCHLOSS, 348; see also

SCHLOSSF R A N K , M., 370F R A N K E L and SCHWARZ, 114, 382F R A S E R and STANTON, IIO, 132, 133,143,

155, 340, 341, 342, 345, 348, 352Frederick theGreat Orphanage, 250, 261F R E I S E , 177, 264, 350, 370FREISE, GOLDSCHMIDT, and F R A N K , R.,

232, 233, 352French Beans, 328Fresh Nutr i en t s , na tura l Crav ing for in

Scurvy, 268F R E U D E N B E R G , 349F R E U D E N B E R G and G Y O R G Y , 147, 380F R E Y , 82, 364F R I T S C H , see E T I E N N EF R O L I C H , 253, 257, 340, 344

F r u i t (see also under specific Names (asOrange, etc.), 209, 215, 217, 218,247, 327

dried, 251, 329fresh, 244, 246, 248,251, 268, 269is poor in A, 224is rich in water-soluble B, 191juice, 251, 256raw, seeFruit, freshsalt-rich,209

Fuel, Food as, 151F U H G E , 84, 86, 366FUHNER, 380FUJITANI, Il8, 34IF U L L E R , see H A R T

F U L M E R , see N E L S O NF U L M E R , N E L S O N , and SHERWOOD, 194,

384FUNGI, certain, cann ot synthetise A, 240,

241F U N K , 9, 10, 12, 13, 21,22,23, 77, 104,

n o , i n , 112,113, 114, 116, 117,118,120,1.21,122, 123,134,135,136,138; *39, 142,156,159,161,181,187,198.199, 200,202,204, 226,239,245,246, 247, 264, 269, 284, 313, 314,316, 317, 333, 336, 341,342,343,344,346, 347, 348, 349,350,352,353,354,369,387:see also COOPER, DRUMMOND

F U N K and D O U G L A S , 349

F U N K and D U B I N , 373, 381, 388F U N K , L Y L E , and MCCASKEY, 52,175,356F U N K and MACALLUM, 52. 142, 198, 221,

226, 228, 349, 352, 356F U N K and P O K L O P , 355F U N K and S C H 6 N B O R N , 104Funk' s V i tamins (ant ineur i t i c ) , see

Chapter Fou r, pass im , 187, 188,194,198.200, 201, 218, 220, 226,228, 239,245, 246, 247, 255, 264, 275, 283,315, 3i6, 317, 325,333i 334> 335, 33$

confounded with D, 333F U R S T , 244, 245, 264, 268, 340, 343, 344F O R T H and N O B E L , 54, 381

GAERTNER, 377GALASSI, see C E N T A N N IGALMOZZI, 303, 376

GARRISON, see SILERGastralgia, 279, 299Gastro-intestinal Disorder as exciting

Cause ofBeriberi, 126Gastro-intestinal Disorder—

in B Deficiency, 198in C Deficiency, 267in malnutrit ional Oedema, 274, 278

281, 283i n Meh lnahrschaden and Milchnahr-

schaden, 296 -298Gastro- intest ina l Disorder in Pel l agra ,

299, 30°, 301, 302, 311Gastro-intestinal Disorder in Ship Beri-

beri, 279Gastro-intestinal Disorder in Sprue, see

SprueGATTI, see V I D O N IG e f a h r e i n e r an K a li u m v e r bi nd u n g xu

a r m e n E r n a h r u n g s w e i s e und i h r eB e z ie h u n g z u E r n d h r u n g s k r a n k h e i t e n ,

r* 3 5 4

GEILING, 33, 359Gelatin, 45, 46, 58,176, 269GELLHORN, see ABDERHALDENG E R A R D , 82, 345Germ (of seed), biological value as

Nutr ient , 42, 45, 191A content of 223, 225,removal of, 210, 211rich in Funk's Vitamins, 124WheaVsee W h e a t

German Prisoners, Pellagra among, 316Scurvy among, 248, 249

German Society for Tropical H ygiene, 280Germinated Beans and Peas as anti-

scorbutic, 248, 249Effect of Boiling, 258, 261Effect of Drying, 261

Germination—of Beans promotes their Digestibility,

48 , 59of Seeds develops antiscorbutic

Principle, 245, 255-256GERSTENBERGER, 387GIBSON, 347, 354GIBSON and CONCEPCION, 348Gigantism, 203G I V E N S , see H U N T E RG I V E N S and C O H E N , 227, 260, 362G I V E N S and MCCLUGAGE, 258, 239, 260,

^ 365, 372,376, 384GIVENS, MCCLUGAGE, and H O R N E , 383GIVENS and MACY, 384Glands—

Behaviour of, 142-146, 153, 154, 201-204, 218, 267, 297, 333

Glands , endocr ine , seeEndocr i neGlaucoma, 281Gliadin, 45, 46,55,176, 3*3Globulin, 50, 176GLOGNER, 341, 343Glutamic Acid, 29, 31Glut am in , 29Glutazin, 123Glutelin, 43, 176

Gluten, 178, 315Maize, 178, 315Glutenin, 43, 45



4 0 0 VITAMINS

Glycogen, 273; see also Hyperglycaemia,and Hypoglycaemia

Glycyl-alanin, 59Glycocoll, 29,31,33GODLEWSXI, 385

Goitre, 319GOLDBERGER, 35O, 356 , 362GOLDBERGER, WARING , and W I L L E T S , 352GOLDBERGER and W H E E L E R , 305, 316,

318, 352, 373, 376GOLDBERGER, WHEELER, and SYDEN-

STRICKER, 315, 317, 362, 374, 377GOLDFLAM, 3 8 1GOLDING, see DRUMMOND, ZILVAGOLDSCHMIDT, see F R E I S EGooseberries, 215Gosio, 312, 350GOXJZIEN, 345GOY, 384GRABER, 382

GRABLEY, 91, 369Grain diet, exclusive, 70, 73, 74-

supplemented with, green Fodder, 182GRALKA, see A R O NGraminivorous Birds require green Food

also, 182Graminivorous Birds, their Young are

carnivorous, 181Grains, seeSeeds, CerealsGrape Juice, 251, 329Grape-fruit, 224, 329Grapes, 329Grass, 192, 330

dried green, 25 3G R E E N , 362; see also RICHARDSON

Green Parts of Plants contrasted withSeeds as Nutrients, 182, 252

Green Parts of Plants as source ofA, 240Green "Vegetables, 124,133, 186,189,192,

222, 224, 227,251, 269, 318, 330Greenness ofVegetables and Fruits, their

Richness in C proportional to, 251GREGERSEN, 98, 342G R E I G , 359, 361GREIG and C U R J E L , 360G R I J N S , 3 3 9 , 340,343GRIMM, see LAVINDERGRIND LEY, see EMMETGROSS, see STEENBOCKGROSSER, 96, 346

Growth {see also Growth-Factor)Arrest of, 199, 204, 208, 226, 230, 231,

239Growth, Conditions of, 172-218, 334

Inhibition of, Effect on subsequentgrowth, 207-209

Maintenance of, 179, 181, r82, 207,222,223

Normal, dependent on Diet, 209 et seqStimulation of, 200

Growth-factor {see also B, water-soluble,an d A, fat-solufcle), 138, 139, 140,141,142,144-, 172-218, 219-222,224,334

Tiel, :ruel, 294, 295,296GUAZON, see MENDOZA-GUAZONGuanin, 121GUERRERO and CONCEPCION, 371GUGGENHEIM, 370

G U I L L A I N , 376Gums, scorbutic Affection of, 265, 265G U R B E R , 358GUTMAN, see H E S SGVORGY, see F R E U D E N B ER G

H A A N , 341Haematemesis, 279Haemoglobin Richness, 231, 267,274Haemophilia, 160, 242, 265, 266, 267, 284Haemorrhages, seeScurvy, passimHaemorrhagic Diathesis, see Haemophil iaHaemotoxin, 281Hair, 200H A L L , see D U T C H E RHALLIBURTON, 221 , 361, 382HALLIBURTON and D R U M M O N D , 357H A L P I N , see H A R THALVERSON, see F O R B E S

H A M S H I R E and H A W K E R , 236, 367,H a n d b u c h der a llg e m e i n e n T h e r a p i e , 212H A R D E N , 383 ; seealso H O P K I N SH A R D E N and R O B I S O N , 365, 368, 374, 388H A R D E N and Z I L V A , 123, 527, 246, 256,

260, 268,357,360,36 3, 364, 3^6, 368,374, 386

H A R D E N , Z I L V A , and S T H X , 364Hardening ofF a t s , 225Haricot Beans, 48, n o, 118,119, 175,182

328H A R L E Y , see J A C K S O N , P. G.H A R R I S , R. H., see D U T C H E RH A R R I S , S., 316, 372H A R R I S , H. C , 306, 348

H A R R O W , 9, 12H A R S H A W , see D U T C H E RH A R T , C, 344, 345H A R T , E. B., see E L L I S , N. A . , S T E B N -

BOCKH A R T , H A L P I N , and MCCOLLUM, 66, 106,

108, 357H A R T , H A L P I N , and STEENBOCK, 43, 44,

181, 190, 359H A R T , H A L P I N , S T E E N B O C K , and J O H N S O N

0 . N., 380H A R T , H A L P I N , and S U R E , 359H A R T , H U M P H R E Y , and L E P K O W S K Y , 381H A R T and MCCOLLUM, 42, 44, 52 ,53, 182,

350, 353HART, MCCOLLUM, and P U L L E R , 98, 340H A R T , M C C O L LU M , S T E E N B O C K , and

H U M P H R E Y , 357H A R T , M I L L E R , W. S.,andMcCoii/UM, 74,

107, 190, 354H A R T and S T E E N B O C K , 181, 207, 368HART, STEENBOCK, and E L L I S , N". R., 255,

„ 379, 385,H A R T , S T E E N B O C K , and H O P P E R T 373,

387H A R T , S T E EN B O C K , and L E T C H E R , 42,367,

375H A R T , S T E E N B O C K , and S M I T H , D. W.,

246,367

H A R T W E L L , 382, 384H A S T I N G S , see S M I T H , P .Hatmaker Process,261HATJSMANN, 341H A U S S L E R , 154, 379



INDEX 4 0 1

H A W K , see S M I T H , C. A.H A W K , F IS H B A C K , and B E R G E I M , 260, 372HAWK, SMITH, C. A., and B E R G E I M , 384,

385HAWK, SMITH, C. A., and H O L D E R , 52,

175, 366H A W K E R , see H A M S H I R EHay, 192, 234, 251, 255, 330Hazel Nuts, 50,191, 329Headache, 299, 305Heart, 57, 138, 193, 223, 328 : see also

Asthenia, cardiacHeartburn, 299, 303Heat, Effect on C, 257-262 ; see also

Boilingprolonged moderate Heating more

destructive than fierce but briefHeating, 258, 263

Heat Production and Heat loss, see

TemperatureH E F T , see E D D YH E H I R , 367H E I M , 253H E I S E R , 342, 344Hemeralopia, 279Hemp Seeds, 49, 59, 185, 224, 232, 329H EN D ER S O N , see P A LM ERH EN D ER S O N and P A LM ER , B. W., 351H E P B U R N , 373H ER B S T, 96, 237, 238, 345, 346Herring, 193, 225

salted, 249H ER R M A N N , see B E G U N

H E R T E R , 338H ER X H EIM ER , 85, 338H E S S , 91, 236, 253, 255, 351, 353, 354,

356, 357, 362, 370, 37 i,378, 384,387; see also PAPPENHEIMER,

H E S S and F I S H , 349H E S S and G U TM A N , 388H E S S and K I L L I A N , 360H E S S , M C C A N N , and P A P P EN H EIM ER , 386HE SS and UNGER, 181,186, 246,251,256,

261, 360, 36 2,36 4, 367, 368, 371,374,376, 383, 387, 389

H E S S , U N G E R , and P A P P E N H E I M E R , 387,

389H ES S , U N G ER , and S U P P L E , 71, 382

H E U B N E R , 96, 352Hickory Nut, 50, 191, 329H I F T , 363H I G H E T , 341H I L L S , 371H I N D H E D E , 41, 51, 374, 375H I N K E L , see SCHOLZH I N T Z E , see K R U S EH IR S C H and M O R O , 362HlRSCHFELDER, 309, 310, 345HlRSCHSTEINT, 96, 168, 345Histidin, 30, 31, 33, 35, 49, «5»

J I7 , 121

H O C H S T, 202H O C S O N , see A R O N

HOESSLIN,369HOFMEISTER, 112, 120, T24, 374H O G A N , 42, 47, 53, 55, 66, 74, " 9 . x8x,_ 356, 358, 360H O L D E R , see H A W KH O L S T , 118, 279, 3O4, 339, 340, 342, 343,

345, 36i

H O L S T and FROLICH, 106, 107, 108, 244,245, 257, 253, 268, 279, 280, 339,

„ 340, 343, 347, 356, 381HOLSTI, 98, 341

H O L T , 60, 374.Honey, 251,3 31HOOGENHUYGE, See ElJKMANH O O P E R , see JOHNSONHOOPER, ROBSCHEIT, and W H I P P L E , 379HOPKINS, 54,55, 75, 80,95 ,101 ,119 ,137 ,

139, *77,184,187,194, 201,229,232,236 ,238, 253, 317, 339, 344,348,365,371, 382, 386; see also ACKROYD

H O P K I N S and CHICK, 365H O P K I N S and N EV ILLE, 220, 346HOPKINS, CHICK, DRUMMOND, HARDEN,

and MELLANBY, 368H O P K IN S , B O Y D , W ILLC O X , W A LLIS ,

R O A F , H U M E , and D E L F , 372H O P P ER T, see H A R THORBACZEWSKI, 305, 308, 34IHORDEIN, 47, 176Hormones, 154, 162, 235H O R N E , see GIVENSHorse Fat, 331HOWARD and INGVALDSEN, 357H O W E , 378HOWLAND and KRAMER, 389HULDSCHINSKY,376HULSHOFF-POL, 21,102, 107, 110, I48,

339,340, 341,343,358, 377H U M E , 383, 384; see also CHICK, BARNESH U M E and CHICK, 101; see also C H I C K

and H U M EH U M E and N IR EN S TEIN , 388H U M P H R E Y , see H A R THunger , seeStarvat ionHunger Oedema, see Oedema, malnu tr i -

t iona lHungerodem, s e e Oedema , m a lnu t r i t i ona lHungerodem, Das, 372H U N T E R , see VOEGTLIN, WATSONH U N TER , G IV EN S , and LEW IS , 354H U N T E R and W A TS O N , C.Husks , 191H U S S E Y , see MACKLINHUTCHISON, 360Hyaline Degeneration, 270, 271, 288

Hydantoin, 121Hydraemia, 273, 285,288-289, 290, 291,• 293

Hydrar thrus , 272Hydrat ion, 165, 167Hydrocithin, 204Hydrogen Concentration, 79, 80, 83Hydrolysis, 59, 97, 114, « o , 135, 168,

170Hydropericardium, 272Hydroperitoneum, 272Hydrothorax,272" Hyj?iea," 243Hygiene , Nutr i t ive , Ins t i tu t es off337Hygiene , Tropica l , German Soc ie ty for,

280Hyperg lycae tn ia , 104Hyperkeratosis , 300Hyperton ic i ty , see ToneHypocarence , 14Hypoch lorhydr ia , 88



402 VITAMINS

Hypoglycaeinia, 74, 273, 282Hypophysin, 202Hypophysis, see Pi tu i ta ryHypotbyroidisrn, 202Hypoxantbin, 121

Iced Drinks, 216I D E , 339, 385Ill-balanced Diet, see DietImmuni ty , 244, 311, 312Importance of an E x c e s s of -Alkaline

Substances , 70-75Importance of inorgan ic Const i tuen t s in

Metabol i sm, 40-41, 62-99 ; se*

a^,°

Inorgan ic Nutr ien t s , Inorgan icSubstances

Importance of N u t r i t i o n of the Mother ,204—207

Importance of Protein, 29-61 , 174-179Importance of methods of prepar ingFood, 183-184

Inanition, see StarvationIndia, Famine Dropsy in, 279, 280Indicanuria, 300,303Infants, Feeding of, 172, ei seq., 178 255,

297; seealso "breast-feedingInfection in malnutr it ional Oedema, 281Infection—

in Osteomalacia, 234in Pellagra, 306et seq., 314, 317in Rickets, 237in Scurvy, 245, ei seq.intestinal, in Mehlnalirschaden, 296

Infections, Resistance to, see ResistanceInfiltration of the Tissues—

haemorrhagic, 285serous, 83, 145, 285, 287, 292, 293

e t s e q .Influenza, 231I N G I E R, 254, 350INGWALDSEN, see HOWARDInorganic Nutr ients—

diet in experiments on, 332-333lack of, causing Arrest of Growth,

208t h e i r Impor t ance in Metabol i sm,

40741, 62-99, 179-183, 184

Inorga n ic Substances , the ir Import -an ce , 62 -99 , t h e*1 m u t u a l i n t e r -dependence, 90—91, 179; see a l so

In somn ia , 299Ins t inc t in the Choice of F o o d , 191,

26 8Insufficiency ofVitam ins (Fun k's) , Conse-

quences of, 126-132Interdependence of the inorgan ic Sub-

s t an ce s , 90-91In tes t ina l F lora , seeFloraIn t ox i ca t i on by d a m a g e d N u t r i e n t s, 281In t roduc t o ry , 17-28Iod in e , 68

Ion ic Concen tra t ion , 78, 79, 83I o n i c D a y s , 78, 79Ion s, va riou s, their Effect on theKidneys ,

290-292their Effect on serous t ransudat ion ,

20.0-29.5

I r o n , 274I ron as s u p p l e m e n t to Milk Die t , 66

def ic iency of, 69, 180d e m a n d for, d u r i n g G r o w t h , 180

I ron toc o u n t e r a c t T o x i c i t y of Cot t on seedMeal, 67

ISENSCHMID, 379

Isolation of Vitamin, 110-116Isoleucin, 29, 33Isomerism, 49Italian Views concerning Pellagra, 307-

308Italy, Pellagra in, 307-308, 315,316, 321

JA C K S O N , C. M., 365

JA C K S O N , C. M., and S T E W A RT , 208, 364,

372JACKSON, L., 360

JACKSON, F. G., and H A R L E V , 339JACKSON, L., and M O O D Y , 356JACKSON, L., and M O O R E , 356J A N S E N , B. C. P. , 365, 370JANSEJT, B. C. P., and MASTGKOEWINOTO,

37oJ A N S E N , W. H., 273, 274-, 275, 2?S, 277,

282, 36O, 372J a p a n und s e i ne G e s u n d h e i t s p f le g e , 342Japanese Exper ience of Beriberi, 100, 125J E P H C O T T and BA CH A RA CH , 384J O B L I N G and P E T E R S E N , 314, 355JO H N S , see F I N K SJ O H N S and F I N K S , 44, 48, 49, 373, 377,

384J O H N S , F I N K S , and PAJUL, 50, 366, 374JOHNSON and H O O F E R , 389J O N G E , 340

JtTR&Eisrs, 281, 354Jus t-Hatmaker Process , 261

Kakke , see Beriber iKanta ra , 316Kapirin, 47K A R R , 160, i6r, 381; set also L E W I SKA.RRan.cL L E WI S , 246, 358Katjang :id jo , 21 ,106 , 107, n o, 135, 328Kawashina, 221, 351

KELIAWAYT, 383K E M P S T E R , see P A L ME RK E N N E D Y , see D U T C H E R , M C C O I X U M *

P A L ME RK E N T , see S T E E N BO CKKeratomalacia, 231-233K E R X E Y and H E R M A N , 375

Ketosis, SoKidney, 223, 328Kidney Fat, 225, 331K id n e y s , B e h a v i o u r of, in c o n n e x i o n

with Oedema, 289—292KILBOTJRNX, see CHAMBERLAINK I L L I A N , see H E S SKIMTJRA, 368

KlTTEIÔN, 373KLEIMTJNGER, 347

K L E I N S C H MI D T , 298

K L I G L E R , 364

K L O C K MA N N , see L A S TK L O T Z , 372



INDEX 403, IOI, 384

KNTACK, 276, 355 ; see also R U M P E LKN-ACK an d N E U M A N N , 282, 358Knee-jerks, 300, 305KOCH, J., 366

KOCH, M\ L., and VOEGTLIN-,355KOCH, W., se e ASCHOFF

KOCHMANN, 63K O C K arid B O N N E , 380K O E H L E R , see ABDERHALDENKohlrabi, 392, 278, 283, 290, 330

intestinal Irritation due to, 278KOHMA>*, 1277, 282, 283, 373KONINTGER, 129, 338

KORENCHEVSKY, 387K O Y A M A , see YANIGAWAK R A M E R , B., see H O L L A N DK R A M E R , 3YL M., see SHERMANK R A P T , 57, 371KRATJS, 212

K R A U S E , 261K R A U T , 112Kreatinuria, 74,199, 274, 303Kronprinz Wilhelra, 280K R U S E and H I N T Z E , 373K C L Z , 91, 365JKUSAMA, see SHIGA

X A B B E , 372, 377Laboratory Factor, 25,189-190Lactalbumin, 34,35, 43, 46,49,54, 56-57,

176, 177, 178, 230, 332Lactation, see Milk, SecretionofLactic Acid,234.Lactone, 167Lactose, 56, 186, 288, 194,221, 245,246L A H M A N N , 28, 63, 64, 65, 212L A K E , see VOEGTLIN:L A N E - C L A Y P O N , 340LANTGSTEIN, see EDELSTEIST

LANGSTEINaadEDELSTEIN, 185, 191,193,361, 363

Lard, 185, 221, 223, 225, 278, 283, 331L A R N E , 344L A R S O N , J. H., 378L A R S O N , L. A., 203, 367Lavage, gastric, as Cause of Acidosis, 80LAVINDER., FRA NC IS, GRIMM:, and LORENZ

306, 350Law of the Mininum, 17, 18, 25, 27, 41,

59, 68, 91, 178, 188,200, 222,241,314, 318,326

Laxatives, 245, 246 ; see also RoughageLeaf-wax,186L E A R Y and S H E I B , 359LEAVEITWORTH, see OSBORNELeaves, seeGreen Vegetables also SeedsLEBLANX, 378Lecithin, 97, 155, *56, 204, 295Lecithinophilia, 281Lecksucht, 7o-7rLECOQ, 58,69,138,192, 372,373LEENT, VAIT, 339L B E R S U M , 385LEETJWENT, see STORM VANLEEUWEW

L E G G A T E , 102, 370L E G G E T , see MCCOLLUML B G R O U X , sec A&XJLKON

Legumin, 47-48, 175Legmninosae, see PulsesL E H M A N S T , 85, 338

Lehrbuch dcr Pathologie des Staffwechsels,

r

3 3 8

LEIMDORFER, see PORGESLEIPZIGER, 97, 338Lemon Cure,77

Jiuce, 244, 249, 251, 260, 261, 330dried,260

Lemons, 192, 224, 243, 251,252, 269, 329Lemons as cause ofAcidosis,77Leatils, 138, 244,269LEPKOWSKY-, see HARTLettuce,330

white, 224Leucin, 29, 33, 49Leucopenia, 304L E V A , 82, 350L E V I , 39

LEVY, MAGNUS, see MAGNUS-LEVYL E W I S , M. J., see D U B I N

L E W I S , H. B ., 32, 50, 57, 359, 369*377

370,

L E W I S , COX, and SIMPSON, 32, 55L E W I S and KARR, 356L E W I S and ROOT, 377Lick, the 70-71L I E B E R S , 277, 373

LlEBIG, 17, 25,26L I E C H T I and RITTER, 71,382LIECHTI and TRUNINGER, 71, 346Life, Prolongation of, seeProlongationLight {see alsoUltraviolet), 229Lime, see Calcium

Lime Jttice, 249, 251, 260dried,260preserved, 249

Limes, 243, 251, 329LIITD, 365LINTOSSIER, 366, 373Linseed, 224, 329Unseed Oil, 147, 185, 305, 314, 331LIMTZ, see MCCOLLUMLipochromes, 186,187, 226

in relation to A,224-226Lipoid Solvents, 286Lipoids, 184,185, 187, 2i£, 220, 221, 22

229, 285, 294LiPSCHtfrz, 96, 341, 364L I T T L E , 107, 346, 350

Liver, 57,r93, 223, 225, 252,328Pig's, Oilexpressed from,223

L L O Y D , 138, 354LOEB, 163L O E B an d NORTHROP, 141, 1^5, 356L O E W , see EMMERICHLOOSER, 339Lords and Ladies, see ArumL O R E N Z , see LAVINDER.

Loss of Weight, see EmaciationL O T Z S C H , see SCHEUNERT

LouGHLiN, see D A N I EX S, BY FI EU >LOVELACE, 103,105,109, 346LtrcATELLO and CARLETCT, 312, 3421Lucerne, 192, 224, 252, 330

L see MCARTHURLin and BACCELXI, 311, 34!L U M I E R E , 194, 375, 37&, 383



4 04 VITAMINS

LUNIN, 184, 338Lupines, 48, 175L U R O S , see EM M ETL U S K , 245

L U S T and KLOCKMANKT, 344L Y L E , see F U N KLYMAN" and RAYMTJND, 65, 80, 369Lymphocytos is , 300, 304Lysin , 29,31, 33, 43, 45, 46, 47, 53, 56,

176, 180, 296

M A A S E and ZO N D EK , 282, 372MeA R TH U R and LU C K ETT, 221, 351MACALLUM, 372MCCANTN, A. W., 280, 363IMCCAN-N, G. Jt.jSee H ES S , P A P P EN H EIM ER .IVICCARRISON-, 12, 14, 15, 104, 145, 238 ,

239, 273,283,292, 294, 368,371, 372,

377, 378, 379, 388M C C A S K E Y , see FXJNKM A C LEA N , 344, 345H C C L E N D O N , 15, 268, 375, 380, 386H C C L E N D O N and B A N G N ES S , 388^ T C 1 , B O W ER S , and S ED G W IC K ,

384H C L E N D O N and C O LE, 367MCCLEN-DON, COLE, ENGSTRAND, and

MlDDLEKAUFF, 369MCCLEN-DON- and D I C K , 384MCCLXJGAGE, see G I V E N SMCCLXJGAGE and M E N D E L , 51, 92, 362MCCOLLUM, 54, 65, 80, 98, 138,182,183,

205, 223, 238, 340, 350, 357, 360,3 61 , 369, 380; see also HART,M C D O N A LD , S H IP LEY , S O U 2 A

MCCOLLUM and DAVIS, 44, 53, 118, 178,i8r, 182,185, 187,190,221, 346, 350,351, 352

MCCOLLUM and H A R T , 44MCCOLLUM and K E N N E D Y , 353MCCOLLUM, LINTZ, VERMILYE, LEGGET,

and B O A S , 370MCCOLLUM and P A R S O N S , 73, 142, 184,

381MCCOLLUM and P I T Z , 245, 359MCCOLLUM and SIMMONDS, 42,44, 47, 48,

57, 71, 91, n o, ir6,137, 188, igr,

195 ,196 , 206 , 222, 232, 233, 240, 241359, 360, 362, 371MCCOLLUM, SIMMONDS, and PARSONS,51 ,

175, 181, 182, 235,246, 314, 316,3*7, 320, 360,363,364, 365, 36 6,385,386

MCCOLLUM, SIMMONDS, PARSONS, SHIP-L E Y and P A R K , 383

MCCOLLUM, SIMMONDS, and P I T Z , 42, 44,46 , 48, 175, 181,182,190, 191, 192,353 ,354 ,355 ,356 ,357 ,358

MCCOLLUM, SIMMONDS, SHIPLE Y, andP A R K , 386, 387, 389

MCCOLLUM, SIMMONDS, and STEENBOCK,

35?M C D O N A LD and MCCOLLUM, 194,383 385,M C D O U G A L, 382MACKAY, 236, 382M C K I M , see EM M ETMACKLIN and H U S S E Y , 387M C L E O D , F. S., see SHERMAN

M C L E O D , J. W., and W Y O N , 385M C N E A L , 355, 386 ; see also S I L E RMACOMBER, see R E Y N O L D SM A C Y and M E N D E L , 381

MAGNXJS-LEVY, 276, 376Magdeburg, 250Magnesium, 180, 209, 234,303,3i8MAIGNON, 38, 39, 53, 55, 57, 75, 358, 362

363, 366, 367,368, 373, 375, 377Maize, 42-44, 48, 52, 53, 54, 55,58, 66,

73, 104, 107, 176, 177,178, 181,186 ,191,223, 225, 234, 244, 329

"boiled, 305Gluten, 178, 315hulled, 106, 316in Relation to Pellagra, 304-322new, more toxic than s tored, 310Oil, 331

Maize Protein, Inadequacy of, 312-313

Starch {see also Maizena , 327,331, 332sterilised, 106, 119wholemeal from, 106

Maize, yellow, 223, 308-310, 317, 329Maizena, 305, 329Maladies de Carence, 10, 24Malaria, 76Malignant Tum ours , 188Malnutri t ional Oedema, see OedemaMal t Ex t rac t , 256Malt Vinegar, 248,252Malted Grain, 191, 329Mangelkrankheiten, 24Mangel-wurzels, 192, 224, 330MANGKOEWINOTO, see J A N S E N

Mangoes, 329M A N N , 236

Marasmus, see Emacia t ioaMARCHOUX, IO I, 105, 376Margarine, 185,223, 224, 232, 331MARIANI, 307 ; see also V O L P I N OMARINUS, 203, 367MARKOYICI , see P O R G ESMARSH, see M E I G SM A R TIN , see CHICKMASON, 210, 370MATHETJ, 388

MATHEXJ and D A M IA N O V IC H , 388M A TTEI , 380MATTILL, 386, 387M A T O L L and CONTKLIN, 177, 380MAXJRER, 105, 339M A Y ER , 284, 378M E A D , see D U T C H E RMEAT, 5 7 , 6 1 , 1 9 3 , 1 9 6 , 209,247 ,269 ,314,

320, 327, 328boiled, 103,106,119, 125,1 6 0 , 1 9 6 , 249,

canned, 125, r.68, 249 ,252 , 258, 280,32B

Diet, exclusive, 74dried, 242, 252, 334Ext rac t , 193, 328Extrac t , Prepara t ion of, 101fresh, 247, 248, 252, 269, 328frozen, 328Juice , raw, 252frozen, 107, 249over-roasted, 125pickled, 278, 283



INDEX 405M E A T {conhnt4.ed)—

Protein, compared with Milk Prote in,54, 58

r a w , 107salt, 107, 27-8, 280, 283, 328smoked, 24.2ster il ised, 12 5, 16 8, 170,196superheated. , 106, 196t inned, se e m e a t c a n n e dunsuitable a s exclusive diet forgrowing

animal, 196Meat-eaters, clamorous, 210M E D E S , see S M I T HMehlnahr schaden , yy, 284, 295-297, 298

possible kdnship to malnutr i t ionalOedema, 284, 295

M E I G S and M A ^ R S H , 347Melancholia, 76MELLANBY, E. , r86 , 187, 227, 235, 236,

365, 375 ; see also H O P K I N SME L L A N B Y , M. , 361M E N D E L , 39, 55, 228, 236, 352, 354*

356, 378 ; see also CO HEN , COWG-ILL,M C C L T J C A G E , MAXy, MI T CH E L L ,O S B O R N E , THOMPSON

M E N D O Z A - G U A Z O N , 356Menstruation, Effect on Metabolism, 60Mental D isord er in Pellagra, 300, 301MER, 387MER and C A M P B E L L , 382MER, C A M P B E L L , and SHERMAN-, 383, 389Merck, Firm, of, 99Mesopotamia, Ber iber i in, 101-102,125,

159, 170

Scurvy in, 246,247—248Metabolism., Importance of inorganicC ons t i t ue n t s in Metabolism, 40-41

Metabolism i n growing Organism, 179inorganic, Anomalies of, as cause of

Oedema, 287-288Metabolism, inorgan ic, Anomalies of, as

Cause of Pellagra, 317-318Me t a phos pha t e s , 169, 170Meteorisrn, 296, 297Methods of Preparing Food, 183-184,

277Methoxypyrxdin , r23Me t hy l py r i don , 123M E T S C H N I K O F F , 31M E Y S E N B U G , 378MI C H E L , zoy ; see also MO RE L , MO U RI -

QUAND, WEIL3LMlCHELSEN, See SWEITZER^

Microorganisms can synthetise A, 24.0MlDDLEKATJIFF, See McCLENDON

M I D O R I K A W A , see YAMIGAWAM I G N E T , see M O R E LM igraine, Acd dosis an d Lacfcof organically

combined Sulphur as contr ibutoryCauses, 322

Milch-cows, Slaughter of,210Milchnahrsct iaden, 77,284, 297, 298Milk, 51, 53—57, 9O, 92, 93) 94, i33> *77,

18 8,1 92 , 193, 203,209,210, 212, 220,2 2 2 , 2 2 5 , 233, 236 ,237,245, 250, 251,2 5 2 , 2 5 3 , 255, 2 57,26 8,29 7, 3O5, 308,315, 320 , 327, 33O, 331; see alsoCasein a n d Lactalburnin, skirn-milk,B u t t e r m i l k

Milk, condensed, 244,258 ,331boiled, 250, 257, 331

Milk Diet in Sprue, 215,et seq.dilution of, in Infant Feeding, 255,297

Milk, dried, 192, 193, 197, 244, 261, 268,33i

Drying Processes, 261Milk, ESects ofHeating, 20, 73,142 , 183,

184, 187, 244, 258Milk Fat, 225

fat-free, 221Milk, hum an, 330Milk, hum an, compared w ith Cow's, 35 ,

193Milk, human , in Beriberi, 162Milk, pasteurised, 1 97,2 58,2 6 1, 262, 297,

33iMilk Protein, 48, 53-57, 58, 176, 177,

178, 184

Milk Protein, as only Protein forAdults,177 ; see alsoCasein and Lactalb um in

Milk, protein-free, 56, 64 ,88 , 90, 140 ,141 ,177,186 , 193, 256

Richness in Calcium, 180Milk, Secretion of, 50, 175, 253-255

Effect ofDiet upon , 206 ,240, 24.1Milk, stab le in quality under varying con-

ditions of materna l nutr it ion, 57,71sterilisation of, se e Milk, heatingtinned, se e Milk, condensed

MILLER, E. M., see PHEMISTERMILLER, E. W., 141, 381, 388MILLER, W. S., see H A R TMillet, 47, 185, 224, 232,329

Minimum, Law of the, se e LawMITCHELL,H.H, 3435, 36, 142,355,3&9MITCHELL, H. S., and M E N D E L , 389Mitieilungen der Beriberikommission, 342MIURA, see ZILVAMixed-organic Compounds, 96, 155,169,

170MOCKERIDGE, 356, 376MOGI, see YAMIGAWA.MOLTRAM, see CRAMERMONACO, 354Monotonous Diet, se e DietMOODY, see JACKSON, L.MOORE, B., see E D I EMOORE, J. J., 361; see also JACKSONMtooRE and JACKSON, 356MOREL, MOURIQUAND, MICHEL, and

T H S V O N , 389MOREL, MOURIQUAND,and MIGTJET, 383MORESCHI, 339MORGEN and BE G E R, 352MORGULIS,38 7MORI, 339, 342MORO, see HiRScaMO R S E , 348Moss, Irish, 236MOSZKOWSKI, 107, 343MOURIQUAND, see MO RE L , W E I L LMOURIQUAND and MI CH E L , 246,371, 377>

383, 389MUCKENFUSS, 364Mucor racamosus, 308Mulberries, 329MCLLER, 14, 84, 212, 25 O, 26 l,M and B R A N D T , 373



406 VITAMINS

MttNZER, see BEGUN

MURATA, 383Murmansk, Scurvy in, 24.8, 249Muscarin, 143, 144Muscle ; see also MeatMuscle, fresh, contains Abundance of

Funk's Vitamins , 124Muscles, Condition in Beriberi and Ex-

perimental Po lyneuritis, 157,et seqMuscles, Effects of Vitamin on, 144

Muscular System, Energetics of, 146-148Mush, 29 6Mutton Fat, 331Mutual Interdependence of theInorganic

Substances, 90-91M Y E R S , see CHASE, VOEGTLIN-M Y E R S and F I N E , 347M Y E R S and VOEGTLIN, 53, 115, H7>

3.70, 375Myositis,128

N a h r u n g s n t i t t e l t h e o r i e n U b e r die TJ-rsached e t B e r i b e r i in kritischerBeleuchtung,343

N a h r u n g s undG e n u s s m i t t e l , 347KAKAMURA., see ONODERANashville, Pellagra in, 314NASSAU, 374Nausea, 279Need for Sta te Aid in Exper iments on

Nutrition, 337N E H R I N G , see S E T T L E RN E I L L , see VOEGTLINN E L S O N , see FULMER, SXEENBOCKNELSON and L A M B , 232, 375N E L S O N , F U L ME R, and CESSNA, 384Nephritis, 81,300N E P P I , 380N E U MA N N , 276 ; see also K N A CK

Neuralgia, 299, 300Neurasthenia, 126, 281, 305, 315, 322Neurin, 121Neuritis, 283 ; sec also Beriberi, Poly-

neuritisN E V I L L E , see H O P K I N SN e w e r K n o w le d ge of N u tr i t io nNICHOLLS, L., 346, 364NICHOLLS, N. B. , see D A N I E L SNICOLAIDI, 346, 347Nicotinic Acid, ir2, ri 3, 121, 122, 123Nicotinic-Acid-Nicotine-Ester, 122N I E L S E N , see SCHMIDT-NIELSEN

NlGHriNTGALE, 316, 349

N I R E N S T E I N , see H U M ENISTICO, 302, 344Nitrogen H unger, 275Nitrogen, residual, 273Nitrogen Retention, 8r, 82,294,313Nitrogenous B alance, 75,81, 82,103 ,130,

275, 303, 314; see also NitrogenReten t ion

Nitrogen-free Diet , Effects of, 36Nitrogenous Ba lance (seea l so Nit rogen

Reten t ion) , 267, 270, 30aNitrogenous Fert i l i sers , Excess of,pro-

duce s a c id Fodder , 71Nitrogenous Res idues , Reten t ion of, see

Residues, a l so Nit rogen Re t en t i on

N I T Z E S C U , 32, 43. 81, 310, 311, 313, 349,

350, 352, 364N I X O N , 275, 277, 282, 379N O B E L , 257, 382, 386 ; see also F O R T HN O C H T , 129, 279, 280, 281, 339, 340, 358NOLLATJ, see B U C K N E RNomenclature , 21-24N O O R D E N , 85, 338Norleucin, 33N O R T H R O P , 208, 358, 359 ; see ulso L O E B

Nosebleed, 242, 266N O V A R O , 372, 374, 375N O V E L L A , see A L P A G O - N O V E L L A , VOLPINONuclein, 123Nucleinic Acid, 121, 156Nucleoproteins, 97,156, 169, 171N u m b e r ofExper im ents , inadequ ate , 325N u t Oil, 224, 331Nutramin , 22, 147, 195Nutr i t ion in Complet t in Exper iments ,

327, 332-336Nutrit ive Pills , 31Nutritive Salts , see Salts

Yeas t , see Yeas tNuts , 50, 232, 329 ; see also under specific

names, as Walnuts , Almonds, etc,Nyctur ia , 273, 290

Oatmeal , 185O a t s , 4 6 , 5 1 , 54,5 5 ,58 ,176 ,181 , 191 ,223 ,

244, 247, 249, 253, 329Observation, Period of, sec Duration of

Exper imentsOccurrence of the Vitamins (Funk's ) ,

124—126O D A K E , see T S U Z U K IOedema, 90, 108, 145, 160, 269

cardiac, 272, 274causes of, 284-293dyscrasic, 285in Beriberi, 130, i3r , 132, 271, 272

Oedema, in Mehlnanrschaden, 296, 297,in Scurvy, 267malnutr i t ional , 109, 126,133, 238—239,

271-298 (for Detai ls see Table ofContents, Chapter Eight)

Oedema—passive, 27r, 272renal , 271, ay2

Oedematogenic Diet, 285, 286,290Offspring affected by parental Diet, see

Dietetic ErrorsO H L E R , 349Oils, 331; seealso under specific Oils, as

Codliver Oil, Olive Oil, etc.mineral, as Laxat ives , 246Olein, 185, 223, 33rOleomargarine, 185, 223, 331Olive Oil, 185, 224,236 ,331OLSKN-, 370Onions, 249, 252, 330

boiled, 249raw, 248,252

O N O D E R A , NAKAMURA, and T A T E N O , 345Orange Juice , 139, 186, 187, 192, 197,

251, 252, 253, 260, 261, 329,dried, 200Peel, api-peel oil, 331



INDEX 407Oranges, 192,224, 251, 252, 329ORGLE-R, 342, 343Oridia , 22,112,120O R M E A , 339

Omith in , 29, 31Orthophosphates, 169, 170Orypan, 22, 143Oryzanin, 22, 112O S BO RN E , 16, 65, 69, 88, 160, 173, 184,

1 8 6 , 3 1 3 , 3 2 7 , 3 3 3 , 3 5 7 , 3 Ô S BO RN E and L E A V E N W O R T H , 384O S BO RN E and IVLENDEL, 31, 32,41,42, 43,

, 44, 45,46,47,48, 49, 52, 53, 55, 56,57, 58 , 6 3 , 6 4 , 65, 69,91,96 ,107,119,140,177,178,184. , 188,190,191,192,193,194, 205, 207,208, 220,221,224,226,228, 235,253, 256,313, 334, 335,342,344,34-5, 348, 349,352,353,355,

357, 358, 360, 362, 364,373, 3S2,383,3S4, 385O S BO RN E , M E N D E L , and FERRY-, 31, 344,

36 5O S BO RN E , M E N D E L , F E R R Y , and W A K E -

MAN, 99, 347, 35r, 358, 359, 36r, 366,367, 368

O S BO RN E , M E N D E L and W A K E M A N , 181,190, 374, 375, 380

OSBORNE and W A K E M A N, 114, 117, 118,35i , 356, 369

O S BO RN E , W AKEMAJ T, and F E R R Y , 368Osmosis, 287, 288, 289Osmotic Pressure, see Pressure

Osteomalacia, 58,72,86,227,233-235,239Osteopathy, 234, 239, 265, 266,267, 269,270 (see also specific Bone Diseases,as Osteomalacia, Rickets)

Osteoporosis, 58, 70, 86, 254O T T O , 307, 339

O U T H O U S E , see D A V I S , M.Ovalbumia (sometinies called "Egg Albu-

min, to be distinguished from theVitellin of theYolk), 43, 53, I7&

Ovaries, 193Overheating of F ood , see Sterilisation

and Sterilised FoodO W E N , 379Oxidation of A,229, 334

C, 257,261, 262,26 3 ,334Oxidation of Acid-formers, its Effect ontheir •biological Value, 94-99

Oxynicotinic Acid, 122, 123Oxyprolin, 30, 35Oxypyridin, 123Ozone,229

P A C I N I and R U S S E L , 193, 360P A D U A , 369Palm Oil, 331P ALMER , B. W., see H E N D E R S O NP ALMER , B. W., and H E N D E R S O N , 81,351,

36 9P ALMER , L. S., 352, 355, 368P ALMER , L. S., and E C C L E S , 348PALMER, L. S., and KEMPSTER. , 187PALMER, L. S., K E N N E D Y , and KEMP S TER ,

385Palmin, 185Pancreas , 138, 193, 239

Pap,183PAFPENHEIMBR, see HE S S , S HERMANPAFPENHEIMER, MCCANN, ZUCKER, and

H E S S , 386

PAFPENHEIMER and MINOR, 385Para Nuts, 50,191, 329Paradoxical Effect of Calcium Salts in

the Organism, 83-87Para esthe sia, 279, 284., 299, 300Paralysis [see also Paresis), 300; see also

Polyneuritis, andBeriberi, passimParaplegia spastic, 300Parasitism, 240, 241Parasympath.etic, 14.3Parathyroid Extract , 122Paxaxanthin, 121Parents' Diet affecting Offspring {see

Dietetic Errors)Paresis (see also Paralysis), 300, 316;

see also Polyneuritis, and Beriberi,passim

PARK, see MCCOIXTJM, SHIPLEY"PARK and HOW LAND, 389Parsnips, 224, 330PARSONS, 381 ; see also MCCOLLUM,

SHIPLEY-P A S CH , 388Pasteurisation, see MilkPATON-, 98, 338 ; see also F I N D I A YPATON-,FINDXAY, and WATSON, A. H.,363PATON and WATSON, A. H., 383P 7 , 3 7 , 3 4P A U L , see J O H N S

Pea Flour, boiled, 305, 314Pea Legurnin, 47-48Pears, 191, 209, 329Peas, 4S-49, 175, 244, 249, 269, 280, 328

germinated, 248, 328green, 106young green, 290, 328,

PECKHAM, 74, 382Pellagra,, 34.8Pellagra, 42, 238, 299-322 (for Details

se e Table of Contents, Chapter Nine)Pellagra and Beriberi, 316, 319

and malmitritional Oedemaand Scurvy, 319

Pellagra sine Pellagra, 300, 321Pellagra Commission Reports (U.S.), 34-9,351, 357,

Pellagrogenic Factors, 304-322Pellagrogenin, 308, 311PENAU and SIMMONTET, 387Penicilliuin, 308Peoicillium glaucum, 307Pericarp [set also Sirverskin), 102, 105,

140 ; seealso BranPeriod of Observation, see Duration of

ExperimentsPeristalsis, 199P E R L Z W E I S , 351PfeRONNET, see WEXLLP E T E RS O N , see TALBOTP ETTENKOF ER , 26PETTERSSON, see E U L E RP E Z A RD , 57, 370Phaseolin, 48, 59, 175Paaseolus radiatus, 21, rd 7; seealso

Katjang-idjo



40 8 VITAMINS

PHEMISTE R, MILL ER, E. M., and BONAR ,

384Phenolphthalein, 246Phenyl-alanin, 29, 31 , 34P H ILLIP S , se e SHERMAN-PHLORIDZINT, 122Phosphatases, 156Phosphates, Deficiency of, 15 5

Deficiency of, as Caiise of Pellagra, 317Excess of, 295

Phosphates, organic, 169, 170, 171Phosphatic Metabolism, 84-87 ,91 , 96-99,

156, 180Phosphorus, 179, 234, 235, 274Phosphorus Balance, 81, 102, 103, 156,

267,275,303,318Phosphorus Compounds in Food, 95

{see also Phosphatic Metalbolism)Phosphorus—

organic Compounds of, 155organic Compounds cannot be reducedby Anirnal Organism, 97

Photodynamism, 313Photophobia, 300Phytin, 155, 156Pica, 70-71P IER S O N , se e DUTCHERPIERSON and DUTC HER, 371Pig Fat, 331Pike, 138Pilocarpin, 122, 143, 144Pine Kernels, 50, 191, 329Pituitary Body, 143, H4, *45, *93> 201,

202, 203, 273

Pirz, 245, 253, 360, 363 ; see alsoMCCOIXUMPlankton ,. 98PLA NT , 199, 381Plants, vegetative (green) portions vs.

storage portions (roots and tubers)as Sources of Funk's Vitamins, 124as Sources of C, 252

Plasmon, 336PJLUMMER, R. H. A., 9, 12, 257, 376PLIMMER, VIO LE T, 9, 12Plums, 191, 329POKXOP, se e F U N KP O L , se e H U L S H O F F - P O LP O LLIN I , se e P R E T I

Polyneuritis [see also Beriberi), 77, 101-171, 292, 305

Etiology, 100-109Experimental, of Birds, 174Gallinarurn, 106

Polyuria, 273, 290, 291P O O LE, se e R I V E R SPO PIE LS KI , 203, 382

PORCHER, 374PORG ES, LEIMDOR FER, and MARKOVICI,

79, 342, 347Pork, salt, 249Porridge, 296PORTER, 377

PO RT IER , 143, 153, 154, 365, 3 74 ; se ealso BIERRYP O R TIER a nd R A N D O IN , 163,197, 368, 372Po tassiu m, 209, 233, 296, 298, 318, 322

Balance, 102, 303Ions and Oedema, 294,295; see also Ions

Potassium Salts , s timulating Influenceof, 82, 290, 293-295

"urinary Excretion and, 290Potato Protein, 175, 176Potato Starch, 160, 332, 333

Potato Water as Source of Nutr it iveSalts , 90Potato-control, 210Potatoes , 51 , 58, 66, 124, 182, 186, 192,

209, 215,2 17,22 4, 227, 232, 244, 248,249, 257, 278, 280, 2 83, 318, 330

baked, 259boiled, 124 ,196 ,249, 252, 257, 258, 259,

330dried, 197, 244, 258, 259, 260, 280, 330raw , 248, 252, 258, 330sweet, 192, 224, 330 A „_

P O V ITS K V , se e WIL LIA MS , A.. W.P O W E R S , se e S H IP LEYPrecipitin, 308, 311, 3* 2

Preserved Foods and Scurvy, 243Pressure, osmotic, 89, 288, 289, 29 1, 293,

294PR ET I and POL LINI , 342 , 344Prison Dropsy, 279, 280

identical with malnutr it ional Oedema,280

PRITCHARD, 368Problems of Co mp lettin Re search, imme-

diate, 336Procreation, Capacity for, affected by

Errors in Diet, 72, 173, *74Proletarische Kind, Das, r 4Prolin, 30, 31, 33,49

Prolongation of Life, 208Properties of Funk's Vitamins, 116-124Proteid v s. non-proteid Substances as

Nutrients, 37—40Protein Diet, an exclusive, is toxic, 38,

in relation to Acidosis, 76Importance of, 29-61 , 172, i74-*79

Protein Insufficiency and Inadequacycausing Arrest of Growth, 208, 321general Re sults of, 321in Relation to M alnutr it iona l Oedema,

277,282in Relation to Pellagra, 315-318, 320,

321

Protein Insufficiency and Inadequacy inRelation to Scu rvy, 246

minimal daily Requirement, 61Protein Requirements -vary at different

Ages, 60Protein-calorie Doctrine, 326Protein-free Milk, se e MilkProteins, biological Va lue of, 29 -6 1

conditions requisite for Efficiency ofvarious kinds, 56-61

Proteins, inadequate, several, can com-pensate one another's deficiencies,244

Proteins , only a m odera te amo untrequisite, 40

over-estimation of their importance indiet, 172, 174, 175, 178

Proteins, specific, se e under source (asMaize, Rice, etc.) , and underspecific names (as Zein, Casein, etc.)



INDEX 409

Psilosis, see SpruePsoriasis, 76Psychical Influences in Exper iments on

Nutrition, 325

Psychosis, War, 281Public must be enlightened regarding theneyv Scien ce of Dietetics, 337

Pulse, infrequent, see BradycardiaPumpkin Seeds, 49, 50, 176

Sauash, 330Pulses, 48-4.9,182,186,191, 223, 269,315,

320,328proteins of, 175 ; seealso under specific

names, as Haricot Beans, FodderPea, Katjang-idjo, etc.

Pur in, r2 iPurpura , 265, 266, 269

kaemorrhagica, 269simplex, 269

PTOTTER, 98, 340PurziG, 377Pylorus, Str icture of, 80Pyrexia , 266; see also Tempera turePyrimidin, 122Pyrophosphates , 169,170

Q U I T T N E R, see F A L T A

Rachitis , see Ricke tsRadishes, 330Radium, 120, 142, 198, 353

RAIMONO, 146, 350, 351R A M S D E N , 228, 230, 361RANTDOIN-F.AISRDARJ>,$££ BLEHRY, PORTIERRape-seed Oil, 185Raspberries, 329Ratios of nutr i t ive Substances in Diet,

37-4ORAUBITSCHEK, 309, 312, 313, 342, 346,

•O3 5 3

T>

RA\T, see ROBERTSONR A V MU N D , sec LYMANTR E A D , see S U R ER E E D , 376Recherches swy le rdle des %raisses dans

Vutilis&Hon, des cdburnoides, 368R E I C H E , 298, 375Relationship of proteid to non-proteid

nutr it ive Substances, 37-40R E N S H A W , 383Report on the present State of Knowledge

concerni ng accessory Food Factors, 10Reserve Alkalinity, 79, 80Residues, Retention of, 44, 45, 82 ; see

also Nitrogen Retent ionResistance to infective Agents, 199, 230,

231, 239, 267, 317Respiration, internal, 144, 145, 146, 147,

158Respira tory Quotient , 104, 146

Retent ion ofNitrogen, etc.,see Nitrogen,e tc .

Retinitis , 300R E V N O L D S and MACOMBER, 387Rhagades ,300R H O D E S , see C H I C KRhubarb , 330

Rice, 41-42,100, 139, 159,176 ,178 , 181,186, 216, 249

Bran , i n , 113,118,133, 134,135, 137,139, 156

damaged,105hulled, r06, 107, 125Halls ,121Husks , 112polished, ior,102, 104, 105, ro6, 107,

i i 2 f 125,132,135,136,137,139, 155,159, 171, 192,196,305

polishings, n o , n r , 143 (see alsoSilyerskin)

sterilised, 119unhulled, 106, 119, 141, 155Vitamin, 122

R I C H , 379RICHARDSON and GREEN-, 50, 55, 178,

182, 354, 358, 359RlCHET, 366

RlCHTER, 346

Rickets, 233, 234,235-238,239, 242, 250,254, 265, 284

RlESELL, 85, 338Ring Com poun ds, Deficiency of, 176Ring-closing, see CyclopoiesisRipening diminishes C Richness of

Frui t s and Vegetables, 251, 255RI O T E R, see L I E C H T IR I V E R S , 386R I V E R S and P O O L E , 387R O A F , 302, 377R O B B , 378

R O B E R T S , 307, 320, 370ROBERTSON, 355ROBERTSON and CUTLER, 355ROBERTSON and DELPRAT, 359ROBERTSON and RAY,60, 145, 190, 195,

202, 203,204,325,326, 353, 365, 366,375, 381

R O B I S O N , 365 ; see also HA.RDENRobots , 15R O B S C H E I T , see HOOPERRo den ts, specially susceptible toAcidosis,

108susceptibili ty to Scurvy, 268

ROGOZINSKI, 99, 341

R 6 H M A N N , 22, 23, 63, 6 9, IIQ,235, *46,313, 339, 353, 354 •R O I X Y , 345Romberg ' s Symptom, 300R O MME L and V E D D E R, 107, 352JRONDONI, 309, 310, 312, 342, 345> 348,

^ 365R O O T , see L E W I SRo ot Crops, se e Roots and Tuber sRoots and Tube rs , 182,186, 224,225, 252,

330R O P E R , see EddyROSE, 92 , 93 , 94, 3/1,373> 389, o£R O S E , 18, 58, 6r, 62, 71, 72, 75, 84, 86,

205, 206,276 ,291 , 339, 343, 35i, 358R O S E and B E R G , 363R O S E N A U , 389R O S E N BAUM, 381R O S E N B E R G , see SALLER

ROSEKHEIM, 356R O S E N H E I M and DRXJMMOND, 225, 226,

37 5



4 i o VITAMINS

Rossi , 362R O TH , see B E N E D I C TROTHSTEIN-, 83, 276, 364, 371Roughage, 160, 190, 327, 333R O U S E , see

SHERMANR O Y , see SHORTENRUBNER, 17, 19, 26, 51R U H L , 316, 352RttHLE, 14Rumania, Pellagra in, 304Rummelsburg Orphanage, 250, 261R U M P EL, 354.R U M P EL and K N A C K , 279, 352, 356R U S S EL, see P A C I N IRussia, Scurvy in, 248, 249R U TH ER F O R D , 383

Rye, 45-46, 47, 59, 175, 176, 223

Salad, 248, 252, 269Salads, see VinegarSALEEBY, 364 ; see also W I L L I A MS , R. R.Salivary Secretion in Scurvy,267Salivation, 299SALLE and ROSENBERG, 370Salmon, preserved, 193Salmon, Spawning of, 98Salonica Front, Scurvy at, 249Salt Mixtures—

Aron's, 6Sy 336McCoUum's, 6 5,18 3Osbome's, 65-66, 180, 183, 327, 333Osbome and Mendel's, 64, 65Rohmann's , 63, 64.

Salt, Table, see Sodium ChlorideSalts (see also Alkalies and Bases), 40-41,43 , 5i, 57, 241

Buffer, 79,81Deficiency of,233, 250, 268Deficiency of in maternal Diet,207

Salts, inorganic, in Maize, 43in Milk, 206in Relation to Scurvy, 268in Relation to Sprue, 217in Relation tourinary Excretion, 290-

292Salts, nutri t ive, 17,18 , 181

natural, 90supply of a Sufficiency of, 62-67 ,

184Salts, Retention of, 294SAMELSON, M., 105, 379SAMELSON, S., see A R O NSand as Roughage, 190SANTOS, 387SAUERKRAUT, 330SAWAZAKI, 105, 346SAWYER, BAUMANN, and STEVENS, 359SCALA, 69, 382 ; see also ALESSAUDRINIScalding ofVegetables, 210, 211SCHABAD, 340SCHAEFER, See DUTCHERSCHAEFFER, 364SCHAMELHOUT, 377

SCHATTKE, See SCHEUNTERTSCHAUMANN, 19, IO3, I06, IO7, 11 3, Ir

7>118,120, 121, 129,133,134,135, 136,

143, 155, 156, 157,170,280, 339,340,

341, 342, 343, 344, 345, 347, 349

SCHEARER, 356

SCHETELIG, 85, 338

SCHETTLER, Se e SOLLMAN

SCHEUNERT, 234, 373

SCHEUNERT, CHATTKE,and L6TZSCH, 334S C H I F F , 343, see CRAMERSCHIPFMANN", see A B D E R H A L D E NSchilde Company, seeBenno-SchildeSCHITTENHELM and ScHLECHr, 273, 275,

276, 277, 284, 367SCHLECHT, See SCHITTENTHELMSCHLESINGER, 283, 371 , 376S C H L O S S , 96 ,237, 238, 340,341, 342, 344»

346, 348, 349, 353, 356 ; see alsoF R A N K

SCHLOSS and F R A N K , 348S C H M ID T, see ABDERHALDENS C H M ID T-N IELS EN , 243,339SCHMORL, 350

SCHN\TDER, 349SCHOLZ and H I N K E L , 83, 349SCHONTBORN, St& F U N KS C H U B ER T, 339SCHULZ, see FORBESSCHWARTZ, 376SCHWARZ, see F R A N K E L

SCHWEIZER, 384, 388Science of Eating,363Sclerotinia cinerea, 240Scorbutogenics, 244, 249, 251:, 254, 255,

256, 258, 267, 268, 269Scofbutus, see ScurvySCOTT, see Eustis, W E L L MA NScurvy, Past andPresent, 370

Scurvy, 106, 108,109, 126, 133, 211, 218,236, 242-270 (for Deta i ls see T a b l eof Contents, Chapter Seven), 2 72 ,27 8279, 280, 283, 299

infantile, 254, 255, 258, 265, 269, 297Sea Voyages and Scurvy,243Seal Meat, fresh, as antiscorbutic in

Polar Exploration, 252S EA M A N , 379Se"borrhoic Dermatitis, 76Secretion, 144Sedgwick, see MCCLENDONSeed Protein, 178, 180Seeds, 1S5,191, 223, 252, 253, 255, 256Seeds deficient in inorganic Nutr ients ,

182,183Seeds, see Cereals, also under specific

names, asCotton Seeds, H em p S eed s,etc.

Seeds andLeaves contrasted as r e g a r d sinorganic contents, 70 et seq.

as regards Acontent, 22 4preparation of, asFood, 107

Seeds are rich in Funk ' s V i t amins ,124S EG A W A , 102, 134, 347, 349S E I D E L L , 113, 355, 357, 383, 386, 387 ;

see also WILLIAMS, R. R.S E O W E , 373S ELL, see STEENBOCKSerin, 29, 31Serological C onstants, 231, 267

Relations inPellagra,312Serum as Remedy for P u r p u r a ,269Serum Albumin,164

Pressure, 285



INDEXSHA»RPE, seeF I N D LA.YSHA.W, 76, 80, 374, 377

S H E I B , seeLEARYSHERMAN, 42, 54, 61, 326, 370, 372, 386;

see also MER.

S H ER MA N , MC L E O D , F. S., and KRAMER,37i

S H E R MA N , MER, and C A MP B E L L , 383, 387

SHERMAN and SMITH, L. H., 14, 326, 389

SHERMAN and P A P P E N H E I ME R J 385, 388

S H E R MA N , R O U S E , A L L E N , and W O O D S ,385

S H E R MA N , W H E E L E R , and Y A T E S , 42,

4-4, 361SHERMAN and W I N T E R S , 42, 44, 362

S H E R MA N , W I N T E R S , and P H I L L I P S , 46,

36 8S H ER W O O D , sec F U L N E RSHIBAYAMA, 341, 345

S H I G A and KTJSAMA, 342

SHIMAMURA, seeT O U Z U K IShip Berberi, see BeriberiS H I P L E Y , zeeMCCOLLUMSHIPLEY, MCCOLLUM, and SIMMONDS,

38 9S H I P L E Y PARK, MCCOIXUM, SIMMONDS,

and P A R K , 383, 386

SHIPLEY, PA RK, PO WE RS, MXCOLLUM,and SIMMONDS, 388

SHORTEN and ROY, 385

SILER, GARRISON, and M C N E A L , 306, 314,

348, 349 ,351 ,354 ,357Silicates inPellagra,318Silicates, soluble, are they essential?

6 8 et seq.Silicic Acid in Pellagra, 318-319SiTverskin {seealso Pericarp, also Rice

Polishings), 102, no', 111SIMMONDS, seeMC C O L L U M, S H I P L E YS I MO N , 368

S I MO N N E T , 159, 160, 161, 333, 381 ; see

also PENAXJSimpler Natural Bases, The, 349SIMPSON, G. E., see E D I E , L E W I SSIMPSON, G. E., and E D I E , 342

S I MP S O N , K, 104, 376

SIMPSON, S., 203, 377

Sitacoid, 22S K E L T O N , seeC H I C K , D E L *

Skim-milk, 186, 193,222, 232, 233, 33*Skin , 200SLATOR, 363

Skorbut, Der, 368Sleeplessness, see InsomniaS L Y K E , seeW H I P P L ES L Y X E , C U L L E N , and STILLMAN, 79> 80,

35i , 352S M I T H , A HE, 363, 365

S M I T H , C A, see H A W KS M I T H , C. A,B E R G E I M , and H A W K , 388

S M I T H , D. W., see H A R TS M I T H , E., and M E D E S , 388

S M I T H , F., and H A S T I N G S , 109, 346

S M I T H , H., 281, 353

S M I T H , L. H., seeSHERMANS M I T H , ~L . ML and L E W I S , 359

S M I T H , P. W\, see B A S S E T - S MI T HS M I T H , X, 338

Smoking, see Tobacco

Sodium, 233, 241

Bicarbonate inTreatment of Scurvy,26 9

Chloride, 274,287-288

Sodium Chloride, Craving for, 276excessive use as Seasoning, 290, 294,. 3 2 1

Sodium Chloride, Excre tion of,276, 291Metabolism, 275-276, 287Retention of,276

Sodium Chloride, storage of, 81, 82Sodium, Deficiency of, inCereals, 296

in diluted Milk, 298Sodium Ions and Oedema, 287-288, 293-

295Sodium S alts, paralysing Influence of, 82,

275, 276,287-288, 293-295urinary Excretion and, 290-292

SOLLMANN, SCHETTLER, and WETZEL, 381

Soup, 250Powders,278Tablets, 278

Sourness of Soil, effect on Plants asNutrients,71

South Carolina, Pellagra in, 307SOUZA and MCCOLLUM, 380

Soxhlet Apparatus, 184Soy Beans, 49, 59, 66, 118, 119,176,186,

191,192,223, 253,328

Spartanbu rg, Pellagra in, 307Spasm, tonic and clonic inPellagra, 300Spasmodic ASections, 76, 160, 235; see

also under specific Names, as Carpo-pedal Spasms, Epilepsy,etc.

Spasmophilia, 284, 294, 295Spastic Paraplegia,300SPIIVLMAN, seeBRTJNTZSpinach, 5r , 92, 192, 200, 209, 217, 224,

225, 251, 252, 330, 332, 335boiled, 249, 330dried, 330raw, 211, 330

Spleen,328SPRAWSON, roo, 101, 378

Sprue, 212—218clinical Picture, 212-213Etiology, 215-218pathological Anatomy, 213—214Prognosis, 214

Treatment ,215Stall-feeding, 194STAMPERS, 382, 387

Standard Diets forExperimental Work,327, 332-336

STANLEY, seeTROWBRIDGESTANTON, A T., see FRASERSTANTON, E. E., see SULLIVAN1

Starch, 221, 277, 33*, 335{see also special Starches, as Potato

Starch, etc.)STARK, 355

Starva t ion, r59, 161, 162, i6<3, 282 309Starvation States, 171Starvation States and Polyneuritis, 148-

153Sta te Adneeded in Experiments onNutrit ion, 337

Steaming of Vegeta"bles, 210, 211 ; seealso Bleaching .



4 1 2 VITAMINS

Stearin, 185, 223, 331STEENBOCK, 357, 360, 362, 367 ; see also

E L L I S , N. R., H A R TSTEENBOCK, BOTJTWELL, GROSS, and S E L L ,

223, 228, 371STEENBOCK, BOTJTWELL, and K E N T , 225,229, 362

STEENBOCK, BOTJTWELL, SELL, and GROSS,

372, 375S TEEN B O C K , G R O S S , and S E L L , 192, 224,

369, 372STEENBOCK and H A R T , 346

STEENBOCK, K E N T and GROSS, 47,362

STEENBOCK, N E L S O N and H A R T , 74, 80

35O, 388S TEEN B O C K , S ELL, and B U E L L , 385S TEEN B O C K , S ELL, and B O U TW ELL, 386STEFANSSON, 361, 364S TEIN A C H , 28

STEINITZ, 97, 338S TEP H EN S O N , 382STEPHENSON and CLARK, A. B., 379S T E P P , 138, 184, 219, 220, 221, 226, 227,

229, 231, 340, 342, 345, 347, 35O,354, 366

Sterilisation, destroys Vitamins, 101Sterilised (superheated) Food, 197

(see also under specific foodstuffs, asMeat, Milk, etc.)

Sterilisation, Effect on Vitamin, 119,etseq., 125

of Meat, see Meatof Milk, see Milk

Sterilised Food ia Dietet ic Experiments,189, 198

Sterins, 226S TER N , 379STERNBERG 349, 350STEVEN'S, see SAWYER.STEVEN-SON-, A. G., 380STEVEN-SON, H. C, see E D D YSTEWART, 201,361, 371 ; see also JACKSONS T I L L , 236 ; see also H A R D E N , 2 I L V ASTILLMAN, see S L Y K EStock-fish, 193STOCKHOLM, see E M M E TStomach, Lavage of,as Cause ofAcidosis,

80

Stomati t is , 266Storage, Effect on C content of anti-scorbutics, 253, 257,2 61 , 262

Storage Fat, 185, 223Tissues, 192

STORM VANL E E U W E N and VERZAR, 385Strangury, 291STRAUSS, 85, 338Straw, 251Strawberries, 215STRONG and C R O W ELL, 105,135,344Strychnine, 121Studies in Deficiency Disease, 12SUAREZ, 304, 309, 353Suet , 236, 331

Sugar, 186,236, 246, 24.9, 26 8,296 , 331Sugar B e e t , see B e e tSUGTURA, 114, 137SUGIURA and B E N E D I C T , 50, 140, 142,

191,198 ,363 ,369SULLIVAN, 373 ; sec also VOEGTLIN

SULLIVAN and J O N E S , 373SULLIVAN and V O EG TLIN , 353,SULLIVAN and STANTON, 378SULLIVAN and D A W S O N , 384SULLIVAN, STANTON, and D A W S O N 386

Sulphates, excess of, 295Sulphur, 56, 95, 96,179, 269, 303

Balance, 81Lack of, 269Neutral , of Urine, 95Organically combined 333Organically combined, Deficiency of,

296, 303, 322Sulphuret ted Hydrogen , 168Sulphhydri l Group,168Sunflower Seeds, 59Superheating (120° C.) for t h ree Ho u rs

destroys all Antiscorbutics, 258S U F P L E E , see H E S S

Supply of a Sufficiency of Nu t r i t i v eSalts, 62-67Suprarenal , see AdrenalS U R E , 33, 56, 32% 380S U R E and R E A D , 382SUZUKI, seeTsvzyKtSweden, Scurvy in, 242, 250, 251Swedes, 192, 330Sweetness of varieties of Cit rus , thei r

richness in C propor t ional to, 251Sweetstuffs, 327S W EITZER and M IC H ELS O N , 76, 374

SWOBODA, 381S Y D EN S TR IC K ER , 352 ; see also G O L D -

BERGERSynthetic Powers of Animal Organism,165 et seq., 253

Syrup, 236

Tahle Sal t , se e Sodium ChlorideT A K A K I , 338, 339T A L B O T , D O D D , and P E T E R S O N , 346Tamar in d s , 330T A N J I , 146, 362T A N N E R and EC H O LS , 386T ar es h6re"ditaires, 15TA S A W A , 103, 348T A T E N O , see 0 NOD ER A

Tea,2r6, 249

Teeth, carious, 209, 248, 265Teeth, loosened in Scurvy,266T E L F E R , 383Temperature , Body , 146,1 4 8 ^ 5 3 , 154*

273, 308, 3ro ; see also P y r e x i aTennessee, Pellagra in, 314TER A U C H I , 341T E R E G , 96T E R E G and A R N O L D , 338Terminology, see NomenclatureT E R R E I N , 173, 378T E R R O I N E , 39, 366Test, Dietetic, 173Testicles, 193

Tetan y , 80, 235, 296 ; see also C a r p o -pedal SpasmsTethelin , 145, 202, 203Tetraoxypyridin, r23T H E V O N , see M O R ELT H J O T T A , 386



INDEX 41 3

T H J O T T A and A V E R Y , 388, 389

T H O L I N , 388

T H O M A S , 51 ; see also R U B N E RTHOMPSON 1

and M E N D I L , 208, 361

T h y m i n , 121

Thymo-nucleinic Acid, 121T h y m u s , 193, 223Thyro id , 193, 273Thyro id Ext ract , 122Thyroidectomy, 203Timothy Grass, 192, 224, 252, 330TI RABOS CHI , 307, 340

Tissue Builders (see also Amino-acids),18, 47, 164, 208

TI ZZONI , 307, 342, 343

Tobacco, 216TOBLER, 364Tomatoes , 192, 196, 224, 251, 329

dried, 260Tone, arterial, 294

muscular , 284, 294, 296, 301nervous, 2 95tissue, 297, 298

Tonsil lar Hypertrophy, 209Tonil in , 22T O T A N I , 58, 357

T O W L E S , see VOEGTLIWTown-dwellers, Scurvy among, 242, 243Toxaenaia, 245, 272Toxins in Maize, 307d seq.TOZER, 383, 386

Tremor, 300Trichoderma lignorum, 308Trigonellin, 122, 123Tricxypyridin, 123Tropica l Hyg iene , German Soc i e ty for,

280T R O W B R I D G E , see F R A N C I STROWBRI DGE and S TANLEY, 170, 341

TRTJtf INGER, S e e . L l E C H T ITryptophan, 30,3 1 , 32, 34, 43> 45, 46, 47,

49»53,54,56, X031176TS CHI RS CH, 37O

TS I RS CH, I 5 6

TSXJZXJKI, 340, 348

TSUZXJKI and SHIMAMXJRA, H I , 341

TSTJZTJKI, SHIMAMURA, and O D A K E , 112,

118, 344Tubers , seeR o o t sT UL L I S, see AL B E RT OUI

T u m o u r s , 188, 193, 201, 216Turk i sh Pr i soner s , Pe l l agra among, 316,

320Turnip Juice, 260Turnips, 192,197, 224, 227, 252, 330

"boiled, 258Turnover , bas ic , 60, 73Turnover , increased , in gr ow ing Or-

gan i sm , 179T w i t c h i n g , 300Typho id B ac i l l i and Growth-fac tor , 193Typhus pe l l agrosus , 301, 321Tyr os i n , 30, 31, 32, 34-,5&> *7 tf

t)ler kiitistliche E r n d k r u n g u n d V U a m i n r ,

UHLMANTN, 78, 143, 144, 358, 362, 378T J N , see EPPIKGER

Ultraviolet Light, 120, 229, 264UMBER, 389

UMMES , 309, 310, 345

UNDERBILL, 73,356; see also CHITTENDENU N G E R , see H E S S

Uni t e d S ta t e s Le ad in d ie te t i c Exper i -m e n t s , 323Uni ted S ta te s , Inve s t i ga t ions r egard ing

t Nutr i t i on , 172Uni ted S ta te s , Inve s t i ga t ions r egard ing

E t i o l o g y of Pel lagra, 306, 307Uni ted S ta t e s , Pe ll agra in,305, 306, 307,r T . 313-315, 320-321University Cream, 236Uracil, I2rU R B E A N U , 72, 102, 205, 304, 310, 318,

320, 3 2 1 ,3 3 8 ,3 5 4Unc Acid, 121Urine in Beriberi, 130, 131Utilisation ; see also Assimilation.

Utilisation of Calcium in various formsof Administration, 92—94

Valin, 29, 33, 49V A L I A R D I , 307, 342

Variety in Diet , 47, 176, 177,191, 221 ;see also Diet

Y E D D E R , 102, 109, 134, 136, 345, 354,

356, 361; see also CHAMBERLAIN,R O M M E L

Y E D D E R an d C L A R K , E., 129, 135, 157,

"VEDDER and "WILLIAMS, 113, 135, 346,

Vegetable Juice, fresh, 212Yegetable Meat, 50Vegetables, 327Vegetables as ultimate Source of A,

240Vegetables, "bleached, seeBleach ing ,

dried, 197, 230, 257, 261, 262,278fresh, 189, 209, 243, 244, 246, 247, 24S,

250, 251, 262, 269, 278green , see G-reen VegetablesFa Sprue, 215, 217Preparat ion of, seeBoi l ingpreserved , 247, 280, 281Steaming , Sca ld ing , and Bleach ing of,

210, sri, 278

Vegetarianism, 37, 73, 290VERMI LZE, see MCCOLLUMVertigo, 300VERZAR, see STORM VAN L E E U W B NVERZAR an d B S G E L , 142, 239. 380

Vichy Water, 215V I D O N I , see G A T T IVI DONI and GATTI , 342

Vie nne s e In s t i t u t e for Mothers andNurse l ings , 25a

Viennese Un iver s i ty Cl in i c , 250Vign in , 48 -49 . *75Viaegar , 248, 252Vinegar as Cause of Acidos i s , 77VISWALHTGAM:, 361, 371

V i ta m i n M a n u a l , T h e ,384V i ta m m e s , E s s e n t i a l F o od F a c to r s , 9V i ta m i n s , xoV i U m m s , T h * > 14, 389



414 VITAMINS

Vitamins and the Choice of Food, gVitamine, ihre Bedeutung filr die JPhysio-

logie und Pathologie, etc., 350Vitamin., Funk's see Funk's Vitamins

Vitamin, term, defined, 21 et seq.Vitamin and Vi.tain.ias, passim ; bu t seealso Funk's Vitamins

Vitamine, Die, yyVitellin, 52, 176V N , 116, n g , 157, 319, 350, 354,

355> 379 ; see also K O C H , M Y E R S ,SULLIVAN

and L A K E , 364.N-, L A K E , and MVER S , 363

VtEGTLiN1 and M Y E R S , 144, 363, 366, 367VtEG-TLiN, N E I L L , and HUNTER. , 370VtEG-TLiNr and T O W L E S , 135, 346VtEGTLiN- and W H I T E , 117, 356VtE&TLiN and HAR R IS , 370VtEG-TLiN, SULLIVAN, and M Y E R S , 375V * G T , 250,372

VfIT, 26, 102VtLPiNO, 3O7, 310, 311, 312, 348, 349VtLPiNO and B OR DONI , 312, 352V BORDONI, and AL P AGO-NO-

VELLA, 343PiNO, MARIANI, BORDONI, and AL-PAGO-NOVELLA, 343

WAELE, 277, 278, 377

WAKEMAN, set OSBORNE

WALLIS, 10I, 360

WALSHE, 360, 370Walnuts, 50, 191, 224, 329WANG, see BLUNT

Wai Psychosis, 281WARING, see GOLDBERGER

Wartime Feeding, 431, 271as cause of malnutritional Oedema, 278

Wartime Feeding of Children in Germanyand German Austria, 210-212

Wartime Feeding of U.S. Soldiers inTrenches, 268

WASON, 385

Wasting, see EmaciationWatercress, 330WATERS, 340

Water-soluble B, see BC, see CD, seel)

WATSON, A. F., see DRTJMMOND

WEISER, 108, 234, 345, 348

Weisser Hirsch, 211WELLMAN, BASS, and EUSTIS, 344

"WELLMAN, EUSTIS, and SCOTT, 346

WELLMANN and EUSTIS, 104WELLS, A. H., 364, 383

WELLS, H . G., 386

WELLS, C. A., and EWING, 355

WELTMANN, 381

WERTHEIMER, see ABDERHALDEN

WERTHEIMEER and WOLF, 386

WETZEL, see SOLLMAHN

Whale Oil, 225, 331Whalers, Scurvy among, 243

Wheat, 44-4-5, 52, 54,55, 58, 59> 108, 140,176, 181, r86, 191, 200,223, 253, 305,314, 315, 328, 329

Germ, 119,140,176, 181,186 ,191, 223,225, 327, 328, 332

Wheatmeal, 192, 328WHEELER, A. G., see G-OLDBERGER

WHEELER, L., see SHERMAN

W H E E L E R , R., 346,352WHEELER, R., and BIESTER, 349

Whey, 186W H I P P L E , B. K., 141, 192,196, 381WHIPPLE, G. H., see HOOPER

WHIPPI-E, G. H., and VAN SLYKE, 751 361

WHITE, see VOEGTLIN

White Flour and White Bread, see Flourand Bread respectively

White of Egg, 53, 55, ro3, 328 ; see alsoOvalbiimin

Wholemeal, 280, 328WlELAlSD, 344." Wiener klinische Wochenschrift," 286WILBUR, see ANDERSON

WILLAMAN, 240, 372

WlLLCOX, IOI, 125, 144, 24.6, 247, 248,

253, 354, 358, 371

WlLLETS, See GOLDBERGERWILLIAMS, A. W.} and POVITZKY, 385

WILLIAMS, LEONARD, 12

WILLIAMS, R. H., see EMMET

WILLIAMS, R. J., 194, 368, 375, 384

WILLIAMS, R. R., 122, 123, 353, 354,

355, 358, 387; see CHAMBERLAIN,

VEDDERWILLIAMS, R. R., and CROWELI,, 351

WILLIAMS, R. E.., and JOHNSTON, 351

WILLIAMS, R. R., and SALEEBY, 351

WILLIAMS, R, R , and SEIDELL, xi4, 118,

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Vitamins - Berg