416

impairment, hypertension, coronary or peripheralarterial disease, chronic infection, or incapacitatingneuropathy, particularly postural hypotension whichis aggravated after operation. Although the prog-nosis for vision without treatment in proliferativediabetic retinopathy is worse in older patients,6 8the presence of vascular and other complications inthis group will often render them unsuitable for

surgery. It is also important that the patient shouldbe of reasonable intelligence, and with a matureadjustment to his disease, in order to cope ade-

quately with the added problems of hormone

replacement therapy; and he should stay within

easy reach of skilled medical care.The results of pituitary destruction in diabetic

retinopathy must be compared with the natural

history of the disease. Spontaneous disappearanceof microaneurysms, retinal haemorrhages, and exu-dates is not uncommon, and may be observed in upto 30% of younger patients.22 Even proliferatingretinopathy may sometimes become arrested spon-taneously, as BEETHAM 6 noted in 35 out of 351

patients. The occasional instance of dramatic

improvement of neovascularisation coinciding withstrict control of diabetes has been reported,23 and,although this event is rare, it may perhaps be morelikely in young female patients. 21 Review of the

early results after pituitary destruction suggestedimprovement or stabilisation of retinopathy in a

little over 50% of patients,21 but these series includedno control patients. Evidence from controlledstudies has been hard to collect since so few patientsfulfil the criteria necessary for treatment. Never-

theless, JoPLIN et al.19 found that in a small seriesof patients treated by yttrium-90 implantation,there was improvement in retinal haemorrhages in50%, in new vessel formation in 30%, and invenous dilatation in 20%, compared with a controlunoperated group. RUCKER et al.,15 using pituitary-stalk section in 33 patients and comparing theresults with a similar number of control patientsnot so treated, found that one-third of patientstreated retained useful vision that might have beenexpected to have been lost had they not had theoperation. These figures indicate that in a pro-portion of patients pituitary destruction gives a usefulmeasure of improvement, but all reports indicatethat in some patients retinopathy continues to

progress in spite of treatment. More recent

results 10 16-18 suggest an improvement on theearlier figures, probably due to better selectionand treatment of patients with less severe disease.At a symposium 24 last year, a review of 11 seriesand 708 patients treated by pituitary ablation22. Burditt, A. F., Caird, F. I., Draper, G. J. Q. Jl Med. 1968, 37, 303.23. Dollery, C. T., Oakley, N. W. Diabetes, 1965, 14, 121.24. Treatment of Diabetic Retinopathy (edited by M. F. Goldberg and

S. L. Fine). U.S. Department of Health, Education and Welfare,1969. Public Health Service publication no. 1890. From Superin-tendent of Documents, U.S. Government Printing Office, Wash-ington, D.C. 20402. Pp. 913.$6.

indicated that retinopathy could be halted in a

majority of the limited number of cases whichmeet the criteria for operation. There is no clearevidence that pituitary destruction has a benefi-cial effect on other diabetic complications, notablyrenal disease, and neuropathy may progress after

operation.14The exact mechanism of any improvement in

diabetic retinopathy after pituitary destruction is notestablished. It is unlikely to be the result of betterdiabetic control, since, although the requirementfor insulin usually falls after operation, most workershave found that the diabetes is no easier to contro1.21

Speedy subjective improvement in vision mayensue within days after operation,12 and is linkedto absorption of retinal oedema and vitreous clearing.This sequence suggests that the removal of a quick-acting factor, perhaps growth hormone, is responsible;on the other hand, no correlation has been foundbetween the retinal improvement after stalk sectionand changes in growth-hormone secretion.25 Thereis evidence that pituitary ablation should be as

complete as possible in order to achieve the bestresults,26 particularly in the prevention of newvessel formation.27 Destruction of the pituitarygland has established a claim for consideration inthe management of a limited number of patientswith vision-threatening diabetic retinopathy, butmore effective and less rigorous forms of treatmentare sorely needed to supersede this mutilatingoperation.

Genetics of Mammalian Somatic Cells

MAN recently landed on the moon, an achieve-ment of great technological virtuosity, but exact

predictions of his future progress in space are

difficult, even apparently for the professional book-maker. Progress with problems of essentially bio-logical orientation is even more uncertain. Thereseems no fundamental reason why they shoulddiffer from problems of space, time, and motion,except in their degree of complexity. But, in prac-tice, rationalisation has been greatly impeded bylack of definition of the working units. Nowhere isthis more apparent than in relation to the workingmechanisms of mammalian cells. Man is in theunenviable position of being almost completelyignorant of the mechanisms of differentiation whichare concerned in the elaboration of his body. Fromsuch a position of ignorance any fundamental under-standing of socially important conditions like cancerwill be slow of achievement. Part of the difficultyin the past has been lack of methods for analysis ofthe genetic apparatus of the somatic cell. The25. Powell, E. D. U., Frantz, A. G., Rabkin, M. T., Field, R. A.

New Engl. J. Med. 1967, 275, 922.26. Fager, C. A., Rees, S. B., Bradley, R. F. J. Neurosurg. 1966, 24, 727.27. Joplin, G. F., Oakley, N. W., Hill, D. W., Kohner, E. M., Fraser,

T. R. Diabetologia, 1967, 3, 406.

417

germ-line cells of mice, men, and sweet peas appearto have much in common, in that they have thesame genetic ingredients, but our bland suppositionthat these are effective in exactly the same way asthe genetic materials of microorganisms is almost

wholly unsupported by hard facts. The very first

steps in a suitable genetic analysis are evident insome recent papers. 1 2

It is now several years since the discovery 3 thatsome mammalian cells could be fused to producehybrids. Initially it was thought that only cells ofthe same species could be fused, but it has nowbecome apparent that almost any nucleated cells canbe hybridised with any other.4 It appears that theresultant hybrid cells initially possess both sets ofchromosomes from the parental cell lines but thatchromosome loss thereafter is common and variablein its extent. Two easily discernible possibilitiesarise from the method. A particular characteristicof the parent cell lines can be observed in the hybridand its descendants, thus giving information as towhether it is " dominant". In addition if chromo-some loss occurs during the further growth of thehybrid cell and a recognisable change in the pheno-type of the hybrid cells takes place, then the changedcharacter can be associated with the lost chromosome.This is a primitive and slow method of geneticanalysis compared with the exquisite refinements

possible in microorganisms. On the other hand,when it is shown that such characteristics as malig-nancy and transplantation antigens 2 can be studied,the implications become apparent. As far as malig-nancy is concerned the first efforts to hybridisenormal and malignant cells led to the productionof malignant hybrid-cell populations. It appearedthat malignancy was genetically dominant. Morerecent studies seem to indicate that a stronglymalignant phenotype can initially be lost in a hybridcell, but, when chromosome loss takes place, themalignant characteristic sometimes reappears. Themost reasonable interpretation of these findings isthat the lost chromosomes from the relatively non-malignant parent somehow suppressed the geneticpotential for malignant growth that is normal in theother parental cells.Of almost equal interest was the finding that, when

a transplanted mouse tumour-cell line of ancient

vintage was hybridised with a normal mouse-fibro-blast line, the transplantation antigens of the fibro-blast line nearly vanished. The tumour itself was

non-strain-specific and, it was thought, may haveevolved the capacity for suppression of its own

transplantation antigens, thus facilitating its growth1. Nabholz, M., Miggiano, V., Bodmer, W. Nature, Lond. 1969, 223,

358.2. Harris, H., Miller, O. J., Klein, G., Worst, P., Tachibana, T.

ibid. p. 363.3. Barslei, G., Sorienl, S., Cornefert, F. R. C.R. Acad. Sci., Paris,

1960, 251, 1825.4. Harris, H., Watkins, J. F., Ford, C. E., Schoefl, G. I. J. Cell Sci.

1966, 1, 1.

in almost any host. This suppressive capacity wasapparently exerted on the normal fibroblast cells. In

hybrids between the same fibroblast line and tumoursof more recent origin, there was not the same sup-pression of the fibroblast antigens.The ramifications of these experiments are

tremendous. They indicate that such apparentlyimmutable characteristics as malignancy and anti-genicity can be genetically regulated. To demon-strate this is a remarkable achievement and holdsout high hopes for the future.

Annotations

EPIDEMIOLOGY OF SERUM-URIC-ACID

DURING the past twenty-five years the focus ofattention of epidemiologists has broadened to includedegenerative and malignant diseases. A further shiftin interest is now taking place, for, in addition toexamining fully developed diseases such as lung cancerand coronary heart-disease, these workers havestarted to study the epidemiology of relatively simplecharacteristics of clinical importance, like blood-

pressure and serum-cholesterol levels. When thesedeviate from the normal each can be associated witha wide variety of diseases. For instance, arterial

degeneration and xanthomatosis are linked with highserum-cholesterol levels; and raised blood-pressurecan lead to cardiac failure, cerebrovascular disease, ormyocardial infarction. Because of their early rolein disease processes, changes in variables such as

these have been described by Morris 1 as precursorpathology.

Serum-uric-acid, which when levels are high canprecipitate gout, and perhaps has a causal role in thedevelopment of coronary heart-disease,2-4 is anothersuch characteristic which has received much attention.The findings recorded on p. 391 by Professor Achesonand Dr. Florey suggest that the epidemiology of uricacid is immensely complex, and a factor like body-build, which is strongly associated with it under oneset of circumstances, may have no obvious connectionwith it under others. Thus, the observation that inyoung men in Colombia serum-uric-acid increaseswith altitude of domicile provides circumstantial con-firmation of an association reported previouslybetween serum-uric-acid and hxmoglobin levels inthe general population in New Haven, 5 6 and in amental hospital. Yet it is compatible with the factthat Evans and his colleagues failed to find thisassociation among two primitive tribes in the SouthPacific.

Equally complex but intriguing are the relation-

ships which Professor Acheson and Dr. Florey1. Morris, J. N. Uses of Epidemiology. Edinburgh, 1969.2. Gertler, M. M., Garn, S. M., Levine, S. A. Ann. intern Med. 1951,

34, 1421.3. Hansen, O. E. Am. Heart J. 1966, 72, 570.4. Hall, A. P. Arthritis Rheum. 1965, 8, 846.5. Acheson, R. M., O’Brien, W. M. Lancet, 1966, ii, 777.6. Acheson, R. M., Chan, Y.-K. J. chron. dis. 1969, 21, 543.7. Kaufman, J. M., O’Brien, W. M. New Engl. J. Med. 1967, 276, 953.8. Evans, J. G., Prior, A. M., Harvey, H. P. Ann. rheum. Dis. 1968, 27,

319.