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RETROSPECTIVE
Francois Jacob memorialArthur B. Pardee
1
Department of Adult Oncology, Dana-Farber Institute, Boston, MA
02115
Dr. Francois Jacob is one of a handful of the20th centurys most
distinguished life scien-tists. His research with Dr. Jacques
Monod,like that of Watson and Crick, provided thefoundations for
understanding mechanismsof genetic regulation of life processes
suchas cell differentiation and defects in diseases.Jacob joined
the College de France in 1964and shared the Nobel Prize in
Physiologyor Medicine 1965 with Jacques Monodand Andre Lwoff. He
was elected to theNational Academy of Sciences (NAS) USA
in 1969.Jacob was born in 1920 in a French Jewish
family; his grandfather was a four-star gen-eral. He began to
study medicine beforeWorld War II, in which he served as a
mil-itary officer in the Free French Army and wasbadly wounded in
an air raid. He receivednumerous high military honors. Then
hecommenced research in the laboratory ofAndre Lwoff, earned an MD,
started a life ofresearch at the Pasteur Institute, Paris, in1950,
and received his Doctorate in Sciencein 1954. He had two marriages
and four
children. He died at age 92.Dr. Jacobs initial major
contribution was
to determine positions of genes on DNA. Hismodel was Escherichia
coli. As discovered byWilliam Hayes, DNA of a donor strain
wasefficiently transferred into a recipient strain.Jacob and his
talented collaborator ElieWollman developed the technique of usinga
Waring blender to interrupt this matingtransfer at any time
following mixing. Theyshowed that different genes were
transferredat different times. For example, the genefor
-galactosidase was transferred 20 min-
utes after mating started. This enzymecleaves the sugar lactose,
making it avail-able for bacterial colony formation. Thismethod
created the first mapping of genepositions in a linear sequence and
revealedthe circular nature of the bacterial chromo-some (1).
Wollman continued in biologicalresearch and received many honors,
in-cluding Foreign Membership in the NASin 1991.
Jacob also studied the mechanisms thatregulate the virulence of
the bacterial virus(bacteriophage) . His work had shown that
carried genes that regulated whether its
DNA would integrate into the bacterial chro-mosome and remain
dormant or, at othertimes, would kill the cell.
Jacobs next major contribution, in collab-oration with Dr.
Jacques Monod, was to in-vestigate how a gene is regulated.
Remark-ably, native E. coli synthesize -galactosidaseonly when
lactose is available. Some mutatedbacteria can make the enzyme in
the absenceof inducer. Monods initial idea was thatthese
constitutive bacteria activate the geneby synthesizing an
intracellular lactose-like
inducer molecule.To investigate this model, interrupted
mating was applied to bring the -galactosi-dase gene of a donor
bacterium into a consti-tutive receptor. According to the
inductionmodel, the mated cell should produce en-zyme
constitutively, without added inducer.These experiments are the
first in which genetransfer was directly determined by
timingproduction of its product (-galactosidase)rather than by much
later counting the num-ber of colonies produced on lactose as
thesource of energy.
The currently accepted mechanism of en-zyme repression for
control of gene expres-sion was produced from the PaJaMo
(Pardee,Jacob, Monod) mating experiments (2). Inthe absence of
inducer, the constitutive (lacZ) bacteria produced -galactosidase a
fewminutes following transfer of lac Z+ DNA,and continued for about
2 hours. However,then an inducer was necessary; a repressiveaction
was seen after a few hours. It wasconcluded that a regulatory gene
R intro-duced into the mated bacterium graduallyproduces enough
protein repressor to shut
off the structural Z gene. The -galactosidaserepressor protein
was subsequently isolated(3). -galactosiderelated compounds
blockrepression by binding to and inactivatingthe repressor
protein. Monod named this adouble bluff mechanism. Both Jacob
andPardee have described these interconnectedstudies (4). Jon
Beckwith provides a fascinat-ing description of this and subsequent
re-search (5). These experiments showed thatbinding a small
molecule to a repressor proteincan modify binding of the protein to
DNA,suggesting that the protein has separate func-tional and
regulatory sites. This property was
named allostery (other site) (6). This allosteric
model is similar to that suggested by the workof Gerhart and
Pardee demonstrating that anenzymes regulatory sites, involved in
feed-back inhibition of biochemical activity, aredistinct from
catalytic sites (7).
Further experiments by Monica Rileyshowed that decay of 32P
incorporated inDNA of the lac Z gene decreased -galacto-sidase
formation, showing that DNA integrityis essential for enzyme
synthesis to continue;a stable intermediate cannot be involved(8).
This research provided one beginningfor the concept of mRNA as a
short-lived
intermediate between DNA and protein.Removal of repressor
protein from its
DNA causes several genes involved in lactoseutilization to
produce several proteins in-cluding-galactosidase and lactose
perme-ase, which transport lactose into bacteria.These results, the
PaJaMo experiment, andJacobs work on regulation in bacteriophage
were combined into Jacob and Monods
Francois Jacob, 1985.
Author contributions: A.B.P. wrote the paper.
The author declares no conflict of interest.
1E-mail: [email protected].
www.pnas.org/cgi/doi/10.1073/pnas.1309173110 PNAS | June 18,
2013 | vol. 110 | no. 25 | 1005310054
RETROSPECTIVE
mailto:[email protected]://www.pnas.org/cgi/doi/10.1073/pnas.1309173110http://www.pnas.org/cgi/doi/10.1073/pnas.1309173110mailto:[email protected]
7/28/2019 Memorial Francois Jacob 2013
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major review of the operon model of generegulation (9). In 2011,
the Pasteur Instituteconducted a 50th anniversary symposium,The
Operon (10).
Jacobs research continues to have majorsignificance for current
developmental genet-ics. Of the transcribed DNA in higher
organ-isms, only about 2% of mRNA makes protein.
It is now known that the great majority ofDNA contains many
sites to which numer-ous regulatory proteins bind. These, for
ex-ample, are involved in the extremely complexdifferentiation of
stem cells into somatic cells,and in diseases such as cancer, which
arebased on defective regulation.
Additional and interacting mechanismsthat regulate gene
expression have recentlybeen discovered. Controls of gene
expressionby postsynthetic (epigenetic) modifications of
chromatin in higher organisms, methylationsof DNA, and
acetylations and methylationsof histones are basic to cell
differentiation.Small RNAs bind to complimentary se-quences in
mRNAs and inhibit their tran-scription into proteins.
Dr. Jacob shifted to performing medicallyrelated research with
higher organisms. Hewrote several books on moral and philosoph-ical
subjects (11, 12). Of major interest is hisbeautifully written and
thoughtful autobiog-raphy (13).
1 Jacob F, Wollman E (1961) Sexuality and the Genetics of
Bacteria
(Academic Press, New York).
2 Pardee AB, Jacob F, Monod J (1959) The genetic control
and cytoplasmic expression of inducibility in the
synthesis of -galactosidase by E. coli. J Mol Biol 1:
165178.
3 Gilbert W, Mller-Hill B (1966) Isolation of the lac repressor.
Proc
Natl Acad Sci USA 56(6):18911898.
4 Ullmann A (2003) Origins of Molecular Biology, A Tribute
to Jacques Monod (ASM Press, Washington, DC),
2nd Ed.
5 Beckwith J (2002) Making Genes, Making Waves. A Social
Activist
in Science (Harvard Univ. Press, Cambridge, MA).
6 Monod J, Changeux JP, Jacob F (1963) Allosteric proteins
and
cellular control systems. J Mol Biol 6:306329.
7 Gerhart JC, Pardee AB (1962) The enzymology of control by
feedback inhibition. J Biol Chem 237:891896.
8 Riley M, Pardee AB, Jacob F, Monod J (1960) On the expression
of
a structural gene. J Mol Biol 2:216225.
9 Jacob F, Monod J (1961) Genetic regulatory mechanisms in
the
synthesis of proteins. J Mol Biol 3:318356.
10 Yaniv M (2011) The 50th anniversary of the publication of
the
operon theory in the Journal of Molecular Biology: Past, present
and
future. J Mol Biol 409(1):16.
11 Jacob F (1973) The Logic of Life. A History of Heredity
(Pantheon
Books, New York).
12 Jacob F (1982) The Possible and the Actual (Univ.
Washington
Press, Seattle, WA).
13 Jacob F (1988) The Statue Within. An Autobiography
(Basic Books, New York).
10054 | www.pnas.org/cgi/doi/10.1073/pnas.1309173110 Pardee
http://www.pnas.org/cgi/doi/10.1073/pnas.1309173110http://www.pnas.org/cgi/doi/10.1073/pnas.1309173110
