August 2013

François Jacob, 1920 – 2013

François Jacob
Image courtesy of Institut Pasteur

The death of François Jacob at age 92 on April 19 should serve as a reminder in this age of virtually instant whole-genome sequencing and 20-plus-person publications that the present-day understanding of gene and cellular regulation rests on the earlier deep thinking and superb critical experimental skill vested in single individuals. Jacob, of course, was spectacularly endowed with both these capabilities. His partnership with Jacques Monod (1) uncovered how inducible genes are controlled in bacteria through synthesis of an unstable intermediate between genes and protein synthesis. This then led to Jacob’s discovery of messenger RNA with Sydney Brenner and Matt Meselson (2).
 
Jacob’s childhood, adolescence and World War II experiences have been preserved for us through the use of a third remarkable trait. He was to me and to legions of others perhaps the finest writer to come out of 20th-century science. “The Statue Within,” first published in French in 1987, has been celebrated by nonscientists and scientists not only as an invaluable autobiography recounting momentous science but also as great art. One is left with the conviction that Jacob easily could have been a highly successful writer.
 
He tells of the very important influence of his grandparents, at whose house he spent his summers as a child. The grandfather, a four-star French general (perhaps the only Jew to achieve such a high rank), furnished the young boy with books and apparently welcome instruction about the classical and European historical worlds. In a few engaging pages, Jacob portrays an adoring mother and somewhat stern father for whom he went through a bar mitzvah and immediately thereafter, at least to himself, disavowed religion.
 
At 18 (and, one gathers, more or less by default) Jacob began medical studies, but Hitler’s invasion of Poland in 1939 and quick conquest of France drove Jacob out of medicine at the end of his second year and into the Free French Forces assembled by Charles de Gaulle in England. As a member of the medical corps, Jacob fought both in North Africa and, after D-Day, in Europe, where he was wounded seriously, ending his plans to become a surgeon. France may have lost a potentially gifted surgeon, but the world gained one of its premier scientists.
 
Deciding that a research career appealed to him after the war, Jacob worked for a brief period on tyrothricin to finish off a thesis for his M.D. Tyrothricin is an antibiotic discovered by René Dubos at the Rockefeller Institute (now The Rockefeller University) that is too toxic for use except topically. Jacob finally had the courage to ask for admittance as a fellow at the Pasteur Institute. He was accepted and in 1949 took the comprehensive introductory course required of all fellows. Because he had become interested in genetics, he approached André Lwoff to serve as his mentor but was rebuffed initially. On his second or third try, he was finally accepted by Lwoff to begin a research career in 1950. Lwoff and two postdoctoral visitors, Lou Siminovitch and Niels Kjeldgaard, just had discovered UV induction of prophage in lysogenic bacteria (3), and Lwoff offered this as a project on which Jacob, now 30 years old, should begin. Jacob divulges in “The Statue Within” that he did not know what “prophage” meant, a fact he kept to himself. He learned his trade quickly and with great delight, working with the lysogenic bacteriophages in Pseudomonas pyocyanea. After a brief and successful training period, he formed a close friendship with Élie Wollman. The two began an imaginative use of bacterial conjugation and chromosome transfer in E. coli. An early surprising result was the discovery of zygotic induction of prophages. When a lysogenic donor (male) transferred its chromosome into a nonlysogenic recipient (female) cell, phage production and lysis occurred. Later, chromosome transfer was the basis of the famous PaJaMo (4) experiments that were key to proposing the existence of an unstable messenger RNA. The clincher here were experiments using 32P-labeled cells (including, of course, their labeled RNA) that the three designed and began in Paris (5) and that Pardee and his student Monica Riley in Berkeley carried to completion (6). Radioactive decay in the labeled RNA with consequent loss of already induced enzyme (β galactosidase) forming capacity suggested that an unstable RNA had to be renewed constantly. Thus the messenger idea was born. Within a year Jacob, with Sidney Brenner and Matt Meselson, had demonstrated bacteriophage T4 messenger RNA.
 
Jacob described vividly his intense discussions with his partner Jacques Monod both in “The Statue Within” and in a commemorative essay in “Origins of Molecular Biology: A Tribute to Jacques Monod” (7). These descriptions document two great minds at work, revealing Jacob’s ability to translate each logical “physiologic (biochemical)” problem Monod introduced into an experimental genetic answer. These conversations not only produced the messenger proposal but also led to the discovery of all the functional genetic sites and the role of repressor proteins that govern regulation of the genes in operons. This story should instruct all students of biology, young and old, in the use of logic in biological discovery.
 
James Watson’s and Francis Crick’s great deduction of the structure of DNA 60 years ago this spring often and correctly is said to be the watershed moment that first led to all the remarkable progress in modern biology. But Jacob, together with his Pasteur colleague Monod and his original mentor Lwoff, brought life to the molecule containing life’s instructions.

REFERENCES
  1. 1.  Jacob, F. & Monod, J. J. Mol. Biol. 3, 318 (1961).
  2. 2.  Brenner, S. et al. Nature 190, 576 (1961).
  3. 3.  Lwoff, A. et al. Ann. Inst. Pasteur (Paris) 79, 815 (1950).
  4. 4.  Pardee, A.B. et al. J. Mol. Biol. 1, 165 (1959).
  5. 5.  Riley, M. et al. J. Mol. Biol. 2, 216 (1960).
  6. 6.  Riley, M. & Pardee, A.B. J. Mol. Biol. 5, 63 (1962).
  7. 7.  “Origins of molecular biology: A tribute to Jacques Monod.” Edited by Agnes Ullmann (Revised edition, 2003). ASM Press.

James DarnellJames E. Darnell Jr. (darnell@mail.rockefeller.edu) is the Vincent Astor professor emeritus and head of the Laboratory of Molecular Cell Biology at The Rockefeller University. He completed a stint as a postdoc with François Jacob from 1960 to 1961.


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