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Francois Jacob memorial

Arthur B. Pardee1 Department of Adult Oncology, Dana-Farber Institute, Boston, MA 02115

Dr. Francois Jacob is one of a handful of the 20th centurys most distinguished life scientists. His research with Dr. Jacques Monod, like that of Watson and Crick, provided the foundations for understanding mechanisms of genetic regulation of life processes such as cell differentiation and defects in diseases. Jacob joined the College de France in 1964 and shared the Nobel Prize in Physiology or Medicine 1965 with Jacques Monod and Andre Lwoff. He was elected to the National Academy of Sciences (NAS) USA in 1969. Jacob was born in 1920 in a French Jewish family; his grandfather was a four-star general. He began to study medicine before World War II, in which he served as a military ofcer in the Free French Army and was badly wounded in an air raid. He received numerous high military honors. Then he commenced research in the laboratory of Andre Lwoff, earned an MD, started a life of research at the Pasteur Institute, Paris, in 1950, and received his Doctorate in Science in 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. His model was Escherichia coli. As discovered by William Hayes, DNA of a donor strain was efciently transferred into a recipient strain. Jacob and his talented collaborator Elie Wollman developed the technique of using a Waring blender to interrupt this mating transfer at any time following mixing. They showed that different genes were transferred at different times. For example, the gene for -galactosidase was transferred 20 minutes after mating started. This enzyme cleaves the sugar lactose, making it available for bacterial colony formation. This method created the rst mapping of gene positions in a linear sequence and revealed the circular nature of the bacterial chromosome (1). Wollman continued in biological research and received many honors, including Foreign Membership in the NAS in 1991. Jacob also studied the mechanisms that regulate the virulence of the bacterial virus (bacteriophage) . His work had shown that carried genes that regulated whether its
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DNA would integrate into the bacterial chromosome and remain dormant or, at other times, would kill the cell. Jacobs next major contribution, in collaboration with Dr. Jacques Monod, was to investigate how a gene is regulated. Remarkably, native E. coli synthesize -galactosidase only when lactose is available. Some mutated bacteria can make the enzyme in the absence of inducer. Monods initial idea was that these constitutive bacteria activate the gene by synthesizing an intracellular lactose-like inducer molecule. To investigate this model, interrupted mating was applied to bring the -galactosidase gene of a donor bacterium into a constitutive receptor. According to the induction model, the mated cell should produce enzyme constitutively, without added inducer. These experiments are the rst in which gene transfer was directly determined by timing production of its product (-galactosidase) rather than by much later counting the number of colonies produced on lactose as the source of energy. The currently accepted mechanism of enzyme repression for control of gene expression was produced from the PaJaMo (Pardee, Jacob, Monod) mating experiments (2). In the absence of inducer, the constitutive (lac Z) bacteria produced -galactosidase a few minutes following transfer of lac Z+ DNA, and continued for about 2 hours. However, then an inducer was necessary; a repressive action was seen after a few hours. It was concluded that a regulatory gene R introduced into the mated bacterium gradually produces enough protein repressor to shut off the structural Z gene. The -galactosidase repressor protein was subsequently isolated (3). -galactosiderelated compounds block repression by binding to and inactivating the repressor protein. Monod named this a double bluff mechanism. Both Jacob and Pardee have described these interconnected studies (4). Jon Beckwith provides a fascinating description of this and subsequent research (5). These experiments showed that binding a small molecule to a repressor protein can modify binding of the protein to DNA, suggesting that the protein has separate functional and regulatory sites. This property was

Francois Jacob, 1985.

named allostery (other site) (6). This allosteric model is similar to that suggested by the work of Gerhart and Pardee demonstrating that an enzymes regulatory sites, involved in feedback inhibition of biochemical activity, are distinct from catalytic sites (7). Further experiments by Monica Riley showed that decay of 32P incorporated in DNA of the lac Z gene decreased -galactosidase formation, showing that DNA integrity is essential for enzyme synthesis to continue; a stable intermediate cannot be involved (8). This research provided one beginning for 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 lactose utilization to produce several proteins including -galactosidase and lactose permease, which transport lactose into bacteria. These results, the PaJaMo experiment, and Jacobs work on regulation in bacteriophage were combined into Jacob and Monods
Author contributions: A.B.P. wrote the paper. The author declares no conict of interest.
1

E-mail: arthur_pardee@dfci.harvard.edu.

PNAS | June 18, 2013 | vol. 110 | no. 25 | 1005310054

RETROSPECTIVE

major review of the operon model of gene regulation (9). In 2011, the Pasteur Institute conducted a 50th anniversary symposium, The Operon (10). Jacobs research continues to have major signicance for current developmental genetics. Of the transcribed DNA in higher organisms, only about 2% of mRNA makes protein. It is now known that the great majority of DNA contains many sites to which numerous regulatory proteins bind. These, for example, are involved in the extremely complex differentiation of stem cells into somatic cells, and in diseases such as cancer, which are based on defective regulation. Additional and interacting mechanisms that regulate gene expression have recently been discovered. Controls of gene expression by postsynthetic (epigenetic) modications of

chromatin in higher organisms, methylations of DNA, and acetylations and methylations of histones are basic to cell differentiation. Small RNAs bind to complimentary sequences in mRNAs and inhibit their transcription into proteins.

Dr. Jacob shifted to performing medically related research with higher organisms. He wrote several books on moral and philosophical subjects (11, 12). Of major interest is his beautifully written and thoughtful autobiography (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: 165 178. 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).

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Pardee