RETROSPECTIVE RETROSPECTIVE 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 DNA would integrate into the bacterial chro- 20th century’smostdistinguishedlifescien- mosome and remain dormant or, at other tists. His research with Dr. Jacques Monod, times, would kill the cell. like that of Watson and Crick, provided the Jacob’s next major contribution, in collab- foundations for understanding mechanisms oration with Dr. Jacques Monod, was to in- of genetic regulation of life processes such vestigate how a gene is regulated. Remark- as cell differentiation and defects in diseases. ably, native E. coli synthesize β-galactosidase Jacob joined the College de France in 1964 only when lactose is available. Some mutated and shared the Nobel Prize in Physiology bacteria can make the enzyme in the absence or Medicine 1965 with Jacques Monod of inducer. Monod’s initial idea was that and Andre Lwoff. He was elected to the these constitutive bacteria activate the gene National Academy of Sciences (NAS) USA by synthesizing an intracellular lactose-like in 1969. inducer molecule. Jacob was born in 1920 in a French Jewish To investigate this model, interrupted family; his grandfather was a four-star gen- mating was applied to bring the β-galactosi- eral. He began to study medicine before dase gene of a donor bacterium into a consti- World War II, in which he served as a mil- tutive receptor. According to the induction itary officer in the Free French Army and was model, the mated cell should produce en- badly wounded in an air raid. He received zyme constitutively, without added inducer. numerous high military honors. Then he These experiments are the first in which gene commenced research in the laboratory of transfer was directly determined by timing Andre Lwoff, earned an MD, started a life of production of its product (β-galactosidase) research at the Pasteur Institute, Paris, in rather than by much later counting the num- Francois Jacob, 1985. 1950, and received his Doctorate in Science ber of colonies produced on lactose as the in 1954. He had two marriages and four source of energy. named allostery (other site) (6). This allosteric children. He died at age 92. The currently accepted mechanism of en- model is similar to that suggested by the work ’ Dr. Jacob sinitialmajorcontributionwas zyme repression for control of gene expres- of Gerhart and Pardee demonstrating that an to determine positions of genes on DNA. His sion was produced from the PaJaMo (Pardee, enzyme’s regulatory sites, involved in feed- Escherichia coli model was . As discovered by Jacob, Monod) mating experiments (2). In back inhibition of biochemical activity, are William Hayes, DNA of a donor strain was the absence of inducer, the constitutive (lac distinct from catalytic sites (7). fi − β ef ciently transferred into a recipient strain. Z ) bacteria produced -galactosidase a few Further experiments by Monica Riley + Jacob and his talented collaborator Elie minutes following transfer of lac Z DNA, showed that decay of 32Pincorporatedin Wollman developed the technique of using and continued for about 2 hours. However, DNA of the lac Z gene decreased β-galacto- a Waring blender to interrupt this mating then an inducer was necessary; a repressive sidase formation, showing that DNA integrity transfer at any time following mixing. They action was seen after a few hours. It was is essential for enzyme synthesis to continue; showed that different genes were transferred concluded that a regulatory gene R intro- a stable intermediate cannot be involved at different times. For example, the gene duced into the mated bacterium gradually (8). This research provided one beginning β for -galactosidase was transferred 20 min- produces enough protein repressor to shut for the concept of mRNA as a short-lived β utes after mating started. This enzyme off the structural Z gene. The -galactosidase intermediate between DNA and protein. cleaves the sugar lactose, making it avail- repressor protein was subsequently isolated Removal of repressor protein from its able for bacterial colony formation. This (3). β-galactoside–related compounds block DNA causes several genes involved in lactose fi method created the rst mapping of gene repression by binding to and inactivating utilization to produce several proteins in- positions in a linear sequence and revealed the repressor protein. Monod named this a cluding β-galactosidase and lactose perme- the circular nature of the bacterial chromo- “double bluff” mechanism. Both Jacob and ase, which transport lactose into bacteria. some (1). Wollman continued in biological Pardee have described these interconnected These results, the PaJaMo experiment, and research and received many honors, in- studies (4). Jon Beckwith provides a fascinat- Jacob’s work on regulation in bacteriophage cluding Foreign Membership in the NAS ing description of this and subsequent re- λ were combined into Jacob and Monod’s in 1991. search (5). These experiments showed that Jacob also studied the mechanisms that binding a small molecule to a repressor protein regulate the virulence of the bacterial virus can modify binding of the protein to DNA, Author contributions: A.B.P. wrote the paper. (bacteriophage) λ. His work had shown that suggesting that the protein has separate func- The author declares no conflict of interest. λ carried genes that regulated whether its tional and regulatory sites. This property was 1E-mail: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1309173110 PNAS Early Edition | 1of2 Downloaded by guest on September 28, 2021 major review of the operon model of gene chromatin in higher organisms, methylations Dr. Jacob shifted to performing medically regulation (9). In 2011, the Pasteur Institute of DNA, and acetylations and methylations related research with higher organisms. He conducted a 50th anniversary symposium, of histones are basic to cell differentiation. wrote several books on moral and philosoph- “The Operon” (10). Small RNAs bind to complimentary se- ical subjects (11, 12). Of major interest is his Jacob’s research continues to have major quences in mRNAs and inhibit their tran- beautifully written and thoughtful autobiog- significance for current developmental genet- scription into proteins. raphy (13). ics. Of the transcribed DNA in higher organ- isms, only about 2% of mRNA makes protein. It is now known that the great majority of 1 Jacob F, Wollman E (1961) Sexuality and the Genetics of Bacteria 7 Gerhart JC, Pardee AB (1962) The enzymology of control by (Academic Press, New York). feedback inhibition. J Biol Chem 237:891–896. DNA contains many sites to which numer- 2 Pardee AB, Jacob F, Monod J (1959) The genetic control 8 Riley M, Pardee AB, Jacob F, Monod J (1960) On the expression of ous regulatory proteins bind. These, for ex- and cytoplasmic expression of “inducibility” in the a structural gene. J Mol Biol 2:216–225. ample, are involved in the extremely complex synthesis of β-galactosidase by E. coli. JMolBiol1: 9 Jacob F, Monod J (1961) Genetic regulatory mechanisms in the 165–178. synthesis of proteins. J Mol Biol 3:318–356. differentiation of stem cells into somatic cells, 3 Gilbert W, Müller-Hill B (1966) Isolation of the lac repressor. Proc 10 Yaniv M (2011) The 50th anniversary of the publication of the and in diseases such as cancer, which are Natl Acad Sci USA 56(6):1891–1898. operon theory in the Journal of Molecular Biology: Past, present and 4 Ullmann A (2003) Origins of Molecular Biology, A Tribute future. J Mol Biol 409(1):1–6. based on defective regulation. to Jacques Monod (ASM Press, Washington, DC), 11 Jacob F (1973) The Logic of Life. A History of Heredity (Pantheon Additional and interacting mechanisms 2nd Ed. Books, New York). that regulate gene expression have recently 5 Beckwith J (2002) Making Genes, Making Waves. A Social Activist 12 Jacob F (1982) The Possible and the Actual (Univ. Washington in Science (Harvard Univ. Press, Cambridge, MA). Press, Seattle, WA). been discovered. Controls of gene expression 6 Monod J, Changeux JP, Jacob F (1963) Allosteric proteins and 13 Jacob F (1988) The Statue Within. An Autobiography by postsynthetic (epigenetic) modifications of cellular control systems. J Mol Biol 6:306–329. (Basic Books, New York). 2of2 | www.pnas.org/cgi/doi/10.1073/pnas.1309173110 Pardee Downloaded by guest on September 28, 2021.