Jacob, FranÇois (1920- )

French molecular biologist

FranÇois Jacob made several major contributions to the field of genetics through successful collaborations with other scientists at the famous Pasteur Institute in France. His most noted work involved the formulation of the Jacob-Monod operon model, which helps explain how genes are regulated. Jacob also studied messenger ribonucleic acid (mRNA), which serves as an intermediary between the deoxyribonucleic acid (DNA ), which carries the genetic code , and the ribosomes , where proteins are synthesized. He also demonstrated that bacteria follow the same general rules of natural selection and evolution as higher organisms. In recognition of their work in genetic control and viruses , Jacob and two other scientists at the Pasteur Institute, Jacques Lucien Monod and André Lwoff, shared the 1965 Nobel Prize for Physiology or Medicine.

Jacob was born in Nancy, France, to Simon Jacob, a merchant, and the former Thérèse Franck. Jacob attended school at the Lycée Carnot in Paris before beginning his college education. He began his studies toward a medical degree at the University of Paris (Sorbonne), but was forced to cut his education short when the German Army invaded France during World War II in 1940. He escaped on one of the last boats to England and joined the Free French forces in London, serving as an officer and fighting with the Allies in northern Africa. During the war, Jacob was seriously wounded. His injuries impaired his hands and put an abrupt end to his hopes of becoming a surgeon. For his service to his country, he received the Croix de Guerre and the Companion of the Liberation, two of France's highest military honors.

Despite this physical setback, Jacob continued his education at the University of Paris. In his autobiography, The Statue Within, Jacob said he got the idea for his thesis from his place of work, the National Penicillin Center, where a minor antibiotic called tyrothricin was manufactured and commercialized. For his thesis, Jacob manufactured and evaluated the drug. Nearing thirty years old, he earned his M.D. degree in 1947, the same year he married Lysiane "Lise" Bloch, a pianist. They would eventually have four children.

With his professional future unsure, Jacob continued to work for a while at the National Penicillin Center. The tide turned when he and his wife had dinner with her cousins, including Herbert Marcovich, a biologist working in a genetics lab. Jacob recalled, "As Herbert spoke, I felt an excitement rising like a storm. If a man of my generation could still go into research without making himself ridiculous, then why not I?" He decided to become a biologist the next day.

Jacob joined the Pasteur Institute in 1950 as an assistant to André Lwoff. Lwoff's laboratory location and its cramped quarters earned it the name of "the attic." The year 1950 was an exciting one in Lwoff's lab. Lwoff had been working with lysogenic bacteria, which are destroyed (lysed) when attacked by bacteria-infecting virus particles called bacteriophages. The bacteriophages invade the bacterial cell, then multiply within it, eventually bursting the cell and releasing new bacteriophages. According to Lwoff's research, the bacteriophage first exists in the bacterial cell in a non-infectious phase called the prophage. He could stimulate the prophage to begin producing infective virus by adding ultraviolet light. These new findings helped to give Jacob the background he would need for his future research.

Jacob continued his education at the University of Paris during his first years at the Pasteur Institute, earning his bachelor of science in 1951 and studying toward his doctor of science degree, which he received in 1954. For his doctoral dissertation, Jacob reviewed the ability of certain radiations or chemical compounds to inducethe prophage, and proposed possible mechanisms of immunity .

Once on staff in the lab, Jacob soon formed what would become a fruitful collaboration with Élie Wollman, also stationed in Lwoff's laboratory. In the summer of 1954 he and Wollman discovered what they termed erotic induction in the bacteria Escherichia coli. They later changed the name of the phenomenon to zygotic induction. In zygotic induction, the chromosome of a male bacterial cell carrying a prophage could be transferred to a female cell which was not carrying the prophage, but not vice versa. Zygotic induction showed that both the expression of the prophage and immunity was blocked in the latter instance by a variable present in the cytoplasm that surrounds the cell's nucleus .

In another experiment, he and Wollman mated male and female bacterial cells, separating them before they could complete conjugation . This also clipped the chromosome as it was moving from the male to the female. They found that the female accepted the chromosome bit by bit, in a certain order and at a constant speed, rather similar to sucking up a piece of spaghetti. Their study became known as the "spaghetti experiment," much to Wollman's annoyance.

In the book Phage and the Origins of Molecular Biology, Wollman explained that by following different genetic markers in the male, they could determine each gene's time of entry into the zygote and correctly infer its position on the DNA. Jacob and Wollman also used an electron microscope to photograph the conjugating bacteria and time the transmission of the genes. "With Élie Wollman, we had developed a tool that made possible genetic analysis of any function, any "system," Jacob said in his autobiography. The two scientists also discovered and defined episomes , genetic strains which automatically replicate as part of the development of chromosomes .

Jacob and Wollman also demonstrated that bacteria could mutate and adapt in response to drugs or bacteriophages. Evolution and natural selection worked in bacteria as well as in higher life forms. Jacob and Wollman summarized their research in the July, 1956, issue of Scientific American: "There is little doubt that the basic features of genetic recombination must be similar whether they occur in bacteria or in man. It would be rather surprising if the study of sexual reproduction in bacteria did not lead to deeper understanding of the process of genetic recombination, which is so vital to the survival and evolution of higher organisms."

In 1956 Jacob accepted the title of laboratory director at the Pasteur Institute. Within two years Jacob began to work with Jacques Monod, who had left Lwoff's lab several years earlier to direct the department of cellular biochemistry at the Pasteur Institute. Arthur Pardée also often joined in the research. Jacob and Monod studied how an intestinal enzyme called galactosidase is activated to digest lactose, or milk sugar. Galactosidase is an inducible enzyme, that is, it is not formed unless a certain substrate—in this case lactose—is present. Inducible enzymes differ from constitutive enzymes which are continuously produced, whether or not the inducer is present. By pairing a normal inducible male bacteria with a constitutive female, they showed that inducible enzyme processes take precedence over constitutive enzyme synthesis. In the experiments conducted by Jacob and Monod, the inducer, lactose, served to inhibit the gene that was regulating the synthesis of galactosidase.

Afterward, Jacob realized that his work with Monod and his earlier work with Wollman on zygotic induction were related. In The Statue Within, he said, "In both cases, a gene governs the formation of a cytoplasmic product, of a repressor blocking the expression of other genes and so preventing either the synthesis of the galactosidase or the multiplication of the virus." Their chore then was to determine the location of the repressor, which appeared to be on the DNA.

By the end of the decade, Jacob and Monod had discovered messenger RNA , one of the three types of ribonucleic acid. (The other two are ribosomal RNA and transfer RNA.) Each type of RNA has a specific function. MRNA is the mediator between the DNA and ribosomes, passing along information about the correct sequence of amino acids needed to make up proteins. While their work continued, Jacob accepted a position as head of the Department of Cell Genetics at the Pasteur Institute.

In 1961, they explained the results of their research involving the mRNA and the now-famous Jacob-Monod operon model in the paper, "Genetic Regulatory Mechanisms in the Synthesis of Proteins," which appeared in the Journal of Molecular Biology Molecular biologist Gunther S. Stent in Science described the paper "one of the monuments in the literature of molecular biology."

According to the Jacob-Monod operon model, a set of structural genes on the DNA carry the code that the messenger RNA delivers to the ribosomes, which make proteins. Each set of structural genes has its own operator gene lying next to it. This operator gene is the switch that turns on or turns off its set of structural genes, and thus oversees the synthesis of their proteins. Jacob and Monod called each grouping of an operator and its structural genes an operon. Besides the operator gene, a regulator gene is located on the same chromosome as the structural genes. In an inducible system, like the lactose operon (or lac operon as it is called), this regulator gene codes for a repressor protein. The repressor protein does one of two things. When no lactose is present, the repressor protein attaches to the operator and inactivates it, in turn, halting structural gene activity and protein synthesis . When lactose is present, however, the repressor protein binds to the regulator gene instead of the operator. By doing so, it frees up the operator and permits protein synthesis to occur. With a system such as this, a cell can adapt to changing environmental conditions, and produce the proteins it needs when it needs them.

A year after publication of this paper, Jacob won the Charles Leopold Mayer Prize of the French Academy of Sciences. In 1964, Collège de France also recognized his accomplishments by establishing a special chair in his honor. His greatest honor, however, came in 1965 when he, Lwoff, and Monod shared the Nobel Prize for Physiology or Medicine. The award recognized their contributions "to our knowledge of the fundamental processes in living matter which form the bases for such phenomena as adaptation, reproduction and evolution."

During his career, Jacob wrote numerous scientific publications, including the books The Logic of Life: A History of Hereditary and The Possible and the Actual. The latter, published in 1982, delves into the theory of evolution and the line that he believes must be drawn between the use of evolution as a scientific theory and as a myth.

See also Bacteriophage and bacteriophage typing; Evolution and evolutionary mechanisms; Evolutionary origin of bacteria and viruses; Genetic regulation of eukaryotic cells; Genetic regulation of prokaryotic cells; Immunogenetics; Molecular biology and molecular genetics; Molecular biology, central dogma of; Viral genetics

JACOB, FRANÇOIS

JACOB, FRANÇOIS (1920– ), French molecular biologist and Nobel laureate. Jacob was born in Nancy, attended the Lycée Carnot, and started his medical studies in Paris. With the German invasion of France in 1940 he joined the Free French Forces in exile and fought in North Africa and Normandy. He was seriously wounded and the damage to his hands destroyed his ambition to become a surgeon. He received the Croix de Guerre and the Croix de la Libération and was made a Compagnon de la Libération, one of France's highest honors. After the war he completed his medical studies (1947) and gained his D.Sc. from the Sorbonne (1954). In 1950 he joined the Pasteur Institute as assistant to Andre *Lwoff. He was appointed laboratory director (1956), head of the Department of Cell Genetics (1960), and professor of cell genetics at the College de France (1964). Jacob's research explored the relationship between bacteriophages (phage) and the bacteria these infect as a model for establishing the fundamental principles of genetic control of protein synthesis. He collaborated with many of the founding fathers of molecular biology, including Elie Wollman, Max Delbruck, Jacques Monod, and Sydney *Brenner. This work defined the operon as the control unit consisting of one or more genes encoding the messenger rna, which dictates protein synthesis. The operon is controlled by regulatory feedback loops incorporating repressor genes which are in turn controlled by operator genes. The operon can collaborate with other operons on the chromosome and is influenced by signals coming from the cytoplasm or the environment. Thus the potential for cell function and division is determined by the nucleotide sequence in dna which is responsive to a network of controlling signals. This framework and the supporting experimental principles have formed the basis for subsequent scientific work on gene action and regulation. He received the Nobel Prize in physiology or medicine (1965) jointly with Andre Lwoff and Jacques Monod. His many honors include the Charles Leopold Mayer Prize of the Académie des Sciences (1962) and foreign membership of the U.S. Academy of Sciences. Jacob is also a distinguished writer on the philosophy and culture of science whose highly regarded books include The Logic of Life (1970) and Of Flies, Mice and Men (1980). His cultural contributions were recognized by the award of the Lewis Thomas Prize (1994). He married the pianist Lise Bloch in 1947.

[Michael Denman (2^nd ed.)]