OBITUARY-In Memoriam- Celebrating the life and works of François Jacob - Blog

FROM A FIGHT FOR FREEDOM, THROUGH THE SEARCH FOR REGULATION PRINCIPLES, TO THE LOGIC OF LIFE.

Recently, when I saw the announcement of the death François Jacob (1920-2013). I felt Sadness, perhaps not only because I admire his many intellectual contributions, but because for years I hoped that I could meet Jacob one day before I had to write an obituary celebrating his life and scientific achievements. François Jacob is known to most biologists due to his contributions about the understanding of protein synthesis, specifically with the model of the operon lactose. Due to the work on the regulation at the genetic and protein level François Jacob’s and his coworkers Jacques Monod and André Lwoff were awarded the Nobel Prize in Physiology and Medicine in 1965.

In his autobiography The Statue Within, Fraçois Jacob takes us trough his childhood, adolescent years at the Lycée Carnot, and then his years as medical student in Paris. After the first two years of medical training the Second World War interrupted his medical studies. Once the war began and Hitler’s invasion of France seemed imminent, and following the family tradition the young medical student Jacob decided to enlist in the army. Jacob’s grandfather, who was an influential figure in his life, was a four star general. Jacob traveled to England, and then, under General de Gaulle’s, command joined what later became The Free French, a resistance force that fought against the Germans, which by then had occupied France. Jacob was taken to Dakar, and then went through Chad and Cameroon and Tunisia in North Africa. Despite he had not finished his medical studies and only had two years of medical training, he became “the doctor” of a region the size of halve of France I North Africa. Jacob spent four years as a physician working for the army and the local communities, and also participated fighting a few battles against Italians and Germans. During the war he was severely injured and returned to France, now under General de Gaulle’s rule.

After Hitler’s defeat and four years of fight, despite serving as physician in the Army, François Jacob decided to abandon his carrier in medicine. He felt that the war years and the war injuries had eroded his medical competence and sharpness. Jacob then tried a variety of professions working as a journalist, actor, also attempting to work for the industry in antibiotic production. After realizing that he could not practice medicine, and that his several otter attempts did not seemed to suit him either, François decided to try to pursue a scientific research. He visited several times Adree Lwoff and asked for a position in his lab at the Pasteur Institute. Despite Jacob was repeatedly rejected until one lucky day, when Andree Lwoff had just discovered “prophage induction”, Lwoff decided to offer Jacob a research position. Lwoff wanted him to study how the bacterial viruses inserted into bacteria and remained silent, later becoming active (prophage induction) and suddenly lysing cells after emerging from an apparently latent state. Lwoff’s and Monod’s labs, which were located in an attic at the Pasteur Institute, were two of the few laboratories in France that were at the forefront of the nascent molecular biology. These labs had constant exchange with American and English labs that were also trying solve the basic puzzles of the time. The key problems were to understand the relationship between genes and proteins, how protein synthesis occurred, and structure of the genetic code.

Jacob had a late scientific start and was already in his thirties when he joined Lwoff’s lab, and have had no real scientific training in biology. For example, when Lwoff agreed and offered him to work on “prophage induction”, Jacob immediately ran to the library to find in a dictionary what a bacteriophage was. In his autobiography Jacob wrote: “Late, very late, I discovered the true nature of science, how it proceeds, of the men who do it. (…) I found in science a mode of playfulness and imagination, of obsessions and fixed ideas” […](The Statue Within, p. 8). What mattered more than the answers were the questions and how they were formulated. […]. I lived in the future. I always waited for the result of tomorrow. I had turned my anxiety into my profession”.

Despite Jacob’s late scientific start and his initial feelings of incompetence and lack of preparedness, he quickly became proficient in bacterial genetics and learned the latest developments in the Lambda Phage, the bacterial virus whose “induction” was studied by Lwoff’s group. Jacob progressively gained confidence and constantly discussed his results with Jacques Monod. The later was studying how bacteria “induced” the beta-galactosidase, an enzyme required for sugar metabolism. Despite initially “induction” of the sugar enzymes, and “induction” prophage virus did not really have a common meaning, Jacob eventually realized that behind a common word hid a common mechanism that gave rise to two apparently distinct and unrelated phenomena. Jacob made a close parallel between the two realms, and even made predictions in one domain using the knowledge gained in the other. As result, Jacob became the link between Lwoff and Monod’s labs. A close and intellectually intense collaboration with Monod started, which eventually gave rise to the research that resulted in the research contribution recognized with the Nobel.

Jacob and Monod were the first to propose a general model that explained how genes are used and regulated during protein synthesis. Their operon lactose model, explained how bacteria induce and regulate the synthesis of enzymes required for sugar metabolism. The model proposed the existence of “Operons”, groups of genes of a given common biochemical pathway that are in close physical proximity in the DNA, and which are co-regulated through common regulatory DNA element (for which they coined the term “Operator”). Jacob and Monod suggested that such regulatory elements operators had a chemical affinity for diffusible substances called “Regulators” that bound an operator site in the chromosome, dictating in a switch-like manner (ON-OFF) the induction or repression of “transcripts” later used by ribosomes to make proteins. Jacob and Monod postulated that such regulators, whose genes were located far from those contained in the operon, could act as “repressors” for the induction of enzymes or structural proteins contained within the operon genes. Repressors were regulatory molecules that would physically and specifically bind a regulatory fragment of DNA and determine the rate of protein production.

Jacob also postulated that the bacterial chromosome was circular, and later anticipated and predicted the existence of an unstable intermediate between the gene and the protein, for which Monod and Jacob coined the term “messenger” RNA because such transcripts would carry “the message” from the gene to the protein. Studying the kinetics of beta-galactosidase enzyme induction Monod and Jacob were able to show that such intermediate between the gene and the protein had to be unstable. Later, together with Sydney Brenner and Mathew Messelson, Jacob experimentally demonstrated the existence of such unstable intermediate using radioactive labeling of Uracil bases in RNA and centrifugation gradients to separate the labeled from unlabeled molecules. Later, together with Monod, Jacob also changed a key notion that acted as an epistemological obstacle to comprehend protein synthesis. Until they published a review on the regulation of protein synthesis, it was accepted that such synthesis occurred in ribosomes, and that somehow the ribosome was the entity that provided the specificity to make different proteins (i.e. it was belied that for each protein type there was a given ribosome). Instead, Jacob and Monod suggested that ribosomes merely acted as interchangeable and reusable parts in the cell, and that the specificity required to make different protein types came from the message (mRNA) instead, such that ribosomes were merely “reading heads” for the unstable information carrying mRNA a “tapes” sent by gene to make a protein. Such concept suggested that the ribosomal RNA (rRNA) had a structural rather than the specificity-providing role, which was derived instead from the messenger RNA (mRNA).

Despite sometimes it has been said that Monod was the great theoretician and Jacob the fantastic experimentalist, Jacob’s autobiography testifies that this was far from accurate. Many times it was Jacob who anticipated the mechanism, proposed it and convinced Monod to eventually accept his ideas. For example, the notion of operons and operators initially occurred to Jacob. Equally central to the Operon Lactose model was Jacob’s idea of an operator and a repressor protein that regulated protein synthesis at the gene level, through physically binding the a specific spot (the operator) in the DNA molecule itself.

The concept of regulation of protein synthesis at the DNA level was completely foreign to biologists trained in the classic genetics. Monod had trained in fly genetics in Thomas H. Morgan’s laboratory at Caltech (Morgan was the founder of fly genetics, and was also awarded a Nobel Prize) and later in Paris, under Boris Ephrussi’s supervision. In retrospect Monod said that the idea of regulation at the DNA level, through physical interaction with the DNA, was very difficult to initially accept: “the gene was something in the minds of people- specially in my generation- which was inaccessible, by definition, as the material of the galaxies. That experiments we were doing would involve an actual physical interaction between a compound in the cell and actually the gene itself, was something extremely difficult to accept” (The eight day of creation, p 416). For his time Jacob thus was revolutionary when he conceived regulation happening at the DNA level. Because Jacob lacked the genetics training that Monod and others had, he did not have the epistemological obstacle (assuming that genes were ideal “sacrosanct objects that could not actually be manipulated without attacking life itself” – The Statue Within, p. 302) that prevented others from conceiving the possibility of regulation at the DNA level itself. The lesson here is that at least lack of training and naïveté can prevent the epistemological obstacles existing in a field from blocking discoveries. Jacob’s finally succeeded in convincing Monod and together they found experimental evidence to support the idea of the repressor acting at the DNA level at a binding site (which they called the “operator”). These notions of operons, and regulation at the gene level through repressors were experimentally supported and became central to model of the operon-lactose model, which would make Monod, Jacob and Lwoff win the Nobel prize later in 1965.

Besides the Nobel Prize, Jacob was also elected a member of the French Academy in 1996. He also received the Lewis Thomas Prize for Writing about Science (1996) for other great intellectual contributions. Among them are two books, one dedicated to the history of biology (The Logic of Life), and a second on evolution (The Possible and the Actual). In the Logic of Life, using the epistemological approach to history developed by Georges Canguilhem school in France, Jacob wrote a history of Biology that takes us from the late XVI century to the second halve of the XX, when the book was published. In contrast to most histories of biology written by biologists, which most frequently lack an epistemological rigor, Jacob wrote what according to the famous philosopher and historian Michel Foucault is “the most remarkable history of biology that has ever been written”. In this fabulous book, Jacob shows the tumbles, and the intricate paths that the Western thought has followed when thinking about physiology, classification, as well as how the multilevel architecture of the living organization, from the morphology to the molecule and molecule, has been progressively anatomically dissected. At the same time Jacob writes a history of developmental and evolutionary biology, showing how these fields revolutionized and shaped the modern biological thought. The Logic of Life is a must read for any serious Biology student or professional in the life sciences.

In his second book, The Possible and the Actual, as well as in a provocative small theoretical paper (Evolution as Tinkering), Jacob wrote about the evolution of biological form. He proposed that evolution occurs through “bricoleur” (tinkering). The notion of evolution as tinkering came from his contact with the work of the ethnologist C. Levi-Strauss. In The Savage Mind, Levi-Strauss compared the engineer with the savage. According to Jacob, unlike the engineer, evolution works more like the savage, creating through tinkering: instead of inventing and pre-designing the new parts through rational design and generation of material specific for the new task, evolution, like the savage, reuses what is at hand (preexisting parts) to make new compositions. Instead of creating new parts from scratch every time, evolution reuses a finite given stock of available structures and materials that were not perfected for the new task, reorganizing and adapting them to new needs (i.e. makes a wing out of an arm, one gene out of two others, etc).¬

Later in his career Jacob also made contributions to developmental biology. He switched to study differentiation and cancer in mammalian systems. His contributions were not only empirical but also theoretical. In the Logic of Life, Jacob had already suggested yet another metaphor that has been cardinal for the modern biological thought: following Watson and Crick’s interpretation of the DNA sequence as the source (emitter) of information, Jacob suggested to interpret development as the execution of a “Genetic Program” for ontogenesis. Jacob’s “genetic developmental program”, which resided in the DNA and instructed the organism how to develop from a fertilized egg to an adult, became a key founding conceptual tool for developmental genetics, and in the minds of many still continues to be the preferred metaphor to interpret development and developmental pathologies.

Overall, Fraçois Jacob life went from a fight for freedom, through the search for regulation principles of metabolism and development, to the history and epistemology of biology. Jacob was not only a prolific and successful experimentalist, but also an important contributor to key theoretical aspects of modern biology. Jacob was also an accomplished thinker and historian.

— Nicolas Pelaez

Follow up:
Interviews about his life and works:
http://www.webofstories.com/play/francois.jacob/1