François Jacob (1920–2013)
2013; Elsevier BV; Volume: 23; Issue: 10 Linguagem: Inglês
10.1016/j.cub.2013.04.059
ISSN1879-0445
Autores Tópico(s)Philosophy, Ethics, and Existentialism
Resumo"Plus que jamais, la recherche me paraissait s'identifier à la nature humaine. En exprimer l'appétit, le désir de vivre. C'était bien le meilleur moyen trouvé par l'homme de braver le chaos de l'univers. De dominer la mort." (More than ever, scientific research seemed to me to be intrinsic to human nature. It expressed the hunger, the desire to live. It has, in fact, been the best means found by humans to endure the chaos of the universe, to triumph over mortality.)François Jacob, La Statue Intérieure (Editions Odile Jacob, Paris: 1987) One of the last giants of the halcyon days of molecular biology is gone. François Jacob who, along with his colleagues at the Institut Pasteur, laid out the fundamental principles of how genes are expressed and regulated, died on April 19th. Not only was he a founder of molecular biology, he was also an inspirational writer and a man engaged with his world: "un homme engagé". His books include one of the most beautifully written memoirs of a scientist in our era, "La Statue Intérieure" (The Statue Within). Much of his extraordinary life is chronicled, often in poetic terms, in this memoir. It begins with the observation: "I see my life less as continuity than as a series of different selves….strangers…" His life can, like this remembrance, be divided into these different strangers — strangers that nevertheless shared a "statue intérieure". As an adolescent, Jacob attended school in early 1930s Paris. There he was involved in brawls, often provoked by the anti-semitic remarks of his fellow students — prefiguring what was to happen in France during World War II. These experiences were understandably difficult for a boy from a Jewish family that had considered itself well-integrated into French society. His grandfather, Albert Franck, had been the first Jew to be named a four-star general after serving in World War I. Jacob witnessed World War II approaching in 1936, the year of his first baccalauréat (high school graduation examination), as Germany entered the Rhineland and the civil war broke out in Spain. Yet, he also spent idyllic summers in Étretat, the coastal Normandy town the landscape of which was the source of inspiration for many of the Impressionist painters. After lycée, he dreamed of becoming a surgeon and began his studies in medicine at the University of Paris. His education was soon interrupted, when in 1940 Germans invaded France. The adolescent quickly became a man as the defense of France collapsed. Jacob was one of the last of the European scientists still alive who were strongly impacted by World War II. In 1940, escaping from one end of Paris as the Germans entered at the other, Francois fled to the southwestern port of St. Jean de Luz. There he boarded a ship for England to join Charles de Gaulle's Free French forces. He was one of the first of the French to join these forces in London after he heard of the June 18 rallying speech by de Gaulle that was broadcast to France by the BBC. In his memoir, he comments that he saw himself as fighting for the freedom of France more as a Frenchman than as a Jew. Despite his abbreviated medical training in Paris and his own desire to enroll in a combat unit as a soldier of the ranks, François Jacob was commissioned as a medical doctor. This did not keep him out of harm's way as he was wounded in battles both in North Africa and later in France itself. In a third incident related in his memoir, he came upon a German machine gunner in North Africa who could have felled the unarmed medic, but for some reason chose not to. As a result of a brave attempt to rescue an officer after landing in Normandy, Jacob was seriously injured and hospitalized for many months. To the end of his life, he carried untold pieces of shrapnel in his leg that not infrequently caused him serious pain. It became difficult for him to sit through long plane rides and even through scientific meetings. Recuperating from his wounds in liberated France, François decided to give up his idea of being a surgeon and began to think of other options for his future. He briefly tried his hand at journalism and acting, and considered training for the civil service or entering politics. While he struggled with his different inspirations, he took a job at the National Penicillin Center seeking new antibiotics. During this period, his readings began to spark an intense interest in biological research; however, he worried that, without much background and at the age of 30, it might be too late for him to embark on a scientific career. A chance meeting with biologist Herbert Marcovich dispelled those concerns and gave him the courage to approach Andre Lwoff at the Institut Pasteur in Paris, who offered him a post, despite his lack of training. Lwoff was well-known for the major advances he had made in the understanding of lysogeny — the property characteristic of those bacteria that harbor a virus (bacteriophage) in a dormant state. Under certain conditions, for example ultraviolet irradiation, the phage would break from its shackles, multiply and lyse the cell releasing a hundred or more active phage. Jacob would start on this exciting project. To improve his background for this new career in research, he had to go back to university for classes. He rapidly picked up the fundamentals of bacteriology. The actual practice of science fueled his inspiration ever more strongly: "I found in science a mode of playfulness and imagination, of obsessions and fixed ideas." Within a few years he had initiated a series of discoveries that was to play a major role in creating the new field of molecular biology. This extraordinarily fruitful period began as Jacob and fellow Pastorien Élie Wollman collaborated on the mechanism of bacterial conjugation. They examined the nature of the mating process between Escherichia coli strains known as high frequency (Hfr) donors and recipient cells. Looking for some way to agitate such mating pairs of bacteria so as to separate them after conjugation had begun — interrupted mating — Jacob and Wollman borrowed François' wife Lise's new Waring Blender. This brute-force technique for breaking up mating pairs revealed to their surprise that specific genetic loci were transferred at characteristic times after mating had been initiated. Thus, mating did not simply generate zygotes with equal contributions from the 'male' (donor) and 'female' (recipient) cell. Instead, the 'male' transferred its chromosome to the 'female' in linear fashion. The interrupted mating apparently broke the chromosomes in mid-transfer between the donor and recipient cells, allowing only the portion of the DNA that had already entered the recipient cells to engage in recombination. The same conclusions were drawn by Bill Hayes in his London laboratory using a different approach. The subsequent finding by Wollman and Jacob that different Hfr donors transferred their markers in different orders and orientations led to the unanticipated conclusion that the chromosome of the bacterium E. coli is circular. The elucidation of the mating properties of E. coli was later to become the foundation for the discovery of the operon model for gene regulation. Jacob and Wollman also collaborated in a study of lysogenic bacteria. They found that bacteria lysogenic for the bacteriophage λ were immune to superinfection by a preparation of phage λ itself. They then used their newfound understanding of bacterial conjugation to examine lysogeny in more depth. When a lysogenic male strain was mated with a non-lysogenic female in an interrupted mating experiment, the time of entrance of the DNA that carried the phage genome into the female strain coincided with the multiplication of that phage in the female and lysis ('zygotic induction'). As with the transfer of other markers, this lethal consequence of conjugation also occurred at a characteristic time after the initiation of mating. The time of transfer corresponded to a position on the chromosome close to the genes encoding the enzymes of galactose metabolism. This was the chromosomal region with which the phage genetic material had become associated. These findings resulted in remarkable insights. First, lysogeny resulted from the positioning of phage DNA at a particular region of the bacterial chromosome. (Later studies showed that different temperate phages insert their DNA at different positions on the chromosome.) This insight was important stimulus for later research on the nature of viruses that cause cancer, leading to the discovery of tumor viruses whose genetic material becomes associated with mammalian chromosomes. Second, the finding that the transfer of lysogenic phage DNA into a non-lysogenic recipient resulted in 'lysogenic induction', along with mutant analysis of the control of lysogeny, played a crucial role in the formulation of the operon model of gene control and its rapid acceptance. In the late 1950s, Jacob began a second, highly fruitful collaboration with another fellow Pastorien, Jacques Monod. Monod had been working for nearly 15 years on the induction of the appearance of the enzyme β-galactosidase after addition of the sugar lactose to growing E. coli. His work had led to an increased understanding of how the enzyme could appear only when needed by the bacteria. He and his coworkers had also selected mutants that were constitutive for the synthesis of β-galactosidase: the mutant strains no longer needed lactose to induce synthesis of the enzyme. The newly discovered mechanism of bacterial conjugation was going to be essential to crack the problem of gene regulation, and Monod and Jacob teamed up. As Jacob joined the project, the researchers discovered that the lacZ gene, which encoded βgalactosidase, was tightly linked to the gene lacI, in which the constitutive mutations were found. But the actual mechanism by which this regulation took place remained obscure. A key experiment,performed in their labs by visiting scientist Arthur Pardee, broke open the problem of gene regulation. The experiment involved a mating between wild-type bacteria (LacI+, LacZ+) with bacteria mutant for both genes (lacI–, lacZ–), and measurement of the appearance of β-galactosidase in the recipient cells. The enzyme was expressed as soon as the lacZ gene entered the recipient, indicating that the appearance of the gene in cytoplasm that lacked the product of the lacI gene resulted in constitutive expression of the enzyme. (The repressive effect of the lacI gene only appeared at a later time after its entry.) Pardee, Jacob and Monod proposed, in what is still referred to as the PaJaMo paper, that the lacI gene encoded a repressor, and the field of molecular analysis of genetic regulation was off and running. Important to the formulation of the repressor model was the information already obtained by Jacob and Wollman on the regulation of lysogeny. The parallels between the immunity to superinfection exhibited by λ lysogens and conferred by the λ cI gene, and the inhibition of gene expression by the lacI gene, strengthened the confidence of the Pasteur team in putting forth their regulatory model. The model gathered even greater force with the characterization of lac operator-constitutive (Oc) mutations, which were resistant to the effects of the repressor, and the parallel between the effects of these mutations and those of the λ vir mutations that cause resistance to the λ cI gene product. The studies on the regulation of the lac operon highlighted by the PaJaMo paper are particularly remarkable in that they generated two of the basic concepts of molecular biology. First, they established the concept that genes, once thought 'inaccessible' to outside forces, could be altered in their expression by regulatory molecules. Second, the kinetics of β-galactosidase synthesis in the mating experiments suggested the existence of an intermediary in the translation of information between that present in genes and their protein products. The nearly instantaneous turning on of gene expression when genes entered into a new cytoplasm pointed to a rapidly made and rapidly degraded macromolecule containing the genetic information. This insight led directly to experiments demonstrating the existence of messenger RNA, experiments in which Jacob took part. For their contributions to the understanding of gene regulation in bacteria, François Jacob, André Lwoff and Jacques Monod received the Nobel Prize in Medicine and Physiology in 1965. Jacob, Monod and their coworkers had, in effect, provided much of the foundation for the nascent field of molecular biology in a remarkably short period of time between the mid 1950s and the early 1960s. (The collaboration on Lac started in 1958, but much was done independently by both scientists before that time.) Their laboratories became a scientific Mecca for many of the leaders of this small but vibrant field. Pilgrimages were made to the Pasteur for sabbaticals or extended stays by visitors such as Seymour Benzer, Gunther Stent, Melvin Cohn, Louis Siminovitch, Aaron Novick, Cyrus Levinthal, Anna-Maria Torriani, Bernie Davis, Dale Kaiser, Bernie Horecker, Raquel Rotman, and Leonard and Lee Herzenberg. In the next several years, Jacob continued in bacterial genetics, making other important foundational contributions to the field. In addition to revealing additional novel features of the Lac system, he, together with Sydney Brenner and François Cuzin, formulated the replicon model for the control of chromosome replication and segregation. This model initiated a new field and is still a touchstone for discussions of DNA replication today. With coworkers Yukinori Hirota and Antoinette Ryter, he was the first to devise a method for studying the genetics of bacterial cell division, isolating a set of temperature-sensitive filamentation (fts) mutants. These mutants, including those that defined the ftsZ gene, later found to encode a tubulin homologue, provided the basis for current studies of bacterial cell division. His work with Harvey Eisen and Luis Pereira da Silva revealed novel features of bacteriophage λ regulation and replication, including a repressor of the repressor. In this post-Lac operon period, Jacob, along with many other molecular biologists, was pondering a move to higher organisms. He briefly considered nematode biology, which Sydney Brenner was beginning to study. But perhaps because of his initial training as a physician, he chose to work with the mouse, an organism that he felt would be more helpful for the understanding of human embryonic development, the causes of diseases and the ways to cure them. Jacob was one of the first of the leaders of molecular biology to argue for the shift from bacteria to higher organisms, a trend that was subsequently followed by many other bacterial geneticists. One theme that attracted his interest concerned the possible link between malignant cell transformation and cell dedifferentiation. This brought him to study teratomas in the mouse as a model for such a link. Together with Hedwig Jakob and Jean-François Nicolas, he established procedures for the isolation of mouse multipotent teratocarcinoma cells and their maintenance in culture. They developed culture conditions that promoted the differentiation of these cells towards specific cell types, a forerunner of current similar efforts with stem cells. His laboratory also attempted to inject such teratocarcinoma cells into blastocysts to see if they would contribute to the genetic makeup of the embryo. Later, his group and other laboratories isolated embryonic stem cells and used them for the generation of mouse mutants. He also studied several classical mouse mutants, such as the T locus mutants, postulating that they regulated key developmental functions. During this period, he was searching for cell-surface proteins that could mark specific cell types and promote their grouping or aggregation during early development of organs. This work, done with Rolf Kemler, Charles Babinet and others, led to an understanding of the nature of the cell surface protein, E-cadherin, which plays a key role in the compaction of the eight-cell-stage morula. Finally, Philippe Brûlet in his laboratory contributed to the development of gene inactivation techniques in the germ line of the mouse. They replaced mouse genes with the bacterial β-galactosidase gene, which also provided a means of following gene expression during development. He educated and nourished a new generation of scientists in the Pasteur and elsewhere who would contribute to the use of the mouse as a model system for the study of development and disease. Coincident with his move into mouse biology, Jacob began a writing career that was to produce some of the finest writing from a scientist in this field. A series of books, 'The Logic of Life: A History of Heredity', 'Of Flies, Mice and Men', 'The Possible and the Actual' and the memoir 'The Statue Within', all written in a fluid and elegant style, present unusually personal and perceptive insights into the doing of science. He draws incomparable portraits of some of the major actors in that period. And in 'The Statue Within' and 'Of Flies, Mice and Men', he describes the intimacy and intensity that can suffuse the collaborations of pairs of scientists like himself and Élie Wollman or he and Jacques Monod: "Our [he and Monod] friendship unfolded like an epic poem." Elsewhere he compared these pairings to love affairs. The beauty of the language and clarity of the writing are not a surprise. Jacob and Monod's scientific papers of the 1950s and early 1960s, particularly the two or three page notes published in the Comptes Rendus de l'Academie des Sciences, were paradigms of efficiency — containing perhaps a table or two of data and an elegantly presented insight into an important biological phenomena. Both in his writing and in his actions, Jacob also directed his attention to the social context and social impact of genetics. A number of articles in Le Monde (one translated into English for the New York Times), an extensive interview in the Nouvel Observateur and chapters in some of his books dealt critically with such issues as eugenics, sperm banks and racist theories emanating from scientific sources. He served for many years on the French Bioethics committee. Devoted to the defense of human rights, Jacob chaired the committee of the French Academy of Sciences that supported persecuted scientists around the world. There, he actively worked to obtain the release of scientists in totalitarian countries who had been imprisoned for their opinions and opposition to their governments. He contributed importantly to convincing French politicians of the need to better support biological and medical sciences. Going public in the French press, Jacob argued that science is not programmable and that funding agencies should continue to support curiosity-driven research. His influence with politicians was likely amplified not only by his prestige as a scientist and his eloquence, but also by his exploits while serving in the Free French army. In addition to the Nobel Prize, Jacob received some of the highest honors that a Frenchman can hope for. In 1965, he was elected a professor in the College de France. This prestigious French teaching and research institution originated in the 16th century when Francois 1er, a monarch who admired the Italian renaissance, established it to compete with the clerical Sorbonne. Between 1965 and 1990, Jacob delivered stimulating and passionate lectures on genetics and developmental biology at the College, motivating a whole generation of young students to enter biological research. He gave a lecture in 1977 that was published under the title 'Evolution and Tinkering' (Science 196, 1161–1166). It is a fascinating text which suggests how evolution works and why it lacks perfection; it predicted much of what we have learnt in the last 30 years and should be read by younger generations who also have to argue against the proponents of 'Intelligent Design'. Because Jacob was one of the few individuals that joined the free French Forces very early in the war, he was named to the elite group of 'Compagnons de la Libération' and served as the chancellor of this order between 2007 and 2011. He was promoted to the highest rank in the French Legion of Honor, receiving the Grand Croix, which is awarded to only a handful of people. François Jacob was also elected to membership of the French Academy, joining the small group of writers (less than fifty) known as 'the immortals' in France. This honor was highly unusual for a scientist and certainly reflected the recognition of the quality of his literary work. On this occasion, friends and students of François offered him the traditional sword and uniform that members of the French Academy still don when they gather for official sessions. The uniform was studded with the impressive collection of medals he had received over the years. A tall, striking man who exuded intensity, Jacob elicited respect and even awe. Yet, his easy smile and the warmth that went with it charmed and readily dispelled the shyness one might feel in his presence. In fact, he was very supportive of young scientists and infused them with enthusiasm and curiosity. The door of his office was always open and anyone could step in and discuss the latest experiments or ask for advice and encouragement. His face lit up when he was presented with a new finding by a student or other researchers. Moreover, he would often surprise them by coming up with a more parsimonious way of describing the implications of their results. François Jacob was one of the handful of scientists who initiated the revolution in biology that took place in the second half of the 20th century. By his elegant logical thinking, his originality, prophecy and 'flaire' for the study of important issues, he was a guide to generations of scientists. Yet, despite the magnitude of his accomplishments and his intense love of science, he still expressed a humility and modesty about science and its social role. "Science cannot answer all questions. It can, however, give some indications, exclude certain hypotheses. Engaging in the pursuit of science may help us make fewer mistakes. It's a sort of gamble." We will miss him as a scientist. We will miss him as a humanitarian. We will miss his charm. We will miss him as a person with a profound curiosity who continued to seek and provide us with scientific insights and insights into the doing of science itself.
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