MONOD, JACQUES LUCIEN

(b. Paris, France, 9 February 1910; d. Cannes, France, 31 May 1976)

molecular biology.

A highly complex personality, Jacques Monod was most of all a scientist, and the totality of the scientific ideas and experimental results of his careeer form an immense theoretical edifice. But he was also a musician, a military officer, a sportsman, a writer, an administrator and politician, and a philosopher. He was a man of action and a gifted organizer, but his domain of choice was the development of theory. His ideal was knowledge: for him that was the highest goal of human activity; it was the thing that made man special and was the destiny of humankind.

Life . The Monod family was descended from a Swiss Huguenot pastor who came to France from Geneva in 1808. Jacques’s father, Lucien Hector Monod, was an artist and art historian, an anomaly in a family of government officials, pastors, and doctors. His mother, Charlotte Todd McGregor, was American. Both parents had an important influence on young Jacques’s education.

Lucien Monod was a sensitive artist, but also a humanist and a positivist. He had a special admiration for the work of Darwin and Ernst Haeckel, and young Jacques showed an early interest in biology, collecting beetles and tadpoles. Lucien Monod was also interested in music, and Jacques learned to play the cello as a young child. Music and biology were his two intellectual loves, and he hesitated between them for many years before finally choosing his profession.

When Jacques was seven years old, the family moved to Cannes; the house they built there, “ClosSaint-Jacques”, remained his favorite residence ever after.

Studies, As a pupil at the Collège de Cannes, Monod was fortunate to find several important mentors, in particular his professor of Greek, M. Dor de la Souchere, After graduating in the summer of 1928, Monod enrolled in the Faculté des Sciences in Paris, where he lived with his older brother Philippe, a lawyer who later became a diplomat and played an important role in Jacques’s life, discreetly helping him in his career and suggesting the right professional chores. Monod received his degree in 1931 but he was dissatisfied with his university education, which, he later noted, “lagged behind contemporary biological science by nearly twenty years or more.” Only one of his professors had any real impact on him: Georges Urbain, who taught thermodynamics. Like many other students of biology, after graduation Monod went to the Roscoff marine biology station, where he became acquainted with four scientists who shaped his conception of science and his scientific practice: Georges Teissier, who gave him the taste for quantitative description; André Lwoff, who introduced him to microbiology; Boris Ephrussi, in physiological genetics; and Louis Rapkine, who taught him that only chemical and molecular descriptions could provide a complete interpretation of how living beings functioned.

In the autumn of 1931 Monod won a fellowship to study at the University of Strasbourg, in the laboratory of Edouard Chatton, the leading French protistologist of the time. Here he became familiar with the techniques of microbiology, learning, among other things, to cultivate pure cultures of ciliates. It was during this period that, in collaboration with Chatton and André and Marguerite Lwoff, he published his first scientific articles, on the stomatogenesis of infusorians. In October 1932 Monod won the Commercy Scholarship and returned to Paris, where he spent two years in the Laboratory on the Evolution of Organized Beings, directed by Maurice Caullery.

In 1934 Monod became an assistant in the zoology laboratory of the Sorbonne. That summer he took part in a scientific expedition to Greenland on the Pourquoi pas? In the spring of 1936 he was about to embark on a new expedition of the Pourquoi pas? when Boris Ephrussi invited him to go along on a trip to America. That invitation was a turning point in Monod’s life, in two senses : the Pourquoi pas? and its entire company were lost off the coast of Greenland, and Monod’s stay in America was decisive in setting the course of his scientific career.

Having obtained a Rockefeller Fellowship, Monod spent a year at the California Institute of Technology, where the “Drosophila group” directed by T. H. Morgan was working. Here he learned not only genetics but also another way of doing science, a new scientific style based on collective effort, ease of personal relations between scientists, and freedom of critical discussion.

When Monod returned to Paris, Louis Rapkine and Boris Ephrussi convinced him that he lacked the basic knowledge he needed to make music his career, and he opted definitively for biology. Monod returned to the Sorbonne to prepare a doctoral dissertation (defended in 1941) on the subject he had finally chosen under the influence of Georges Teissier: bacterial growth.

Monod also continued his activity as an amateur musician. He formed a Bach choir, La Cantate, which he directed until 1948. It was there that he met Odette Bruhl, an archaeologist and orientalist who specialized in the art of Nepal and Tibet and later became curator of the Guimet Museum. They married in 1938, and Odette brought him the enrichment of a visual culture and sensibility complementary to his own. They had twin sons, Olivier and Philippe, who both became scientists, the former a geologist and the latter a physicist.

The War and the Resistance. Monod was exempted from military service because of a minor physical handicap (the consequence of polio), but he joined a Resistance group after the German army occupied France. His Sorbonne laboratory became a meeting place and an underground print shop for propaganda bulletins. Many armed Resistance groups were formed after the Allied invasion of Normandy in 1944, and Monod decided to join the Franc-Tireurs Partisans (FTP). The year before, he had joined the French Communist Party (PCF), the only political party with significant weight in the Resistance leadership. He resigned from the PCF in 1945 because he disagreed with the party’s postwar policy and, with his spirit of independence, he was unable to accept the organization’s rigid discipline.

Assigned to coordinate resistance actions as the head of the Troiséme Bureau, Monod organized the general strike that led to the liberation of Paris. After the liberation, he became an officer in the Free French Forces and a member of General de Lattre de Tassigny’s general staff. For his military activity Monod was awarded the Croix de Guerre, the Legion of Honor, and the American Bronze Star.

The Pasteur Institute. In late 1945 Monod joined the Pasteur Institute as laboratory director in the department headed by André Lwoff. He spent the rest of his scientific career in this prestigious institution. The National Center of Scientific Research allowed him a post of technical aide, and he hired Madeleine Jolit, who worked as the main technician in his laboratory until 1971. In collaboration with Alice Audureau, Monod continued his research on bacterial growth and enzyme adaptation, in particular studying the enzyme that became the classic subject of his later research, β-galactosidase.

During his days in the military, Monod had come across an issue of the journal Genetics in a mobile library of the American army. In it he read an article by Salvador Luria and Max Delbrück demonstrating the spontaneous character of bacterial mutations. In 1946 he attended the Cold Spring Harbor symposium at which Alfred Hershey demonstrated genetic recombination among viruses and Joshua Lederberg and Edward Tatum announced the discovery of bacterial sexuality. All the biologists at this symposium realized that bacteria, and even crystallizable viruses, really did have mutable genes capable of sexual recombination and replication, just like the genes of animals and plants. It was also at this symposium thatMonod made contact with the small group of researchers gathered around Max Delbrück who later detailed the mechanisms of transference of genetic information by studying the system constituted by Escherichia coli bacterium and its series-T viruses.

Upon his return to Paris, Monod joined with Elie Wollman in experiments on growth inhibition among bacteria infected with bacteriophages, and he was strongly tempted to continue working on bacteriophages. But in the end he decided not to opt for this shift in research program, and instead continued working on various other subjects until 1947, when he was invited to present a general report on enzyme adaptation at the Growth Symposium. Examining the existing literature, including his own earlier research, Monod realized the importance and scope of this phenomenon, recognized yet still unexplained, in which a genetic and a chemical determinant were linked. It became clear to Monod that the fundamental problem of enzyme adaptation lay in assessing the respective roles of the hereditary and environmental factors (the substratum) in enzyme synthesis. This became the point of departure of his research program.

The “Grenier.” Lwoff’s department, in which Monod worked, became a place of truly mythic proportions in the history of molecular biology. There were two research groups, housed at opposite ends of a long, narrow corridor in the famous grenier, an attic of the biological chemistry building: Monod’s group on enzyme adaptation and Lwoff’s, which in 1949 began a fresh approach to the study of lysogeny. That same year another major protagonist of French molecular biology joined the grenier: Francois Jacob, who collaborated very closely with Elie Wollman.

There was a constant and ever-changing flow of trainees through the grenier, especially foreigners. The department was part of a narrow network of advanced biological research centers for the members of the small scientific community that was then in the process of creating a new discipline: molecular biology. Despite the cosmopolitan atmosphere, the science conducted in the grenier retained a typically French character, not only in the subjects chosen and in the tendency to emphasize the more strictly physiological aspects, but above all in a scientific style that combined extreme experimental rigor with the boldest speculation. The elegance and deductive clarity of demonstration were considered just as important as the results achieved.

From 1948 on, a fundamental contribution to the implementation of the research program on enzyme adaptation was made by the American immunologist Melvin Cohn, who spent five years in Paris. Collaboration (and debate) with his colleagues, and later with his students, was of great importance to Monod, for his own thinking was stimulated by confrontation with the ideas of others, and his theories were refined in the course of discussion and debate. This challenge was essential in the rethinking of his own ideas, and in the constant proposal of new ones.

Department Director. In 1953, after the death of Michel Macheboeuf, Monod was assigned to create and direct the department of cellular biochemistry (Service de Biocheme Cellulaire). The establishment of this department was the result of a carefully theorized project based on the definition of a clear research program. Monod believed that fundamental chemical organization would be revealed at the level of cellular constituents rather than at the level of tissue or differentiated organs. Modern biochemistry had been oriented to the study of the processes of biosynthesis, and Monod possessed a powerful tool for this study: the investigation of bacterial growth. Biochemistry would thus become cellular, microbial biochemistry. Monod managed to obtain the funds necessary for a complete and modern department partly from the National Center for Scientific Research but also, to a large extent, from donations from Mmes. Edouard de Rothschild and Bethsabée de Rothschild and grants from American institutions such as the Rockefeller Foundation, the National Science Foundation, and the National Institutes of Health. In 1955 the department moved into new headquarters on the ground floor of the same building in which the grenier had been housed.

The new department finally had sufficient space, and many students began to arrive, primarily (and this was Monod’s choice) specialists in the physical and mathematical sciences. His characteristic combination of powerful self-assertion and great sensitivity and generosity made him an ideal mentor. He had the capacity to delineate both problems to be studied and techniques that could maximize everyone’s potential. Himself an excellent experimenter, Monod was able to predict theoretically the results of an experiment and to draw all the requisite consequences. A skilled architect of advanced research programs, he had the characteristic of a true master thinker: the ability to pick out the most important elements of a problem or a theory. His implacable Cartesian deductive logic, which always seemed to isolate the weak points in an argument or an experimental procedure, enabled him to eliminate all that was secondary in logical reasoning, such that everything seemed to fall into a coherent, inevitable, and therefore comprehensible framework.

At the end of 1958, Monod was invited to become professor of biochemistry at the Faculty of Sciences of the University of Paris. After long consideration, he decided to accept, provided he would be able to continue working at the Pasteur Institute. The post he took up in 1959 was originally called chair of the chemistry of metabolism, but in April 1966 the name was changed to chair of molecular biology. In 1967 Monod was elected to the Collège de France and named chair of molecular biology. His inaugural lecture in November 1967 was a solemn occasion for raising the philosophical implications of modern biology.

The Great Collaboration. Beginning in 1957, Monod and François Jacob established a very close collaboration. At the time, the development of research on inductible systems required the methods of crossing bacteria and of zygotic induction developed by Jacob in collaboration with Elie Wollman. Whereas Cohn played a major role in the initial, biochemical phase of Monod’s study of the relations between genes and enzymes, Jacob’s participation was essential during the second, genetic and regulatory phase. But the consequences of what Francis Crick called “the great collaboration” went well beyond the solution to the problem of enzyme adaptation, uncovering the general mechanism of the regulation of protein synthesis and its genetic determination. The constant exchange of ideas and experimental results, and the interminable conversations between Jacob and Monod, were decisive in this.

The great collaboration produced three theoretical models that proved fundamental in the development of molecular biology: operon, messenger RNA, and allosteric interactions.

The Nobel Prize. In 1965 Jacob and Monod were awarded the Nobel Prize in physiology or medicine for all this research, together with André Lwoff, who had laid the scientific and institutional ground work that made it possible. This honor for the three French biologists was not unexpected. Lwoff and Monod had been brought to the Nobel Committee’s attention in the 1950’s, and after the triumph of the operon model in the early 1960’s, proposals to award the prize to Jacob, Monod, and Wollman had come from various quarters.

The Nobel Prize entailed fresh responsibilities for Monod. He was suddenly a celebrity, and his ideas and statements carried great weight in public opinion. He used his fame to demand university reform and to fight for the advancement of French science. During May 1968 Monod supported the student movement against the academic establishment, which he had always considered one of the major causes of France’s cultural and scientific backwardness. He took part in student assemblies, but soon had to acknowledge a deep division between himself and the students. They considered him a member of the establishment against which they were rebelling, and he criticized the irrational and purely destructive aspects of the student movement.

Monod had always been an ardent defender of human rights, never shirking commitment when it was necessary. In the early 1950’s he publicly protested the repression of intellectuals in America and any restriction of the free circulation of people and ideas. In 1960, after a difficult campaign that included a trip to Budapest, he succeeded in getting Agnés Ullmann and her husband out of Hungary. He came out against the French Secret Army Organization, met in 1966 with the Reverend Martin Luther King, Jr., in Paris, and condemned the treatment of Jews in the Soviet Union, as well as assaults on freedom in various other countries. He supported the activities of the French family planning movement, fighting for the legalization of abortion, and signed in 1974 a plea in favor of beneficent euthanasia. The value and dignity of the individual was his fundamental ethical guideline.

Director of the Pasteur Institute. In 1965, during a broad movement for the renovation of the Pasteur Institute, Monod and his colleagues had proposed thoroughgoing changes in the management of the institution. It was felt that the combination of financial difficulties and an accumulated lag in scientific progress had made such changes long overdue.

It was therefore no surprise when Monod was offered the post of director of the institute in 1970; after lengthy consideration, he accepted the appointment. His decision reflected both his sense of duty (sharpened by his Protestant sense of responsibility) and his deep gratitude to the institution that had permitted him to pursue his research in complete freedom. In 1971 the institute’s financial situation was so catastrophic that its very existence seemed threatened. Monod wanted to infuse the prestigious institution with fresh vitality, and he felt that he alone would be able to accomplish that. Moreover, to lead the Pasteur Institute at that time was an extraordinary challenge, and Monod loved challenges. Risk excited him, a trait that had made him a rock climber in his youth and later an expert sailing skipper.

On 15 April 1971 Monod became the director general of the Pasteur Institute. He assumed the post with a fully developed plan and with clear ideas—perhaps even dreams—of what an institution of biomedical research should be like. He completely restructured the institute, creating a subsidiary company—Institut Pasteur Production—for the revitalization of industrial activities. Monod improved the financial situation, which was definitively stabilized when a permanent state subsidy was won. When necessary, he reorganized research, eliminating or recasting many departments and creating others. Authoritarian and inflexible, he made decisions firmly and courageously, though sometimes without sufficient consultation. This gave rise to resentment and opposition, and many friendships were broken.

Monod’s years as head of the Pasteur Institute were difficult for personal reasons as well. In 1972 he suffered a six-month bout of viral hepatitis, and that same year his wife died after a long illness. His administrative tasks made it impossible for him to continue his scientific activity, and he was compelled to resign his chair at the Collège de France and to cede his post as director of the cellular biochemistry department to Georges Cohen.

Because of the urgency of the administrative and financial reforms, Monod was unable to elaborate any real plan of scientific development, and the difficulties he faced undermined his hope of turning the Pasteur Institute into a model research center. Only in 1975 did he sketch out a medium-term policy of scientific development for the institute, centered on what he considered his fundamental vocation: the advance of the biological sciences in the service of humankind.

But Monod had no time to implement this project. In October 1975 an incurable disease, aplastic anemia, was diagnosed. Though well aware of the prognosis, he continued to serve as director of the Pasteur Institute. From time to time he left to rest at his home in Cannes, where he died on 31 May 1976.

Scientific Work . Monod divided his research into four periods corresponding to different phases of a single scientific trajectory. Despite the apparent diversity of these phases, they unfolded with remarkable continuity, each as a necessary and inevitable consequence of its predecessors.

Kinetics and Physiology of Bacterial Growth (1935–1947). In 1935 Monod became interested in the quantitative aspects of the growth of bacterial cultures, demonstrating in particular that the growth rate relative to the concentration of available food was not linear but asymptotically approached a value representing the maximum rate of cell division. This function turned out to be identical to the kinetic equation describing the speed of an enzyme reaction relative to the concentration of substratum. The growth rate was therefore determined by an enzyme-type reaction. The growth of bacterial cultures obeys simple quantitative laws. By measuring the growth in the presence of various sugars, Monod showed that the growth yield relative to energy source was independent of the growth rate. This suggested that there was no such thing as a “maintenance concentration” and that nearly all of the available energy was used in biosynthesis.

During a study of the interaction of two carbon sources, Monod noted a new phenomenon of growth of cultures of Escherichia coli. When two carbohydrates instead of one are placed in the milieu as food sources, it is normally observed that the total growth yield equals the sum of the yields of each sugar. However, certain mixtures of sugars show quite different curves, indicating two clearly distinct phases of exponential growth separated by a phase of latency in which there is most often no growth or even a decrease of the cultures. Monod called this phenomenon “diauxy,” or double growth. The study of the phenomenon showed that it was a result of a variation in the enzyme constitution of the bacteria caused by the presence of the different substrata.

In December 1940 Monod asked André Lwoff’s opinion of this new phenomenon; Lwoff replied that it could be considered an instance of bacterial “enzyme adaptation.” This phenomenon— in which the formation of certain enzymes is selectively stimulated by the specific substratum of the enzyme—had been noted by Émile Duclaux and Frédéric Dienert in 1901, and in 1926 Hans von Euler-Chelpin had clearly shown that the phenomenon had to do with protein synthesis. In the 1930’s the Finnish researcher Henning Karström called this “enzyme adaptation,” distinguishing between constitutive and adaptive enzymes. Later, Marjory Stephenson had noted that the appearance of new enzyme activity in a bacterial population in process of multiplication could result either from a chemical stimulus (induction) exercised by a substratum on the totality of individuals in the population or from a gradual selection of spontaneous genetic variants.

During the war, Monod was forced to leave his laboratory at the Sorbonne, and Lwoff brought him into his department of microbial physiology at the Pasteur Institute, where Monod was able to continue his research, showing that enzyme adaptation corresponded to the synthesis of a particular protein. In collaboration with Alice Audureau, he worked on the genetic determination of enzyme adaptation in bacteria. The problem was to isolate the cellular mechanisms by which the presence of a given substratum, lactose, could “stimulate” the synthesis of a specific enzyme that would permit the assimilation of this substratum. The research on β-galactosidase also concerned the explanation of the mutation that brought a bacterial strain from a state in which the synthesis of the enzyme was inductible to one in which the synthesis occurred continuously (constitutivity). The problem of the apparent duality of the particular determinism of the biosynthesis of enzymes—genetic determinism on the one hand, chemical on the other—was therefore clearly posed.

The importance of this research was that enzyme adaptation seemed to be the only phenomenon that allowed direct experimentation on the construction—or ontogeny, as it was then called—of enzymes. There were also hopes of developing an explanation of cell differentiation, in particular of the synthesis of antibodies. Most of all, this problem was considered an aspect of the more general problem of biological specificity and offered an ideal experimental system for understanding the “physical basis of specificity” (1947). The analysis of the genetic determination of enzyme specificity showed that it was linked to the enzyme’s configuration, which was controlled by a single gene. Enzyme induction thus constituted a model system for the study of protein synthesis and of the relations between genetics and cellular physiology.

Enzyme adaptation (1947–1957). In the late 1940’s the problem was to understand why the addition of a substratum could provoke either an increase in the rate of enzyme synthesis (adaptation) or a diauxic inhibition. This latter phenomenon was also called the “glucose effect”; the synthesis of a large number of enzymes was sometimes completely inhibited when the growth of the organisms occurred in the presence of certain glucides, more particularly glucose.

Explaining this effect (in Growth Symposium, 1947), Monod revived a simple model proposed by John Yudkin in 1938. According to this model, the enzyme was formed from a precursor, through an equilibrium reaction. The inductive action of a substratum could then be interpreted by assuming that the formation of the enzyme-substratum complex shifted the balance in favor of the formation of the enzyme. The hypothesis was that “different enzymes can be issued by a common precursor,” the specificity of the enzyme being determined by “a preexisting self-replicating entity (the gene).” The particular configuration of an enzyme was thus determined by a master pattern, which could be the enzyme itself, another molecule formed by the cell independently of the presence of the substratum, or even the substratum. The immunological methods developed by Cohn and Monod and applied to the study of β-galactosidase (in collaboration with Annamaria Torriani, a young Italian biologist who came to Paris in February 1948) permitted the exploration of lines of descent and kinship between protein molecules. Indeed, if one protein is derived from another through differentiation, then we ought to expect that these molecules must inevitably have very close antigenic structures, which could be brought out by crossed serological reactions. The results showed that bacteria induced by galactose contained two distinct antigens, called Gz and Pz, Gz being β-galactosidase and Pz an enzymatically inactive protein. The noninduced bacteria seemed to contain only Pz. The very closely related antigenic structures of Gz and Pz showed that Pz could be a precursor of the enzyme:

In 1950, in order to be able to study bacterial growth in the most stable and controlled conditions possible, Monod developed a method of continuous culture of bacteria (bactogène) through which a physiologically stable state could be maintained indefinitely. If a “continuous dilution at constant volume” is maintained, the growth rate is limited by the concentration of food, which can be controlled by the rate of dilution. By using this method—which had been independently developed and published by Leo Szilard and Aaron Novick—the growth rate could be considered an independent variable and the speed of the process of synthesis could be studied as a function of different variables.

Three hypotheses had been advanced to explain the mechanism of enzyme induction: (1) the functional hypothesis, which held that the synthesis of the enzyme was related to its activity and that the inductor acted as a substratum; (2) the hypothesis that synthesis was limited by a dynamic equilibrium that was broken when the enzyme was exposed to a specific complex (this was proposed by Monod in 1947 and 1949); (3) the organizing or formation hypothesis, which held that the inductor played an organizing role in the synthesis of the enzyme, through its action (whether direct or not) on a “forming system.” This last hypothesis was the model proposed by Monod in 1943 and 1945.

Since it was impossible to obtain the enzyme in crystalline form, Monod and Cohn undertook the study of a series of substitutions in the molecule of the glactosides, determining the inductive power of each analogue and its properties as substratum of the enzyme. The β-thiogalactosides, in which the oxygen of the galactosidic group is replaced by sulfur, proved highly useful for the study of β-galactosidose induction. The results showed that, contrary to theories current at the time, the inductive power was not related to the enzyme’s action on the inductor, or even on its affinity for it. The induction of an enzyme is independent of its activity, and the activity of the inductor therefore could not be due to a combination with the enzyme. Consequently, neither the functional nor the equilibrium hypothesis could be accepted. The inductor must act as an organizer, and Monod revived the hypothesis of a catalytic action at the level of the formation center of the enzyme in the cell. The basic idea, borrowed from immunology, was that the inductor served as a model in the formation “matrix” of the protein. Melvin Cohn called this paradoxical situation a “theatre of the absurd”, since the bacteria produce a useless enzyme, β-galactosidase, in response to a substance, such as thiomethylgalactoside, that they cannot metabolize. To explain these results, Monod introduced the notion of “gratuitous” induction: since the inductor had no necessary affinity for the protein that it induced, certain distinct cellular sites of the protein itself must be capable of forming a specific combination with it.

One consequence of this “theatre of the absurd” was that the expression “enzyme adaptation” seemed ill suited to describe an effect that in certain cases was not at all functionally adaptive. Monod therefore proposed to abandon the expression in favor of “induced biosynthesis of enzymes.” This proposal was accepted by all the major researchers working in the field, who signed a sort of encyclical published by Nature in 1953.

Since the physical, chemical, and immunochemical properties of the “constitutive” enzyme were identical to those of the “induced” enzyme, it was natural to suppose that the underlying mechanism of synthesis must be the same. In 1953 Monod and Cohn formulated the hypothesis that the synthesis of all enzymes was subject to a like mechanism of specific control. A simple hypothesis was that the constitutive systems could be induced by endogenous inductors (the theory of generalized induction, known by its French initials, TIG).

The essential problem posed by the phenomenon of the induced biosynthesis of enzymes was to find out whether it consisted of the activation of a pre-existing protein or whether, on the contrary, it was a question of the synthesis of a new protein. The model Monod accepted until 1952 supposed that the intervention of the inductor was reflected not in the synthesis of a protein de novo but rather in the transformation of the precursor Pz into the enzyme Gz.

With Alvin Pappenheimer and Germaine Cohen-Bazire, Monod showed that the induced formation of the enzyme required the simultaneous presence of each of the essential amino acids, which itself indicated that the process involved the complete biosynthesis of a protein. On the other hand, the kinetics of this biosynthesis obeyed a remarkably simple law:

or

in which δz is the increase of the enzyme, δx the growth of the total bacterial mass from the point of addition of the inductor, and ρ (the differential synthesis rate) the coefficient expressing the speed of enzyme synthesis.

This linear kinetics (“Monod’s plot”), which stated that the synthesis of the enzyme after the addition of the inductor is a constant fraction of the rate of total protein synthesis, was incompatible with the hypothesis of the conversion of an accumulated precursor, which implied an autocatalytic mechanism, and supported “complete synthesis”, the formation de novo of a protein entirely new not only in its specific structure but also in the origin of its elements. The study of the incorporation of the radioactive isotope sulfur 35 into the protein in the course of its induced synthesis confirmed this indirect reasoning, showing that the formation of β-galactosidase corresponded to the total synthesis of the protein on the basis of its elements, without the formation of precursors or intermediaries. This result definitively eliminated the idea of any conversion of Pz into Gz. The immunological similarity of two proteins therefore proved to be a false track.

One of the consequences of this research was that it challenged the theory of the “dynamic state” of intracellular proteins, proposed by Rudolf Schoenheimer in 1941. This theory held that proteins continually exchange radicals with other cellular chemical constituents. Monod’s results, on the contrary, showed a practically complete (and surprising) stability of proteins among multiplying bacteria : the synthesis of proteins is the result not of a dynamic equilibrium but of a series of irreversible parallel processes.

Factors of Specific Permeation (1953–1957), Concurrently with the research on induction, Monod’s laboratory was interested in the phenomenon of certain Lac (lactose-negative) mutants called “cryptics.” These mutants cannot develop on lactose, even when they have large quantities of β- galactosidase. Kinetic measurements had shown a difference in the behavior of cellular extracts and intact cells.

To explain this phenomenon, Georges Cohen, who joined Monod’s laboratory in 1954, had proposed the hypothesis that there were specific permeation factors in bacteria. At first Monod rejected this suggestion, but he soon changed his mind and made a fundamental contribution to the understanding of the phenomenon. Cohen had proposed a model based on stoichiometric receptors that absorbed the substratum on stereospecific acceptors, but Monod, after converting the radioactivity measured in milligrams into number of molecules, concluded that there had to be some catalytic action. This soon led to the isolation of a functionally specialized factor, distinct from metabolic enzymes. This factor-first considered an enzyme, called ε, then called system y and later galactoside-permease-is an inductible protein quite similar to an enzyme in its kinetic action and in its narrow specificity. The permease concentrates the galactosides in the cell without modifying the cell chemically. The cryptic mutants had clearly lost their system y.

It must be remembered that at this point permease was only a theoretical construct (the first of many) that was ill received by biochemists and enzymologists, who were accustomed to isolating enzymes first and then deducing their function. Though inferred theoretically in 1956, β-galactoside-permease was not isolated until 1965, by Eugene P. Kennedy.

The discovery of permeases had important, unforeseen consequences. Since galactosidase and permease appeared more or less simultaneously after induction, there had to be a functional relationship between the enzyme and the corresponding permeation factor. Moreover, the two systems were genetically linked. The analysis of constitutive mutants showed that the constitutive mutation affects the two systems simultaneously. Studying the genetic determination as a whole, Monod and his collaborators classed the mutants into three elementary types, on the basis of (a) their capacity (y⁺) or incapacity (y^–) to permease;(b)their capacity (z⁺) or incapacity (z^–) to synthesize β-galactosidase; (c) the inductible (i⁺) or constitutive (i^–) character of the synthesis of the two systems.

Once Monod’s program had reached this point, toward the beginning of 1957, he had to find methods suitable for genetic exploration of the kinetics of genetic expression and for studying the structure of the loci. Such a study presupposed an analysis of the genetic determination of constitutive mutations and of the relations between the determinants governing constitutivity and those governing the structure of the synthesized protein.

Genetic Regulation (1957–1961). New methods of studying the genetics of the synthesis of bacterial enzymes had been formulated in the framework of another research program, which had been developed in a “parallel universe” (Cohn) to the one inhabited by Monod and his group, a universe initially housed at the other end of the grenier’s corridor. This research program was focused on lysogeny and the mechanisms of bacterial sexuality.

In 1950 Lwoff and his collaborators discovered that lysis could be induced in lysogenic bacteria by exposing them to ultraviolet radiation. In 1953 François Jacob and Elie Wollman undertook the systematic study of genetic and biochemical mechanisms concerning the localization, latency, induction, and expression of the genetic determinant of the phage, the prophage. They used the technique of genetic recombination established by Tatum and Lederberg in Escherichia coli K12 and the discovery, achieved independently by Luigi L. Cavalli-Sforza in 1950 and William Hayes in 1953, of bacterial strains exhibiting a high frequency of recombination (Hfr).

Jacob and Wollman’s experiments on the conjugation of bacteria soon produced evidence of the phenomenon that would later be called “zygotic induction”: the chromosome of a donor bacterium bearing a prophage penetrates a nonlysogenic receptive cell and there stimulates the expression of phages and bacterial lysis. The essential event in the conjugation of bacteria is the transfer of a segment of the genetic material and the donor bacterium to the receptor. This transfer occurs in only one direction and at a constant rate. Proof of this was given in an elegant experiment conducted by Wollman and Jacob in 1955, known as the “spaghetti experiment” because the explanatory model depicted the female swallowing the male chromosome like a strand of spaghetti. The conjugating pairs of bacteria were separated by means of a high-speed homogenizer that pulled the bacteria apart and broke the chromosome. By applying this treatment at varying times, the length of the chromosome segment penetrating the female could be selected at will, the expression of the penetrated genes could be studied, and a genetic map could be drawn up in units of time. With this system it became possible to analyze the bacterial chromosome not merely by classical genetic methods but also by physical and chemical measures.

In a conjugation between Hfr bacteria bearing the prophage and nonlysogenic female bacteria, the prophages that enter the cytomplasm of the receptor bacterium are immediately induced. The zygotic induction shows that the transferred genes can be expressed immediately after their entry into the host cytoplasm, quite apart from any genetic recombination. Moreover, for some amount of time the receptor bacterium possesses two copies of a sequence of genes, which permits the study, in bacteria, of genetic phenomena (such as dominance) peculiar to sexually reproductive organisms. That was exactly the technical and theoretical instrument needed by the research program on enzyme induction.

The experimental problem Monod was interested in was to verify the hypothesis of generalized induction, which could be tested by using methods of zygotic induction, in order to determine dominance. The development of this program was the result of collaboration between Monod and Jacob, which began in the spring of 1957 and was not immediately and deliberately applied to the core of the two programs. Together, Jacob and Monod conceived the famous Pa-Ja-Mo experiment, conducted in collaboration with Arthur Pardee, an American biochemist spending a sabbatical year in Paris. The experiment bore a name formed of the initial syllables of the names of its three designers, and later came to be called, for obvious reasons, the Pyjama experiment. The aim of this series of experiments (1957-1958) was to study the biosynthesis of β-galactosidase during the crossing

Hfr lac⁺ X F⁻ lac⁻.

An experiment conducted in December 1957 was designed to use the complementary crossings

and

to clarify the mechanism of transfer and the kinetics of the expression of the gene for β-galactosidase. None of the initial bacterial strains was capable of synthesizing β-galactosidase, for in the case of z⁻i⁻ there was no gene for the enzyme, and in the case of z⁺i⁺the synthesis did not take place in the absence of the inductor.

The results of the first experiment confirmed the theory of generalized induction: in crossing (1), there is no synthesis of β-galactosidase among the merozygotes, while in a type (2) crossing this synthesis almost immediately follows the gene’s entry into the host cytoplasm, which according to the theory contains the internal inductor.

The second phase of the experiment was conducted three months later, to examine the kinetics of the enzyme synthesis over a period of several hours after conjugation. This phase produced a genuine “surprise,” according to Jacob. After a certain time lapse, enzyme synthesis was blocked and would restart only after the addition of the inductor. The cell had therefore passed form the state of constitutivity to the state of inductivity. This suggested, contrary to all expectations, that of the two alleles i⁻and i⁻ the dominant one was not the constitutive but the inductible. This dominance dictated the inevitable conclusion that the i gene was responsible for the synthesis of a “repressor” that blocks the synthesis of β-galactosidase and permease at the same time.

The most important conclusion to be drawn from the Pyjama experiment was the existence of a double genetic determinism in protein synthesis. Two distinct genes intervened, one determining the structure of the synthesized molecule and the other controlling the expression of the first, either permitting it or preventing it. Another conclusion was that different genes determining the structure of distinct proteins were subject to the same regulation system and that this functional association was correlated with their genetic association.

The elaboration of a unified model of cell regulation was not merely the consequence of linear deductive reasoning based on the Pyjama experiment, but was also the result of a kind of assembly process at the insight of which lay a bold theoretical beginning by François Jacob. As he was preparing his 1958 Harvey Lecture, Jacob and the idea of driving the parallel between the genetic determinism of lysogeny and of the lactose system to its ultimate consequences. He draws three conclusions: (1) the regulation must be located at the level of genes, and not in the cytoplasm; (2) the regulating action must be exercised on a structure common to several genes at once; (3) this locking together must occur through a simple switch —in other words, a yestor-no principle.

These conjectures by Jacob were at first categorically rejected by Monod, who was shocked by the idea of genetic localization of the control of protein synthesis and by the notion of a simple binary interrupter, a switch that either sets in motion or blocks a complex chemical machinery. Although Monod alone among the members of the group had studied classical genetics (or perhaps exactly because he had), he could not accept this kind of direct action on genes, which geneticists considered distant and inaccessible objects, “like the material of galaxies”, as Monod put it. In the end, however, the link that Monod had long ago established between genetic determinism and protein biosynthesis, and his capacity to grasp the consequences of an unorthodox idea rigorously and creatively, enabled him to contribute decisively to the full exploitation of the parallel between lysogeny and enzyme induction.

In a preliminary note presented to the Académie des Sciences in October 1959, and analogical interpretation of the observations of the two systems paved the way for the distinction between the structural genes responsible for the structure of proteins and the regulator genes that govern their expression through the intermediary of a cytoplasmic repressor. The existence of groupings of genes whose expression is subject to a single repressor suggested to Jacob and Monod the hypothesis that there might be a single structure sensitive to the repressor and controlling the activity of the entire group of genes. A theoretical note presented to the Académie des Sciences in 1960 introduced the concept of operon, a unit of coordinated expression made up of an operator and the group of structural genes that it coordinates.

The operon model posed three problems. The first was the nature of the repressor, another theoretical entity whose chemical nature was wholly unknown. The second was the mechanism of the repressor’s chemical action and its relation to the target and the inductor. The third concerned the molecular mechanisms of the transfer of genetic information for protein synthesis, a problem that lay at the root of the idea of the messenger.

Monod did not participate in the “search for the repressor” which was completed only in 1966 by Benno Müller-Hill and Walter Gilbert, or in the development of the messenger idea. After elaborating the theory of the messenger (in collaboration with François Jacob and with Francis Crick and Sydney Brenner) and proposing that the role was played by very short-lived RNA capable of linking up with the ribosomes, he left the task of isolating this new theoretically deduced chemical substance to others: his collaborator François Gros, François Jacob, and British and American molecular biologists.

Monod concentrated instead on the action mechanisms of the repressor and its chemical interactions with the target and the inductor, a problem that enabled him to turn again to models of stereospecific interactions, a constant theme throughout his scientific career.

In the original operon model, the repressor was considered a ribouncleic acid, probably because an RNA could have interacted more easily, owing to its complementarity, with genes, which are themselves made up of nucleic acid. But in 1960, the oretical considerations, as well as experimental results principally obtained by Agneès Ullmann in Monod’s laboratory, made it clear that the repressor had to be a protein. The major reason for this was that the repressor had to recognize very different chemical structures, such as the inductor (a small metabolite) and the operator (a genetic structure). Only proteins could have this property.

Regulatory Interactions in the Control of Cell Metabolism (1961–1976). Monod and his pupil J.-P. Changeux elaborated a mechanism based on an interaction between two distinct and separate (“nonoverlapping”) sites of protein structure, one for the substratum and the other for the regulatory ligand, or “effector.” The interactions of the ligands are completely indirect, transferred by the protain. The attachment or detachment of effectors governs the conformation of the enzyme, and therefore its catalytic action. The model for this mechanism was hemoglobin, in which the binding of oxygen entails a concerted conformational alteration that exhibits “coordinative” properties.

Jacob and Monod generalized the concept of allosteric transition in the conclusions of the Cold Spring Harbor symposium in 1961, and the first systematization of the concept was presented in an article drafted by Monod in 1962 and published in 1963 under the signatures of Changeux, Jacob, and Monod.

The basic notions derived from the operon model were (1) the repressor is only a transductor of controlling signals; (2) the effect of the substrate on the synthesis of the enzyme is indirect, and the repressor must be therefore an allosteric protein; (3) there is no necessary chemical or metabolic relation between the fact that β-galactosidase hydrolyzes β-galactosides and the fact that its biosynthesis is induced by the same chemical compounds. The relation is gratuitious, chemically arbitrary. The allosteric interactions allow complete freedom in the choice of chemical mechanisms, escaping all chemical constraints and obeying only the physiological constraints imposed by the system’s consistency and submitted to the action of natural selection. Monod therefore considered the concept of allosteric interaction “the second secret of life”, the first being the double helix and the genetic code.

In 1965 Monod elaborated a formalized model of allosteric transitions based on the idea of interaction between equivalent subunits in a regulatory protein. The work was done in collaboration with Changeux and Jeffries Wyman, who between 1948 and 1960 had published articles on the correlation between symmetry and binding cooperativity. The central idea, a purely formal one, was of the conformational transition of an oligomeric protein that conserves structural symmetry. The concerted transition of subunits entails a concerted transition of affinity of sites. A modification of quaternary structure thus explains function.

This model, considered excessively philosophical, was not well received in scientific circles. Francis Crick, for instance, with whom Monod exchanged a long series of letters on the subject, could not see the logical necessity or experimental basis of the postulate of conservation of symmetry, which for Monod was central.

This model was counterposed to the hypothesis suggested by Daniel Koshland—that conformational change was induced by interaction with the ligand (“induced fit”), which led to a multiplicity of varied structural states. For Koshland, structural cooperativity was the consequence of the distortions induced by the ligands, which altered the energy relations between subunits, whereas Monod regarded conservation of symmetry as a basic principle.

Symmetry allowed for regularity and structural order of molecular sequences, and this order corresponded to the specific and unique functions of living systems. Monod wondered about the role and forms of globular proteins, seeking to establish the rules governing the folding and stability of a protein. He had always been fascinated by the symmetrical, formal beauty of organisms, especially the simplest ones, the beauty that had fascinated all the great morphologists of the nineteenth century, from Cuvier to Haeckel. Monod considered symmetry a fundamental natural constant, for “without invariants, without order and symmetry science would be not merely boring, but impossible.” Order, symmetry, and beauty were part of the foundation of the scientific method: “A beautiful model or theory may not be right, but an ugly one must be wrong.”

An Ethics of Knowledge . At the beginning of the 1960’s Monod had started to ponder the general problems raised by the development of molecular biology. Life seemed finally to be yielding its secrets, and in view of the upheaval in the conception of life, evolution, and humanity itself, Monod felt an ethical duty to place science in modern culture as a whole.

During a conference at the University of Oregon at Eugene in October 1960, Monod expounded his idea that modern biology stood in contradiction to any anthropomorphic interpretation of the universe or of life. The old ethical values no longer applied, and new ones had to be discerned. In a world in which science had demonstrated that human existence itself was contingent, acquisition of knowledge had to become the supreme value. Monod dealt with this same question of the social responsibilities of scientists in the face of political power in Le puits de Syéne, a play he wrote in 1964.

Monod presented these long-pondered themes to the general public on a number of occasions: his inaugural lecture at the Collége de France (1967), the Robbins Lectures of 1969, a course he taught at the Collége de France in the year 1969-1970, and most of all his best-selling book, Le hasard et la nécessité (1970). This essay on “natural philosophy”—often considered no more than a popular exposition of the ideas of molecular biology or even a conceited attempt to invade uncharted territory—is actually an effort to examine the problem of existence itself on the basis of the scientific experience. Monod believed that the sense of alienation from scientific culture exhibited by a number of trends in contemporary philosophy and literature was the result of a distrust of science; the book is also a response to the irrationalism that underlies such positions. The deep malady of our society, which gives rise to the constant existential anguish of modern man, is our awareness of being alone in the universe.

The book’s title is taken from a quotation that is attributed to Democritus but in fact exists nowhere in the Greek philosophical texts that have come down to us and was probably an invention of Monod himself: “All that exists in the universe is the product of chance and necessity.” Monod considered this conclusion to be the quintessence of the molecular theory of the genetic code, of cell regulation, and of evolution by natural selection.

By interpreting the essential properties of organisms in terms of molecular structures, molecular biology had wrought a new definition of life, one that Monod summarized in three basic characteristics of biological objects; teleonomy, the existence of an “internal program”; independent morphogenesis; and reproductive invariance.

By the very nature of these mechanisms, evolution constructs unique objects, products of the interplay of chance and necessity. Each organism is the latest link in a four-million-year-old chain. Chance alone lies at the source of every novelty, of every creation in the biosphere. The “noise” that creeps into the perfect mechanism of invariant reproduction—noise that is preserved with the music—stands at the origin of our universe and of our lives.

This position, a kind of scientific existentialism, is quite close to French philosophical and literary existentialism, but with one big difference: for Monod, communication between the world of knowledge and the world of values is not only possible but also necessary.

The basis of Monod’s position is the “objectivity postulate”: the exclusion of any interpretation in terms of ultimate causes. This was also a reflection of his scientific trajectory and his philosophical battles against any instructive theory in biology (including that of Lysenko). For Monod, to build knowledge on the basis of a postulate is a choice—or, more precisely, an ethical choice: “To accept the objectivity postulate is therefore to state the basic proposition of an ethic: the ethic of knowledge.” In the end man must realize that he is alone in the universe, “from which he emerged by chance.” He alone is aware of his position and his destiny; and it is here, too, that the essence of man lies, in the dualism between biology and knowledge and between nature and ethics, “that rending dualism that is expressed in art, in poetry, and in human love.”

Scientific Honors . In addition to the Nobel Prize, Monod received numerous scientific honors, including the Prix Montyon de Physiologie (Académie des Sciences, 1955), the Louis Rapkine Medal (1958), the Prix Charles Léopold Mayer (Académie des Sciences, 1962). He was also named chevalier of the Ordre des Palmes Académiques (1961) and officer of the Legion of Honor (1963). He was an honorary foreign member of the Deutsche Akademie der Naturforscher Leopoldina (1965) and foreign member of the Czechoslovakian Academy of Sciences (1965), the Royal Society (1968), the National Academy of Sciences of the United States (1968), the American Philosophical Society (1969), the American Society for Microbiology (1970), the Institute of Medicine and Medical Research of New Delhi (1970) and the Accademia dei XL (1975). He was awarded honorary doctorates by the University of Chicago (1965), Rockefeller University (1970), Oxford University (1973), and the Free University of Brussels (1975).

BIBLIOGRAPHY

I.Original Works. Monod published only one book, Le hasard et la nécessité Essai sur la philosophie naturelle de la biologie moderne (Paris, 1970), trans. by Austryn Wainhouse as Chance and Necessity (New York, 1971). He published 131 scientific papers, of which a complete bibliography is given by Lwoff (1977; see below), who also gives a selected list of other publications. A large selection of Monod’s scientific papers has been collected in André Lwoff and Agnès Ullmann, eds., Selected Papers in Molecular Biology by Jacques Monod (New York, 1978). The more important scientific papers are Recherches sur la croissance des cultures bactériennes (Paris, 1941); “Sur un phénomène nouveau de croissance complexe dans les cultures bactériennes,” in Comptes rendus de l’Académie des sciences, Paris, 212 (1941), 934–936; “Sur la nature du phénomène de la diauxie,” in Annales de l’Institut Pasteur, 71 (1945), 37–40; “Mutation et adaptation enzymatique chez Escherichia coli-mutabile,” ibid., 72 (1946), 868–878, with A. Audureau; “The Phenomenon of Enzymatic Adaptation and Its Bearing on Problems of Genetics and Cellular Differentiation,” in Growth Symposium, 11 (1947), 223–289; “La technique de culture continue. Thérie et applications,” in Annales de l’Institut Pasteur, 79 (1950), 390–410; “Sur la biosynthèse de la β-galactosidase (lactase) chez Escherichia coli. La spécificité de l’induction,” in Biochimica et Biophysica Acta, 7 (1951), 585–599, with G. Cohen-Bazire and M. Cohn; “La biosynthèse induite des enzymes (adaptation enzymatique),” in Advances in Enzymology, 13 (1952), 67–119, with M. Cohn; “Specific Inhibition and Induction of Enzyme Biosynthesis,” in R. Davies and E. F. Gale, eds., Adaptation in Micro-Organisms (Cambridge, 1953), 132–149, with M. Cohn; “Terminology of Enzyme Formation,” in Nature, 172 (1953), 1096, with M. Cohn, M. R. Pollock, S. Spiegelman, and R. Y. Stanier; “Studies on the Induced Synthesis of β-galactosidase in Escherichia coli: The Kinetics and Mechanism of Sulfur Incorporation,” in Biochimica et Biophysica Acta, 16 (1955), 99–116, with D. S. Hogness and M. Cohn; “Remarks on the Mechanism of Enzyme Induction,” in Oliver H. Gaebler, ed., Enzymes: Units of Biological Structure and Function (New York, 1956), 7–28; “La galactoside-per-méase d’Escherichia coli,” in Annales de l’Institut Pasteur, 91 (1956), 829–857, with M. V. Rickenberg, G. N. Cohen, and G. Buttin: and “Bacterial Permeases,” in Bacteriological Reviews, 21 (1957), 169–194, with G. N. Cohen.

After the beginning of the collaboration with F. Jacob, the more important papers published by Monod are “Sur l’expression et le rôle des allèles ‘inductible’ et ‘constitutif’ dans la synthèse de la β-galactosidase chez des zygotes d’Escherichia coli,” in Comptes rendus de l’Académie des sciences, Paris, 246 (1958), 3125–3128, written with A. B. Pardee and F. Jacob; “The Genetic Control and Cytoplasmic Expression of ‘Inducibility’ in the Synthesis of β-galactosidase by Escherichia coli,” in Journal of Molecular Biology, 1 (1959), 165–178, with A. B. Pardee and F. Jacob; “Gènes de structure et gènes de régulation dans la biosynthèse des protélines,” in Comptes rendus de l’Académie des sciences, Paris, 249 (1959), 1282–1284, with F. Jacob; “L’opéron: Groupe de gènes à expression coordonnée par un opérateur,” in Comptes rendus de l’Académie des sciences, Paris, 250 (1960), 1727–1729, with F. Jacob, D. Perrin, and C. Sanchez.

Three classic papers, written with F. Jacob, constitute the synthesis of the work on the operon model and outline its main consequences: “Genetic Regulatory Mechanisms in the Synthesis of Proteins,” in Journal of Molecular Biology, 3 (1916), 318–356; “On the Regulation of Gene Activity,” in Cold Spring Harbor Symposium on Quantitative Biology, 26 (1961), 193–211; and “General Conclusions: Teleonomic Mechanisms in Cellular Metabolism. Growth and Differentiation,” ibid., 389–401.

After 1961, other important scientific papers are “Summary of the Columbia Symposium,” in Alfred Gellhorn, ed., Basic Problems in Neoplastic Disease (New York, 1962), 218–237; “Genetic Repression, Allosteric Inhibition, and Cellular Differentiation,” in Michael Locke, ed., Cytodifferentiation and Macromolecular Synthesis (New York, 1963), 30–64, with F. Jacob; “Allosteric Proteins and Cellular Control Systems,” in Journal of Molecular Biology, 6 (1963), 306–329, with F. Jacob and J.-P. Changeux; “Quelques réflexions sur les relations entre structures et fonctions dans les protéines globulaires,” in L’année biologique, 4 , fasc. 3–4 (1965), 231–240; “On the Nature of Allosteric Transitions: A Plausible Model,” in Journal of Molecular Biology, 12 (1965), 88–118, with J. Wyman and J.-P. Changeux; “The Operon: A Unit of Coordinated Gene Action,” in Royal A. Brink and E. Derek Styles, eds., Heritage from Mendel, (Madison, 1967), 155–177, with G. Buttin and F. Jacob; and “Introduction,” in Jonathan R. Beck with and David Zipser, eds., The Lactose Operon, (Cold Spring Harbor, N.Y., 1970), 1–14, with F. Jacob.

After 1965 most of Monod’s writings were devoted to general reflections on science, its history, and its bearings on culture and society. Among them are “De l’adaptation enzymatique aux transitions allostériques,” in Les Prix Nobel en 1965 (Stockolm, 1966), English version “From Enzymatic Adaptation to Allosteric Transitions,” in Science, 154 (1966), 475–483, repr. in David Baltimore, ed., Nobel Lectures in Molecular Biology 1933–1975 (New York, 1977), 259–280; De la biologie moléculaire à l’éthique de la connaissance, his inaugural lecture at the Collège de France (Paris, 1967); “On Symmetry and Functions in Biological Systems,” in A. Engstrom and B. Strandberg, eds., Symmetry and Function of Biological Systems at the Macromolecular Level (Stockholm, 1968), 15–27; “On Values in the Age of Science,” in Arne Tiselius and Sam Nilsson, eds., The Place of Value in a World of Facts (Stockholm, 1971), 19–27; and “On the Molecular Theory of Evolution,” in Rom Harré, ed., Problems of Scientific Revolution (Oxford, 1975), 11–24.

Monod left a large quantity of manuscripts, collected with his correspondence, notebooks, photos, and other documents, in the Monod Papers, Service des Archives, Institut Pasteur. The more important manuscripts are the drafts of two unpublished books, “Enzymatic Cybernetics” (1958), to be published with M. Cohn, and “Principes de biochimie,” a tutorial for the Sorbonne course (1963); the Jessup Lectures, the Harvey Lecture, and the Robbins Lectures; and the preliminary versions of Le hasard et la nécessité.

II. Secondary Literature. The main source of information on Monod’s life, work and personality is André Lwoff and Agnès Ullmann, eds., Les origines de la biologie moléculaire. Un hommage à Jacques Monod (Paris and Montreal, 1980), English ed., Origins of Molecular Biology: A Tribute to Jacques Monod (New York, 1979). See also some of the papers in Ernesto Quagliariello, Giorgio Bernardi, and Agnès Ullmann, eds., From Enzyme Adaptation to Natural Philosophy: Heritage from Jacques Monod (Amsterdam and New York, 1987). Horace F. Judson, The Eighth Day of Creation: Makers of the Revolution in Biology (London, 1979), contains many details of Monod’s work and thought, the result of a series of interviews with the author, and much material on the history of molecular biology. F. Jacob’s autobiograhy, La statue intérieure (Paris, 1987), contains many insights on Monod’s personality and on the history of the operon model. A short autobiography was written by Monod for McGraw-Hill’s Modern Men of Science, I (New York, 1968), and for Scienziati e technologi contemporanei (Milan, 1974), 258–262.

For an account of Monod’s life, see Melvin Cohn, “In Memoriam,” in Jeffrey H. Miller and William S. Reznikoff, eds., The Operon (Cold Spring Harbor, N.Y., 1978), 1–9: F. H. C. Crick, “Jacques Monod, 1910–1976,” in Nature, 262 (1976), 429–430; Bernardino Fantini, “Jacques Monod, 9 febbraio 1910–31 magiio 1976,” in Scientia, 110 (1975, published 1976), 899–905; André Lwoff, “Jacques Monod, 1910–1976,” in Nouvelle presse médicale, 1976, 2002–2004, and “Jacques Monod,” in Biographical Memoirs of Fellow of the Royal Society, 23 (1977), 385–412; M. R. Pollock, “Obituary: Jacques Monod,” in Trends in Biochemical Sciences, 1 (1976), N208; M. Rouzé, Les Nobel scientifiques francais (Paris, 1988); R. Y. Stanier, “Jacques Monod, 1910–1976,” in Journal of General Microbiology, 101 (1977), 1–12. For a recent biography that takes into account the documents preserved in the archives of the Pasteur Institute, see Pour une éthique de la connaissance. Textes choisis et présentés par Bernardino Fantini (Paris, 1988).

More material for the history of the French contribution to the development of molecular biology is in Pnina G. Abir-Am. “How Scientists View Thier Heroes: Some Remarks on the Mechanism of Myth Construction,” in Journal of the History of Biology, 15 (1982), 281–315; Georges N. Cohen, “Four Decades of Franco-American Collaboration in Biochemistry and Molecular Biology,” in Perspectives in Biology & Medicine, 29 (1986), S141–S148; A. Danchin, Ordre et dynamique du vivant; Chemins de la biologie moléculaire (Paris, 1978); Claude Debru, Philosophie moléculaire. Monod, Wyman, Changeux (Paris, 1987); Bernardino Fantini, “Les origines de la biologie moléculaire,” (book review), in Revue d’ histoire des sciences, 35 (1982), 178–180; C. Galperin, “Le bactériophage, la lysogénie et son déterminisme génétique,” in History and Philosophy of the Life Sciences, 9 (1988), 175–224; M. D. Grmek and B. Fantini, “Le rô du hasard dans la naissance du modèle de l’opéron,” in Revue d’histoire des sciences, 35 (1982), 193–215; F. Gros, Les secrets du gène (Paris, 1986); Jacques Monod and Ernest Borek, eds., Of Micrabes and Life (New York, 1971); K. F. Schaffner, “Logic of Discovery and Justification in Regulatory Genetics,” in Studies in the History and Philosophy of Science, 4 (1974), 349–385; and Gunther S. Stent, “The Operon: On Its Third Anniversary,” in Science, 144 (1964), 816–820.

Bernardino Fantini

Monod, Jacques Lucien (1910-1976)

French biologist

French biologist Jacques Lucien Monod and his colleagues demonstrated the process by which messenger ribonucleic acid (mRNA) carries instructions for protein synthesis from deoxyribonucleic acid (DNA ) in the cell nucleus out to the ribosomes in the cytoplasm , where the instructions are carried out.

Jacques Monod was born in Paris. In 1928, Monod began his study of the natural sciences at the University of Paris, Sorbonne where he went on to receive a B.S. from the Faculte des Sciences in 1931. Although he stayed on at the university for further studies, Monod developed further scientific grounding during excursions to the nearby Roscoff marine biology station.

While working at the Roscoff station, Monod met André Lwoff, who introduced him to the potentials of microbiology and microbial nutrition that became the focus of Monod's early research. Two other scientists working at Roscoff station, Boris Ephrussi and Louis Rapkine, taught Monod the importance of physiological and biochemical genetics and the relevance of learning the chemical and molecular aspects of living organisms, respectively.

During the autumn of 1931, Monod took up a fellowship at the University of Strasbourg in the laboratory of Edouard Chatton, France's leading protistologist. In October 1932, he won a Commercy Scholarship that called him back to Paris to work at the Sorbonne once again. This time he was an assistant in the Laboratory of the Evolution of Organic Life, which was directed by the French biologist Maurice Caullery. Moving to the zoology department in 1934, Monod became an assistant professor of zoology in less than a year. That summer, Monod also embarked on a natural history expedition to Greenland aboard the Pourquoi pas? In 1936, Monod left for the United States with Ephrussi, where he spent time at the California Institute of Technology on a Rockefeller grant. His research centered on studying the fruit fly (Drosophila melanogaster ) under the direction of Thomas Hunt Morgan, an American geneticist. Here Monod not only encountered new opinions, but he also had his first look at a new way of studying science, a research style based on collective effort and a free passage of critical discussion. Returning to France, Monod completed his studies at the Institute of Physiochemical Biology. In this time he also worked with Georges Teissier, a scientist at the Roscoff station who influenced Monod's interest in the study of bacterial growth . This later became the subject of Monod's doctoral thesis at the Sorbonne where he obtained his Ph.D. in 1941.

Monod's work comprised four separate but interrelated phases beginning with his practical education at the Sorbonne. In the early years of his education, he concentrated on the kinetic aspects of biological systems, discovering that the growth rate of bacteria could be described in a simple, quantitative way. The size of the colony was solely dependent on the food supply; the more sugar Monod gave the bacteria to feed on, the more they grew. Although there was a direct correlation between the amounts of food Monod fed the bacteria and their rate of growth, he also observed that in some colonies of bacteria, growth spread over two phases, sometimes with a period of slow or no growth in between. Monod termed this phenomenon diauxy (double growth), and guessed that the bacteria had to employ different enzymes to metabolize different kinds of sugars.

When Monod brought the finding to Lwoff's attention in the winter of 1940, Lwoff suggested that Monod investigate the possibility that he had discovered a form of enzyme adaptation, in that the latency period represents a hiatus during which the colony is switching between enzymes. In the previous decade, the Finnish scientist, Henning Karstroem, while working with protein synthesis had recorded a similar phenomenon. Although the outbreak of war and a conflict with his director took Monod away from his lab at the Sorbonne, Lwoff offered him a position in his laboratory at the Pasteur Institute where Monod would remain until 1976. Here he began working with Alice Audureau to investigate the genetic consequences of his kinetic findings, thus beginning the second phase of his work.

To explain his findings with bacteria, Monod shifted his focus to the study of enzyme induction . He theorized that certain colonies of bacteria spent time adapting and producing enzymes capable of processing new kinds of sugars. Although this slowed down the growth of the colony, Monod realized that it was a necessary process because the bacteria needed to adapt to varying environments and foods to survive. Therefore, in devising a mechanism that could be used to sense a change in the environment, and thereby enable the colony to take advantage of the new food, a valuable evolutionary step was taking place. In Darwinian terms, this colony of bacteria would now have a very good chance of surviving, by passing these changes on to future generations. Monod summarized his research and views on relationship between the roles of random chance and adaptation in evolution in his 1970 book Chance and Necessity.

Between 1943 and 1945, working with Melvin Cohn, a specialist in immunology , Monod hit upon the theory that an inducer acted as an internal signal of the need to produce the required digestive enzyme. This hypothesis challenged the German biochemist Rudolf Schoenheimer's theory of the dynamic state of protein production that stated it was the mix of proteins that resulted in a large number of random combinations. Monod's theory, in contrast, projected a fairly stable and efficient process of protein production that seemed to be controlled by a master plan. In 1953, Monod and Cohn published their findings on the generalized theory of induction.

That year Monod also became the director of the department of cellular biology at the Pasteur Institute and began his collaboration with François Jacob . In 1955, working with Jacob, he began the third phase of his work by investigating the relationship between the roles of heredity and environment in enzyme synthesis, that is, how the organism creates these vital elements in its metabolic pathway and how it knows when to create them.

It was this research that led Monod and Jacob to formulate their model of protein synthesis. They identified a gene cluster they called the operon , at the beginning of a strand of bacterial DNA. These genes, they postulated, send out messages signaling the beginning and end of the production of a specific protein in the cell, depending on what proteins are needed by the cell in its current environment. Within the operons, Monod and Jacob discovered two key genes, which they named the operator and structural genes. The scientists discovered that during protein synthesis, the operator gene sends the signal to begin building the protein. A large molecule then attaches itself to the structural gene to form a strand of mRNA. In addition to the operon, the regulator gene codes for a repressor protein. The repressor protein either attaches to the operator gene and inactivates it, in turn, halting structural gene activity and protein synthesis; or the repressor protein binds to the regulator gene instead of the operator gene, thereby freeing the operator and permitting protein synthesis to occur. As a result of this process, the mRNA, when complete, acts as a template for the creation of a specific protein encoded by the DNA, carrying instructions for protein synthesis from the DNA in the cell's nucleus, to the ribosomes outside the nucleus, where proteins are manufactured. With such a system, a cell can adapt to changing environmental conditions, and produce the proteins it needs when it needs them.

Word of the importance of Monod's work began to spread, and in 1958 he was invited to become professor of biochemistry at the Sorbonne, a position he accepted conditional to his retaining his post at the Pasteur Institute. At the Sorbonne, Monod was the chair of chemistry of metabolism , but in April 1966, his position was renamed the chair of molecular biology in recognition of his research in creating the new science. Monod, Jacob, Lwoff won the 1965 Nobel Prize for physiology or medicine for their discovery of how genes regulate cell metabolism.

See also Bacterial growth and division; Microbial genetics; Molecular biology and molecular genetics