Origins of Molecular Biology: A Tribute to Jacques Monod, Revised Edition
Editor: Agnes Ullmann1Category: History of Science
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Jacques Monod was undoubtedly one of the most creative minds in 20th century science. His career spanned the early years of molecular biology, a “golden age” of creative thought and hypothesis-driven research. Monod's work at the Pasteur Institute was marked by an unbroken succession of great discoveries. Many of the concepts he developed are still central to modern biology, including the elegant theory of allostery, which arose from his interest in how proteins recognize chemical signals. Scientists now recognize that most mechanisms of cell signaling involve allosteric interactions, and even the prion theory rises from this concept.
A collection of personal accounts from friends and colleagues, this revised volume offers the reader a glimpse of the charismatic personality of Jacques Monod. Many aspects of his life are touched on lightly: music, sailing, philosophy, rock climbing. His skills as theoretician, experimentalist, administrator, and mentor, on the other hand, appear often and powerfully in many of these essays. Each chapter reveals the excitement and camaraderie of Monod's laboratory and the compelling fascination of the birth and development of concepts, the building of a discipline. This book enriches modern biologists, and nonscientists as well, with an understanding of defining events of the past.
The new Origins of Molecular Biology incorporates the complete text of Monod's Nobel Prize lecture and the complete bibliography of his scientific papers. Dozens of personal photos of Monod and his colleagues are included, with thumbnail biographies of the contributors, eminent scientists in their own right.
Hardcover, 335 pages, illustrations, index.
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Chapter 1 : Jacques LucienMonod: 1910–1976
- Author: A. M. Lwoff
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This chapter talks about Jacques Monod, who became Director of the Pasteur Institute in April 1971. It talks about the outer and inner man. Shortly after his arrival in Lwoff’s attic, Jacques Monod had collaborated with Elie Wollman in a study of the effect of phage infection on β-galactosidase synthesis. The scientists, technicians, and secretaries who worked with him could always count on his sympathy, advice, and support; in return, he received an unreserved loyalty and devotion from nearly all of them. If Jacques Monod’s faults have been evoked here, that is because one cannot write other than honestly about such a man. At the risk of eliciting sniggers from readers for whom the very notion of the hero is a medieval anachronism, it must be said that he was of heroic stature. The author hopes that this is evident from the preceding account of his life. One common French quality which Monod did not share was the Latin brand of sentimentality. Desperately searching as Director for solutions to the problems ofthe Institute, he hit on the notion of rebuilding it on the suburban campus at Garches, financing the operation by the sale of the very valuable land which it occupies in Paris.
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Chapter 2 : Lwoff (1902–1994): Remembrances
- Author: Agnes Ullmann
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Madeleine Jolit provides information on her experience in lab. The author and her group were isolating mutants and carrying out the first assays of amylomaltase and galactosidase. Jacques Monod invented the “bactogène,” an apparatus designed to maintain “a continuous process for the cultivation of microorganisms, involving continuous and simultaneous addition of nutrient medium into, and removal of culture liquid from a fermenter." Monod was busy setting up his new service, welcoming and taking care of his students both in the lab and at the university. He would work only occasionally at the bench now, participating in some permease assays, having a look at the petri dishes. The author is thankful to this unique atmosphere which everyone in her group had created. She had known many labs in France and abroad, but had never seen anything like the one she had worked at. In that sense, she and her group had been very lucky.
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Chapter 3 : The Outer and The Inner Man
- Author: Roger Y. Stainer
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This chapter provides an overview of Madeleine Brunerie’s experience with Jacques Monod in the Institut Pasteur. On June 29, 1954, in the reserve room for laboratory material of the old Service de Chimie Biologique, Jacques Monod appeared forever in the author’s life as a charming and very courteous man. The author first believed she would not be as impressed by him as she had been by Professor Macheboeuf. Sometime in late October 1959 she understood that her secret hopes might come true. A close friend of Jacques Monod asked the author for a curriculum vitae and reprints to support a proposal for a scientific prize to be shared with Andr´e Lwoff (in fact the Nobel Prize). The author felt it was a confirmation of her high opinion of him, and afterward, each fall, the author waited hopefully for Nobel news. He was also generous with people he did not even know. He never answered Christmas cards, but he never failed to reply to letters from troubled or ill people who asked him for moral help or medical advice. Not a physician himself, he always tried to give either the adequate information or the opinion from a specialist. On April 15, 1971, Jacques Monod became General Director of the Institut Pasteur. Accepting this leadership, he undertook it with the same passion he exerted in whatever he did. A few days later, on Monday, May 31, 1976, Jacques Monod died in Cannes, where he had gone for a rest.
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Chapter 4 : A Bit of Luck
- Author: Madeleine Jolit
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In this chapter, the author relates his experiences as Jacques assistant at the laboratory. The core of the question in those days (1948–1950) was to understand why there was an increased rate of enzyme formation upon addition of the substrate (adaptation) or a diauxic inhibition. The working hypotheses in the lab were that “many different enzymes may stem from a common precursor or pool of precursor molecules” and that the “master pattern configuration determining the specificity was not the enzyme itself but a pre-existing self-duplicating unit (the gene).” On April 11, 1949, the author and Jacques spent the day at 37№C to give birth to the “bactogène.” The results were encouraging and Jacques wrote in his notebook the theory which was the basis of the bactogène.
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Chapter 5 : Once Upon a Time . . .
- Author: Madeleine Brunerie
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The author narrates how she was supposed to study the hypothetical relationships between lycopene and vitamin A2 and was provided with a barrel of spoiled tomato juice from which to extract lycopene. Experiences of the author and her old friend, Georges Cohen, are narrated in this chapter, highlighting the opportunity they had to listen to and meet, in an informal and congenial atmosphere, some of the leading contemporary biochemists and experimental biologists. Next the author talks about her experiences with Jacques Monod. The club was Jacques Monod’s creation and reflected his generosity and devotion to the education of younger scientists. The author had attended the meeting "Les unites douees de continuite genetique" at which Andre Lwoff and Jacques Monod had participated, and read with great fascination the recent review published in the Growth Symposium by Jacques Monod. The study of the effect of cations on the activity of β-galactosidase and the affinity of its substrates was also part of the author's occupations.
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Chapter 6 : Le Labo de Jacques
- Author: Annamaria Torriani
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On arriving at the Pasteur Institute, the author told Jacques Monod that he had come there to learn about adaptive enzymes and that he wished him to suggest a problem for him to work on. As a matter of fact, a strong candidate for a “preenzyme” had already been found in noninduced E. coli by Mel Cohn and Annamaria Torriani. Cohn and Torriani had shown that there was present in extracts from noninduced cells an enzymatically inactive protein which they called Pz. This protein cross-reacted with antibodies raised in rabbits by immunization with purified β-galactosidase (Gz). The experiment that Jacques proposed was indeed very simple. He had recently received a series of twenty auxotrophic mutants of E. coli from Bernard Davis, each requiring a different amino acid or accessory factor for growth. Enzyme synthesis began almost immediately upon adding back the required amino acid or growth factor. At this time, the kinetics of enzyme production were being followed as a function of time. It seemed to the author that if growth were indeed required, enzyme production should be measured with respect to the increase in bacterial mass. The final and complete elimination of the Pz protein as a precursor having anything to do with induction of β-galactosidase synthesis came a few years later when Cohn, Lennox, and Spiegelman transduced the lacZ gene into an i+z- Shigella dysenteriae containing no Pz, and obtained lac+ recombinant Shigella.
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Chapter 7 : Remembrance of Things Past
- Author: Germaine Stanier (Cohen-Bazire)
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In this chapter the author talks about Jacques Monod and provides a wide range of personal memoirs: the reactions, experiences, and subjective impressions of his friends and colleagues, compiled as a historical record of how Jacques appeared to those who knew him well. There are a few who, through ignorance or envy, have regarded Jacques mainly as a conceited and arrogant egoist. There are others, dazzled by his brilliance and charm, who could see nothing but genius and virtue. It was mainly during 1952–1953, in close association with Jacques at the Pasteur Institute, that the author was able to look behind the scenes and become involved in some of the scientific problems of enzyme induction as they were being studied in Jacques’ group in the early days before the Great Enlightenment. Jacques had worked almost exclusively with E. coli β-galactosidase, where basal enzyme was so low in the commonly used wild type that it could, in principle, have been explained (as he was always emphasizing) by the few constitutive mutants that were known to be present.
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Chapter 8 : What Happened to Pz?
- Author: A.M. Pappenheimer, Jr.
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After the liberation, in 1945, Jacques Monod joined André Lwoff’s laboratory at the Pasteur Institute. The organizers of a symposium had asked the author to trace in a personal way the contributions of Monod to the origins of their present concept of induced enzyme synthesis. The key to the power of these Monod theories, 1947, 1961, or 1965, was simply that they were physiological-level theories capable of reductionism; that is to say, they were capable of an analysis at the level of chemistry. The author believes that Monod had one of the most creative minds of our time because he had one of the most creative minds simply because he thought deeply, ascetically, about how knowledge is acquired; and it is this process that he insisted should be the only basis for a system of ethical and aesthetic values.
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Chapter 9 : An Exciting but Exasperating Personality
- Author: Martin Pollock
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Soon after 1944, Jacques Monod organized informal meetings at which Monod and the author presented their work, subjecting it to the criticism of all the attendants. During 1948, the author and Marie-Louise Hirsch observed that the growth of a leucine-requiring mutant of Escherichia coli was inhibited by valine or isoleucine, whereas its growth on leucylglycine or glycylleucine was unaffected by the antagonists. In the discussion of the paper, one of the hypotheses put forward was the existence of a selective permeation system in E. coli, stereo-specific for the three branched-chain amino acids. Jacques struck out the corresponding paragraph with a choleric red pencil and told the author, "Every time a microbiologist has no clear explanation for a nutritional puzzle, he calls upon permeability to conceal his ignorance." The paper appeared in 1953 with alternative explanations, which turned out to be entirely wrong. The fact that more than one activity is controlled by the same pleiotropic mutation did in an indirect manner help the development of the operon concept. The author says that people have recalled how Jacques' lab was associated with the discovery of the repression of biosynthetic enzymes by their end products and with the generalization of the negative-regulation model in biosynthetic systems, and some others have described the rationale by which Jacques arrived at the concept of allosteric enzymes.
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Chapter 10 : In Memoriam
- Author: Melvin Cohn
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The most promising approach to the study of the lactose system appeared to lie through genetic analysis. Conjugation had become a useful instrument for the analysis of any bacterial function. Starting from the viewpoint of the phage system, the author wanted Jacques’ opinion about the implications for the lac system of two basic concepts: (1) Repression (or induction) operates not progressively, but like a switch, by a yes-or-no, an on-or-off mechanism that involves only two states; and (2) Genetic units of an order higher than the gene must exist: “units of activity” that contain several genes subject to unitary expression, such expression probably being regulated at the level of DNA. Actually," Jacques concluded, "there is no direct evidence either for or against the idea of repression at the level of DNA, and we should keep this possibility in mind." His objection to the switch, the on-or-off concept of protein synthesis, appeared more serious to the author. During a small meeting in Sydney Brenner's room at King's College, the author described the latest results obtained in Paris and Berkeley on the regulation of protein synthesis and mentioned once again the unstable RNA hypothesis. The whole system could be viewed as an on-or-off switch alternating between two states, just like the switch of the small electric train. In the fall of 1960, Jacques and the author decided to assemble the various pieces of information then available into a story, mainly written by Jacques.
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Chapter 11 : Permeability as an Excuse to Write What I Feel
- Author: Georges N. Cohen
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This chapter states that initial rates of β-galactosidase production were very similar with and without inducer. The author thinks it is safe to say that this PaJaMa experiment provided the basis and frame of reference for further studies on the mechanism of enzyme regulation. The PaJaMa experiment is the basis of a historical-philosophical study of the nature of discovery by Kenneth Schaffner, who interviewed the individuals involved and reconstructed a composite of what happened. From the PaJaMa studies on the molecular nature of induction—proposed to be the effects of interaction of a lactose-related inducer with the repressor protein, which initiates a quite different process of gene expression—Jacques Monod became interested in how a small molecule can modify a protein’s function. The author says that the time spent by him in Monod’s laboratory was certainly one of the most remarkable of his career, as he learned there of the great power of genetics in combination with biochemistry.
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Chapter 12 : The Switch
- Author: François Jacob
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The epoch, that of molecular biology, may in its turn be seen as a composition of various “scenes,” as those which are threaded along a play by Bertolt Brecht, where a multitude of protagonists move about and spread their energy with passion. Jacques Monod has been, and will be remembered as, one of those very great men around whom the main events of contemporary biology have synthesized and harmoniously gathered, as the large tableaux around Brecht’s hero. According to the author, the history of RNA is that of a mysterious substance which did not interest anybody except a few cytologists. The finding that plant viruses contain, apart from proteins, ribonucleic acid has not only led one to perceive the functional universality of the RNA in biological systems, but has also helped in the analysis of its physicochemical composition. Jacob, Meselson, and Brenner brilliantly demonstrated that Volkin and Astrachan's RNA operated on preexisting ribosomes as a template biopolymer, organizing as a real "viral messenger" the proteins newly synthesized by the phage. The birth, at times difficult, of messenger RNA was received with great acclaim. The finding of a strict complementarity in the sequences of the messenger RNA and the homospecific DNA (Spiegelman) was also a major contribution.
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Chapter 13 : The PaJaMa Experiment
- Author: Arthur B. Pardee
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The author undertook a systematic screening of the inducing capacity of all available thiogalactosides, of their affinity to the purified β-galactosidase, and of their “apparent affinity” to the intracellular enzyme. Constitutive strains, which synthesized β-galactosidase in media devoid of inducer, had been isolated. The prevailing hypothesis was that they accumulated an “internal” inducer. The availability of powerful inhibitors of induction prompted the author's group to check their ability to block the constitutive synthesis, with entirely negative results. The author attempted to map the operator gene. The bias was that the strains utilized were heterogeneous in the activity of a galactose transport system. The operator moved back to one end of the galactose operon. The striking similarity exhibited by the regulatory elements of the lactose and galactose systems strengthened both the repressor hypothesis and the notion that the unit of genetic expression can comprise several genes. Taking advantage of the fact that the lactose regulator gene i is close enough to the genes it controls to also remain associated to them in the transducing phages, Salvador Luria could establish that the cointegration of an active i gene was necessary and sufficient to prevent the derepression of the lactose enzymes during the phage vegetative growth. Unfortunately, the structure of the galactose system did not enable one to decide if the same explanation accounted entirely for the derepression of galactokinase. The switch "from lactose to galactose" induction analysis also supplied unexpected insights on the deregulation of host enzyme synthesis by viral induction.
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Chapter 14 : The Messenger
- Author: François Gros
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The two-month lab course designed by Jacques Monod in 1956 and 1957 was intended to breach the gap between university teaching and living research. It was the author's real introduction to what was to become molecular biology—covering DNA, proteins, physiology, and biochemistry of bacteria and phages. The study of cross-reacting material (CRM) was of course prompted by the need to map the structural gene for galactosidase so it could be distinguished from genes involved in induction. But it was also to understand the obscure relation between that old ghost Pz and CRM of galactosidase. A scheme of competition between galactosidase and CRM was devised in which the only thing measured was enzyme activity. The is mutant which became a cornerstone of the theory of induction by negative control appeared by luck. It was a strange lac negative, giving numerous revertants which were all constitutive. It proved to be trans-dominant and fit nicely with the theory.
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Chapter 15 : From Lactose to Galactose
- Author: Gérard Buttin
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The hypothesis of catabolite repression predicts that energy sources other than glucose should repress glucose-sensitive enzymes in cells grown in media that limit their ability to utilize the catabolites rapidly for the synthesis of macromolecules; and in fact, partial amino acid, purine, pyrimidine, or phosphate starvation has this effect. As the names imply, in a physiological sense, induction is a positive control and catabolite repression a negative control. Nevertheless, for lac and hut (histidine degradation) and many other systems, induction actually reflects negative control at the molecular level, and in all cases catabolite repression appears to reflect positive control at the molecular level. The observation by Ullmann and Monod and independently by Perlman and Pastan that the addition of cyclic AMP can overcome the repressive effect of glucose led to the discovery that the transcription of genes coding for enzymes subject to catabolite repression requires activation by the catabolite-activating protein (CAP) charged with cyclic AMP. Glucose appears to lower the intracellular level of cyclic AMP by an as-yet-undiscovered mechanism. In short, the apparent escape from catabolite repression of histidase really reflects a phenomenon distinct from catabolite repression: the activation by glutamine synthetase (GS) of the transcription of genes coding for enzymes that can supply the cell with ammonia or glutamate.
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Chapter 16 : The Wonderful Year
- Author: David Perrin
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During the course of an analysis of the ability of compounds related to lactose to act as inducers of β-galactosidase, Howard Rickenberg, working with Georges Cohen and Gérard Buttin in Monod’s laboratory, discovered the inducible transport system (“permease”) for β-galactosidases. Monod's earlier studies had shown that the genetic regulation of the galactoside permease was coordinated with that of the β-galactosidase, and indeed that the gene for β-galactosidase (the z gene) and that for the permease (the y gene) were part of the same genetic unit, or operon. Monod proposed that the permease would have the property of binding its substrate and suggested that the author's group try to identify it by this property. The active galactoside permease has not yet been isolated, but Fox and Kennedy have isolated and characterized the y gene product, which they called the M-protein, after modifying it with the N-ethylmaleimide, using a clever modification of the binding idea based on Adam Kepes' observation that the β-galactosidase permease contains essential sulfhydryl groups that are protected by the substrate. The exit of galactose was also found to be inhibited by substances, such as α-methyglucoside and succinate that were not substrates for the galactose permease. Monod was intimately involved in everything that was going on in the laboratory, from sporulation to permeation, and in those days he was always in the laboratory, available for discussion of the work.
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Chapter 17 : From Diauxie to the Concept of Catabolite Repression
- Author: Boris Magasanik
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The most universally known and the most often misquoted is "Whatever is true for E. coli is true for an elephant." Jacques Monod's faith in the universality of the laws and mechanisms of biology contrasting with his provocative attitude of apparent cynicism in front of the great problems of "the secrets of life" was fascinating to those of us who surrounded him. Monod showed with Melvin Cohn that the kinetic parameters as well as the immunochemical properties of β-galactosidase did not change when a variety of inducers were utilized with the inducible strain or compared to the enzyme of the constitutive mutants, where no inducer was used. The rapid regulatory switches pointed toward an unstable intermediate embodying the genetic information between gene and protein. The intermediate, called "the messenger," soon became the messenger RNA, (mRNA). The progress of translation is independent of both the termination of the transcription and the survival of the initial end of mRNA. The survival of the initiating end of mRNA is independent of the intracellular concentration of inducer and largely, although not completely, independent of transcription. The mRNA is polycistronic and stays probably as a single piece for the major part of its functional lifetime. At the steady state of all processes, the polycistronic mRNA is, however, seldom integral. The major part of it should be pieces: some unfinished, some already missing the initiating end, some devoid of both, still growing on one side while losing the other side at the same speed.
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Chapter 18 : Permeases and Other Things
- Author: B. L. Horecker
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The enzymological and purification data on acetylase, pointed out some of the difficulties in believing that acetylase was permease or part of it, but left it an open question. One of the first things to do was to get acetylase in pure form, find out how much was made in the cell, and measure its size. The surprise from the purification data was that there was very much less acetylase produced than β-galactosidase, 10 to 35 times less by weight, depending on conditions of growth. Acetylase was fairly straightforward. By physical and chemical studies it was clearly a dimer of two identical chains, each of about 30,000 daltons. Antibody to acetylase did not cross-react with β-galactosidase, nor with anything else in the cell. The subunit structure of β-galactosidase was a difficult problem. But when end-group and other studies were carried out, it became clear that β-galactosidase contains long, not short chains. In fact, the polypeptide contains 1,021 amino acids. β-Galactosidase has been a challenge, worthy of a lot of work. It still hasn’t lost its interest. There were and still are interesting mutants, as well as the structure to wonder about. Though acetylase was and is revisited from time to time, β-galactosidase has been the focus of attention in the author's lab for many years.
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Chapter 19 : Early Kinetics of Induced Enzyme Synthesis
- Author: Adam Kepes
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The author arrived too late at the Pasteur Institute to participate in the great adventure: the founding of molecular biology. But she was around long enough to witness many later developments. A few years later, a paper by the Jacques Monod impressed the author profoundly. Jacques was now ready to admit that cyclic AMP plays an important regulatory role. Many of the members of the group had decided at that time to assume new directions. This gave Jacques mixed feelings of loneliness, nostalgia, and freedom. At the beginning of 1970 Jacques was asked to become Director of the Pasteur Institute, and he immediately gave up the idea of a sabbatical leave and a few months later he became Director of the Pasteur Institute. A few months later he became ill and had to slow down his activities. Vicky was the only one who for months and months still desperately waited every evening at the door and could not understand why his master did not call for him anymore.
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Chapter 20 : From Acetylase to β-Galactosidase
- Author: Irving Zabin
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Enzymes involved in the degradation of substrates similar in structure seemed likely to derive from the same precursor. For this reason Monod decided to study the enzymes involved in the degradation of two similar disaccharides: lactose and maltose. As a result, two communications were presented on July 12, 1948, at the French Academy of Sciences. One, signed by J. Monod, A. M. Torriani, and J. Gribetz, described the occurrence, in Escherichia coli, of lactase, only present in lactose-grown cells. In the other, signed by J. Monod and A. M. Torriani, was reported the existence of an "amylomaltase," present exclusively in maltose-grown cells. Because the "lactase" was in fact a β-galactosidase of broad specificity, it became possible to synthesize a chromogenic substrate for this enzyme, and therefore to render its assay both very simple and very sensitive, while the assay of amylomaltase still required the use of the cumbersome Warburg apparatus. The corresponding mutations generally mapped in the vicinity of the amylomaltase-phosphorylase operon. Other mutations, mapping in this second region, led to the most incredible phenotypes. The unwarranted complexity of the two most well-known positively regulated systems made Monod, and many others, suspicious that something basic could be wrong. Still, over the years the author could not escape imagining what would have happened if Monod had focused on amylomaltase, rather than on β-galactosidase.
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Chapter 21 : Being Around
- Author: Agnes Ullmann
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During the spring of 1962, a biochemistry course on “the biosynthesis of macromolecules,” presenting experiments which were being done at that very time, was given at the Faculté des Sciences de Paris by Jacques Monod. The courses one usually attended at that time consisted of the boring recitation of formulas, like that of vitamin B12 or testosterone without any reference to the ideas and the experiments which had led to the comprehension of these structures. The topography of the lab favored communication: it was a long corridor with one pole of attraction, “le labo bleu,” which opened to Jacques Monod’s office. Another pole of attraction came later at the other end of the corridor: Françcois Jacob’s door. The last room was the kitchen, in which Jacques Monod used to come and talk with people. In this forum, theoretical and technical problems were discussed amiably, and we learned to know and appreciate one another.
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Chapter 22 : Another Route
- Author: Maxime Schwartz
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At the meeting of the author and Jacques Monod, Monod explained to him how he intended to organize his biological training. By deciding that his essay should bear on "prediction of the conformation of a protein from its amino acid sequence," Monod put the author right into the field of protein folding, a theme which has since remained the subject of his research. When, after a decade, the author tries to understand why he got so deeply involved in that subject, he can find two main reasons, both related to the fact that Monsieur Monod himself had become particularly interested in protein folding. To account for the large size of proteins, Monod tried to analyze the constraints which the functional features of a protein exert on its structure: the existence of a catalytic site, requiring the exact relative positioning of half a dozen amino acids; the stability of the protein conformation, requiring, according to the “oil drop model,” a hydrophobic core; the solubility of the molecule, requiring the presence on its surface of polar residues that are able to interact with the solvent. Monod's interest in protein conformation survived his involvement in the direction of the Pasteur Institute.
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Chapter 23 : The Lively Corridor
- Author: Marie-Hélène Buc
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Jacques Monod attached as much importance to the manner in which ideas were expressed as to the ideas themselves. The study of regulatory enzymes was becoming one of the research topics of Jacques Monod's laboratory. First, the fact that Um-barger's observations were confirmed: the inhibitory effect of L-isoleucine was specific. One of the highlights of the symposium was, undoubtedly, Jacques Monod's presentation of the concluding remarks. These ideas were further elaborated in the Journal of Molecular Biology, in a review article entitled "Allosteric proteins and cellular control systems." This text was written by Jacques Monod during 1962. Models of steric hindrance and allosteric effect were being completed by a less plausible model by direct interaction. The general discussion in the 1963 review finishes with the generalization of the concept of allosteric protein. These molecules would be the key component of any system of biological control, from the regulation of enzyme activity to enzymatic adaptation, passing by hormone action. The hypothesis is put forward that gene repressors are also allosteric proteins. In the course of the year 1963, the author presented to Jacques Monod a first draft of his thesis work. They then had to find a mechanism which would create interactions between identical sites within the oligomer. A presentation beginning with the mathematical model was finally adopted, which could not fail to please Jacques Monod by its highly theoretical and formal aspect.
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Chapter 24 : To Fold or Not to Fold: The Way Toward Research
- Author: Michel Goldberg
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The author's plan was to learn phage genetics for use in later physicochemical studies of genetic problems. Two surprises were awaiting him. One was a student (Alex Fritsch) who wanted to work with him; he was particularly interested in the uses of the analytical ultracentrifuge. The second surprise was a manuscript by Jacques Monod on a model for allosteric enzymes. It proposed a general model for allosteric enzymes. The particular protein which was discussed in detail was hemoglobin, which was not then known to be an allosteric protein. He looked down at the set of four dice, glued together, which he used as a model in thinking about the symmetry properties of oligomeric proteins. But the logic of the allosteric model seemed to require that proteins be flexible. Jacques admitted then that the answers to allosteric mechanisms would probably come from physicochemical studies of purified proteins, together with their crystal structures. Hemoglobin, in particular, became one of the most intensively studied molecules known to chemists.
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Chapter 25 : A Ph.D. with Jacques Monod: Prehistory of Allosteric Proteins
- Author: Jean-Pierre Changeux
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By his theories and experiments, Jacques Monod permanently altered the thinking of scientists in genetics and molecular biology. Scientific discussions with him always seemed to the author like a deep-sea diving expedition in which one plunges into a new world with exciting terrain and a colorful fish flashing by at breathtaking speed. One discussion is particularly memorable to the author as illustrating the strong philosophical and Descartian logic which permeated Jacques' thinking. They were discussing their alternate theories of cooperativity which had recently appeared in the literature and in particular the role of symmetry. The more they talked the more it became apparent that the two theories were internally consistent but each proceeded from different premises. No logical argument can prove or disprove internally consistent theories any more than they can prove or disprove Euclidean versus non-Euclidean geometry. They discussed at length the analogy between scientific dangers and physical dangers. They both agreed that scientists must venture into uncharted seas to make progress and fear of the turbulence of controversy and the disaster of being wrong inevitably leads to repetitive science. Monod left contributions of great brilliance in the annals of science and memories of enchanted interludes in the hearts and minds of friends over the whole world.
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Chapter 26 : Discussions about Proteins
- Author: Robert L. Baldwin
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This chapter focuses on mother nature and the design of a regulatory enzyme. Jacques Monod was looking at a nascent science from his peculiar point of view, molecular evolution. Each new result was presented in the lecture as one tiny piece in the puzzle that Mother Nature had solved. Many scientists appreciate the Monod–Wyman–Changeux model (M–W–C model) because it is a simple, elegant, and imaginative proposal. The author feels sad that a very significant confrontation between two different approaches of molecular biology is reduced to a formal conflict between two hypothetical kinetic pathways. He thinks that what is really at stake is a triple issue. First, it is a good example of classical opposition between informative and selective theories in biology (in the M–W–C model, preexisting states are selected by small metabolites, the concentrations of which reflect the various physiological needs of the cell; according to Koshland and his collaborators, the ligand informs the protein structure and directs its conformational change). Second, they diverge on the basic unity or on the diversity of the structural solutions historically retained by evolution to solve a problem of regulation. Third, Monod’s theory is falsifiable: to refute it does not simply mean to show how significantly the real solutions differ from a model. In Monod, as a public man, the author found the basic need for creative freedom.
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Chapter 27 : Some Memories of Jacques Monod
- Author: D. E. Koshland, Jr.
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The author's first encounter with Jacques Monod was over forty years ago when he gave the Dunham lectures at the Harvard Medical School. In 1965 that Monod and the author published their joint paper with J.- P. Changeux on what has come to be known as the M–W–C allosteric model. This paper, which appeared in the Journal of Molecular Biology, grew out of a seminar the author gave in Paris in 1964; and in turn was the result of a talk given the preceding summer at Cold Spring Harbor. The underlying linkage principles, in accordance with which ligand-linked conformational changes can give rise to both homotropic and heterotropic control, had already been laid down, and it was this subject that formed the basis of the talk the author gave in Paris. The introductory part dealing with the possible role of symmetry in the assembly of oligomeric proteins was largely due to Jacques. Although the author had introduced the concept of symmetry, pointing out that insofar as site interactions were the reflection of the spacing of the sites, symmetry of function as represented by symmetry of the binding curve implied a certain geometric symmetry in a macromolecule. The rest of the paper was based largely on the sure principles of classical thermodynamics. In the talks by Jacques and the author, Jacques stressed the geometric symmetry concept; the author stressed more on abstract thermodynamic ideas, taking the occasion also to introduce the closely related concept of the binding potential.
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Chapter 28 : Mother Nature and the Design of a Regulatory Enzyme
- Author: Henri Buc
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Abstract:
The author thinks his first meeting with Jacques Monod was in the mid-1950s, probably after Jim Watson, and he had put forward the DNA structure. He clearly recalls giving a seminar at the Pasteur Institute in which he suggested the quite erroneous theory that during protein synthesis the inducer was needed to fold up the enzyme correctly. Monod was an excellent sailor who could manage his 37-foot sloop by himself, whereas he was always a rather bumbling amateur. One year there was a scientific meeting at Naples. This chapter discusses the author`s most rewarding sailing experience with Jacques. Jacques was very companionable—one always enjoyed an evening when he was there—and it’s not everyone that one can go sailing with. Their general attitude to most scientific matters was very similar, yet their backgrounds were sufficiently different to make both of them eager to hear what the other thought. As each new thing comes up, one regrets so much not being able to talk it over with Jacques. Jacques would understand so quickly; he would appreciate the importance of the point; he would say something illuminating that hadn’t occurred to one; one could reach agreement together and a deeper understanding. It is for this reason that the author finds that he has no stomach for writing a book about Jacques` work even though the author still feels a small nagging sense of duty.
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Chapter 29 : Recollections of Jacques Monod
- Author: Jeffries Wyman
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This chapter discusses the author’s relationship with Jacques Monod, who is a Nobel Prize-winning French biologist and director of the Pasteur Institute in Paris. Having chosen Jacques for a role model, the year the author spent in Jacques’ ambience had a profound effect on his formation as a scientist. The author talks about the lunchtime conversations at Jacques’ table that covered a broad range of scientific, political, and cultural subjects. According to Jacques, the most recent of the evolutionary accidents was responsible for the emergence within the biosphere of a new realm, the noosphere, or realm of knowledge. Once the noosphere had come into being there began within it an evolutionary process based on the natural selection, not of genes, but of ideas. Of all the ideas in the noosphere, the most powerful to have emerged is that of objective knowledge. Jacques now attempts to explicate the concept of objectivity that was to be central to Chance and Necessity: for him objective knowledge is that which has no source but the systematic confrontation of logic and experience. The author met Jacques one more time, at the 1974 Colloquium “Biology and the Future of Man” held at the Sorbonne, and they exchanged a few amicable civilities, without finding words for a substantive conversation.
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Chapter 30 : Sailing with Jacques
- Author: Francis Crick
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The author recalls a visit of Jacques to Urbana in the early 1950s, in the course of which they talked of enzyme induction and of host-induced phage modification. The author's experiments at that time dealt with the expression of phage-transduced lactose genes. It was a well guarded secret that similar experiments on lactose-transferring episomes were underway in the laboratory, the experiments which later led to the formulation of the operon theory. In his last years Monod became concerned with the impact of biology on human society, and, characteristically, tried actively to promote the field of bioanthropology. The author believes Monod was inclined to put more confidence in the ethological and sociobiological approaches than the author thought was warranted. However, Monod was not dogmatically “biologizing” the human predicament, but simply trying to choose and develop a feasible approach.
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Chapter 31 : The Ode to Objectivity
- Author: Gunther S. Stent
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The author and Jacques Monod regularly had numerous conversations. Two major themes were present in Monod’s thoughts. The first one was concerned with the methodology necessary for investigating phenomena; it is developed at length in K. Popper's books, and, indeed, Monod has contributed to their diffusion in France: the best way to contribute to building science is to progress by making conjectures and trying to refute them. The second theme is clear in the allostery theory. The author emphasizes the hierarchical order of the allosteric regulation and regulations of transcription. He describes the main lines of a conjecture which would help to state precisely the question—Is a still more general system, allowing, for instance, the coupling between the cellular metabolism and macromolecular syntheses, possible?—keeping in mind the methodology alluded. This chapter outlines the conjecture and questions raised by research work of Jacques Monod. The author used to submit all the problems for comment to Monod, just a short time before his death. As he always did, Monod offered new conjectures and then proposed experiments to refute them.
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Chapter 32 : Jacques Monod: Scientist, Humanist, and Friend
- Author: S. E. Luria
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In the course of research work, the author's group observed a fact that seemed very significant. A certain compound, phenyl-β-D-thiogalactoside, devoid of inductive capacity, proved capable of counteracting the action of an effective inducer such as methyl-β-D-thiogalactoside. The study of galactoside permease was to reveal another fact of great significance. Several years earlier, following Lederberg’s work, the group had isolated some “constitutive” mutants of β-galactosidase, that is, strains in which the enzyme was synthesized in the absence of any galactoside. The author then had to admit that a constitutive mutation, although very strongly linked to the loci governing galactosidase, galactoside permease, and transacetylase, had taken place in a gene (i) distinct from the other three (z, y, and Ac), and that the relationship of this gene to the three proteins violated the postulate of Beadle and Tatum. The model that the group had studied is interesting primarily because it proposes a functional correlation between certain elements of the molecular structure of proteins and certain of their physiologic properties, specifically those that are significant at the level of integration, of dynamic organization, of metabolism. If the proposed correlation is experimentally verified, then it is an additional reason for having confidence in the development of our discipline which, transcending its original domain, the chemistry of heredity, today is oriented toward the analysis of the more complex biological phenomena: the development of higher organisms and the operation of their networks of functional coordinations.
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Chapter 33 : Conjectures and Refutations
- Author: Antoine Danchin
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This chapter presents a list of the scientific publications written by Jacques Monod from 1931 to 1976.
There are no separately available contributors for this publication.