Monod and Jacob became famous for their work on the E. colilac operon, which encodes proteins necessary for the transport and breakdown of the sugar lactose (lac). From their own work and the work of others, they came up with a model for how the levels of some proteins in a cell are controlled. In their model, the manufacture of a set of related proteins, such as the ones encoded within the lac (lactose) operon, is prevented when a repressor protein, encoded by a regulatory gene, binds to its operator, a specific site in the DNA sequence that is close to the genes encoding the proteins. (It is now known that a repressor bound to an operator physically blocks RNA polymerase from binding to the promoter, the site where transcription of the adjacent genes begins.)
Study of the control of expression of genes in the lac operon provided the first example of a system for the regulation of transcription. Monod also suggested the existence of messenger RNA molecules that link the information encoded in DNA and proteins. For these contributions he is widely regarded as one of the founders of molecular biology.[7][8]
Career and research
As a student at the University of Paris, Monod discovered that the coursework was decades behind the current biological science. He learned from other students a little older than himself, rather than from the faculty. "To George Teissier he owes a preference for quantitative descriptions; André Lwoff initiated him into the potentials of microbiology; to Boris Ephrussi he owes the discovery of physiological genetics, and to Louis Rapkine the concept that only chemical and molecular descriptions could provide a complete interpretation of the function of living organisms."[9]
Before his doctoral work, Monod spent a year in the laboratory of Thomas Hunt Morgan at the California Institute of Technology working on Drosophila genetics. This was a true revelation for him and probably influenced him on developing a genetic conception of biochemistry and metabolism.[10]
Monod's interest in the lac operon originated from his doctoral dissertation, which explored the growth of bacteria on mixtures of sugars and documented the sequential utilization of two or more sugars.[9][11][12] The work was conducted at the University of Paris, with André Lwoff of the Pasteur Institute having provided important advice.[13] Monod coined the term diauxie to denote the frequent observations of two distinct growth phases of bacteria grown on two sugars. He theorized on the growth of bacterial cultures and promoted the chemostat theory as a powerful continuous culture system to investigate bacterial physiology.[14]
Monod joined the Pasteur Institute in 1943 and Jacob in 1949. The experimental system ultimately used by Jacob and Monod was a common bacterium, E. coli, but the basic regulatory concept (described in the Lac operon article) that was discovered by Jacob and Monod is fundamental to cellular regulation for all organisms. The key idea is that E. coli does not waste energy making such enzymes if there is no need to metabolize lactose, such as when other sugars like glucose are available. The type of regulation is called negative gene regulation, as the operon is inactivated by a protein complex that is removed in the presence of lactose (regulatory induction).
With Jean-Pierre Changeux and François Jacob,[15] Monod proposed a theory of allosteric transitions to explain how conformational effects could allow enzyme effectors that are structurally quite different from the enzyme's substrates and products to activate or inhibit the reaction: binding at an allosteric site of the enzyme remote from the active site could bring about a change at the active site. He made an important contribution to enzymology when he collaborated with Jeffries Wyman and Changeux to extend this concept to explain cooperative behaviour of some multi-subunit proteins.[16] This has become the most widely accepted explanation of cooperativity.[17]
Philosophical contributions
Monod was not only a biologist but also a musician and writer on the philosophy of science. He was a political activist and chief of staff of operations for the Forces Françaises de l'Interieur during World War II. In preparation for the Allied landings, he arranged parachute drops of weapons, railroad bombings, and mail interceptions.
In 1970, Monod published Le hasard et la nécessité – English translation Chance and Necessity (1971) –, a book based on a series of lectures that he had given at Pomona College in 1969.[18] The book is a short but influential examination of the philosophical implications of modern biology, written for a general readership.[19] Monod acknowledges his connection to the French existentialists in the epigraph of the book, which quotes the final paragraphs of Camus's The Myth of Sisyphus. In summarizing recent progress in several areas of biology, including his own research, Monod highlights the ways in which information is found to take physical form and hence become capable of influencing events in the world. For example, the information allowing a protein enzyme to "select" only one of several similar compounds as the substrate of a chemical reaction is encoded in the precise three-dimensional shape of the enzyme; that precise shape is itself encoded by the linear sequence of amino acids constituting the protein; and that particular sequence of amino acids is encoded by the sequence of nucleotides in the gene for that enzyme.
In the title of the book, "necessity" refers to the fact that the enzyme must act as it does, catalyzing a reaction with one substrate but not another, according to the constraints imposed by its structure. While the enzyme itself cannot be said in any meaningful way to have a choice about its activity, the thrust of Jacob and Monod's Nobel prize-winning research was to show how a bacterial cell can "choose" whether or not to carry out the reaction catalyzed by the enzyme. As Monod explains, one way the cell can make such a choice is by either synthesizing the enzyme or not, in response to its chemical environment. However, the synthesis/no synthesis choice is in turn governed by necessary biochemical interactions between a repressor protein, the gene for the enzyme, and the substrate of the enzyme, which interact so that the outcome (enzyme synthesis or not) differs according to the variable composition of the cell's chemical environment. The hierarchical, modular organization of this system clearly implies that additional regulatory elements can exist that govern, are governed by, or otherwise interact with any given set of regulatory components. Because, in general, the bacterial activity that results from these regulatory circuits is in accord with what is beneficial for the bacterial cell's survival at that time, the bacterium as a whole can be described as making rational choices, even though the bacterial components involved in deciding whether to make an enzyme (repressor, gene, and substrate) have no more choice about their activities than does the enzyme itself.
Monod shows a paradigm of how choice at one level of biological organization (metabolic activity) is generated by necessary (choiceless) interactions at another level (gene regulation); the ability to choose arises from a complex system of feedback loops that connect these interactions. He goes on to explain how the capacity of biological systems to retain information, combined with chance variations during the replication of information (i.e. genetic mutations) that are individually rare but commonplace in aggregate, leads to the differential preservation of that information which is most successful at maintaining and replicating itself. Monod writes that this process, acting over long periods of time, is a sufficient explanation (indeed the only plausible explanation) for the complexity and teleonomic activity of the biosphere. Hence, the combined effects of chance and necessity, which are amenable to scientific investigation, account for our existence and the universe we inhabit, without the need to invoke mystical, supernatural, or religious explanations.
While acknowledging the likely evolutionary origin of a human need for explanatory myths, in the final chapter of Chance and Necessity Monod advocates an objective (hence value-free) scientific worldview as a guide to assessing truth. He describes this as an "ethics of knowledge" that disrupts the older philosophical, mythological and religious ontologies, which claim to provide both ethical values and a standard for judging truth. For Monod, assessing truth separate from any value judgement is what frees human beings to act authentically, by requiring that they choose the ethical values that motivate their actions. He concludes that "man at last knows he is alone in the unfeeling immensity of the universe, out of which he has emerged only by chance. His destiny is nowhere spelled out, nor is his duty. The kingdom above or the darkness below: it is for him to choose".[20] While apparently bleak, in comparison to the concepts that humanity belongs to some inevitable, universal process, or that a benevolent God created and protects us, an acceptance of the scientific assessment described in the first part of the quotation is, for Monod, the only possible basis of an authentic, ethical human life. It is reasonable to conclude that Monod himself did not find this position bleak; the quotation he chose from Camus to introduce Chance and Necessity ends with the sentence: "One must imagine Sisyphus happy."
Sociologist Howard L. Kaye has suggested that Monod failed in his attempt to banish "mind and purpose from the phenomenon of life" in the name of science.[22] It may be more accurate to suggest that Monod sought to include mind and purpose within the purview of scientific investigation, rather than attributing them to supernatural or divine causes. While Monod does not explicitly address mind or consciousness, his scientific research demonstrated that biology includes feedback loops that govern interacting systems of biochemical reactions, so that the system as a whole can be described as having a purpose and making choices. Monod's philosophical writing indicates that he recognized the implication that such systems could arise and be elaborated upon by evolution through natural selection. The importance of Monod's work as a bridge between the chance and necessity of evolution and biochemistry on the one hand, and the human realm of choice and ethics on the other, can be judged by his influence on philosophers, biologists and computer scientists such as Daniel Dennett, Douglas Hofstadter, Marvin Minsky and Richard Dawkins.
Monod was born in Paris to an American mother from Milwaukee, Charlotte (Sharlie) MacGregor Todd, and a French Huguenot father, Lucien Monod, who was a painter and inspired him artistically and intellectually.[26][9] He attended the lycée at Cannes until he was 18.[26] In October 1928 he started his studies in biology at the University of Paris.[26]
Monod, then a professor at the University of Paris, supported the student protests of May 68 and, along with several fellow Nobel laureates, appealed to president Charles de Gaulle on the students' behalf.[13]
Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.
In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splicing to create monocistronic mRNAs that are translated separately, i.e. several strands of mRNA that each encode a single gene product. The result of this is that the genes contained in the operon are either expressed together or not at all. Several genes must be co-transcribed to define an operon.
François Jacob was a French biologist who, together with Jacques Monod, originated the idea that control of enzyme levels in all cells occurs through regulation of transcription. He shared the 1965 Nobel Prize in Medicine with Jacques Monod and André Lwoff.
The lactose operon is an operon required for the transport and metabolism of lactose in E. coli and many other enteric bacteria. Although glucose is the preferred carbon source for most enteric bacteria, the lac operon allows for the effective digestion of lactose when glucose is not available through the activity of β-galactosidase. Gene regulation of the lac operon was the first genetic regulatory mechanism to be understood clearly, so it has become a foremost example of prokaryotic gene regulation. It is often discussed in introductory molecular and cellular biology classes for this reason. This lactose metabolism system was used by François Jacob and Jacques Monod to determine how a biological cell knows which enzyme to synthesize. Their work on the lac operon won them the Nobel Prize in Physiology in 1965.
A transcriptional activator is a protein that increases transcription of a gene or set of genes. Activators are considered to have positive control over gene expression, as they function to promote gene transcription and, in some cases, are required for the transcription of genes to occur. Most activators are DNA-binding proteins that bind to enhancers or promoter-proximal elements. The DNA site bound by the activator is referred to as an "activator-binding site". The part of the activator that makes protein–protein interactions with the general transcription machinery is referred to as an "activating region" or "activation domain".
Isopropyl β-d-1-thiogalactopyranoside (IPTG) is a molecular biology reagent. This compound is a molecular mimic of allolactose, a lactose metabolite that triggers transcription of the lac operon, and it is therefore used to induce protein expression where the gene is under the control of the lac operator.
Jean-Pierre Changeux is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins, to the early development of the nervous system up to cognitive functions. Although being famous in biological sciences for the MWC model, the identification and purification of the nicotinic acetylcholine receptor and the theory of epigenesis by synapse selection are also notable scientific achievements. Changeux is known by the non-scientific public for his ideas regarding the connection between mind and physical brain. As put forth in his book, Conversations on Mind, Matter and Mathematics, Changeux strongly supports the view that the nervous system functions in a projective rather than reactive style and that interaction with the environment, rather than being instructive, results in the selection amongst a diversity of preexisting internal representations.
In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.
In genetics, a regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcription of the gene they regulate. In addition, these sequences can also be found at the three prime end (3') to the transcription start site. In both cases, whether the regulatory sequence occurs before (5') or after (3') the gene it regulates, the sequence is often many kilobases away from the transcription start site. A regulator gene may encode a protein, or it may work at the level of RNA, as in the case of genes encoding microRNAs. An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator.
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
Enzyme induction is a process in which a molecule induces the expression of an enzyme.
Galactosidases are enzymes that catalyze the hydrolysis of galactosides into monosaccharides.
The blue–white screen is a screening technique that allows for the rapid and convenient detection of recombinant bacteria in vector-based molecular cloning experiments. This method of screening is usually performed using a suitable bacterial strain, but other organisms such as yeast may also be used. DNA of transformation is ligated into a vector. The vector is then inserted into a competent host cell viable for transformation, which are then grown in the presence of X-gal. Cells transformed with vectors containing recombinant DNA will produce white colonies; cells transformed with non-recombinant plasmids grow into blue colonies.
The L-arabinose operon, also called the ara or araBAD operon, is an operon required for the breakdown of the five-carbon sugar L-arabinose in Escherichia coli. The L-arabinose operon contains three structural genes: araB, araA, araD, which encode for three metabolic enzymes that are required for the metabolism of L-arabinose. AraB (ribulokinase), AraA, and AraD produced by these genes catalyse conversion of L-arabinose to an intermediate of the pentose phosphate pathway, D-xylulose-5-phosphate.
Chance and Necessity: Essay on the Natural Philosophy of Modern Biology is a 1970 book by Nobel Prize winner Jacques Monod. Aimed at a general audience, the book describes the basic characteristics of life, reviews findings of modern biochemistry and molecular biology, and argues that life arose by blind chance guided by natural selection, could not have been predicted, and does not have a higher purpose. The author concludes that traditional philosophical or religious systems of value, explanation and meaning are untenable, and advocates for an "ethic of knowledge": committing to objectivity in the pursuit of knowledge.
The gal operon is a prokaryotic operon, which encodes enzymes necessary for galactose metabolism. Repression of gene expression for this operon works via binding of repressor molecules to two operators. These repressors dimerize, creating a loop in the DNA. The loop as well as hindrance from the external operator prevent RNA polymerase from binding to the promoter, and thus prevent transcription. Additionally, since the metabolism of galactose in the cell is involved in both anabolic and catabolic pathways, a novel regulatory system using two promoters for differential repression has been identified and characterized within the context of the gal operon.
Carbon catabolite repression, or simply catabolite repression, is an important part of global control system of various bacteria and other microorganisms. Catabolite repression allows microorganisms to adapt quickly to a preferred carbon and energy source first. This is usually achieved through inhibition of synthesis of enzymes involved in catabolism of carbon sources other than the preferred one. The catabolite repression was first shown to be initiated by glucose and therefore sometimes referred to as the glucose effect. However, the term "glucose effect" is actually a misnomer since other carbon sources are known to induce catabolite repression.
Diauxic growth, diauxie or diphasic growth is any cell growth characterized by cellular growth in two phases. Diauxic growth, meaning double growth, is caused by the presence of two sugars on a culture growth media, one of which is easier for the target bacterium to metabolize. The preferred sugar is consumed first, which leads to rapid growth, followed by a lag phase. During the lag phase the cellular machinery used to metabolize the second sugar is activated and subsequently the second sugar is metabolized.
Stuart J. Edelstein is a biophysicist, emeritus professor from the University of Geneva, professeur extraordinaire at the École Normale Supérieure and visiting scientist at the Babraham Institute.
Maxime Simon Schwartz, born in June 1940 in Blois (Loir-et-Cher), is a French molecular biologist who has been a research director at the CNRS, a professor at the Pasteur Institute and Director General of the Pasteur Institute. He is a correspondant of the French Academy of sciences.
↑ Of Microbes and Life, Jacques Monod, Ernest Bornek, June 1971, Columbia University Press, ISBN0-231-03431-8
↑ The Eighth Day of Creation: makers of the revolution in biology by Horace Freeland Judson, Simon and Schuster, 1979. ISBN0-671-22540-5. Expanded Edition Cold Spring Harbour Laboratory Press, 1996. ISBN0-87969-478-5. History of molecular biology recounted through the lives and work of the major figures, including Monod.
↑ Origins of Molecular Biology: a Tribute to Jacques Monod edited by Agnes Ullmann, Washington, ASM Press, 2003, ISBN1-55581-281-3. Jacques Monod seen by persons who interacted with him as a scientist.
1 2 3 4 Jacques Monod on Nobelprize.org , accessed 11 October 2020 with the Nobel Lecture on December 11, 1965 From Enzymatic Adaption to Allosteric Transitions
Sean B. Carroll (2014). Brave Genius: A Scientist, a Philosopher, and Their Daring Adventures from the French Resistance to the Nobel Prize. Broadway Books. ISBN978-0307952349.
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