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rieure Paris, France ` s, Ecole normale supe Michel Morange, Centre Cavaille Based in part on the previous version of this Encyclopedia of Life Sciences (ELS) article, History of Molecular Biology by William C Summers.
Introductory article
Article Contents
. Introduction . The Emergence of the Molecular Programme in the 1930s . The Era of Major Discoveries (1940 1965) . The Transformations of Molecular Biology: 1965 2009 . Some Philosophical Issues Raised by the History of Molecular Biology . Conclusion . Biographical Information
Despite the huge place molecular biology has acquired in biological research, it remains difficult to provide a definition of it. Is molecular biology a scientific discipline, or a new vision of organisms? When did it emerge? Is molecular biology still alive, or has this discipline died, and been replaced by new disciplines such as systems and synthetic biology? Were molecular biologists too reductionist? Three successive steps can be distinguished in the history of molecular biology: the 1930s, with the development of new technologies aimed at describing the structure of macromolecules, and an effort to naturalize life; a relatively short period (1940 1965) in which the main results were obtained; and the huge accumulation of molecular data that has modified biology since this time. Despite the fact that molecular explanations have in part reached their limits, I consider that molecular biology has succeeded in naturalizing life.
Introduction
To give a denition of molecular biology seems simple: it corresponds to that part of biological research in which explanations are looked for at the level of molecules, by a description of their structures and interactions. Molecular biology obviously belongs to a reductionist project. See also: Reduction: A Philosophical Analysis Behind this simplicity, many diculties appear when more precise questions are asked. When was molecular biology
born? Taking the previous denition seriously, we would answer at the end of the eighteenth century and in the nineteenth century, when the isolation and characterization of the molecules present within organisms were painfully initiated. In fact, the answer that is commonly provided is the middle of the twentieth century, either before the World War II when powerful technologies were designed and gave early results on the structure of macromolecules, or at the end of this war, when the informational vision of the world invaded the realm of organic phenomena. The explanation of this discrepancy comes from the fact that molecular biology meant in fact macromolecular biology, and that its rise is linked with the study of macromolecules, not of the simple molecules of the organic chemist. When the symmetrical question of the persistence of molecular biology to the present day is asked, the same heterogeneity of answers is encountered: molecular biology is still active today, and dominates most elds of biological research, or molecular biology has disappeared, and left its place to new emerging disciplines such as systems and synthetic biology. A similar diculty consists in determining whether molecular biology is a scientic discipline, or something else, a new molecular vision of organisms to use the beautiful title of Lily Kays book. The roots of these diculties, and a better way to answer these questions, lies in the complex history of molecular biology. We will deconstruct it into three successive and partially overlapping periods: the elaboration of the molecular programme in the 1930s, the era of major discoveries (19401965), and the complex transformations that occurred between 1965 and 2009. The philosophical issues emerging from this historical description will be addressed in the last section.
ELS subject area: Science and Society How to cite: Morange, Michel (December 2009) History of Molecular Biology. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0003079.pub2
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century emerged the idea that between the world of molecules studied by the organic chemist and the subcellular structures barely detectable under the light microscope, existed the realm of colloids, governed by distinct physicochemical laws. These laws underpinned the peculiar characteristics of organisms, such as their capacity to catalyse a rich palette of chemical reactions at room temperature, and their power to reproduce. The rise of molecular biology was made possible by the progressive replacement of the colloid world by that of macromolecules. This was the result of the development of new technologies such as ultracentrifugation, electrophoresis, UV spectroscopy, X-ray diraction, electron microscopy, designed to provide data on this part of the world that so far had remained inaccessible. See also: Macromolecular Structure Determination by X-ray Crystallography
A prolongation of biochemistry
In this sense, molecular biology can be seen as an extension of a biochemical approach to macromolecules. But molecular biology is also an extension of biochemistry in the nature of the questions that were asked. The description of the metabolic pathways in the rst decades of the twentieth century had revealed the importance of enzymes in life. With the help of traditional methods of organic chemistry, enzymes had been puried, and shown to be, at least in some cases, pure proteins. To understand how proteins were able to full their functions became in the 1930s a dicult, but pivotal endeavour.
organisms: rst, at the biochemical level when it was shown that they had the same intermediates in metabolic pathways, and subsequently, when it was demonstrated that bacteria did mutate, and therefore probably contained genetic material. The place of viruses in biological research followed the same trajectory, but some years in advance. When bacteriophages, viruses of bacteria, were independ lix dHerelle ently discovered by Frederick Twort and Fe during the World War I, they were immediately seen as potential weapons against infectious diseases. Whereas the therapeutic use of bacteriophages did not full the hopes that had been placed in it, their value as the simplest forms of life, the study of which was not very far beyond technological capacities, progressively grew. Their identication by the American geneticist Hermann Muller as pure genes pressed many biologists to develop their study. They were puried and crystallized. They were wrongly reported by William Stanley in 1935 to be protein-only, and rightly shown soon after by Frederick Bawden and Norman Pirie to be a combination of nucleic acids and proteins. The bacteriophage was the experimental system chosen by Max Delbru ck, a German physicist who turned to biology under the inuence of Niels Bohr. He emigrated to the United States in 1935, and created with another immigrant, the Italian Salvador Luria, and with the American microbiologist Alfred Hershey, the American Phage Group. The inuence of this group was not so much in the results obtained by its members, as in the aura of its founders, and in particular Max Delbru ck, who designed a new way to do biology, a way derived from what already existed within physics. This group, and the annual course it created in Cold Spring Harbor near New York, became an obligatory point of passage for those, and in particular physicists, who decided to turn towards this new form of biology. See also: Bacteriophages; Cold Spring Harbor Laboratory; Delbru ck, Max Ludwig Henning; Muller, Hermann Joseph; Stanley, Wendell Meredith
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the help of methods and concepts from physics was a priority. Lily Kay, and many other historians of molecular biology, have emphasized the important contribution of the Rockefeller Foundation and of its policy in the development of molecular biology. Lily Kay is also right in arguing that strong support for this policy originated in the conviction that this increase in knowledge would immediately aord solutions to the problems aecting society. But she is wrong in considering that the leaders of the Rockefeller Foundation originated this conviction. Years before the development of this new policy, an institute named the IBPC (acronym for Institute of Physico-Chemical Biology in French) was founded in Paris. Its objective, for its creators, was to generate the knowledge required to transform (and improve) human beings, by applying techniques and concepts from physics to develop biological knowledge. My aim is not to argue that IBPC, and its creators, were the true founders of molecular biology, but simply to acknowledge that they shared in the convictions that the biological sciences were still in their infancy, that this low level of development had prevented society from getting to grips with its problems, and that this deepening of knowledge required a transfer of technologies and approaches from physics. The brilliant successes of physics in the rst decades of the twentieth century supported a deep-rooted idea, held since the seventeenth century, that physics was the rst experimental science to be rmly established, and for this reason, was a model for other, less developed, scientic disciplines. The target theory, according to which the best way to acquire knowledge on a system is to observe what happens when it is bombarded by radiation or particles, an experimental approach highly fruitful in physics, was directly applied to viruses and genes: it is emblematic of the way the transfer of knowledge and practices to biology was conceived. See also: Rockefeller Foundation: Biomedical and Life Sciences Oshoots The foundations of molecular biology were to be found in an obvious fact total ignorance of the domain of reality extending between organic molecules and subcellular visible structures, and in the conviction that physics could help to reduce this gap, and stimulate the development of the biological sciences. The importance of reductionist approaches within molecular biology was a mere consequence of this programme. In fact, the value of reductionism was far from being shared by all the founders of molecular biology. For instance, Max Delbru ck expected the discovery of new global laws specic to the organic world, which would explain the capacity of organisms to reproduce. See also: Reduction: A Philosophical Analysis
not only for their scientic importance, but also for what they reveal of the transformations linked with the rise of molecular biology.
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sexuality, were the last organisms expected to reveal the laws of genetics. To this long list of reasons explaining why Averys results were not immediately accepted, and correctly interpreted, one should add the accepted opinion that DNA was a high-molecular-weight molecule with a repetitive (monotonous) structure, and with a presumed function in the energetics of chromosome replication. See also: Avery, Oswald Theodore Both social scientists and philosophers of science can nd likely explanations for this delay. If the experiment of Avery was not accepted, it was not rejected either, and it inuenced subsequent events. After Averys results, many researchers considered DNA dierently, and in a few years, thanks to the new technique of paper chromatography, were able to give a better description of DNA, and to overcome the obstacles that had so far prevented the attribution to this molecule of an important physiological function within cells.
in the characterization of protein structure. Emil Fisher performed decisive experiments in the rst years of the twentieth century, with the characterization of the peptide bond and the chemical synthesis of small peptides. Nevertheless, it was not until the 1930s, with the abandonment of colloid theory and the accumulation of data on proteins from ultracentrifugation and X-ray diraction studies, that the idea that native proteins are the result of a precise folding process of a long polypeptide chain became dominant. This immediately generated the related hypothesis that the folding process is guided by the molecules that interact with the native proteins, substrates for enzymes and antigens in the case of antibodies. At the beginning of the 1950s, the rst experimental determination of protein sequences done by Frederick Sanger for insulin provided clear, but intriguing results. The sequence was dierent from one protein to another, even for homologous proteins belonging to dierent organisms, and no simple rule for the succession of amino acids in the polypeptide chain emerged. These results shifted attention from the folding process to the problem of the sequential attachment of amino acids in a polypeptide chain, and the role that genes might play in this process. The discovery by Vernon Ingram and Crick that a mutation in the gene coding for one of the chains of haemoglobin could substitute one amino acid for another at a precise place in the polypeptide chain (1957) supported the eorts made after the characterization of the DNA double helix to decipher the relation between the sequence of nucleotides in DNA, and that of amino acids in proteins. See also: Sanger, Frederick After an initial phase of optimism, the solution of the coding problem appeared more and more dicult at the end of the 1950s. In 1957, Crick tried to bring order to the complex results that had recently accumulated, and to establish simple relations between the dierent classes of informational molecules present within a cell, in what he unfortunately called the central dogma of molecular biology. The success came from a shift to a traditional biochemical approach: try to reconstitute protein synthesis in vitro, with the minimum set of components partially puried from cells. The development of these in vitro systems, in particular by the group of Paul Zamecnik, paralleled the progressive description of cell structure by electron microscopy. Ribosomes were shown to be the site of protein synthesis, and transfer (soluble) ribonucleic acids (RNAs) an obligatory intermediate in the activation of amino acids and their incorporation into proteins. In 1960, Marshall Nirenberg and Johann Heinrich Matthaei synthesized an articial protein, uniquely formed of phenylalanine, by adding to the reconstituted in vitro system an articial RNA formed of uracils. Only four years were necessary to fully decipher the genetic code, the rule of correspondence between the triplets of nucleotides and the dierent amino acids. Where the theoretical approaches had failed, traditional methods of biochemistry rapidly provided clear answers. But this detour through theoretical biology was useful to build the informational mould into
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which the results of molecular biology were progressively incorporated. See also: Genetic Code: Introduction
discovery of the messenger RNA, the intermediate between genes and proteins. This negative form of regulation has since been complemented by positive regulation through the action of activators, which are particularly important in eukaryotic cells. Despite the huge progress made since the elaboration of the operon model, two of the hypotheses made then are still valid: gene expression is mainly controlled at the transcriptional level, through the action of proteins directly interacting with DNA. See also: Jacob, Michel; Franc ois; Lederberg, Joshua; Lwo, Andre Lysogeny; Monod, Jacques Lucien; Tatum, Edward Lawrie The operon model is emblematic of the place microorganisms had in the elaboration of models valid for all biology, and the importance of genetic tools in disentangling complex biological processes. It also demonstrates the role that biochemical methods and systems played in the elaboration of the main results of molecular biology. But the operon model is also a turning point in the molecular description of organisms. It shows how the environment can modulate the activity of genes. And the description of the genetic regulatory circuits was the rst step towards the development, several decades later, of systems biology (see later).
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The early application of the new techniques led to rapid biotechnological developments, such as the production of human therapeutic proteins in microorganisms, and the discovery of new, totally unexpected phenomena, which were specic to eukaryotic organisms and challenged the picture that had emerged from the study of microorganisms. Genes were fragmented into pieces exons and introns only the rst contributing to protein sequences. The mature mRNA was the result of a complex process of modication and splicing of the primary product of transcription. The mRNA sequence can itself be modied enzymatically by the addition of bases or by the chemical modication of one base to another, a process called editing. It occurs particularly in mitochondria, but only a handful of examples are known in relation to human nuclear genes. Genes can be rearranged during the development of organisms: such is the case in the immune system, where the diversity of antibodies and receptors is the result of very precise programmed rearrangements of short coding sequences. Recently, the place of microRNAs and their mechanisms of production and action have been described. See also: Splicing of pre-mRNA
acquired by molecular biology was considered by most evolutionary biologists as a regression towards a time when scientists looked for direct physico-chemical explanations of biological facts. See also: Evolution: Views of To their credit, Linus Pauling and Emile Zuckerckandl showed the value of protein and later DNA sequences for the classication of organisms, and the resolution of evolutionary relations. The rapid increase in the power of computers was responsible for the increasing role that sequence comparisons played in biology. The initial results of this comparison demonstrated the existence of a molecular clock, in agreement with the neutralist model of Motoo Kimura, an additional cause of conicts with most evolutionary biologists. See also: Evolution: Neutralist View; Pauling, Linus Carl It was only after the discovery of the conservation of the homeotic genes in 1984, and the development of Evo-Devo, that evolutionary and molecular biologists interacted eectively. From the simple, direct comparison of sequences rapidly emerged an observation: macromolecular components have been conserved during evolution, even if they were recruited for diverse functions. This led to the comparison, proposed by Franc ois Jacob in 1977, between the action of evolution and that of a tinkerer: a vision which is dominant today among biologists.
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Genome sequencing
The project to sequence the human genome was launched in 1986. The ambitions were diverse, from reading the book of life to the search for unknown genes involved in cancer. I think that such a project was inescapable once the structure of DNA had been discovered, and the techniques to isolate and sequence it had been developed, in particular when a fast sequencing method was proposed by Frederick Sanger. Many discussions took place about the way to reach this objective, which were progressively solved with the advance of the work. Although the public consortium created to sequence the genome adopted a rational strategy of mapping and sequencing, Craig Venter pushed a shotgun approach consisting in sequencing aleatory fragments, followed by a long process of computer-assisted fragment assembly. This second strategy proved more ecient than was initially anticipated, the result probably of the rapid increase in computing capacity. No revolutionary new way to sequence DNA was required, and an automated version of Sangers method applied on a large scale in specialized centres did the job. Human genome sequencing was achieved ahead of schedule, and at a lower cost than anticipated. This sequence, as well as that of many other organisms, represents a large reserve of information to which biologists have rapid access, and it is progressively changing the form of work done in biology laboratories. It is nonetheless necessary to acknowledge that there is a sharp contrast between the amount of work that was done to sequence the human genome, the huge amount of information obtained and the paucity of knowledge that could be extracted from it, and immediately applied in practice. See also: Sequencing the Human Genome: Novel Insights into its Structure and Function
Post-genomic approaches
Such is not the case for the dierent approaches called postgenomic, which were developed even before the human genome sequencing programme was completed. With the production of DNA chips plastic plates on which a huge number of short dierent DNA fragments have been attached it became possible to determine in one experiment the rate of expression of all the genes in a cell or an organism, or to detect in a single experiment a battery of dierent genetic mutations. The interactions between all the proteins of a cell can also be characterized through another post-genomic methodology called interactomics. Other technologies aimed at providing information on a large scale have also been developed. In contrast to these global approaches, much eort and many technological developments have been made to track individual macromolecules within cells. A new dynamic vision of the cell is emerging, in which molecular noise has a fully acknowledged place. Three new disciplines have also emerged or gained credit: systems biology, synthetic biology and epigenetics. The rst aims to describe the global organization of macromolecules within a cell, and to characterize the network formed by
these macromolecules and its dynamic behaviour. Systems biologists emphasize the importance of isolated functional parts within these networks, called modules. Although systems biology aims to give an integrated view of what happens within cells and organisms, the characterization of these networks, and of their dynamics, is dramatically dependent on the wealth of information accumulated by molecular biologists on the molecular components and their interactions in previous decades. See also: Systems Biology: Genomics Aspects Synthetic biology has much in common with systems biology, in particular the same conception of networks formed of partially independent modules. But synthetic biology aims to manipulate these modules, to introduce new, more or less synthetic modules to force the organisms to accomplish new functions to respond to new signals, to generate or degrade new molecules, etc. Synthetic biology therefore clearly has an applied dimension. But it has also a fundamental dimension. The best way to ascertain the level of knowledge of organisms that has been obtained is to try to synthesize (part of) organisms, in the same way that organic chemists synthesize molecules, whose structures they determine. Therefore, synthetic biology represents an important change in the epistemology of biology. So far, a biological system could be considered as explained even when it was totally impossible to reproduce it. With the development of synthetic biology, a new criterion of the validity of an explanation is the possibility of reproducing the system under study. Synthetic biology can therefore be considered as the achievement of the project to naturalize organisms initiated by molecular biologists in the 1930s. The denitive proof that the organic world has been naturalized would be obtained by the synthesis of a fully articial organism, an objective which is no longer out of reach. The place of epigenetics in the present landscape of biological disciplines is less clear. Recent studies have revealed a whole set of complex mechanisms of modication of the histones, proteins closely associated with DNA, with which they form (plus additional proteins) what is called chromatin. These modications can modulate the access of RNA polymerases, the enzymes that transcribe DNA into RNA, and therefore the expression of genes. Epigenetic modications complement, more than they oppose, the traditional genetic regulations by repressors and activators. Some of these epigenetic marks can, in some organisms, be transmitted through the germline to new generations. In addition, alteration in epigenetic modications might be involved in some human diseases, such as the cancers, coronary artery disease, hypertension and the other common degenerative disorders, and more generally age-related diseases. But epigenetics is clearly more, at least for its supporters. It is, since its inception (with a dierent meaning) by Conrad Waddington in 1940, a word used to designate diverse experimental approaches that aim to complement, and frequently to oppose, the models of genetics. Epigenetic eects are seen as less deterministic than genetic eects, and open to the action of the environment. My feeling is that epigenetics is clearly
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not a new discipline. Its heterogeneity prevents it from being the new revolutionary conception of biological phenomena that some of its supporters dream of! Beyond the creation of new disciplines, what is most striking in contemporary biology is the progressive abandonment of the model systems that were so dominant in twentieth century biology. The accumulation of genomic sequences, and the rapid comparison of these sequences, allows a permanent passage from one organism to another. The second characteristic is the growing role of mathematicians and physicists in biology, and of modelling approaches: not to support the results previously obtained by biologists but, as in physics, to anticipate these results and guide future experimental work.
way to more sophisticated explanations in terms of statistical thermodynamics, microvibrations of molecules, that is to explanations at a lower level of organization. The second limit is evolution. Molecular mechanisms are the result of a long evolution; when the molecular explanations are pushed to their limits, the characteristics of the systems under study can no longer be understood independently of the evolutionary history which generated them. Finally, when the macromolecules work together in networks, the organization of these networks obeys design principles familiar to engineers, in relation with the functions that the ensemble of macromolecules has to full. These principles of organization cannot be directly deduced from knowledge of macromolecular structures.
The question of life was actively debated in the 1930s and 1940s. Two decades later, the question disappeared, as if it had been solved. Recently, it re-emerged, supported by the development of research on the origin of life and astrobiology. Does this mean that the claim of (many) molecular biologists to have solved the riddle of life was wrong? I do not think so. Molecular biology was obviously the description of the most fundamental mechanisms governing organisms. But what remains unknown is the way these complex mechanisms have been progressively established. The question of life is no longer a question of the nature of the mechanisms supporting it, but a historical (i.e. evolutionary) question.
Conclusion
So, is molecular biology dead or alive? Molecular biology is an historical object, and the answer depends on what form of molecular biology one refers to. The informational face of molecular biology, with an emphasis on the notion of programme, has clearly lost its dominant position. Of course nucleic acid information remains of crucial importance but the focus of research is moving to the dynamic structures of proteins as they execute their functions and this is important, not only at the fundamental level, but also at the practical level, for the development of new drugs. It is also not obvious what kind of a new vision would eventually replace the molecular one. What is nevertheless evident is that the molecular vision has to be complemented: by models generated from molecular descriptions, and by evolutionary explanations, the only ones likely to explain the specic characteristics that these molecular mechanisms have adopted.
Biographical Information
Michel Morange is a researcher in molecular and developmental biology, and an historian and philosopher of
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science. He has studied the rise of molecular biology, and the recent transformations of this discipline: emergence of new disciplines synthetic biology, systems biology reemergence of the question of life, the role of genes and the place of epigenetics in contemporary biology.
Further Reading
Brock TD (1990) The Emergence of Bacterial Genetics. Cold Spring Harbor: Cold Spring Harbor Laboratory Press. Creager ANH (2002) The Life of a Virus: Tobacco mosaic virus as an Experimental Model 1930 1965. Chicago: University of Chicago Press. de Chadarevian S (2002) Design for Life: Molecular Biology after World War II. Cambridge: Cambridge University Press.
Judson HF (1996) The Eighth Day of Creation: Makers of the Revolution in Biology. Cold spring Harbor: Cold Spring Harbor Laboratory Press. Kay LE (1993) The Molecular Vision of Life: Caltech, The Rockefeller Foundation, and the Rise of the New Biology. Oxford: Oxford University Press. Kay LE (2000) Who Wrote the Book of Life? A History of the Genetic Code. Stanford: Stanford University Press. Morange M (1998) A History of Molecular Biology. Cambridge: Harvard University Press. Morange M (2008) Life Explained. New Haven: Yale University Press. Olby R (1974) The Path to the Double Helix. London: Macmillan. Summers WC (1999) Felix dHerelle and the Origins of Molecular Biology. New Haven: Yale University Press.
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