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History of MolecularBiologyMichel Morange, Centre Cavaille`s, Ecole normale superieure Paris, France

Based in part onthe previous version of this Encyclopediaof Life Sciences(ELS) article, History of Molecular Biology by William C Summers.

Despite the huge place molecular biology has acquired in

biological research, it remains difficult to provide a def-

inition of it. Is molecular biology a scientific discipline,

or a new vision of organisms? When did it emerge? Ismolecular biology still alive, or has this discipline died,

and been replaced by new disciplines such as systems and

synthetic biology? Were molecular biologists too reduc-

tionist?

Three successive steps can be distinguished in the his-

tory of molecular biology: the 1930s, with the develop-

ment of new technologies aimed at describing the

structure of macromolecules, and an effort to naturalize

life; a relatively short period (19401965) in which the

mainresultswereobtained;andthehugeaccumulationof

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 definition of molecular biology seems simple: it

corresponds to that part of biological research in which

explanations are looked for at the level of molecules, bya description of their structures and interactions. Molecu-

lar biology obviously belongs to a reductionist project.See also: Reduction: A Philosophical Analysis

Behind this simplicity, manydifficulties appear when more

precise questions are asked. When was molecular biology

born? Taking the previous definition seriously, we wouldanswer at the end of the eighteenth century and in the nine-teenth century,when the isolation and characterizationof the

molecules present within organisms were painfully initiated.In fact,the answer that is commonly provided is themiddle ofthe twentieth century, either before the World War II whenpowerful technologies were designed and gave early resultson the structure of macromolecules, or at the end of this war,when theinformational visionof theworldinvadedthe realmof organic phenomena. The explanation of this discrepancycomes from the fact that molecular biology meant in factmacromolecular biology, and that its rise is linked withthe study of macromolecules, not of the simple moleculesof the organicchemist.When thesymmetrical questionof thepersistence 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 fields ofbiological research, or molecular biology has disappeared,and left its place to new emerging disciplines such as systemsand synthetic biology. A similar difficulty consists in deter-mining whether molecular biology is a scientific discipline, orsomething else, a new molecular vision of organisms to usethe beautiful title of Lily Kays book.

The roots of these difficulties, and a better way to answerthese questions, lies in the complex history of molecular

biology. We will deconstruct it into three successive andpartially overlapping periods: the elaboration of themolecular programme in the 1930s, the era of major dis-coveries (19401965), and the complex transformations

that occurred between 1965 and 2009. The philosophicalissues emerging from this historical description will beaddressed in the last section.

The Emergence of the MolecularProgramme in the 1930s

From colloids to macromolecules

From the initial work on the physico-chemical characteris-

tics of biological components performed at the end of thenineteenth century and at the beginning of the twentieth

Introductory article

Article Contents

. Introduction

. The Emergence of the Molecular Programme in the

1930s

. The Era of Major Discoveries

(19401965)

. The Transformations of Molecular Biology: 19652009

. Some Philosophical Issues Raised by the History of

Molecular Biology

. Conclusion

. Biographical Information

Online posting date: 15th December 2009

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 mol-

ecules studied by the organic chemist and the subcellularstructures barely detectable under the light microscope,existed the realm of colloids, governed by distinct physico-

chemical laws. These laws underpinned the peculiar char-acteristics of organisms, such as their capacity to catalyse a

rich palette of chemical reactions at room temperature, andtheir power to reproduce.

The rise of molecular biology was made possible by theprogressive replacement of the colloid world by that ofmacromolecules. This was the result of the development ofnew technologies such as ultracentrifugation, electro-phoresis, UV spectroscopy, X-ray diffraction, electronmicroscopy, designed to provide data on this part of theworld that so far had remained inaccessible. See also:Macromolecular Structure Determination by X-rayCrystallography

A prolongation of biochemistryIn this sense, molecular biology can be seen as an extensionof a biochemical approach to macromolecules. Butmolecular biology is also an extension of biochemistry inthenature of thequestions that were asked.The descriptionof the metabolic pathways in the first decades of thetwentieth century had revealed the importance of enzymesin life. With the help of traditional methods of organicchemistry, enzymes had been purified, and shown to be, atleast in some cases, pure proteins. To understand howproteins were able to fulfil their functions became in the1930s a difficult, but pivotal endeavour.

A natural development of genetics

The rise of molecular biology was also the consequence ofthe rapid development of genetics in the first half of thetwentieth century, after the rediscovery of the laws ofMendel in 1900, and the adoption of experimental systems(Drosophila, maize, later microbiological systems) welladapted to genetic studies. Therole of genes in theeconomyof cells became more and more evident, and the nature ofthe gene, and of its relation to the other components of thecells, progressively became a priority on the agendas of

geneticists.

Other contributing disciplines

Molecular biology is frequently seen as the result of theconvergence of more than the two disciplines of bio-chemistry and genetics. Cytology and microbiology alsocontributed. Cytological studies provided a precisedescription of the localization of the different macro-molecules within the cell, a step necessary but not sufficientto attribute a functional role to these macromolecules. One

important part of microbiology remained closely linkedwith the description of diseases, not only of humans butalso of animals and plants, and the way to fight them by the

production of sera and vaccines. But studies on micro-organisms progressively merged with studies on higher

organisms: first, at the biochemical level when it was shown

that they had the same intermediates in metabolic path-ways, and subsequently, when it was demonstrated thatbacteria did mutate, and therefore probably contained

genetic material. The place of viruses in biological researchfollowed the same trajectory, but some years in advance.

When bacteriophages, viruses of bacteria, were independ-ently discovered by Frederick Twort and Felix dHerelleduring the World War I, they were immediately seen aspotential weapons against infectious diseases. Whereas thetherapeutic use of bacteriophages did not fulfil the hopesthat had been placed in it, their value as the simplest formsof life, the study of which was not very far beyond tech-nological capacities, progressively grew. Their identifi-cationby theAmericangeneticist Hermann Mulleras puregenes pressed many biologists to develop their study. Theywere purified and crystallized. They were wrongly reportedby William Stanley in 1935 to be protein-only, and rightlyshown soon after by Frederick Bawden and Norman Pirieto be a combination of nucleic acids and proteins. Thebacteriophage was the experimental system chosen by MaxDelbru ck,a German physicist who turnedto biology underthe influence of Niels Bohr. He emigrated to the UnitedStates in 1935, and created with another immigrant, theItalian Salvador Luria, and with the American micro-biologist Alfred Hershey, the American Phage Group. Theinfluence of this group was not so much in the results

obtained by its members, as in the aura of its founders, andin particular Max Delbru ck, who designeda new way todobiology, a way derived from what already existed withinphysics. This group, and the annual course it created in

Cold Spring Harbornear New York, becamean obligatorypoint of passage forthose, and in particular physicists, whodecided to turn towards this new form of biology. See also:Bacteriophages; Cold Spring Harbor Laboratory; Del-bru ck, Max Ludwig Henning; Muller, Hermann Joseph;Stanley, Wendell Meredith

The role of physics and physicists

The role of physicists in the emergence of molecular biol-ogy was not linked to their major contribution to thedevelopment of new technologies designed to characterizethe properties of macromolecules. The late Lily Kay saw a

more fundamental influence of physicists through the deci-sive role that the Rockefeller Foundation played in thedevelopment of molecular biology. Many problems affect-ing society, from economic crises to the rise of criminalityand the degeneration of the race were considered by thetrustees of theFoundation as thedirect consequences of thecontrast between the increasing mastery of the inanimateworldthrough progress in physics, and poorunderstandingof human behaviour, and more generally of the animate

world. The overly slow development of biological studies,viewed by many physicists as stamp collection, and theresulting important place within biology of metaphysical

conceptions such as vitalism, were a scandal that had to berapidly corrected. Development of biological studies with

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the help of methods and concepts from physics was a

priority.Lily Kay, andmany other historians of molecularbiology,

have emphasized the important contribution of the Rock-

efeller Foundation and of its policy in the development ofmolecular biology. Lily Kay is also right in arguing that

strong support for this policy originated in the convictionthat this increase in knowledge would immediately affordsolutionsto theproblems affecting society. Butshe is wrongin considering thatthe leaders of the Rockefeller Foundationoriginated this conviction. Years before the development ofthis new policy, an institute named the IBPC (acronym forInstitute of Physico-Chemical Biology in French) wasfounded in Paris. Its objective, for its creators, was to gen-erate the knowledge required to transform (and improve)human beings, by applying techniques and concepts fromphysics to develop biological knowledge. My aim is not toargue that IBPC, and its creators, were the true founders ofmolecular biology, but simply to acknowledge that theyshared in the convictions that the biological sciences werestill in their infancy, that this low level of development hadpreventedsociety from getting to grips with itsproblems, andthat this deepening of knowledge required a transfer oftechnologies and approaches from physics. The brilliantsuccesses of physics in the first decades of the twentiethcentury supported a deep-rooted idea, held since the seven-teenth century,thatphysics was the firstexperimental science

to be firmly established, and for this reason, was a model forother, less developed, scientific disciplines. The target theory,according to which the best way to acquire knowledge on asystem is to observe what happens when it is bombarded by

radiation or particles, an experimental approach highlyfruitful in physics, was directly applied to viruses and genes:it is emblematic of the way the transfer of knowledge andpractices to biology was conceived. See also: RockefellerFoundation: Biomedical and Life Sciences Offshoots

The foundations of molecular biology were to be foundin an obvious fact total ignorance of thedomain of realityextending between organic molecules and subcellular vis-ible structures, and in the conviction that physics couldhelp to reduce this gap, and stimulate the development ofthe biological sciences. The importance of reductionistapproaches within molecular biology was a mere con-sequence of this programme. In fact, the value of reduc-

tionism was far from being shared by all the founders ofmolecular biology. For instance, Max Delbru ck expectedthe discovery of new global laws specific to the organicworld, which would explain the capacity of organisms toreproduce. See also: Reduction: A Philosophical Analysis

The Era of Major Discoveries(19401965)

The major discoveries of what has been called the classical

era of molecular biology are contained in a short period little more than two decades. We have selected five of them,

not only for their scientific importance, but also for what

they reveal of the transformations linked with the rise ofmolecular biology.

The one gene one enzyme relation (1940)

The search for the relations between genes and thephenotype was initiated by Boris Ephrussi and GeorgeBeadle in work done jointly at the IBPC and Caltech in the1930s. The phenotypic trait selected was eye colour inDrosophila, a trait affected by many mutations. Thetechnique used was the reciprocal transplantation ofimaginal disks between different mutated strains. Thecomplexity of the results pressed George Beadle andEdward Tatum to turn towards a very different experi-mental system: the search for mutations affecting well-defined steps in the metabolic pathways of a mould. Withthis experimental system, combining well-defined bio-chemical traits with simple genetic analyses, Beadle andTatum were able to establish the generality of the relationbetween genes and enzymes. Each enzyme, responsible forone specific step in a metabolic pathway, is controlled by adifferent gene. See also: Beadle, George Wells; Tatum,Edward Lawrie

Comparison between the initial efforts and the late suc-cesses outlines one shift that accompanied the rise ofmolecular biology: the abandonment of a developmental

relation between the genotype and the phenotype for adirect relation, more easily and rapidly studied inmicroorganisms.

The nature of the gene 1944

1952

Two experimental approaches separately pointed todeoxyribonucleic acid (DNA) as the major constituent ofthe genes. The first was initiated by Oswald Avery soonafter Fred Griffith demonstrated that something fromdead bacteria (Pneumococci, a type of Streptococcus) wasable to transform the polysaccharide capsule surroundingliving bacteria. After 10 years of intensive purificationwork, and the use of a combination of chemical, bio-chemical and molecular techniques, Avery and his col-laborators demonstrated in 1944 that the transformingfactor was DNA. Eight years later, Alfred Hershey and

Martha Chase assembled a complex set of experiments toshow that a bacteriophage is simply a container and avector of its genetic material, DNA. Much hasbeen writtenabout the apparent necessity to confirm Averys experi-ment, and the long delay between the two experiments.Whereas Avery was a respected, but rather solitaryresearcher, Hershey was one of the founders of theAmerican Phage Group. Transformation of Pneumococcirequired a lot of experience, whereas bacteriophage

reproduction was a highly standardized process. Studies onPneumococci belonged to a medical tradition of research,whereas studies on bacteriophage were considered basic

research, and their results scrutinized by geneticists. Bac-teria, with their lack of nuclei and their apparent lack of


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sexuality, were the last organisms expected to reveal the

laws of genetics. To this long list of reasons explaining whyAverys results were not immediately accepted, and cor-rectly interpreted, one should add the accepted opinion

that DNA was a high-molecular-weight molecule with arepetitive (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 canfind likely explanations for this delay. If the experiment ofAvery was not accepted, it was not rejected either, and itinfluenced subsequent events. After Averys results, manyresearchers considered DNA differently, andin a fewyears,thanks to the new technique of paper chromatography,were able to give a better description of DNA, and toovercome the obstacles that had so far prevented theattribution to this molecule of an important physiologicalfunction within cells.

The double helix structure of DNA

The discovery of the double helix structure of DNA dem-onstrated that structural knowledge could explain thefunctions of macromolecules. The second article published

by Jim Watson and Francis Crick in Nature in 1953acknowledged that the structure of DNA explained howthis molecule was the bearer of genetic information, and

opened up interesting vistas on the origin of mutations andon the relation between genes and proteins, the so-calledcoding problem. See also: DNA Structure

These two authors symbolized different contributions to

the rise of molecular biology. Jim Watson belonged to theAmerican Phage Group. His involvement in DNA research

was a sign of the limits reached by a nonmaterial attack onthe problem of gene reproduction, and the necessity felt bythe members of the phage group to open the black box andto dive into its biochemical complexity to find the explan-ation of the properties of the gene. Crick represented thetradition of structural chemistry, and the slow, but steadyprogress that had been made in the interpretation of X-raydiffraction patterns, not only those obtained with crystals,but also theless precise ones resultingfrom theuse of fibres,an approach developed by William Astbury in the 1930s inLeeds. The quality of the X-ray diffraction pictures

obtained by Rosalind Franklin at Kings College in Lon-don, to which Crick and Watson had access withoutFranklins agreement and even knowledge, and the use ofthe modelling methods developedby the American chemistLinus Pauling, were the roots of Watson and Cricks suc-cess. The beauty of the structure helped attract manybiologists to this new field of research. See also: Crick,Francis Harry Compton; Franklin, Rosalind Elsie; Paul-ing, Linus Carl; Watson, James Dewey

The mechanisms of protein synthesis

The progress made in the elucidation of the mechanisms ofprotein synthesis cannot be distinguished from those made

in the characterization of protein structure. Emil Fisher

performed decisive experiments in the first years of thetwentieth century, with the characterization of the peptidebond and the chemical synthesis of small peptides.

Nevertheless, it was not until the 1930s, with the aban-donment of colloid theory and the accumulation of data on

proteins from ultracentrifugation and X-ray diffractionstudies, that the idea that native proteins are the resultof a precise folding process of a long polypeptide chainbecame dominant. This immediately generated the relatedhypothesis that the folding process is guided by the mol-ecules that interact with the native proteins, substrates forenzymes and antigens in the case of antibodies.

At the beginning of the 1950s, the first experimentaldetermination of protein sequences done by FrederickSanger for insulin provided clear, but intriguing results.The sequence was different from one protein to another,even for homologous proteins belonging to differentorganisms, and no simple rule for the succession of aminoacids in the polypeptide chain emerged. These resultsshifted attentionfrom thefolding process to the problem ofthe sequential attachment of amino acids in a polypeptidechain, and the role that genes might play in this process.The discovery by Vernon Ingram and Crick that a muta-tion in thegene codingfor oneof thechains of haemoglobincould substitute one amino acid for another at a preciseplace in the polypeptide chain (1957) supported the efforts

made after thecharacterization of the DNA doublehelix todecipher the relation between the sequence of nucleotidesin DNA, and that of amino acids in proteins. See also:Sanger, Frederick

After an initial phase of optimism, the solution ofthecoding problem appeared more and more difficult at theend of the 1950s. In 1957, Crick tried to bring order to thecomplex results that had recently accumulated, and toestablish simple relations between the different classes ofinformational molecules present within a cell, in what heunfortunately called the central dogma of molecularbiology. The success came from a shift to a traditionalbiochemical approach: try to reconstitute protein synthesisin vitro, with the minimum set of components partiallypurified from cells. The development of these in vitrosystems, in particular by the group of Paul Zamecnik,paralleled the progressive description of cell structure by

electron microscopy. Ribosomes were shown to be the siteof protein synthesis, and transfer (soluble) ribonucleicacids (RNAs) an obligatory intermediate in the activationof amino acids and their incorporation into proteins. In1960, Marshall Nirenberg and Johann Heinrich Matthaeisynthesized an artificial protein, uniquely formed ofphenylalanine, by adding to the reconstituted in vitro sys-tem an artificial RNA formed of uracils. Only four yearswere necessaryto fully decipher the genetic code, therule ofcorrespondence between the triplets of nucleotides and the

different amino acids. Where the theoretical approacheshad failed, traditional methods of biochemistry rapidly

provided clear answers. But this detour through theoreticalbiology 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

The control of gene expression

The existence of mechanisms controlling gene expression

became evident as soon as it was known that all cells ofhigher organisms contain the same genes, but that thesegenes are differentially expressed in the different cells of theorganism. The explanation of embryological developmentprogressively became equivalent for most molecularbiologists to the description of the mechanisms by whichgene expression is controlled during development. The firstmodels of gene regulation were elaborated from the resultsobtained with two experimental systems totally unrelatedto the previous questions: the study of the adaptation ofbacteria to new nutrient sources, and the study of lysogeny,a complex process of interaction between a bacteriumand a bacteriophage. The former phenomenon, alreadydescribed by Emile Duclaux and Frederic Dienert at theend of the nineteenth century, was converted into a modelsystem to study the control of gene expression during dif-ferentiation by Marjory Stephenson in the 1930s. JacquesMonod initiated in the mid-1940s the study of this phe-nomenon, and the many experimental approaches triedduring the next 15 years led him to the conclusion that themodel proposed by John Yudkin in the 1930s, according towhich theinduced protein wasformed by moulding aroundits inducer, was wrong and that the explanation of thephenomenon of enzymatic adaptation would only come

from characterization of the mutations affecting it. The

other experimental system in the discovery of regulatorymechanisms was the study of lysogeny, a phenomenon

discovered a few years after the description of the bac-teriophage. Studied by a small number of groups, andconsidered by Max Delbru ck as an artefact, lysogeny

became the main research project of Andre Lwoff, ElieWollman and Francois Jacob, in 1950 at the PasteurInstitute in Paris. In the lysogenic process, a bacteriophageis able to remain silent in a cryptic state within a bacteriumfor many generations. Seven years of intense work led ElieWollman and Francois Jacob not only to localize theinactive state of the bacteriophage, called a prophage, onthe chromosome and to demonstrate the role of a cyto-

plasmic repressor in the maintenance of the inactiveprophage state, but also to give a precise description ofthe sexual genetic exchanges occurring in bacteria, firstdescribed in 1946 by Edward Tatum and Joshua Leder-berg. The joint efforts of Jacob and Monod in the threeyears between 1957 and 1960 showed through the famousPaJaMo experiment (done in collaboration with theAmerican researcher Arthur Pardee) that a repressor wasalso involved in the control of lactose induction, and led toelaborate a precise molecular model, the so-called operonmodel, explaining the control of gene expression in bothsystems. A regulatory gene, coding for a repressor protein,

regulates the transcription of a group of genes called anoperon. The PaJaMo experiment also underpinned the

discovery of the messenger RNA, the intermediate betweengenes and proteins. This negative form of regulation hassince been complemented by positive regulation throughthe action of activators, which are particularly important in

eukaryotic cells. Despite the huge progress made since theelaboration of the operon model, two of the hypotheses

made then are still valid: gene expression is mainly con-trolled at the transcriptional level, through the action of

proteins directly interacting with DNA. See also: Jacob,Francois; Lederberg, Joshua; Lwoff, Andre Michel;Lysogeny; Monod, Jacques Lucien; Tatum, EdwardLawrie

The operon model is emblematic of the place micro-organisms had in the elaboration of models valid for allbiology, and the importance of genetic tools in dis-entangling complex biological processes. It also demon-strates the role that biochemical methods and systemsplayed in the elaboration of the main results of molecularbiology. But the operon model is also a turning point inthe molecular description of organisms. It shows how theenvironment can modulate the activity of genes. And thedescription of the genetic regulatory circuits was the firststep towards the development, several decades later, ofsystems biology (see later).

The Transformations of MolecularBiology: 19652009

So many years and results separate present-day biological

research from what wasmolecular biology in themid-1960sthat one might have the feeling that biology has enteredinto a new era. My conviction is that, despite importanttransformations that I will describe in a more or lesschronological order, no dramatic changes have occurred inthe description of organisms since this early period, and

that the molecular paradigm provided that such anexpression can be used is still valid.

The genetic engineering revolution

Description of the most fundamental molecular mech-anisms did not immediately open the way to a precise

description of higher organisms and their development. A10-year interval separates the results we have describedpreviously from the elaboration of a complex toolboxallowing biologists to isolate genes, to sequence and modifythem, and to reintroduce them into organisms. The devel-opment of the DNA amplification technique, called poly-merase chain reaction, or PCR, was the last step in thecreation of the complex network of techniques calledgenetic engineering. Even before the development of

PCR, genetic engineering had generated a huge debate,which culminated in Asilomar in 1975, and resulted in theelaboration of a complex set of rules required to manipu-

late the newly created transgenic organisms, rules whichwere progressively relaxed.


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The early application of the new techniques led to rapid

biotechnological developments, such as the production ofhuman therapeutic proteins in microorganisms, and thediscovery of new, totally unexpected phenomena, which

were specific to eukaryotic organisms and challenged thepicture that had emerged from the study of microorgan-

isms. Genes were fragmented into pieces exons andintrons only the first contributing to protein sequences.The mature mRNA was the result of a complex process ofmodification and splicing of the primary product of tran-scription. The mRNA sequence can itself be modifiedenzymatically by the addition of bases or by the chemicalmodification of one base to another, a process calledediting. It occurs particularly in mitochondria, but only ahandful of examples are known in relation to humannuclear genes. Genes can be rearranged during the devel-opment of organisms: such is the case in the immune sys-tem, where the diversity of antibodies and receptors is theresult of very precise programmed rearrangements of shortcoding sequences. Recently, the place of microRNAs andtheir mechanisms of production and action have beendescribed. See also: Splicing of pre-mRNA

The development of molecular and cellbiology

These results were spectacular, unexpected, but they didnot really challenge the molecular vision of organisms.Other developments were more important in the long term,such as the rapid rise of cell biology at the end of the 1960sand beginningof the 1970s. As we describedpreviously, thefirst results of molecular cell biology were obtained in the1950s and helped decipher the informational relationswithin cells. But the influence gained by cell biology in the1960s and 1970s was due to two dramatic changes: thedevelopmentof a newtechnique immunolabeling whichdirectly localizes macromolecules within cells; and theparallel discovery of the cellular principles of organiza-

tion. The signals reaching the cell surface are relayedwithin the cell by a series of molecular components,enzymes, adaptors, organized in pathways and networks.

In the followingyears, descriptions emerged of the complextrafficking of lipid vesicles between endoplasmic reticulum

and the different compartments of the Golgi, and betweenthe Golgi, the endosomes and the cell surface. The mech-anisms behind this trafficking, and the rules that address aprotein to a precise cellular compartment, were discovered.Cells were no longerconsidered as bags full of enzymes, butas highly organized structures, whose principles of organ-ization have to be fully described to understand the func-tions of individual proteins within them.

The difficult convergence between molecularand evolutionary biology

The relations between molecular biology and evolutionarybiology were difficult. The dominant position progressively

acquired by molecular biology was considered by most

evolutionarybiologists as a regression towards a time whenscientists looked for direct physico-chemical explanationsof biological facts. See also: Evolution: Views of

To their credit, Linus Pauling and Emile Zuckerckandlshowed the value of protein and later DNA sequences

for the classification of organisms, and the resolution ofevolutionary relations. The rapid increase in the power ofcomputers was responsible for the increasing role thatsequence comparisons played in biology. The initial resultsof this comparison demonstrated the existence of amolecular clock, in agreement with the neutralist model ofMotoo Kimura, an additional cause of conflicts with mostevolutionary biologists. See also: Evolution: NeutralistView; Pauling, Linus Carl

It was only after the discovery of the conservation of thehomeotic genes in 1984, and the development of Evo-Devo,that evolutionary and molecular biologists interactedeffectively. From the simple, direct comparison of sequencesrapidly emerged an observation: macromolecular com-ponents have been conserved during evolution, even if theywere recruited for diverse functions. This led to the com-parison, proposed by Francois Jacob in 1977, between theaction of evolution and that of a tinkerer: a vision which isdominant today among biologists.

The exponentially growing amount of data instructural biology

Although the description of protein structures started very

slowly in 1960 only one protein, myoglobin, had beenisolated and examined by X-ray diffraction at low reso-

lution the number of structures rapidly grew from the1980s due to new advances in X-ray diffraction, with theuse of synchrotron radiation, the development of geneticengineering technologies to obtain large amounts of pureproteins, labelled for the convenience of diffraction studiesat precise positions, and increasing computing power thatenabled modelling on computer screens. All these trans-formations led to an accumulation of data but, moreimportantly, to a new description and representation ofproteins.Proteinscontain rigidparts, motifs, formed by theassociation of a limited number of secondary structures,

especially a helices and b-pleated sheets. These rigid partsmove relative to one another, allowing the proteins tofunction as micro(nano) machines. The comparison ofproteins with nanomachines became highly fashionable atthe end of the 1990s when it was discovered that adenosinetriphosphatase (ATPase), the enzyme which synthesizesATP, the energetic currency within cells, works as a motor,with a rotor and a stator. The behaviour of proteins asnanomachines provides a mechanistic explanation of their

fantastic power. When the description of macromoleculeswas initiated in the 1930s, it could not have been antici-pated that the explanation of the most fundamental

organic processes would be found in a mechanisticdescription of these macromolecules.


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Genome sequencing

The project to sequence the human genome was launched

in 1986. The ambitions were diverse, from reading thebook of life to the search for unknown genes involved incancer. I think that such a project was inescapable once the

structure of DNA had been discovered, and the techniquesto isolate and sequence it had been developed, in particularwhen a fast sequencing method was proposed by FrederickSanger. Many discussions took place about the way toreach this objective, which were progressively solved withthe advance of the work. Although the public consortiumcreated to sequence the genome adopted a rational strategyof mapping and sequencing, Craig Venter pushed a shot-gun approach consisting in sequencing aleatory frag-ments, followed by a long process of computer-assistedfragment assembly. This second strategy proved moreefficient than was initially anticipated, the result probablyof the rapid increase in computing capacity. No revo-

lutionary new way to sequence DNA was required, and anautomated version of Sangers method applied on a largescale in specialized centres did the job. Human genomesequencing was achieved ahead of schedule, and at a lower

cost than anticipated. This sequence, as well as that ofmany other organisms, represents a large reserve of infor-mation to which biologists have rapid access, and it is

progressively changing the form of work done in biologylaboratories. It is nonetheless necessary to acknowledgethat there is a sharp contrast between the amount of workthat was done to sequence the human genome, the hugeamount of information obtained and the paucity ofknowledge that could be extracted from it, and immedi-ately applied in practice. See also: Sequencing the HumanGenome: Novel Insights into its Structure and Function

Post-genomic approaches

Such is not the casefor the different approachescalled post-genomic, which were developed even before the humangenome sequencing programme was completed. With theproduction of DNA chips plastic plates on which a hugenumber of short different DNA fragments have beenattached it became possible to determine in one experi-ment the rate of expression of all the genes in a cell or an

organism, or to detect in a single experiment a battery ofdifferent genetic mutations. The interactions between all theproteins of a cell can also be characterized through anotherpost-genomic methodology called interactomics. Othertechnologies aimed at providing information on a largescale have also been developed. In contrast to these globalapproaches, much effort and many technological develop-ments have been made to track individual macromoleculeswithin 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 first

aims to describe the global organization of macromoleculeswithin a cell, and to characterize the network formed by

these macromolecules and its dynamic behaviour. Systems

biologists emphasize the importance of isolated functionalparts within these networks, called modules. Althoughsystems biology aims to give an integrated view of what

happens within cells and organisms, the characterization ofthese networks, and of their dynamics, is dramatically

dependent on the wealth of information accumulated bymolecular biologists on the molecular components andtheir interactions in previous decades. See also: SystemsBiology: Genomics Aspects

Synthetic biology has much in common with systemsbiology, in particular the same conception of networksformed of partially independent modules. But syntheticbiology aims to manipulate these modules, to introducenew, more or less synthetic modules to force the organismsto accomplish new functions to respond to new signals, togenerate or degrade new molecules, etc. Synthetic biologytherefore clearly has an applied dimension. But it has also afundamental dimension. The best way to ascertain the levelofknowledge oforganismsthathas beenobtainedis to try tosynthesize (part of) organisms, in thesame way that organicchemists synthesize molecules, whose structures theydetermine. Therefore, synthetic biology represents animportant change in the epistemology of biology. So far, abiological system could be considered as explained evenwhen it was totally impossible to reproduce it. With thedevelopment of synthetic biology, a new criterion of thevalidity of an explanation is the possibility of reproducingthe system under study. Synthetic biology can therefore beconsidered as the achievement of the project to naturalizeorganisms initiated by molecular biologists in the 1930s.

The definitive proof that the organic world has been nat-uralized would be obtained by the synthesis of a fully arti-ficial organism, an objective which is no longer out of reach.

The place of epigenetics in the present landscape ofbiological disciplines is less clear. Recent studies haverevealed a whole set of complex mechanisms of modifi-cation of the histones, proteins closely associated withDNA, with which they form (plus additional proteins)what is called chromatin. These modifications canmodulatethe access of RNA polymerases, the enzymes thattranscribe DNA into RNA, and therefore the expression ofgenes. Epigenetic modifications complement, more thanthey oppose, the traditional genetic regulations by repres-

sors and activators. Some of these epigenetic marks can, insome organisms, be transmitted through the germline tonew generations. In addition, alteration in epigeneticmodifications might be involved in some human diseases,such as the cancers, coronary artery disease, hypertensionand the other common degenerative disorders, and moregenerally age-related diseases. But epigenetics is clearlymore, at least for its supporters. It is, since its inception(with a different meaning) by Conrad Waddington in 1940,a word used to designate diverse experimental approaches

that aim to complement, and frequently to oppose, themodels of genetics. Epigenetic effects are seen as less

deterministic than genetic effects, and open to the action ofthe 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 biologicalphenomena that some of its supporters dream of!

Beyond the creation of new disciplines, what is most

striking in contemporary biology is the progressive aban-donment of the model systems that were so dominant in

twentieth century biology. The accumulation of genomicsequences, and the rapid comparison of these sequences,allows a permanent passage from one organism to another.The second characteristic is the growing role of mathem-aticians and physicists in biology, and of modellingapproaches: not to support the results previously obtainedby biologists but, as in physics, to anticipate these resultsand guide future experimental work.

Some Philosophical Issues Raised by

the History of Molecular BiologyThe place of reductionism

In recent years, it has become usual to consider thatmolecular biology has been too reductionist in its approachto biological phenomena the full reality of organisms and that it is high time now to redirect research towards

more global approaches. From the seventeenth century andthe rise of modern science, there was a constant trend tolook for the explanations of organismal phenomena at the

lowest level of organizationhitherto described: tissues at thebeginning of the nineteenth century, cells in the middle of

the same century and subcellular structures at its end. Therise of molecular biology was the prolongation of thisdownward movement. But, as we have seen, the motiv-ations of its founders were simply to explore the neglectedworld between organic molecules and subcellular struc-tures. And most of the explanations of molecular biologyare not at the atomic or electronic level, but at the macro-molecular level. The latter only gradually became afavoured level of explanation, an evolution which had notbeen anticipated. Nothing presently suggests that anotherlevel of organization is ready to replace the molecular level.And the word emergence remains too vague to have truescientific value, and to represent an alternative to moleculardescriptions. See also: Reduction: A Philosophical Analysis

The place and limits of mechanisticexplanations

At the molecular level, the explanations that are providedare mechanistic. Mechanistic explanations have in generalan important place in biology, but the form of mechanismfavoured at this level of organization is that advocated by

Descartes or Galileo Galilei: the functions of proteins areexplained by the existence within these nanomachines oflevers, springs, etc.

These mechanistic explanations presently face threelimits. In some cases, the mechanistic explanation gives

way to more sophisticated explanations in terms of stat-

istical thermodynamics, microvibrations of molecules, thatis to explanations at a lower level of organization. Thesecond limit is evolution. Molecular mechanisms are the

result of a long evolution; when themolecular explanationsare pushed to their limits, the characteristics of the systems

under study can no longer be understood independently ofthe evolutionary history which generated them. Finally,when the macromolecules work together in networks, theorganization of these networks obeys design principlesfamiliar to engineers, in relation with the functions that theensemble of macromolecules has to fulfil. These principlesof organization cannot be directly deduced from know-ledge of macromolecular structures.

The question of life

The question of life was actively debated in the 1930s and1940s. Two decades later, the question disappeared, as if

it had been solved. Recently, it re-emerged, supportedby the development of research on the origin of life andastrobiology.

Does this mean that the claim of (many) molecularbiologists to have solved the riddle of life was wrong? I do

not think so. Molecular biology was obviously thedescription of the most fundamental mechanisms gov-erning organisms. But what remains unknown is the waythese complex mechanisms have been progressively estab-lished. The question of life is no longer a question of thenature of the mechanisms supporting it, but a historical(i.e. evolutionary) question.

Conclusion

So,is molecular biology dead or alive?Molecular biology isan historical object,and theanswer depends on what formof molecular biology one refers to. The informational

face of molecular biology, with an emphasis on the notionof programme, has clearly lost its dominant position. Ofcourse nucleic acid information remains of crucial

importance but the focus of research is moving to thedynamic structures of proteins as they execute their func-tions and this is important, not only at the fundamental

level, but also at the practical level, for the development ofnew drugs. It is also not obvious what kind of a new visionwould eventually replace the molecular one. What isnevertheless evident is that the molecular vision has to becomplemented: by models generated from moleculardescriptions, and by evolutionary explanations, the onlyones likely to explain the specific characteristics that thesemolecular mechanisms have adopted.

Biographical Information

Michel Morange is a researcher in molecular and develop-mental 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 ofnew disciplines synthetic biology, systems biology re-emergence 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 19301965. 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 Rock-

efeller Foundation, and the Rise of the New Biology. Oxford:

Oxford University Press.

Kay LE (2000) Who Wrote the Book of Life? A History of theGenetic 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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