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Hist. Phil. Life Sci., 28 (2006), 491-512

A World in One Dimension: Linus Pauling, Francis Crick and the Central Dogma of

Molecular Biology

Bruno J. Strasser

Program in the History of Science and Medicine Yale University

New Haven, CT, 06520-8015, USA

ABSTRACT ? In 1957, Francis Crick outlined a startling vision of life in which the great diversity of forms and shapes of macromolecules was encoded in the one-dimensional sequence of nucleic acids. This paper situates Crick's new vision in the debates of the 1950s about protein synthesis and gene action. After exploring the reception of Crick's ideas, it shows how they differed radically from a different model of protein synthesis which enjoyed wide currency in that decade. In this alternative model, advocated by Linus Pauling and other luminaries, three-dimensional templates directed the folding of proteins. Even though it was always considered somewhat speculative, this theory was supported by a number of empirical results originating in different experimental systems. It was eventually replaced by a model in which the forms and shapes of macromolecules resulted solely from their amino acid sequence, dramatically simplifying the problem of protein synthesis which Crick was attempting to solve in 1957.

KEYWORDS ? Central Dogma, Molecular Biology, Protein Synthesis, Protein Folding, Template, Sequence

Introduction

The world comes in three dimensions. Yet, the living world is perpetuated in one. The bewildering diversity of forms and shapes that constitutes life, from macromolecules to whole organisms, is specified in a linear sequence of simple units. This perplexing vision of life is one of the key landmarks in the intellectual history of the life sciences in the twentieth century. Today, the success of genomics and bioinformatics testifies to the power of this original conception of nature. In 1957, Francis Crick, one of molecular biology's leading theorizers, played an essential role in promoting this new vision by formulating several bold propositions, including one he called `the Central dogma'. He defined the problem of protein synthesis, or how cells produce a wide variety of molecular structures, as a question about the transfer of one-dimen-

? 2006 Stazione Zoologica Anton Dohrn

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sional information from nucleic acids to proteins. In this sense, he departed from previous conceptions, such as Linus Pauling's, where three-dimensional structures served as molds or templates for the production of other three-dimensional structures. This shift represented a major step in the reductionist agenda of the life sciences, since it reduced some of the major problems of biology to a single dimension (Morange 2000, chapter 13).

In exploring how this particular change came about and attempting to situate the central dogma in the intellectual history of the life sciences, I will argue that it represented a radical departure from another model of protein synthesis, whose importance and generality has generally not been recognized in the literature on the history of molecular biology (Olby 1970; Thieffry and Sarkar 1998; Morange 2000, chapter 12; Fruton 1999, chapter 8; Kay 2000, chapter 4; de Chadarevian 2002, chapter 6; Judson 1996, chapter 6).1 By considering Crick's 1957 paper (Crick 1958) in this context, one can gain a better understanding of its historical significance and of its current meaning, as it still serves today as one of the intellectual foundations of the life sciences.

The Central Dogma

Francis Crick, a physicist-turned-biologist from Cambridge formulated the central dogma in a lecture on protein synthesis given at University College London in September 1957. He presented several hypotheses to account for a number of experimental facts that had recently been published. Most of Crick's claims were unoriginal. Following his tendency to interpret the work of others, he spelled out assumptions that colleagues had left implicit in their own work (Olby 1970, 976). He asserted, for example, that the specificity of a piece of nucleic acid resulted from the sequence of its bases (not its three-dimensional structure), and that `this sequence is a (simple) code for the amino acid sequence.' He called this proposition the `Sequence hypothesis', and believed it to `be rather widely held' (Crick 1958, 152).2 The second key idea he proposed was that `once "information" has passed into proteins it cannot get out again' what Crick called the `Central Dogma' (Crick 1958, 153). By `information', Crick meant the precise order of

1 However, H.F. Judson does emphasize the `working out of the idea of specificity' as one-dimensional sequence (p. 582), but ignores how this idea replaced the alternative model discussed in this paper.

2 Crick published a similar account a year earlier in Scientific American, where he discussed `the hypothesis which my colleagues and I call the Central Dogma' (Crick 1957, 198).

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the units along a nucleic acid or protein chain, i.e. its sequence. In other words, proteins did not influence the sequence of nucleic acids or other proteins; they contained information, but did not pass it on. Thus, nucleic acids were causally prior to protein, and in a certain way, more fundamental. This view reflected the then growing idea that DNA was the most important component of the cell, its `master plan' (Gaebler 1956, 170; Keller 1995, chapter 2) or as geneticist George Beadle put it in 1957, `a recipe for constructing a person' (Beadle 1957, 399).3 What is perhaps most remarkable in Crick's views of protein synthesis is what it leaves out. For Crick, giving an answer to the problem of protein synthesis amounted to explaining how a protein acquired its amino acid sequence. On the subject of protein conformation, the three-dimensional folding up of the polypeptide chain, he remained almost completely silent. Given the fact that such diverse phenomena as the ability of hemoglobin to carry oxygen, of antibodies to recognize antigens, and of enzymes to carry out their catalytic activity all rested on the respective conformation of these proteins, how could Crick simply ignore this question? How could he claim to review the problem of protein synthesis without addressing the essential feature that made protein uniquely functional?

This intellectual step was made possible by making a bold assumption, namely that protein `folding is simply a function of the order of the amino acids' (Crick 1958, 144). Thus, for a cell to make a specific protein, it was only necessary to specify its amino acid sequence, since its conformation and function would follow automatically. This key assumption simplified the problem of protein synthesis tremendously, as Crick recalled in 1970:

Because it was abundantly clear by that time that a protein had a well defined threedimensional structure, and that its activity depended crucially on this structure, it was necessary to put the folding-up process on one side, and postulate that, by and large, the polypeptide chain folded itself up. This temporarily reduced the problem from a three-dimensional one to a one-dimensional one. (Crick 1970, 561)

Crick could thus focus on the relationships between nucleic acid and protein sequences, speculating on the biochemical underpinnings (the role of RNA, the adaptor hypothesis) and the theoretical consequences (the coding question) of this problem. This assumption also gave the central dogma its empirical content. Indeed, protein sequences and conformations were tremendously difficult to

3 Beadle acknowledged that it also required, in addition to an egg, `some ten tons of food and a suitable environment' (p. 399).

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determine experimentally, but protein activity could easily be monitored by a number of biochemical essays. Changes in sequences would then be inferred from changes in protein activity. Before examining how it became scientifically reasonable to make this key assumption, something Crick did not address in his recollection, I will briefly outline the reception of the central dogma, which will show how this assumption came to be embedded in the more popular understanding of the central dogma.

The Reception of the Central Dogma

The central dogma rapidly gained wide acceptance and by the mid 1960s, one is hard pressed to find any criticisms of its main ideas in the scientific literature.4 Even though some of Crick's proposals were quite speculative when he presented them in 1957, they gained empirical support in the immediate following years. By 1961, a biochemist wrote in Nature that `[the Central dogma] is almost universally accepted' (Leslie 1961), and another one claimed that its core idea was `so fundamental to present day thinking in the field of molecular biology that it has rightfully been referred to as the "central dogma''' (Mahler and Fraser 1961). A few years later, another researcher wrote in The Lancet that `the Crick dogma is so authoritative that a good deal of experimental evidence would be needed to disestablish its all-embracing validity' (Field 1967). Another editorial published in 1967 noted that `modern trinitarians have a deep faith in the Central dogma of molecular biology' (Anonymous 1967, 705).5 Biochemist Felix Haurowitz, from Indiana University, was one of the rare dissenting voices. In the 1963 edition of his book entitled Chemistry and Biology of Proteins, he remarked that it would seem `strange indeed that nature should not have made use of the transfer of information from protein to protein and also from protein to nucleic acids' (Haurowitz 1963, 438). The central dogma became more widely known when James Watson described it in his popular textbook, Molecular Biology of the Gene, published for the first time in 1965, a text that would train several generations of molecular biologists. For Watson, the central dogma amounted to a simple diagram, `DNA' RNA'Proteins', or `DNA makes RNA makes Proteins' (Watson 1965,

4 The major exception being the biologist Barry Commoner, whose views will not be discussed here because they remained extremely marginal, see Commoner 1964, 3316-3317.

5 They were called `trinitarians' for their belief in the exclusive importance of DNA, RNA and proteins.

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315),6 a slogan that conveniently summarized the intellectual agenda of the new discipline.

In order to understand, beyond its sheer acceptance, the reception of the central dogma, one can examine episodes in which it was purportedly challenged, for moments of transgression reveal accepted norms, values and theoretical commitments. Reverse transcription, i.e. the production of DNA from an RNA template, and the replication of the scrapie agent, have represented two such challenges.

In 1970, Howard Temin and David Baltimore announced independently that they had isolated an enzyme, reverse transcriptase, that could copy RNA sequences into DNA sequences. An editorial in Nature claimed that this discovery had `reversed the Central dogma' (Anonymous 1970), prompting Crick to publish a note restating that RNA-to-DNA information transfer was not excluded in his original scheme, but only in Watson's simplified version (Crick 1970; Darden 1995). The claims that information transfer from RNA to DNA challenged the central dogma were thus short lived.

The case of the agent causing the scrapie disease represented a much more serious challenge and the only one Crick worried about in 1970 (Crick 1970). In the 1960s, a number of experimental results pointed to the fact that the agent causing scrapie in sheep might be composed solely of proteins, not of nucleic acids, unlike all viruses and other pathogens (Keyes 1999a; Keyes 1999b). Thus, if this unusual agent replicated without the intervention of DNA or RNA, it would violate the central dogma, as several authors remarked, since information would be passed from proteins to proteins. However, this was not the only possible interpretation. The scrapie agent could also activate an existing gene in the cell, inducing its own synthesis, or change the conformation of preexisting proteins (Griffith 1967). Surprisingly, both of these cases have also been interpreted as violations of the central dogma. A comment published on the second interpretation in The Lancet in 1967 asserted that `this would invalidate the accepted dogma of present day molecular biology in which D.N.A and R.N.A. control all biological activity' (Lewin 1972). An editorial about the third mechanism, published in Nature Genetics in 2002, claimed that `Crick's original proposal [...] simply stated that information flow in the cell goes from nucleic acids to proteins. The obvious exception to this statement is the prion hypothesis, whose father, Stanley Prusiner, was awarded a Nobel Prize' (Anonymous 2002).

6 In this scheme, Watson even omits the DNA to DNA transfer, which is however included on p. 298.

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