Following the Second World War, the face of genetics was transformed as biochemists and geneticists teamed up to explore what genes do in the cell, and what they are. What was new was not the concept that genes function by way of enzymes, but the use of microorganisms. Single-celled microbes allowed geneticists to avoid the complexity of tissue differentiation and cellular integration when searching for a bridge between gene and character. The geneticist isolated mutants that were found to be unable to grow, or that grew poorly on a well-defined growth medium, and the biochemist sought the reason for this inability. Thus, a suitable organism for biochemical genetics was one whose sex life and growth could be brought under meticulous control. The model organisms of classical genetics, Drosophila, corn, and mice, so useful for establishing the chromosome theory of inheritance, were quickly outcompeted by rapidly reproducing microorganisms: fungi, yeast, algae, protists, and bacteria.
In their landmark paper of 1941 on the genetics of the bread mold Neurospora crassa, Beadle and Tatum argued that because the cell was a highly integrated system, "there must be orders of directness of gene control ranging from simple one-to-one relations to relations of great complexity."21 However, by the mid-1940s, Beadle's views had hardened. The numerous instances in which singlegene mutations resulted in a block of a metabolic step led him to hypothesize that many or all genes have single primary functions. The idea that one gene produce one metabolic block soon became well known as the "one-gene: one-enzyme hypothesis."22 Although this hypothesis offered the hope that one could know what genes actually do in the cell, many geneticists were reluctant to accept such a simple one-to-one relationship. As Beadle commented years later, "I recall well the year 1953 when, at the Cold Spring Harbor Symposium on Synthesis and Structure of Macromolecules there appeared to be no more than three of us who remained firm in our faith."23
This was the context in which Beadle "rediscovered" Garrod's work. He had first learned of it in reviews of physiological genetics by Sewall Wright and J. B. S. Haldane in the early 1940s.24 He saw in Garrod's writings the idea that each inborn error of metabolism in humans, like those in Neurospora, could be interpreted as a block at some particular point in the normal course of metabolism that resulted from a congenital deficiency of a specific enzyme. In other words, genes control single metabolic functions. But, unlike many of those who followed him, Beadle fully recognized that Garrod himself had made no such announcement about gene action. "Thus, while he did not express it exactly so, the relation gene-enzyme-specific chemical reaction was certainly in his mind. It is proper that he should be recognized as the father of chemical genetics."25
Garrod had said just enough for Beadle. The story of Garrod's creative insight and subsequent neglect was important for bolstering his one-gene: one-enzyme hypothesis. The notion of the independence and the inevitability of the truth is embedded in the notion of rediscovery: the true concept of gene action, lost and found, would be vindicated, just as Mendel's laws had been. Thus began, in 1950, the legendary myth about the long neglect of Archibald Garrod.
At the centenary of Mendel's paper, geneticists embellished the Garrod story further, referring erroneously to him as a "geneticist" and asserting that he had been ignored by his colleagues. Bentley Glass wrote in 1965, "The first big steps forward in understanding the nature of gene action were those made by Garrod, so ignored by the fraternity of geneticists who perhaps were too engrossed in their own experiments to read anything not published by another recognized geneti-cist."26 Beadle compared the neglect of Garrod to that of Mendel, commenting that "I strongly suspect that an important component of the unfavorable climate for receptiveness in these two instances is the persistent feeling that any simple concept in biology must be wrong."27
Beadle's suspicion that Garrod's one-to-one theory was doubted because of the feeling that it was too simple holds some truth. However, we should remember two points. First, ample experimental evidence had accumulated over previous decades indicating that one gene may be concerned with many characters, and one character may depend on many genes. Secondly, no satisfactory proof of the one-gene: one-enzyme theory existed. This limitation was addressed by prominent scientists of the 1940s and 1950s. The physicist-turned-geneticist Max Delbrück offered the most significant criticism of the one-gene: one-enzyme hypothesis in 1946, when he pointed out that the data were only compatible with the interpretation; they did not prove it. He emphasized that the procedures of isolating mutations in the Neurospora work precluded the results by restricting alternative possibilities. If in fact one gene normally controlled many enzymes, no mutations in such genes could be detected. He challenged geneticists to devise methods by which the hypothesis could be disproved. "If such methods are not available, then," he argued, "the mass of 'compatible' evidence carries no weight whatsoever in supporting the thesis."28
Delbrück's challenge was easy to make but difficult to meet. Neurospora geneticists argued that since the data could be accounted for on a one-to-one basis, there was little value in making up a more complex interpretation.29 Beadle himself confessed that he knew "no way of proving it in a single instance." Nevertheless, he argued that the hypothesis "served a useful purpose" and that there were "no compelling reasons for abandoning it," even though it might be later found to
"err in the direction of oversimplification."30 Indeed, it was a useful heuristic. The idea that each gene specified one enzyme was genetic orthodoxy for decades, and the gene itself was generally defined in terms of specifying a single protein (see chapter 18).
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