Biochemical Genetics and Molecular Biology: The Contributions of George Beadle and Edward Tatum

Abstract

It will concern us particularly to take note of those cases in which men not only solved a problem but had to alter their mentality in the process, or at least discovered afterwards that the solution involved a change in their mental approach (Butterfield 1962). SEVENTY-FIVE years ago, George Beadle and Edward Tatum published their method for producing nutritional mutants in Neurospora crassa. Their study signaled the start of a new era in experimental biology, but its significance is generally misunderstood today. The importance of the work is usually summarized as providing support for the “one gene–one enzyme” hypothesis, but its major value actually lay both in providing a general methodology for the investigation of gene function and in suggesting a simple biochemical relationship between genes and the characters they control. I discuss the reasons for this misunderstanding and the role of Beadle and Tatum in the development of molecular biology. This year (2016) marks the 75th anniversary of an article by George Beadle and Edward Tatum that ushered in a new era in experimental biology (Beadle and Tatum 1941a). Their work is properly seen as a major foundation stone of what is now called molecular biology, yet today its precise significance is largely misapprehended. It is worthwhile revisiting the biological scene at the time of their work, considering what they accomplished, and investigating the factors that may have led to what was really their major contribution being relatively overlooked. By the end of the 1930s, geneticists had developed a sophisticated, self-contained science. In particular, they were able to predict the patterns of inheritance of a variety of characteristics, most morphological in nature, in a variety of organisms although the favorites at the time were clearly Drosophila and corn (Zea mays). These characteristics were determined by mysterious entities known as “genes,” known to be located at particular positions on the chromosomes. Furthermore, a variety of peculiar patterns of inheritance could be accounted for by alteration in chromosome structure and number with predictions as to inheritance pattern being quantitative and statistical. The state of genetics in this period was described in a textbook by Alfred Sturtevant and George Beadle, An Introduction to Genetics (Sturtevant and Beadle 1939), which remains one of the best statements of the field at that time. Notwithstanding the predictive powers of the theory, genetics remained innocent of significant contact not only with (bio) chemistry but also with embryology. An original goal, understanding the mechanism of development, had essentially been abandoned in favor of pursuit of the more easily understood mechanics of inheritance. The chemical nature of the gene was especially elusive. Indeed, it was not clear whether genes were single molecules or complex organelles, and the steps that must exist between gene and character were completely unknown. The only clue to the nature of the gene was that radiation experiments and target theory gave size estimates for a very large molecule. It was not even clear to all geneticists that individual genes, as distinct from chromosomes, had a separable existence. Richard Goldschmidt in Physiological Genetics (Goldschmidt 1938) proposed that only the whole chromosome could be considered as the unit of inheritance (a point of view from the early 20th century that could once again be defended). We knew about “genes” as such only because mutation of a segment changed the phenotype, but that did not show that there was a normal segment that by itself produced the wild-type version. Sturtevant and Beadle (1939) devoted only a few pages at the end of their text to genes and phenotypes. They did mention the studies of anthocyanin pigments and noted that “the fact that an oxygen atom difference between pigment molecules is gene controlled, while it does not solve the problem of the relation between gene and character, is at least one step in the desired direction” (p. 356). There is no mention, however, of Archibald Garrod’s Inborn Errors of Metabolism (Garrod 1909), discussed below. Goldschmidt, mentioned above, had spent his career in studying gene action, and he had concluded (Goldschmidt 1938) that genes act “by changing the rates of partial processes of development.” Nevertheless, the processes that Goldschmidt and others studied (wing development in Drosophila as an example) were complex and not accessible to biochemists. Although genetics developed in large part in an effort to explain development, the problem was too complex for solution by the biochemical methods of the late 1930s and early 1940s. “The theory of the gene” was in large part the product of the work of a former embryologist, Thomas Hunt Morgan, who had initially been intent on accounting for the mysteries of development, and his students. By the mid-1930s, however, the attempt to reconcile genetics and embryology seemed to be at a dead end. The following anecdote illustrates the situation. After reading T. H. Morgan’s book Embryology and Genetics (1934), Boris Ephrussi said to Morgan that he seemed not to have integrated the two fields adequately. Morgan replied, with a smile, “You think the title is misleading. What is the title?” “Embryology and Genetics” Ephrussi answered. “Well,” Morgan countered, “is there not some embryology and some genetics?” (Ephrussi 1958). It is so obvious to us today that proteins are linear polymers of amino acids arranged in a specific sequence and connected by peptide bonds that it is difficult to put oneself in the mind-set of a student of biochemistry in the years around 1940. To do so, it is instructive to look at successive editions of standard textbooks written in this period (Bodansky 1938; Harrow 1935, 1940, 1943, 1947, 1950, 1954, 1958, 1962, 1966). Not only were there some odd notions, to our eyes, about the nature of protein structure, but also many assumed that the genes themselves were proteins. The second (1940) edition of the text by Harrow discusses the structure of proteins in terms of the Bergmann–Niemann hypothesis of repeating 288 amino acid units. They supposed that the proteins were constructed along simple lines with a limited number of amino acids repeating at regular intervals. Also seriously considered was the “cyclol” hypothesis of Dorothy Wrinch, which supposed the proteins to be made up of a series of hexagonal structures composed of amino acids. Stanley’s crystallization of tobacco mosaic virus (TMV) was discussed as an example of the genetic role of protein. The Bergmann hypothesis was still discussed in the third (1943) edition of Harrow although the cyclol hypothesis had been discarded. TMV was recognized as a nucleoprotein but not much was made of the nucleo portion. The fourth edition (1947) did not change much. The fifth (1950) edition no longer discusses either the Bergmann or the cyclol hypothesis. The importance of hydrogen bonds in determining the three-dimensional structure of molecules, in particular proteins, had been recognized, however. In 1942, Linus Pauling published an article in the Journal of Experimental Medicine claiming the formation of specific antibodies by denaturing and renaturing globulin around an antigen (Pauling and Campbell 1942). As late as 1954, Chemical Reviews could publish an article on the “Microheterogeneity of Proteins” (Colvin et al. 1954). Why was the connection between metabolic reactions and genetic factors not given more attention? One explanation might be that it was unclear what to do about it. That is, it was not obvious how the problem could be approached experimentally. After all, alkaptonuria and the other conditions discussed in Archibald Garrod’s book Inborn Errors of Metabolism (Garrod 1909) were rare and, as he stressed, not life threatening. It was not clear how these observations on a metabolic oddity fit into a general pattern linking biochemistry and genetics, especially since it was uncertain whether the “gene” was a molecule or an organelle and the basis of enzyme specificity could not even be guessed, given the then current knowledge of protein structure. In the late 1930s, George Beadle and Boris Ephrussi were studying the production of eye color in the fruit fly Drosophila using a demanding technique of transplanting the imaginal discs of developing mutant flies into larvae of different genetic types. Boris Ephrussi was a Russian émigré embryologist who had come to T. H. Morgan’s Department at Caltech on a Rockefeller fellowship to gain a genetic perspective on his studies. [According to the Wikipedia entry on him, Ephrussi was part of the Russian branch of a Jewish family of major bankers and art collectors thriving at the end of the 19th century with branches in Paris and Vienna and who are the subject of an equally fascinating but unrelated story (de Waal 2010).] There he met George Beadle who was a postdoctoral fellow at the time, studying crossing over in Drosophila. The two decided to work together on the problem of reconciling genetics and embryology (see Beadle’s biography by Berg and Singer 2003 for details). According to Beadle, they decided to study the development of the eye-color mutant vermilion because of an earlier observation of Sturtevant that vermilion eyes fail to develop autonomously; that is, they can be affected by the genetic nature of the surrounding tissue (Beadle with of the mutant by some from that of to study the of eye however, had been by in the as described in was a and was a time for such to be an career in As a was to up the work although his Alfred to have as as the to at and then to the After an initially difficult time, he had a very the Department at was of the Genetics of and this Journal from to Beadle and Ephrussi to in Paris they their to be a more demanding in the Drosophila as to that of The this work do the earlier contribution of By transplanting the imaginal discs of developing mutant flies into larvae of different genetic they were able to that some in the development of wild-type eye pigment in the mutant imaginal Beadle and Ephrussi a sequence of reactions on the production of but the biochemistry of these Their of the is in with the of the but they that what they was a metabolic The of as such an however, was made by a student of in with Alfred had this with a in chemistry for studies on in the The of was made by a student in There was clearly a to the structure of the vermilion and with Beadle and Tatum both and with Ephrussi and with both with It is of a that the have been by the in which the observation had been in this to Beadle’s with the of the fly for biochemical studies and to his for a new and According to Berg and Singer he had been by the of the although I this to be a According to Beadle, it was at this one of on that he the of the of to the biochemical of known and to look for that known biochemical reactions and Singer They was on the Neurospora as experimental The genetics of Neurospora had been by a student at Caltech in T. H. Morgan’s while Beadle was a postdoctoral fellow Beadle had about Neurospora and its life while a student at from a by about this made it for Beadle’s it a which that one can and the of This it to that a mutant from the by a change in a single its is The on a of and one As a change in is to Beadle’s but it biology (Beadle and Tatum 1941a). of for mutant organisms with that could be an could an and a with the desired Beadle and Tatum and on a complex the time, was the generally for They then the of the mutants for to on either a complex or a on the but not the It was then to which of the complex were to The of their experiments were mutants that either or acid to at an essentially normal were that the mutants from the by change in a single By the Beadle had mutants with for amino acids and an genes et al. One can only the that these produced in the The were up with the of amino acid and The few cases in which a mutant factors were by or by between the The of so many cases in which a mutation in the for a single was as for the “one gene–one enzyme” hypothesis. Beadle however, that this hypothesis the Neurospora experiments and the for the work being the other that the hypothesis itself the product of with and to by and that it had been given its by and (Beadle 1958). Beadle its to “one gene–one but the hypothesis in either not the of time. The developing understanding that single of can as a of start and patterns of and of the nature of protein structure it clear that single may in reactions and that single proteins may in In the were in and or start for their This of the complex relationship between single genes and may have the importance of Beadle’s One might however, a of about could be to theory, that it of itself point the to the of a more theory, in which it on as a Although the “one gene–one enzyme” hypothesis led to our current understanding of gene action, it is not the most part of Beadle and In that contribution is they an experimental a general for the investigation of a variety of biological and of mutants for studies from metabolic to the of development and and The with Neurospora Tatum to the work to providing the by and Tatum to in a that in led to the of in these Not only was what was for also for but also the had chromosomes. The most significant of this work, however, may have been its The of the that there is a and connection between gene and The experiments are to to and to the simple that in a new student could be given the to an do H. this with the in the of gene on development in Drosophila (Goldschmidt 1938) or the of and in title of a in with the attempt to for complex morphological the problem of with biochemical seemed that could be approached with the of at the of biochemical investigation following the the that this a of to look for molecular In particular, I that the that the of biological might to molecular was a major in a new of to up such studies. Beadle was in for the of the relationship between genes and to (Beadle 1958). In particular, he to Garrod’s studies on Inborn Errors of Metabolism (Garrod 1909) the of biochemical Beadle’s is so however, that one might be to think of Garrod’s work as to that of and of Beadle and as to the of This however, was by in his of Tatum concluded while understood how genetic could in the of metabolic he had no theory of gene It is however, that Garrod’s was In his he may that the of the enzyme in normal is the work of a that in alkaptonuria this enzyme is in its may be or even completely It is also clear that he understood as of a series of reactions and that a that was to the and of the We not the however, of our of his made with our current to that of a in the early that made the from the by the mutant gene to the of its normal did he as the of genes in their normal function but to as or to be with the of or Garrod’s to that but it does clear that was of a quantitative relationship that could also be affected by a of Furthermore, to point that these are for the most part and he to as the of a normal of This may be a of the current the that genes determined only of genetics and biochemistry textbooks of the period this There is no mention of Garrod’s work in Physiological a Beadle that Goldschmidt that he had known of Garrod’s work and to it earlier and that could not how he had not Sturtevant and Beadle’s textbook to Genetics does not mention in the on and (Sturtevant and Beadle 1939), although Beadle does to the work in a (Beadle and Tatum The is and peculiar of to acid (Garrod and and the of acid in the and is not by a of in the of biochemistry textbooks of the period do mention Garrod’s work, however. for both Inborn Errors of Metabolism and that to be although as to what that might the of a series of textbooks that in the that the rare known as the on but there is no mention of It does however, that the of Garrod’s work the importance to the contribution of Beadle and biology as it Beadle was able to the work on Neurospora the period of the in the Beadle’s work was by the Rockefeller for the was an role in this story since he is the of the to the he to support was a major of both Pauling and Beadle, work was not while the Rockefeller support for Beadle’s studies the It seemed that proteins could be and that of protein structure be particularly the crystallization of tobacco mosaic The end of and was up one of the of the There a series of for the development of molecular biology. In particular, the development of the methods of and and and made the quantitative of both proteins and acids for the time. It was these that made it for to the structure of and and for to the of acids One can only with an of that of the amino acid sequence of and to a the and (1950) of the of different made it to how the specific structure of the genes could to the specific structure of proteins. In this two other more they have that amino acid sequence was and that this protein structure was it was who the of a single mutation to change a single amino acid in the in a protein with different and it was who that the linear structure of the as in genetic with the linear structure of a protein is usually as by and earlier of the mutants of to the nature of the et al. but the are different in their nature, being on second view as to the of molecular biology a major role to the of and especially of to biology. was a who had as a simple that the of biological processes the by As he was the of a of their entry into biology and These start with the of a by in in which the of to biological of the career of was up in the for such made in his book What The of the in which he about a of the gene had book a of that biology was a field in which new could be There is no that book and the major to molecular biology. goal, however, of new to biology was The was the of the structure of itself and the as the that it a of on biochemical and This that much in biology for the at be by The that Beadle’s experiments a into biology is explanation for to the “one gene–one enzyme” hypothesis to in made the Beadle methodology for in only a simple in or in could not be by on the complex so that it from the that generally in single This however, was by the of mutants by and Their approach on the hypothesis that simple and complex have in One could then and what had simple The that a of mutants could be on complex as by the hypothesis. one might that by the of organisms the were the might have given a different there were a of the at the time it was an The of are but it is also the that his involved for new of that to biology that the Beadle and Tatum experiments too a relationship between chemistry and biology. It is clear from at the on and that was not in his The known of made many of the of simple relationship between gene and It new in biochemistry to it clear how genes could both protein specificity and the of their which in to an understanding of third of proposed of molecular biology with the by in of his that the was et al. It a however, for the general that the genetic was It is not that the work was unknown. Although the fourth edition (1947) of the Harrow general biochemistry text does not mention work on by the fifth (1950) edition there the that the nucleoprotein and the gene are from the work of Why did it take so to the protein from one might whether a is really a time, considering the state of acid chemistry at the was a of in generally is that because of a earlier proposed structure of as a repeating it was to the specificity The by and (1950) of the between of and the of the structure for and were in the understanding of the role of The and is as a but in fact their are no more was and may have seemed because by then the genetics was to be of the importance of I to an experimental work was not up more is not an experimental with not by the new to biology. variety of factors was

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