Tatum, Edward Lawrie
TATUM, EDWARD LAWRIE
(b. Boulder, Colorado, 14 December 1909;
d. New York City, 5 November 1975), biochemistry, embryology, physiology, genetics, microorganisms.
Tatum was an American-born biologist who together with George Beadle received the 1958 Nobel Prize in Physiology or Medicine “for their discovery that genes act by regulating definite chemical events.” Tatum worked primarily within biochemistry, studying the nutrition and genetics of microorganisms and of Drosophila. He was a seminal figure in the development of physiological genetics, made fundamental contributions to understanding biochemical processes and their relation to gene action, and was a pioneer in the use of microorganisms as genetic models. He also was one of the first to experimentally demonstrate the importance of “sex” in bacteria.
Early Years. Edward Lawrie Tatum was the son of Arthur Lawrie Tatum, a pharmacologist, and Mabel Webb Tatum. Carla Harriman was his stepmother. The elder Tatum held a variety of positions, including one at the University of Chicago from 1918 to 1928, and moving from there to the Madison Wisconsin where he had been appointed as a professor of pharmacology at the University of Wisconsin Medical School. Edward Tatum attended the University of Chicago for two years, then transferred to the University of Wisconsin, receiving his BA in chemistry in 1931, MS in microbiology in 1932, and PhD in biochemistry in 1934. Tatum’s undergraduate work focused on the growth of bacteria. He continued to work on Clostridium septicum in his graduate work, studying the effects of an aspartic acid derivative on its growth. This substance was later shown to be asparagines. His PhD in biochemistry concerned nutrition and metabolism of bacteria, work he carried out under the direction of Edwin Broun Fred and William Harold Peterson. He identified vitamin B1, or thiamine, as one of the required growth factors for microorganisms. (Before this time, the need for B vitamins was underappreciated.) After receiving his PhD he married June Alton on 28 June 1934; the couple would have two daughters, Margaret and Barbara, before divorcing in 1956.
Tatum stayed at Wisconsin from 1934 to 1937, though visiting during 1935 at the University of Utrecht in Holland. At Utrecht he worked with Fritz Kögl, who had himself recognized the importance of biotin, and with Nils Fries. Tatum worked on identifying growth factors in staphylocci, though he was apparently unsatisfied with the results.
At the University of Wisconsin, together with H. G. Wood, Esmond E. Snell, and Peterson, Tatum worked on factors affecting the growth of bacteria, indicating that thiamine was crucial. They showed that vitamins were critical to the growth of a variety of bacterial species. For comparative biochemistry, it was an illustration of the conservation of biochemical processes across diverse species. This suggested that insofar as biologists were interested in metabolism, the simplest method might be to attack problems of growth in microorganisms. That was a theme to which Tatum returned throughout his career.
Work on Drosophila. When Beadle moved to Stanford University from Harvard University in 1937, he invited Tatum to join him working on Drosophila. Tatum was a research associate with Beadle’s group from 1937 through 1941 and an assistant professor from 1941 to 1945. The Rockefeller Foundation supported this work as one of the ventures into molecular biology. They worked on the genetics underlying eye color in Drosophila, and subsequently on Neurospora crassa. It was this work that ultimately earned Tatum and Beadle the 1958 Nobel Prize, which was shared with Joshua Lederberg.
This research was intended to follow up on the work that had been initiated by Beadle and Boris Ephrussi at California Institute of Technology and subsequently in Paris. Beadle and Ephrussi had shown that there were “hormones” involved in the synthesis of eye pigment in Drosophila, and that their contributions to the synthesis of eye pigment are not independent. Tatum’s training as a chemist made him an ideal choice for Beadle. The idea was that a biochemist might be able to identify the specific substances involved. Jobs were scarce during the Depression, and Tatum accepted Beadle’s offer. Tatum brought substantial expertise in microbiology and biochemisty. Beadle brought a deep understanding of classical Mendelian genetics.
From 1937 through 1941 Tatum focused on extracting precursors to pigments from Drosophila larvae. Ephrussi and Simon Chevais had reported that normal eye color could be restored in mutant flies when provided with tryptophan. Tatum showed that a bacterial contaminant actually was the source of the hormone, which again, in his mind, confirmed the functional equivalence of growth factors in bacteria and animals. After visiting Caltech and learning some additional techniques from Arie J. Haagen-Smit, Tatum returned to the problem of identifying the hormones involved in Drosophila eye colors, isolating one of them, the v+ hormone in a crystalline state, and identifying it as kynurenine. Tatum was preceded in this discovery by Adolf Butenand. That experience encouraged Beadle and Tatum to look for another model organism that might prove to be more tractable.
Work on Neurospora. They turned to Neurospora, a bread mold. Tatum knew from previous work that biotin (another B vitamin) was required if Neurospora was to be cultivated on inorganic media. They set about to investigate its nutritional requirements, recognizing that genes must control the biosynthetic processes in nutrition and, furthermore, that these processes would exhibit considerable complexity at the genetic or physiological level. Their plan was to reveal the underlying genetic complexity by investigating the nutritional requirements of mutant strains.
As an experimental organism Neurospora offered a number of distinct advantages. They knew that Neurospora could be grown on a variety of well-understood media. It requires only biotin as a supplement to a medium otherwise, including only inorganic salts and sugars. This means that Neurospora is capable of synthesizing most of what is necessary for growth. In addition to having such simple nutritional requirements, since Neurospora is haploid in its vegetative phase, there is no masking of the effects of mutant genes. The genes will be expressed, and a gene that is inactivated by mutation will have the effect of disabling any pathway of which it is a constituent. Finally, Neurospora can reproduce either sexually or asexually. Asexual reproduction allows for a sizable culture of genetically identical individuals whose nutritional requirements can be experimentally determined.
Early in 1941 Beadle and Tatum set about to x-ray Neurospora in order to induce mutations and identify them. This work depended crucially on Wilhelm Röntgen’s work with x-rays and on Hermann Muller’s demonstration that x-rays induced mutations in Drosophila. From a technical standpoint, the important fact was that they could induce mutations and did not have to wait for natural spontaneous mutations to occur. They assumed that mutations would have the effect of selectively inactivating the genes and eliminate the intermediate reactions they control. After irradiating the organisms, and allowing meiosis to take place, Beadle and Tatum were able to obtain a host of genetically homogeneous spores. Having grown them all on amply supplemented mediums, they transferred samples to a medium having the minimal amount of supplements required for the growth of non-mutant strains. Any strains that could grow on more generous mediums but not on the minimal medium had to be incapable of synthesizing some product that normal, wild-type, strains could synthesize. By then transferring the mutant strains to a variety of alternately supplemented mediums, they were able to identify the specific products that the organisms could not synthesize. As a result, they could also reconstruct the biosynthetic pathways in the original wild-type organisms.
Once they began to work with Neurospora it took Beadle and Tatum only five months to find the first three nutritional mutants. Isolate 299 was the first identifiable mutant, requiring pyridoxine for normal synthesis. The other two required para-aminobenzoic acid and thiamine. (Subsequently they identified a large number of mutants, literally cataloging hundreds of mutants.) The mutants behaved properly from a Mendelian standpoint, suggesting it had an identifiable location on the chromosomes. They concluded that their assumption that genes control enzymatic reactions must be correct. In May 1941 Beadle and Tatum sent their report to the Proceedings of the National Academy of Sciences. Their first studies of Neurospora were published that year. The key conclusion was straightforward: “A single gene may be considered to be concerned with the primary control of a specific chemical reaction” (Tatum and Beadle, 1942, p. 240). As a consequence, “the gene and enzyme specificities are of the same order” (Beadle and Tatum, 1941b, pp. 499–500).
Different mutants responded to different nutritional supplements. There are, for example, at least four mutant strains of Neurospora that are deficient in thiamine. The first two strains would grow with a wide variety of supplements, which means the mutations must have blocked the initial stages of the pathway; other intermediate compounds were available for the organism to complete the synthesis. The third strain required thiamine, indicating that the metabolic block must have occurred somewhere prior to the synthesis of thiamine. The fourth strain would not grow on a pyrimidine supplement, but it would if offered thiamine or a precursor to thiamine, so the block must occur between those two steps. The differences can be summarized as follows:
thi-1. Growth with any of the pathway intermediates.
thi-2. Growth with any of the pathway intermediates.
thi-3. Growth only when supplemented with thiamine.
thi-4. Growth if supplemented by either thiamine or its precursor.
It was also possible to conduct “crosses” of the strains, using a methodology analogous to that developed by Beadle and Ephrussi in Drosophila. Beadle and Ephrussi transplanted imaginal disks (which develop into eyes) onto genetically distinct larvae. This allowed them to assess the substances produced by the different strains. Beadle and Tatum could do something quite similar with Neurospora strains. When strains of thi-1 and thi-2 were grown in close proximity, it was found that the resulting hybrid cells (heterokaryons) containing both nuclei did not require complex nutritional supplements. Since the heterokaryon could once again grow on a minimal medium, without nutritional supplements, these two mutations had to affect different genes.
The key contributions of this work were to the study of gene action and the development of a variety of experimental techniques. The reports on this work suggested there were varying degrees of genetic control for enzymes affecting growth. They wrote in one of their first papers that “genes control or regulate specific reactions in the cell system either by acting directly as enzymes or by determining the specificities of enzymes” (Beadle and Tatum, 1941, p. 499). They were not yet decided on whether enzymes are produced by genes or whether genes might themselves be enzymes. (At this point, it is worth remembering, proteins were prime candidates for being genes, and nucleic acids were thought to be secondary.)
One very important practical consequence of their work with Neurospora and subsequently with mutants in Acetobacter and Escherichia coli was that it promoted bacteria as useful resources for genetic analysis. Another practical consequence was the introduction of induced mutations as a standard technique. The centerpiece of the program is what came to be seen as the one gene–one enzyme hypothesis: Each gene controls the production of a specific enzyme, and the function of that enzyme is determined by the genetic structure. Since their earliest announcements, the hypothesis has been modified to a one gene–one protein principle and then to one gene–one polypeptide, recognizing that not all gene products are enzymes and that proteins are often complexes of polypeptides. Still, the thought that genes and enzymes are “of the same order of specificity” was foundational for biochemical genetics.
Many of the principles they deployed have become standard views in biochemistry:
- All biochemical processes are under genetic control;
- these processes can be described as a series of steps;
- each step is a reaction that is controlled by a single gene;
- mutation in any of these genes inhibits the capacity of the organism to carry out just one reaction. These simple assumptions have a variety of important consequences:
- Mutations sometimes result in altered proteins;
- those alterations can render to the products either enzymatically inactive, or modify the activity;
- this can include changes relevant not only to enzymatic properties but also, for example, to stability of the molecules.
Overall, Beadle and Tatum developed a methodology for exploring the impact of genes on the physiology of cells and promoted the one gene–one enzyme theory committed to the idea that chromosomal genes control the synthesis of proteins and thereby influence development. Along with the establishment of Neurospora as a model organism within genetics, they more generally promoted the place of bacteria in genetic research.
Bacterial Sex. For a variety of reasons, many involving university politics, Tatum’s position at Stanford became tenuous. He was, after all, trained as a chemist and occupying a position in a Biology Department. Tatum moved briefly to Washington University in St. Louis and in 1945 landed a position at Yale University. (Shortly thereafter, Beadle left Stanford for Caltech.) Tatum’s task at Yale was to develop the microbiology program.
Joshua Lederberg, who had been at the Columbia University Medical School, worked with Tatum starting in 1946 before moving to Wisconsin. In a series of important papers they showed that there was recombination between mutant strains of E. coli. This is sometimes thought of as bacterial sex. Tatum had already developed mutant strains of E. coli, using techniques similar to those deployed in the Neurospora work with Beadle. Tatum used these same techniques of inducing mutations, applying them to bacteria. By facilitating bacterial sex Lederberg and Tatum showed that bacterial genetics was not significantly different from the genetics of higher organisms and that they could be fruitful organisms for genetic study.
Once again, Tatum’s strong biochemical orientation meant that he did not get the level of support that he thought was necessary at Yale. So in 1948 Douglas Whitaker enticed Tatum to return to Stanford. The academic leadership at Stanford put considerable energy into the development of scientific fields. Tatum encouraged not only the development of biochemistry but also the development of a curriculum in the medical school. In 1956 he was appointed head of the newly formed Department of Biochemistry. For personal reasons, with the dissolution of his marriage, he found it desirable to leave Stanford, moving to the Rockefeller Institute and marrying Viola Kanter in New York City on 16 December 1956.
Later Years. At the Rockefeller Institute, Tatum again found himself occupied with institutional affairs. He devoted a significant amount of time to national science policy, encouraging fellowship support for young scientists. He also served as chairman of the board for the Cold Spring Harbor Biological Laboratory. In terms of research, he continued to work on Neurospora, studying the effects of various changes on their morphology.
Tatum’s Nobel Prize in 1958 added to his list of honors, which included election to the National Academy of Sciences (1952), the Remsen Award from the American Chemical Society (1953), presidency of the Harvey Society (1964–1965), and numerous honorary degrees.
His wife Viola died of cancer on 21 April 1974. He married Elsie Bergland later that year, but Tatum’s own health was already compromised. He died on 7 November 1975 from heart failure, no doubt promoted by chronic emphysema.
WORKS BY TATUM
“Studies in the Biochemistry of Microorganisms.” PhD diss., University of Wisconsin, 1934.
With George W. Beadle. “Development of Eye Colors in Drosophila: Some Properties of the Hormones Involved.” Journal of General Physiology 22 (1938): 239–253.
“Development of Eye Colors in Drosophila: Bacterial Synthesis of v+ Hormone.” Proceedings of the National Academy of Sciences USA 25 (1939): 486–490.
“Nutritional Requirements of Drosophila melanogaster.” Proceedings of the National Academy of Sciences USA 25 (1939): 490–497.
With George W. Beadle. “Experimental Control of Development and Differentiation.” American Naturalist 75 (1941): 107–116.
With George W. Beadle. “Genetic Control of Biochemical Reactions in Neurospora.” Proceedings of the National Academy of Sciences USA 27 (1941): 499–506.
With George W. Beadle. “Vitamin B Requirements of Drosophila melanogaster.” Proceedings of the National Academy of Sciences USA 27 (1941): 193–197.
With George W. Beadle. “Genetic Control of Biochemical Reactions in Neurospora: An ‘Aminobenzoicless’ Mutant.” Proceedings of the National Academy of Sciences USA 28 (1942): 234–243.
With Norman H. Horowitz, David Bonner, Hershel K. Mitchell, et al. “Genetic Control of Biochemical Reactions in Neurospora.” American Naturalist 79 (1945): 304–317.
With Joshua Lederberg. “Gene Recombination in Escherichia coli.” Nature 158 (1946): 558.
“Induced Biochemical Mutations in Bacteria.” Cold Spring Harbor Symposia in Quantitative Biology 11 (1946): 278–284.
With Joshua Lederberg. “Novel Genotypes in Mixed Cultures of Biochemical Mutants of Bacteria.” Cold Spring Harbor Symposia in Quantitative Biology 11 (1946): 113–114.
“A Case History in Biological Research.” Science 129 (1959): 1711–1715. Also in Les prix Nobel en 1958, edited by Göran Liljestrand. Stockholm: Nobel Foundation, 1959.
“Perspectives from Physiological Genetics.” In The Control of Human Heredity and Evolution, edited by Tracy M. Sonneborn. New York: Macmillan, 1965.
Kay, Lilly E. “Selling Pure Science in Wartime: The Biochemical Genetics of G. W. Beadle.” Journal of the History of Biology 22 (1989): 73–101.
Lederberg, Joshua. “Genetic Recombination in Bacteria: A Discovery Account.” Annual Review of Genetics 21 (1987): 23–46.
———. “Edward Lawrie Tatum.” Biographical Memoirs, National Academy of Sciences 59 (1990): 356–386.
Robert C. Richardson
Tatum, Edward Lawrie (1909-1975)
Tatum, Edward Lawrie (1909-1975)
Edward Lawrie Tatum's experiments with simple organisms demonstrated that cell processes can be studied as chemical reactions and that such reactions are governed by genes. With George Beadle, he offered conclusive proof in 1941 that each biochemical reaction in the cell is controlled via a catalyzing enzyme by a specific gene . The "one gene-one enzyme" theory changed the face of biology and gave it a new chemical expression. Tatum, collaborating with Joshua Lederberg , demonstrated in 1947 that bacteria reproduce sexually, thus introducing a new experimental organism into the study of molecular genetics . Spurred by Tatum's discoveries, other scientists worked to understand the precise chemical nature of the unit of heredity called the gene. This study culminated in 1953, with the description by James Watson and Francis Crick of the structure of DNA . Tatum's use of microorganisms and laboratory mutations for the study of biochemical genetics led directly to the biotechnology revolution of the 1980s. Tatum and Beadle shared the 1958 Nobel Prize in physiology or medicine with Joshua Lederberg for ushering in the new era of modern biology.
Tatum was born in Boulder, Colorado, to Arthur Lawrie Tatum and Mabel Webb Tatum. He was the first of three children. Tatum's father held two degrees, an M.D. and a Ph.D. in pharmacology. Edward's mother was one of the first women to graduate from the University of Colorado. As a boy, Edward played the French horn and trumpet; his interest in music lasted his whole life.
Tatum earned his A.B. degree in chemistry from the University of Wisconsin in 1931, where his father had moved the family in order to accept as position as professor in 1931. In 1932, Tatum earned his master's degree in microbiology. Two years later, in 1934, he received a Ph.D. in biochemistry for a dissertation on the cellular biochemistry and nutritional needs of a bacterium. Understanding the biochemistry of microorganisms such as bacteria, yeast , and molds would persist at the heart of Tatum's career.
In 1937, Tatum was appointed a research associate at Stanford University in the department of biological sciences. There he embarked on the Drosophila (fruit fly) project with geneticist George Beadle, successfully determining that kynurenine was the enzyme responsible for the fly's eye color, and that it was controlled by one of the eye-pigment genes. This and other observations led them to postulate several theories about the relationship between genes and biochemical reactions. Yet, the scientists realized that Drosophila was not an ideal experimental organism on which to continue their work.
Tatum and Beadle began searching for a suitable organism. After some discussion and a review of the literature, they settled on a pink mold that commonly grows on bread known as Neurospora crassa. The advantages of working with Neurospora were many: it reproduced very quickly, its nutritional needs and biochemical pathways were already well known, and it had the useful capability of being able to reproduce both sexually and asexually. This last characteristic made it possible to grow cultures that were genetically identical, and also to grow cultures that were the result of a cross between two different parent strains. With Neurospora, Tatum and Beadle were ready to demonstrate the effect of genes on cellular biochemistry.
The two scientists began their Neurospora experiments in March 1941. At that time, scientists spoke of "genes" as the units of heredity without fully understanding what a gene might look like or how it might act. Although they realized that genes were located on the chromosomes , they didn't know what the chemical nature of such a substance might be. An understanding of DNA (deoxyribonucleic acid , the molecule of heredity) was still 12 years in the future. Nevertheless, geneticists in the 1940s had accepted Gregor Mendel's work with inheritance patterns in pea plants. Mendel's theory, rediscovered by three independent investigators in 1900, states that an inherited characteristic is determined by the combination of two hereditary units (genes), one each contributed by the parental cells. A dominant gene is expressed even when it is carried by only one of a pair of chromosomes, while a recessive gene must be carried by both chromosomes to be expressed. With Drosophila, Tatum and Beadle had taken genetic mutants —flies that inherited a variant form of eye color—and tried to work out the biochemical steps that led to the abnormal eye color. Their goal was to identify the variant enzyme, presumably governed by a single gene that controlled the variant eye color. This proved technically difficult, and as luck would have it, another lab announced the discovery of kynurenine's role before theirs did. With the Neurospora experiments, they set out to prove their one gene-one enzyme theory another way.
The two investigators began with biochemical processes they understood well: the nutritional needs of Neurospora. By exposing cultures of Neurospora to x rays, they would cause genetic damage to some bread mold genes. If their theory was right, and genes did indeed control biochemical reactions, the genetically damaged strains of mold would show changes in their ability to produce nutrients. If supplied with some basic salts and sugars, normal Neurosporacan make all the amino acids and vitamins it needs to live except for one (biotin).
This is exactly what happened. In the course of their research, the men created, with x-ray bombardment, a number of mutated strains that each lacked the ability to produce a particular amino acid or vitamin. The first strain they identified, after 299 attempts to determine its mutation, lacked the ability to make vitamin B6. By crossing this strain with a normal strain, the offspring inherited the defect as a recessive gene according to the inheritance patterns described by Mendel. This proved that the mutation was a genetic defect, capable of being passed to successive generations and causing the same nutritional mutation in those offspring. The x-ray bombardment had altered the gene governing the enzyme needed to promote the production of vitamin B6.
This simple experiment heralded the dawn of a new age in biology, one in which molecular genetics would soon dominate. Nearly 40 years later, on Tatum's death, Joshua Lederberg told the New York Times that this experiment "gave impetus and morale" to scientists who strived to understand how genes directed the processes of life. For the first time, biologists believed that it might be possible to understand and quantify the living cell's processes.
Tatum and Beadle were not the first, as it turned out, to postulate the one gene-one enzyme theory. By 1942, the work of English physician Archibald Garrod, long ignored, had been rediscovered. In his study of people suffering from a particular inherited enzyme deficiency, Garrod had noticed the disease seemed to be inherited as a Mendelian recessive. This suggested a link between one gene and one enzyme. Yet Tatum and Beadle were the first to offer extensive experimental evidence for the theory. Their use of laboratory methods, like x rays, to create genetic mutations also introduced a powerful tool for future experiments in biochemical genetics.
During World War II, the methods Tatum and Beadle had developed in their work with pink bread mold were used to produce large amounts of penicillin , another mold. In 1945, at the end of the war, Tatum accepted an appointment at Yale University as an associate professor of botany with the promise of establishing a program of biochemical microbiology within that department. In 1946. Tatum did indeed create a new program at Yale and became a professor of microbiology. In work begun at Stanford and continued at Yale, he demonstrated that the one gene-one enzyme theory applied to yeast and bacteria as well as molds.
In a second fruitful collaboration, Tatum began working with Joshua Lederberg in March 1946. Lederberg, a Columbia University medical student 15 years younger than Tatum, was at Yale during a break in the medical school curriculum. Tatum and Lederberg began studying the bacterium Escherichia coli . At that time, it was believed that E. coli reproduced asexually. The two scientists proved otherwise. When cultures of two different mutant bacteria were mixed, a third strain, one showing characteristics taken from each parent, resulted. This discovery of biparental inheritance in bacteria, which Tatum called genetic recombination , provided geneticists with a new experimental organism. Again, Tatum's methods had altered the practices of experimental biology. Lederberg never returned to medical school, earning instead a Ph.D. from Yale.
In 1948 Tatum returned to Stanford as professor of biology. A new administration at Stanford and its department of biology had invited him to return in a position suited to his expertise and ability. While in this second residence at Stanford, Tatum helped establish the department of biochemistry. In 1956, he became a professor of biochemistry and head of the department. Increasingly, Tatum's talents were devoted to promoting science at an administrative level. He was instrumental in relocating the Stanford Medical School from San Francisco to the university campus in Palo Alto. In that year Tatum also was divorced, then remarried in New York City. Tatum left the West coast and took a position at the Rockefeller Institute for Medical Research (now Rockefeller University) in January 1957. There he continued to work through institutional channels to support young scientists, and served on various national committees. Unlike some other administrators, he emphasized nurturing individual investigators rather than specific kinds of projects. His own research continued in efforts to understand the genetics of Neurospora and the nucleic acid metabolism of mammalian cells in culture .
In 1958, together with Beadle and Lederberg, Tatum received the Nobel Prize in physiology or medicine. The Nobel Committee awarded the prize to the three investigators for their work demonstrating that genes regulate the chemical processes of the cell. Tatum and Beadle shared one-half the prize and Lederberg received the other half for work done separately from Tatum. Lederberg later paid tribute to Tatum for his role in Lederberg's decision to study the effects of x-rayinduced mutation. In his Nobel lecture, Tatum predicted that "with real understanding of the roles of heredity and environment, together with the consequent improvement in man's physical capacities and greater freedom from physical disease, will come an improvement in his approach to, and understanding of, sociological and economic problems."
Tatum's second wife, Viola, died in 1974. Tatum married Elsie Bergland later in 1974 and she survived his death the following year, in 1975. Tatum died at his home on East Sixty-third Street in New York City after an extended illness, at age 65.
See also Fungal genetics; Microbial genetics; Molecular biology and molecular genetics; Molecular biology, central dogma of