Experimental Basis for the One-Gene, One-Protein Hypothesis

In diseases like sickle cell anemia and Huntington's disease, a single genetic mutation leads to illness. Common knowledge today, this idea evolved from Archibald Garrod's 1909 formulation of the concept of "inborn errors of metabolism" and the 1941 studies of George Beadle (1903-1989) and Edward Tatum (1909-1975) in which they proved that genes determine the structure of enzymes or proteins. For this discovery they received the Nobel Prize in 1958, shared with Joshua Lederberg (1925-2008).

Beadle, George
Courtesy of Institute for Biomedical Research, 1970

Beadle and Tatum studied the bread mold, Neurospora. It was cultured easily in "minimal" medium, so they knew it had enzymes to convert sugars and salts into the amino acids and vitamins necessary for growth. They exposed mold spores to x-rays to induce genetic mutations, some of which disrupted the mold's ability to make particular nutrients, and thus to grow. Then, by adding supplements to the growth medium one-by-one to test which supplement made the mold grow again, they could determine which enzyme was missing. Crossing the mutant strains with normal ones showed that the metabolic defects were recessive traits, proving that genes had been altered. At the start Beadle and Tatum knew that it would be a long shot to produce identifiable nutritional mutations with x-rays, so the two agreed to stop work if they hadn't found a nutritional mutant by their 5,000th attempt. They achieved success with culture number 299, which grew only when vitamin B6 was added to minimal medium. Using their selection and supplementation technique, they soon isolated more Neurospora mutants, showing that genetic mutations affect metabolic pathways, and detailing the multi-step synthesis pathways for many vitamins and amino acids.

In his Nobel lecture, given shortly after he joined the Rockefeller Institute, Tatum outlined the concepts, fundamental to genetics, underlying the one-gene, one-enzyme (understood today as one-gene, one-polypeptide) hypothesis: all biochemical processes in all organisms are under genetic control; these overall biochemical processes are resolvable into a series of individual stepwise reactions; each single reaction is controlled in a primary fashion by a single gene, or in other terms, in every case a 1:1 correspondence of gene and biochemical reaction exists, such that mutation of a single gene results only in an alteration in the ability of the cell to carry out a single primary chemical reaction.

Tatum, Edward
Photo by Ingbert Grütner

George W. Beadle received the BS from the University of Nebraska (1926) and the PhD from Cornell University (1931). In 1931 he went to the California Institute of Technology with a National Research Council Fellowship. He spent part of 1935 in Paris working with Boris Ephrussi, doing experiments on the development of eye pigment in Drosophila that led to the later Neurospora work. Beadle moved to Harvard University in 1936, and in 1927 to Stanford University. He returned to CalTech in 1946 as professor and chairman of the Division of Biology. In 1961 he became chancellor, and later president, of the University of Chicago. Beadle's many honors in addition to the Nobel Prize (1953) include the Lasker Award (1950), the National Award of the American Cancer Society (1959), and the Kimber Genetics Award of the National Academy of Sciences (1960). He was an elected member of the U.S. National Academy of Sciences.

Edward L. Tatum received his bachelor's degree (1931) and PhD (1934) from the University of Wisconsin. After a year of research at the University of Utrecht, Netherlands, Tatum joined George Beadle's laboratory at Stanford University as a research associate in 1937. In 1945 he moved first to Washington University in St. Louis, and then to Yale. He returned to Stanford in 1948; then, in 1957 he joined the Rockefeller Institute as professor. In addition to the Nobel Prize (1953), Tatum's achievements were recognized with the Remsen Award of the American Chemical Society (1953) and other awards. He was an elected member of the U.S. National Academy of Sciences.

Selected Publications

Beadle GW and Tatum EL. The genetic control of biochemical reactions in Neurospora. Proc Natl Acad Sci USA, 1941, 27:499-506.

Further Reading

Edward L. Tatum (1909-1975): A Biographical Memoir. Washington, DC: National Academy of Sciences, Volume 59, 1990

George W. Beadle (1903-1989): A Biographical Memoir. Washington, DC: National Academy of Sciences, Volume 59, 1990


DNA From the Beginning: Chapter 16, One Gene Makes One Enzyme

Video interview of Joshua Lederberg describing Edward Tatum