The seeds of this hypothesis were spawned by Sir Archibald Garrod, who reported in 1909 that alkaptonuria - an inherited condition in which the urine is colored dark red by the chemical alkapton - results from a single recessive gene, which causes a deficiency in the enzyme that normally breaks down alkapton.
After graduating from Cornell in 1931, George Beadle arrived at T.H. Morgan's CalTech lab determined to follow up on Garrod's work. Morgan's lab, at that time, was perhaps the premier genetics lab in the world. There Beadle teamed up with Boris Ephrussi to examine eye pigment development in the fruit fly, Drosophila. Together, they proposed that eye color changes in mutant strains of Drosophila could be caused by inactivation of specific proteins, acting in a single biosynthetic pathway.
However, Beadle soon realized that Drosophila were entirely inappropriate for the work he had in mind.
"Isolating the eye-pigment precursors of Drosophila was a slow and discouraging job. Tatum and I realized this was likely to be so in most cases of attempting to identify the chemical disturbances underlying inherited abnormalities; it would be no more than good fortune if any particular example chosen for investigation should prove to be simple chemically."1
The other major epiphany Beadle had was that finding mutants in Drosophila was complicated by the lack of biochemical knowledge of the fruit fly's developmental pathways. He and Tatum decided to reverse the procedure and look for mutations that influence known chemical reactions, but for what organism?
Beadle recalled from grad school a seminar given by B.O. Dodge on inheritance in the bread mold Neurospora. The team soon discovered that Neurospora could be grown on a simple mixture of salt, sugar and biotin, a vitamin.
The procedure was then simple: "Induce mutations by radiation or other mutagenic agents. Allow meiosis to take place so as to produce spores that are genetically homogeneous. Grow these on a medium supplemented with an array of vitamins and amino acids. Test them by vegetative transfer to a medium with no supplement. Those that have lost the ability to grow on the minimal medium will have lost the ability to synthesize one or more of the substances present in the supplemented medium. The growth requirements of the deficient strain would then be readily ascertained by a systematic series of tests on partially supplemented media."1
Their only worry was that the frequency of mutation would be so low that they would give up before finding one.
"We believed so thoroughly that the gene-enzyme reaction relation was a general one that there was no doubt in our minds that we would find the mutants we wanted.... [but we] were so concerned about the possible discouragement of a long series of negative results that we prepared more than thousand single-spore cultures on supplemented medium before we tested them. The 299th spore isolated gave a mutant strain requiring vitamin B6 and the 1,085th one required B1. We made a vow to keep going until we had 10 mutants. We soon had dozens."1
Thus through years of persistence and experimental drudgery, Beadle and Tatum finally procured the data for their famous 1941 PNAS paper. They had experimentally demonstrated that a single gene specifies the production of a single enzyme.2 Many authors point to this study as the cornerstone of molecular biology and the beginning of the field of biochemical genetics. Beadle and Tatum shared (with Joshua Lederberg) the 1958 Nobel Prize in Medicine for their work.
Photo credit: http://www.snf2.net/index.html
"Identification of multiple distinct Snf2 subfamilies with conserved structural motifs" Flaus A, Martin
DMA, Barton GJ and Owen-Hughes T Nucleic Acids Research v34 pp2887-2905 (2006)
(published as open access, so full text is freely available).
1. Beadle, G. W. 1958. Nobel lecture: Genes and chemical reactions in Neurospora.
2. Today we now know that each gene specifies the production of a single polypeptide—that is, a protein or protein component. Thus, two or more genes may contribute to the synthesis of a particular enzyme. Also,
depending on transcription regulation, multiple proteins can be transcribed from essentially the same gene. In addition, some products of genes are not enzymes per se, but structural proteins. But the general accuracy of Beadle and Tatum's statement stands. Beadle, G.W.&Tatum, E.L. 1941. The genetic control of biochemical reactions in Neurospora. Proceedings of the National Academy of Science, 27:499-506.