Genetic Control of Biochemical Reactions in Neurospora.

One gene, one enzyme. What a simple concept, how obvious! This fundamental relationship between gene and gene product, hinted at by several previous investigators, did not become firmly established until George W. Beadle and Edward L. Tatum performed their pioneering analyses with Neurospora crassa. Prior to their proposing the one-gene–oneenzyme hypothesis, in the early 1940s, there was little understanding of how genetic material determined the characteristics of every living organism. One need only recall how little was known about genes and proteins prior to their pathfinding investigations, to appreciate the significance of their impressive contribution. The chemical nature of genetic material had not yet been established, and it was not yet proven that proteins (polypeptides) consist of linear sequences of amino acids. Not until the early 1950s did the initial findings of Avery, MacLeod, and McCarty (see Section II), and the more significant observations of Hershey and Chase (see Section V), convince the scientific community that genetic material was most likely DNA. And it was not until the mid-to-late 1950s, some years after Watson and Crick presented their elegant structure of DNA, that our view of genetic material became fixed forever. The first complete amino acid sequence of a protein, insulin, was presented in the early 1950s, by Fred Sanger and co-workers (A. P. Ryle et al., Biochem. J. 60:541–556, 1955). Only when these essential findings were in place could the significance of the one-gene–one-enzyme concept be fully appreciated. Beadle points this out in a retrospective article written in 1966 for the book “Phage and the Origins of Molecular Biology.” He states that at the Cold Spring Harbor Symposium of 1951, “The number whose faith in one-gene–one-enzyme remained steadfast could be counted on the fingers of one hand—with a couple of fingers left over.” How did Beadle and Tatum come to make this momentous discovery? Did their scientific backgrounds, interests, and prior experience direct them along the right path? As we so often note in reviewing progress in science, great contributions stem from insight gained from ongoing investigations on a related subject or question. This was certainly true for Beadle, and for Tatum. Prior to initiating his Neurospora studies, Beadle had spent several years collaborating with Boris Ephrussi in an attempt to determine the sequential steps in an eye pigment pathway in Drosophila. Similarly, before he joined Beadle in these eye pigment studies, Tatum’s research focussed on identifying growth factors required by different species of bacteria. What could be more logical than for these two investigators to combine their interests and expertise, and ask the basic unanswered question: do mutations altering a specific gene, mutations that change the characteristics of an organism, do so by altering the structure and enzymatic activity of a single, corresponding enzyme? If this relationship was correct, they argued, couldn’t we use a haploid organism with a simple life cycle, an organism that grows on a chemically-defined medium, to isolate nutrient-requiring mutants that prove the one-gene–one-enzyme relationship? The rest is history. Many of us consider this contribution by Beadle and Tatum to be one of the most important in the 20th century! CHARLES YANOFSKY