"one gene, one enzyme" hypothesis

The one gene–one enzyme hypothesis is the idea that genes act through the production of enzymes, with each gene responsible for producing a single enzyme that in turn affects a single step in a metabolic pathway. The concept was proposed by George Beadle and Edward Tatum in an influential 1941 paper on genetic mutations in the mold Neurospora crassa, and subsequently was dubbed the "one gene–one enzyme hypothesis" by their collaborator Norman Horowitz. In 2004 Norman Horowitz reminisced that “these experiments founded the science of what Beadle and Tatum called ‘biochemical genetics.’ In actuality they proved to be the opening gun in what became molecular genetics and all the developments that have followed from that.” The development of the one gene–one enzyme hypothesis is often considered the first significant result in what came to be called molecular biology. Although it has been extremely influential, the hypothesis was recognized soon after its proposal to be an oversimplification. Even the subsequent reformulation of the "one gene–one polypeptide" hypothesis is now considered too simple to describe the relationship between genes and proteins.

Although some instances of errors in metabolism following Mendelian inheritance patterns were known earlier, beginning with the 1902 identification by Archibald Garrod of alkaptonuria as a Mendelian recessive trait, for the most part genetics could not be applied to metabolism through the late 1930s. Another of the exceptions was the work of Boris Ephrussi and George Beadle, two geneticists working on the eye color pigments of Drosophila melanogaster fruit flies in the Caltech laboratory of Thomas Hunt Morgan. In the mid-1930s they found that genes affecting eye color appeared to be serially dependent, and that the normal red eyes of Drosophila were the result of pigments that went through a series of transformations; different eye color gene mutations disrupted the transformations at a different points in the series. Thus, Beadle reasoned that each gene was responsible for an enzyme acting in the metabolic pathway of pigment synthesis. However, because it was a relatively superficial pathway rather than one shared widely by diverse organisms, little was known about the biochemical details of fruit fly eye pigment metabolism. Studying that pathway in more detail required isolating pigments from the eyes of flies, an extremely tedious process.

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