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Modern Genetic Analysis Chapter 3. Gene Function Protein Function and Malfunction in Cells
Genetics In Process3-1: Beadle and Tatum and the nature of gene action

In 1908 the English physician Archibald Garrod suggested that certain human diseases were caused by "inborn errors of metabolism." For example, the recessive disease alkaptonuria ("black urine disease") is characterized by the excretion in the urine of homogentisic acid, which turns black upon exposure to air. Garrod surmised that this unusual excretion was because those afflicted by the disease lacked an enzyme that normally broke this sub-stance down, and it therefore built up in tissues and was excreted. This work was the dawn of the idea that genes act by enzymatically regulating the chemistry of the cell. The same idea arose in the literature several times over the next three decades, but it was the research of George Beadle and Edward Tatum on the fungus Neurospora that provided a clear statement of this mode of gene action.

Beadle later wrote the following reminiscence:

In 1940 we decided to switch from Drosophila to Neurospora. It came about in the following way. Tatum was giving a course in biochemical genetics and I attended the lectures. In listening to one of theseor perhaps not listening as I should have beenit suddenly occurred to me that it ought to be possible to reverse the procedure we had been following and instead of attempting to work out the chemistry of known genetic differences, we should be able to select mutants in which known chemical reactions were blocked. Neurospora was an obvious organism on which to try this approach, for its life cycle had been worked out by Dodge and Lindegren, and it probably could be grown in a culture of known composition. The idea was to select mutants unable to synthesize known metabolites such as vitamins and amino acids which could be supplied to the medium. In this way a mutant unable to make a given vitamin could be grown in the presence of that vitamin and classified on the basis of its differential growth response in media lacking or containing it.

Sure enough, nutritionally defective mutants were easily found by irradiating cells. Such mutants would grow only when the medium was supplemented with one of a number of essential cellular substances (for example, the amino acid arginine), implying that it was the synthesis of this substance that was defective in the mutant. Furthermore, known or suspected precursors of arginine could be tested, for example, ornithine and citrulline. The arginine-requiring mutants could be classified into three groups on the basis of their different responses to ornithine and citrulline:

Beadle and Tatum and their students deduced that groups 1 through 3 must each have a different mutation in one of three genes acting sequentially to make the end product:

Only substances that normally came after the mutationally inactivated step could support growth of the mutants.

From such experiments Beadle and Tatum devised the hypothesis that a gene generally acts by determining some specific enzyme activitythe "one-geneone-enzyme" hypothesis. Subsequent work showed that this powerful catchphrase, which effectively united the two fields of biochemistry and genetics, could more accurately be stated "one-geneone-polypeptide."

© 1999 by W. H. Freeman and Company. All rights reserved.