is thus blocked by a gene-enzyme defect was a part of the interpretation and 

 accounted for the accumulation and excretion of homogentisic acid. Garrod 

 recognized this as a means of idantifying an intermediate compound that might 

 otherwise not appear in sufficient amounts to be detected. 



He also clearly appreciated that alcaptonurics would be used experimentally 

 to explore the metabolic pathways by which homogentisic acid was formed. 

 He summarized a large body of evidence indicating that when normal precursors 

 of homogentisic acid are fed to alcaptonurics there is an almost quantitative 

 increase in homogentisic acid excretion. In this way evidence was accumulated 

 that phenylalanine, tyrosine and the keto acid analog of the latter were almost 

 certainly the direct precursors of homogentisic acid. 



Despite the simplicity and elegance of Garrod's interpretation of alcap- 

 tonuria and other inborn errors of metabolism as gene defects which resulted 

 in inactivity of specific enzymes and thus in blocked reactions, his work had 

 relatively little influence on the thinking of the geneticists of his time. Bate- 

 son's ''Mendel's Principles of Heredity" and a few other books of its time 

 discuss the concept briefly. But up to the 1940's, no widely used later text 

 book of genetics that I have examined even so much as refers to alcaptonuria. 

 It is true that a number of other workers had seriously considered that genes 

 might act in regulating chemical reactions by way of enzymes (2, 13, 17, 21, 

 23). But there was no other known instance as simple as alcaptonuria. It is 

 interesting — and significant, I think — that it was approximately 50 years 

 after Garrod proposed his hypothesis before it was anything like fully verified 

 through the resolution into six enzymatically catalyzed steps of phenyl- 

 alanine-tyrosine metabolism via the homogentisic acid pathway, and by the 

 clear demonstration that homogentisate oxidase is indeed lacking in the liver 

 of an alcaptonuric (17). Perhaps it is also well to recall that it was not until 

 1926 that the first enzyme was isolated in crystalline form and shown in a 

 convincing wa}' to consist solely of protein. 



Eye Pigments of Drosophila. 



I shall now shift to a consideration of an independent line of investigation 

 that ended up with conclusions very much like those of Garrod and which 

 led directly to the work with Neurospora that Tatum and I subsequently 

 began. 



In 1933, Boris Ephrussi came to the California Institute of Technology 

 to work on developmental aspects of genetics. During his stay he and I had 

 many long discussions in which we deplored the lack of information about 



s-29 



