both genetic and chemical studies and the work has continued to yield new 

 information ever since and almost without interruption. Many workers and 

 many species of plants have been involved (2, 4, 13, 22, 23). 



It became clear very soon that a number of genes were involved and that 

 they acted by somehow controlling the onset of various identifiable and 

 specific chemical reactions. Since an understanding of the genetics helped 

 in interpreting the chemistry and vice versa, the anthrocyanin work was well 

 known to both geneticists and biochemists. It significantly influenced the 

 thinking in both fields and thus had great importance in further develop- 

 ments. 



A second important line of investigation was begun even earlier by the 

 Oxford phvsician-biochemist Sir Archibald E. Garrod. At the turn of the 

 century he was interested in a group of congenital metabolic diseases in man, 

 which he later named, "inborn errors of metabolism". There are now many 

 diseases described as such; in fact, they have come to be recognized as a cate- 

 gory of diseases of major medical importance. 



One of the first inborn errors to be studied by Garrod was alcaptonuria. 

 Its most striking symptom is blackening of urine on exposure to air. It had 

 been recorded medically long before Garrod became interested in it and 

 important aspects of its biochemistry were understood. The substance respon- 

 sible for blackening of the urine is alcapton or homogenetisie acid (2,5-dihydr- 

 oxyphenylacetic acid). Garrod suggested early that alcaptonuria behaved in 

 inheritance as though it were differentiated by a single recessive gene. 



By 1908 a considerable body of knowledge about alcaptonuria had accumu- 

 lated. This was brought together and interpreted by Garrod in his Croonian 

 lectures and in the two editions of his book, "Inborn Errors of Metabolism", 

 which were based on them (11). It was his belief that alcaptonuria was the 

 result of inability of affected individuals to cleave the ring of homogentisic acid 

 as do normal individuals. He believed this to be due to absence or inactivity 

 of the enzyme that normally catalyzes this reaction. This in turn was depen- 

 dent on the absence of the normal form of a specific gene. 



Thus Garrod had clearly in mind the concept of a gene-enzyme-chemical- 

 reaction system in which all three entities were interrelated in a very specific 

 way. In the 1923 edition of "Inborn Errors" (11) he wrote: 



"We may further conceive that the splitting of the benzene ring of homo- 

 gentisic acid in normal metabolism is the work of a special enzyme, that in 

 congenital alcaptonuria this enzyme is wanting . . ." 



Failure to metabolize an intermediate compound when its normal pathway 



s-76 



