Sir Archibald. E. Garrod, an Oxford physician-biochemist, in his research (1908), clearly expressed his interest in the congenital diseases found in human beings, which he later named as “Inborn errors of metabolism” and also categorized them as diseases of major medical importance. A considerable body of evidence was accumulated in his studies compiled in the Croonian lectures followed by two editions of his book “Inborn errors of metabolism”.
The very first of these “inborn errors” identified by Garrod was alcaptonuria (described in greater details, in the two book volumes), basically symptomatic of blackening of urine on exposure of air. A substance which was found to be responsible for blackening of urine is alcapton or homogentisic acid (2, 5-dihydrophenylacetic acid). During inheritance, the behavior of this gene encoding alcaptonuria was recognized as being differentiated by a single recessive gene. Garrod believed that alcaptonuria resulted from the failure to cleave the ring of homogentisic acid by affected individuals/patients which were found to lack an enzyme that normally catalyzes this reaction. This, in turn was related to the absence of normal form of a specific gene. Thus, the concept of gene-enzyme-chemical reaction system in which all the three entities were correlated, was realized by Garrod. Also the failure to metabolize a compound (identified by Garrod) when its normal pathway is blocked by a gene-enzyme defect was part of his interpretation, and this compound was found to greatly account for the accumulation and excreation of homogentisic acid. He appreciated the fact that alcaptonurics could also be used as experimental models to explore the metabolic pathways by which homogentisic acid was formed. A large body of evidence was gathered which only pointed to a crucial fact that when normal precursors of homogentisic acid are fed to alcaptonurics there is a quantitative increase of homogentisic acid excreation. Thus, phenylalanine, tyrosine, and the keto acid analogue of latter were found to be the most immediate and direct precursors of homogentisic acid in this metabolic pathway.
Although, it was found later, that a number of other genes might be useful in regulating any bio-chemical reaction by way of enzymes and consequently the genes encoding for these enzymes. But, there was no other instance as simple as alcaptonuria. Despite the simplicity and elegance to Garrod's interpretation of alcaptonouria and other inborn errors of metabolism as gene defects which mainly resulted from inactivity of specific enzymes and thus a blocked chemical reaction, his work had less influence on the thinking of his contemporary geneticists. But, later when his work was publicly acknowledged by scientists like Beadle and Tatum (1935), Garrod’s great work on this metabolic pathway got a major breakthrough. This served as an important start point for the resolution of complex steps involved in phenyl-alanine-tyrosine metabolism via the homogentisic pathway, and a demonstration that the homogentisate oxidase is indeed lacking in the liver of an alcaptonuric. Also, later deployment of several simpler model systems like Drosophila and Neurospora to understand fully Garrod’s hypothesis proved to be quite useful. The available genetic tools in these organisms were and still are far more elegant and easy to manipulate and thus, investigations that followed conclusively proved that there is a genetic basis to several metabolic disorders/pathways (e.g., aberrant eye pigmentation in Drosophila ). And that, the fact that, each and every biochemical reaction in a particular metabolic pathway is catalyzed by a particular assigned enzyme coded by a gene, was mostly accepted.