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In 1896, Archibald E. Garrod became interested in patients with a rare but rather harmless disorder known as alkaptonuria. When exposed to air, patients' urine turns distinctively dark. Garrod soon concluded that alkaptonuria is a congenital disorder, not the result of a bacterial infection as was commonly thought. Rare in the general population but frequent in children of first-cousin marriages, the incidence of alkaptonuria conformed to the pattern of recessive inheritance described by Gregor Mendel in his experiments with peas.

Archibald E. Garrod
Courtesy American Philosophical Society

Garrod, a prominent physician at St. Bartholomew's Hospital in London, understood both the new science of biochemistry and the emerging discipline of genetics. He suspected that, due to a genetic defect, patients with alkaptonuria lacked an enzyme involved in the chemical breakdown of protein, one of many chemical pathways collectively called metabolism. The result: the accumulation of a chemical that darkens urine. Fifty years would pass before biochemists understood all of the steps in the pathway Garrod described.

Garrod immediately grasped the larger implications of his work on alkaptonuria in terms of genetics and serious disease.

• While the signs of alkaptonuria are highly visible, many more disorders of metabolism undoubtedly exist with more subtle manifestations. Garrod called such disorders "inborn errors of metabolism."

• Both normal variation and abnormal differences in chemical makeup are determined by genetics. "I believe that no two individuals," wrote Garrod, "are exactly alike chemically any more than structurally."

In 1908, Garrod lectured on inborn errors of metabolism, and his book by that title appeared in 1909. In 1931, he published Inborn Factors in Disease. In spite of his prominence in the medical community, Garrod's work did not excite great interest among his contemporaries. Geneticists were busy grappling with the simplest of organisms, biochemistry was still in its infancy and many of the diseases Garrod discussed were rare disorders that physicians seldom saw in clinical practice. But by the 1950s, as the direct role that genes play in producing specific proteins became understood, Garrod began to acquire the reputation he currently enjoys—as the "father of chemical genetics."

Garrod, A. The incidence of alkaptonuria: A study in chemical individuality. Lancet 2, 1616-1620 (1902).

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