A: London, England, United Kingdom
In 1908 English physician Archibald Garrod delivered the Croonian Lectures at the Royal College of Physicians in London on inborn errors of metabolism. In his studies of the rare disease alkaptonuria, which affects about one in one million people, Garrod noted that over twenty-five percent of the recorded cases were the offspring of first cousins. In 1902 he consulted the pioneer English geneticist William Bateson about whether the disease might be hereditary. In a footnote to the first of his "Reports to the Evolution Committee of the Royal Society" (1902), pp. 133-134 Bateson noted Garrod's work and suggested that since first cousins are often similar genetically, Garrod's data might be best understood if one assumed alkaptonuria to be caused by a recessive gene:
"In illustration of such a phenomenon we way perhaps venture to refer to the extraordinarily interesting evidence lately collected by Garrod regarding the rare condition known as "Alkaptonuria." In such persons the substance, alkapton, forms a regular constituent of the urine, giving it a deep brown colour which becomes black on exposure. The condition is exceedingly rare, and, though met with in several members of the same families, has only once been known to be directly transmitted front parent to offspring. Recently, however, Garrod has a noticed that no fewer than five families containing alkaptonuric members, more than a quarter of the recorded cases, are the offspring of unions of first cousins. In only two other families is the parentage known, one of these being the case in which the father was alkaptonuric. In the other case the parents were not related. Now there may be other accounts possible, but we note that the mating of first cousins gives exactly the conditions most likely to enable a rare and usually recessive character to show itself. If the bearer of such a gamete mates with individuals not bearing it, the character would hardly ever be seen; but first cousins will frequently be bearers of similar gametes, which may in such unions meet each other, and thus lead to the manifestation of the peculiar recessive characters in the zygote. See A. E. Garrod, 'Trans. Med. Chir. Soc.,' 1899, p. 367, and 'Lancet,' November 30, 1901."
Bateson's statement in this footnote published in 1902 was the first proof of Mendelian heredity in humans, and the foundation of human biochemical genetics. Garrod recognized alkaptonuria to be a genetic disease and, in his Croonian lectures of 1908, hypothesized that each such biochemical defect, or "inborn error of metabolism," was caused by an interruption or block in a metabolic sequence due to the congenital lack of a particular enzyme. Little notice was taken of Garrod's work at the time, in part because his hypothesis regarding the "one gene-one enzyme" link could not be tested until the late 1930s-early 1940s, notably in the work of Beadle and Tatum (1941).
Garrod's lectures were first published as "The Croonian Lectures on Inborn Errors of Metabolism," Lancet 2 (1908) 1-7, 142-8. 173-9, 214-20. They were published in book form as Inborn Errors of Metabolism (London, 1909). Garrod's first paper on the subject dealt with alkaptonuria (Lancet 2, 1901, 1484-6.)
J. Norman (ed) Morton's Medical Bibliography 5th ed (1991) nos. 244.1, 3921.