Molecular Foundations Of Early Pharmacology And Genetics

The implications of Mendel's discoveries did not dawn on anyone until the turn of the twentieth century when their revival prompted an intense flurry of research. Lucien Cuenot in France was investigating the genetics of coat color in mice while Archibald Garrod and William Bateson in England were investigating various inborn traits in human subjects. Cuenot, Garrod, and Bateson suggested that the genetic material played an essential role in directing chemical transformations within organisms, and that enzymes, which were termed "diastases" or "ferments" at that time, were related in some unknown manner to the genetic material.

In 1902, Garrod proposed the concept of ''chemical individuality'' to explain the predisposition of certain individuals to alcaptonuria, and he concluded that alcaptonuria was an inherited condition. On Garrod's consultation with Bateson, the latter appears to have given the first suggestion of gene action in terms of ''ferments,'' and of a recessive condition whose features depended on the absence of a particular ''ferment'' (enzyme). Stemming from earlier interest on a case of porphyria accompanying the ingestion of the hypnotic drug sulfonal, and observations on urinary pigments, Garrod extended his idea of chemical individuality to include the transformation of drugs into nontoxic conjugates such as hippurates and glycuronates. He said the formation of conjugates protected individuals from the poisonous effects of these agents.

Applying Bateson's suggestion to exogenous chemicals, Garrod proposed that the noxious effects these substances produce in some persons might be due to failure of their enzymes to detoxify them. In the course of these and later studies, Garrod came to believe that ''substances in foods, drugs and in exhalations of particular animals and plants may produce in some people effects wholly out of proportion to any they bring about in most persons, and that such effects were due to derangement of metabolic factors.'' He also pointed out that ''the ultimate toxic agent could be a product of normal metabolism formed in undue amount, or it could be an intermediate product that escaped the further changes it normally undergoes, or possibly an abnormal product formed by way of derangement of normal metabolic processes,'' and because metabolic deviations from the average were less obvious than variations in form, he believed ''they would attract little attention and the great majority of them would most likely escape observation.'' Garrod spoke out firmly about these ideas until his life ended in 1936, yet they are as fresh and true today as when he first stated them nearly 100 years ago.1,2

Several studies on Drosophila (fruit fly) by Thomas Hunt Morgan and his students also contributed major advances to an understanding of heredity and hereditary mechanisms during the early years of this period. In 1913, Sturtevant constructed the first genetic map and showed that genes are arranged in a linear order. In 1914 and 1916, Bridges provided the first proof that chromosomes contained genes, ruling out the possibility that genes and chromosomes were separate hereditary elements.

Eventually, a few biologists began to take note of Garrod's keen foresight regarding the chemical individuality of humans (Figure 1.2). In 1918, Marshall and co-workers reported that black soldiers were much more resistant than whites to the blistering of skin from exposure to mustard gas, a substance introduced as a chemical warfare agent in the first World War.3 In 1919, Hirschfeld and Hirschfeld, building on Landsteiner's analysis of isoagglutinins in human blood, were the first to describe serological differences between the blood of Europeans, Middle Easterners, and Asians by examining 500-1000 persons of each of 10 racial groups, finding remarkable racial differences in the proportions of blood groups A and B.4 By 1929, reports on racial differences in ophthalmic effects of cocaine, euphthalmine, ephedrine, and atropine had appeared,5 and during the 1920s and 1930s hereditary deficits in two modalities of sensory perception, ''odor

First racial studies Emergence of modern pharmacogenetics

Figure 1.2 Timeline of the pharmacogenetics of raciogeographic variation.



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