Ephrussi/beadle/tatum: Genes Encode Enzymes

The first clear recognition that novel phenotypes may reflect discrete biochemical differences was provided by the English physician Archibald E. Garrod at the turn of the 20th century. In 1902, barely after the rediscovery of Mendel’s work, Garrod described a disease, alkaptonuria, in which affected patients produced urine that turned black upon exposure to air—a rather disconcerting symptom. The blackening proved to be due to the oxidation of homogentisic acid (alkapton) in the urine of affected patients. Normally, homogentisic acid is broken down in the liver and is not present in the urine. Garrod concluded that alkaptonuric patients lack the liver enzyme (homogentisic acid oxidase) necessary to metabolize homogentisic acid. Unable to process homogentisic acid, the patients accumulate it and excrete it in their urine.