The Development of Penicillin: Genesis of a Famous Antibiotic

Eric Lax. The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle. New York: Henry Holt, 2004. Pp. 307. $25.

Eric Lax's Breezy Account of the development of penicillin includes biographical material on the three Nobel Laureates, Ernst Chain, Alexander Fleming, and Howard Florey, paraphrased from existing full-length biographies; describes Fleming's original observation and the development work by Florey's group at Oxford; and concludes with industrial production. The story has been told many times. This review focuses on three topics: the discovery of penicillin, the scientific profiles of the protagonists, and the elucidation of the b-lactam structure.

The Enigma of Fleming's Discovery of Penicillin

Exactly how Fleming discovered penicillin will never be known. His original paper (Fleming 1929a) and later accounts lack detail. He himself noted that "After a lapse of fifteen years it is very difficult to say just what processes of thought were involved" (Fleming 1944). In 1927–1928, he was preparing an account of staphylococci (Fleming 1929b). Fleming reinvestigated color variants of S. aureus, originally described by other workers, that were produced by room temperature incubation after initial incubation at 37°C. Before a vacation, he collected his experimental Petri plates together to clear temporary space for another worker. During a brief return, he examined and discarded many of them. When his former colleague, D. M. Pryce, came to visit, Fleming showed him some discarded plates, noticing what he (apparently) had overlooked previously: a fungal contaminant was present on one plate with extensive bacterial lysis.

A compelling and generally accepted reconstruction of the discovery was given by Fleming's colleague, Ronald Hare (1970). The contaminant could not have developed on a plate containing fully developed bacterial colonies, since later work showed that penicillin inhibits growth only of young cultures. The lytic phenomenon is complex. In brief, a spore (or spores) of the contaminant must have been present either before or at the time of inoculation with bacteria. A period of cool room temperature allowed fungal growth and penicillin production. Subsequently, with or without 37°C incubation, the bacteria began to grow, but in the presence of penicillin underwent lysis. Hare discovered that there had been a cool spell in London for nine days beginning July 27, 1928. Had Fleming inoculated the plate before leaving for vacation (end of July or early August?), the appropriate conditions for fungal growth and penicillin formation would have existed. With Fleming's original fungus and bacteria, and careful temperature control, Hare "rediscovered" penicillin—he produced lysed bacterial cultures with the same properties as those of the original.

In contrast, in The Mold in Dr. Florey's Coat, Lax asserts that "the most plausible explanation" for penicillin discovery was given in R. S. Root-Bernstein's book Discovering (1989). In Root-Bernstein's work, six fictional characters study invention in a hypothetical colloquium. The rambling, tendentious "explanation" is hard to follow, but the book both deconstructs Hare's experimentally verified explanation and appears to question Fleming's integrity.

Root-Bernstein suggests that Fleming, looking for new sources of lysozyme, found a fungus on a culture in mid-September. The fungus was established on a new dish, then inoculated further with the lysozyme-sensitive Micrococcus lysodeikticus. Obtaining only a poor result, Fleming discarded the plate but then reexamined it during Pryce's visit. The fictional speaker sneers: "This is the experiment he shows his colleagues. Not very novel. Not very impressive. Not even worth recording. Just another lysozyme experiment, with a mold this time" (p. 177). Pryce, a collaborator on Fleming's staphylococcal work, was well acquainted with these bacteria. Had Fleming actually shown him a contaminated plate of M. lysodeikticus, as required by this explanation, Pryce immediately would have realized that the organisms were not...