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A Review by Clif Cleaveland, MD
"There is a lot of axe grinding going on at present in England," Howard Florey wrote to a colleague in the United States in the summer of 1945. At stake was credit for the discovery of penicillin. Pitted against one another were Alexander Fleming who in 1928 at London's St. Mary's Hospital observed that a mold, Penicillium notatum, killed Staphylococci, and an Oxford team of Howard Florey, Ernst Chain, and Norman Heatley who made possible the wide applications of penicillin in clinical medicine.
Eric Lax provides a compelling study of the discovery of penicillin in The Mold in Dr. Florey's Coat (Henry Holt and Company, New York 2004). Science is blended with studies of the complex cast of characters who changed forever mankind's battle with bacterial infection.
Various stories describe Fleming's observation that a contaminating mold suppressed bacteria growing upon an agar plate on the windowsill of his lab. These stories are essentially untrue. Fleming did isolate a mold that he serendipitously observed in a stack of Petri dishes on his lab bench. Two months later he recorded an experiment in which the mold suppressed Staphyloccal growth. Subsequently, he showed that an extract of broth in which the mold was grown suppressed bacteria from a sinus infection. The extract showed no toxicity when injected into the ear of a rabbit, nor did it cause a reaction when applied to a human wound. In February 1929 Fleming named the substance produced by the mold as "penicillin." Later that month he delivered a paper on his observations to the Medical Research Club at St. Mary's. He published his findings in the British Journal of Experimental Pathology later that year. He dropped his work on penicillin by 1932 and turned his attention to other research.
Australian Howard Florey came to Oxford as a Rhodes Scholar in 1922. By 1935 he had been elected Professor and Chair of Pathology. In 1935 Ernst Chain, a biochemist who had arrived from Germany all but penniless two years earlier, joined Florey's department. In 1936 Florey interviewed and offered a position to chemist Norman Heatley. Soon Florey requested that Chain and Heatley begin a study of lysozyme. In preparation for that study Chain read widely and by chance came upon Fleming's 1929 paper on penicillin. Studying penicillin further, Chain brought it to Florey's attention. Florey recognized the potential of penicillin as a breakthrough in the suppression of bacterial infection. Soon after Great Britain's entry into World War II Florey appealed for support for further work on penicillin. Scientific interest rather than possible clinical application propelled the initial requests for funding. Vital monies came from Britain's Medical Research Council and America's Rockefeller Foundation.
Crucial to the success of the Oxford team were Heatley's expertise in assaying and producing penicillin in meaningful quantities. Heatley devised a countercurrent machine that would produce twelve liters of broth per hour. Freeze-drying allowed preservation of penicillin's antibacterial activity.
A succession of studies on mice, rabbits, and guinea pigs demonstrated the efficacy of penicillin against a variety of bacterial infections and demonstrated the non-toxic nature of the substance. Studies of penicillin began in the United States.
On January 27, 1941 the first dose of penicillin was tested on a human subject, a lady dying of cancer. Rigors followed which were attributed to contaminants in the dose. A subsequent dose caused no reaction. Eight injections of penicillin, the total amount that the lab had produced, provided dramatic, though temporary, improvement in a police constable with a severe scalp infection.
Realizing that mass production of penicillin would be impossible in war-ravaged Britain, Florey and Heatley embarked for America to enlist support for production of the new drug. Heatley would remain in America for months to work out production strategies.
In a curious twist an assistant, Mary Hunt, was sent in the summer of 1942 by her lab in Peoria to search the markets for new molds to produce penicillin. On one trip she located a cantaloupe with a Penicillium mold of such potency that it became the progenitor of much of the world's penicillin. Finally, adequate penicillin could be manufactured for widespread use on the fields of battle.
By war's end thousands of lives of wounded servicemen had been saved from bacterial infection by the use of penicillin. Its use had wrought similar results in the civilian sector.
Well into the struggle to purify and mass produce penicillin Alexander Fleming reappeared. The Florey team did not conceal any of their studies from Fleming. Powerful political and academic figures in Great Britain rallied behind Fleming who garnered most of the publicity in the popular press for penicillin's discovery and application. Only after repeated intervention by British and American scientists who were familiar with the crucial roles of Florey and Chain in the discovery of penicillin did the Nobel Prize committee decide to award the 1945 medal for physiology and medicine to Fleming, Florey, and Chain. Norman Heatley received no recognition despite his vital role in purifying and manufacturing penicillin. Fleming's fame subsequent to the awarding of the Nobel Prize continued to outstrip that of his co-winners. In 1990 Heatley finally received acknowledgement for his contributions when Oxford University awarded him an honorary Doctor of Medicine degree, the first such award in the university's history.
Eric Lax captures the personalities, their conflicts, and their triumphs as well as the complex political and economic landscape of the time. His first-rate narrative reminds us of the convoluted process of scientific discovery.