Notes from Underground - by David Rose

Penicillin Research During World War II

This column originally appeared in the Summer 2000 issue of Spores Illustrated, the newsletter of the Connecticut-Westchester Mycological Association (COMA).

            A curious story about Alexander Fleming, the discoverer of penicillin, has circulated recently in a number of mycology newsletters, including the spring issue of Spores Illustrated. According to the story, Fleming’s father, a poor Scottish farmer, rescues from death a young boy (who turns out to be Winston Churchill) whose father repays the elder Fleming for his life-saving act by sponsoring the education of his son Alexander. The ironic twist to the tale comes with the knowledge that Winston Churchill’s life is saved a second time years later, this time by the antibiotic penicillin, thanks to its discovery by Alexander Fleming. It seems the message here is that the action of fate is always surprising and coincidental, and that the liberal application of the wealth of a great Lord to a poor farm family can never do harm.

Alexander Fleming, as is well-known, discovered the bacteriostatic action of penicillin in – once again – fateful circumstances when an experimental culture in a petri dish in his laboratory was inadvertently contaminated by spores of an air-borne mold of the genus Penicillium. While Fleming is deservedly recognized as the discoverer of this antibiotic in 1928 from his subsequent research, an equally, if not more important chapter of the penicillin story took place in the United States during World War II. Fleming’s discovery at St. Mary’s Hospital in London, published in 1929, attracted the attention of the scientific community for a time, only to languish in neglect for nearly ten years before the ravages of the war sparked an extremely urgent need for the treatment of injuries.

In 1940, Howard Florey and Norman Heatley, British scientists of Oxford University who were researching methods to increase penicillin production, visited the U.S. to seek the aid of American industry only to find that the pharmaceutical companies they enjoined for help were not particularly interested. They were referred to Charles Thom, a mycologist who was head of the Bureau of Plant Industry of the U.S. Department of Agriculture. Early in his USDA career Thom had done research in the microbiology of dairy products at the Agricultural Experiment Station at Storrs, Connecticut and was an internationally recognized authority on molds used in cheese ripening. Dr. Thom first described Penicillium roqueforti and P. camemberti, active ingredients of two popular cheeses. He published a major monograph, The Penicillia in 1930.

Thom, who knew Fleming’s Penicillium rubrum very well, was responsible for its correct identification as Penicillium notatum Westling. He referred Florey and Heatley to the USDA Northern Regional Research Laboratory (NRRL) in Peoria, Illinois where his protégé, Dr. Kenneth Raper, was working with a team of scientists on fermentation processes. The NRRL accepted the challenge to seek methods of large-scale, high-yield penicillin production and began actively collaborating with the British scientists on 14 July 1940. Raper, by the way, became not only a world authority on fungi in the genera Aspergillus and Penicillium but also on the life history and taxonomy of the cellular slime molds, The Dictyostelids, based on his discovery and identification of Dictyostelium discoideum from North Carolina soils in 1935.

Beginning with a Penicillium strain from Alexander Fleming, the NRRL “Penicillin Team” initiated a threefold research program to increase penicillin yields from the Penicillium molds. First, they began to develop molds of the Penicillium notatum-chrysogenum group – the penicillin producers – on more productive substrates. In examining different culture media they found that corn steeping liquor used in fermentation in the yeast industry produced dramatic increases in mold growth. Second, since Penicillium was observed to grow best on surface cultures, the team tried to find ways to grow it in broths, or submerged cultures. The problem was a practical one: when one compares the enormous number of petri dishes of surface-growing Penicillium needed for large-scale production to the simplicity of producing it in large tanks or vats that cost less and take up much less space, the need for a solution became imperative.

The difficulty was, however, that these molds normally germinate on the surface of a substrate. Germination below the surface tended to produce stringy clumps of hyphae without fruit. Developing a practical method of growing Penicillium in a “submerged culture” was thus a second approach to the overall problem. Finally, finding a more productive culture was really the paramount issue and the thorniest problem of all. The Fleming strain of P. notatum worked, but it was the only one known at the time, and it simply didn’t produce the vast quantity of antibiotic needed. When you stop for a moment to think that while the mycologists and microbiologists of the NRRL Penicillin Team strategized and worked, the bombing of Great Britain continued and the United States entered the war, you may realize what a critical issue this was. Indeed, it was one of those world-historical moments when the importance of mycology was felt most acutely.

Though the project at the NRRL was not exactly the “Manhattan Project” of mycology, it was conducted in a certain degree of secrecy. Yet there was also a degree of publicity that helped stimulate wide interest in antibiotic medicines. As Kenneth Raper later reflected, antibiotics were big news, and the press readily scrambled after information about miracle medicines that captured the public imagination. The story has a folkloristic aspect as well, for the NRRL put out a call for people to send in their moldy foods and other material for examination. At the height of the war it even employed a person, who entered the folklore of penicillin as “Moldy Mary,” who regularly made the rounds of Peoria groceries to buy moldy vegetables and fruits. In the end, however, it was a Peoria housewife who sent in a moldy cantaloupe to the NRRL that proved to be the major breakthrough.

The mold from this piece of fruit, identified by the lab as “NRRL 1951,” was a strain of Penicillium chrysogenum, which, when later subjected to x-ray and ultraviolet radiation tests, produced mutant strains that dramatically increased yields of penicillin. In fact, the derivatives of this mold were the only ones used by the American pharmaceutical industry for decades to come. The NRRL went on to develop further improvements of penicillin production in submerged culture that were of critical therapeutic impact for WWII combat injuries and which launched the “Age of Antibiotics.” By 1944, the demands for penicillin were “unbelievable” according to Dr. Raper, and the U.S. War Production Board had coordinated projects with the NRRL and several major universities. In 1945 Alexander Fleming himself visited the NRRL for consultation; in the year before (1944), Fleming and Florey won the Nobel Prize in Physiology or Medicine for their research.

Penicillin has proven successful not only for military medicine but for a wide range of human and veterinary applications in the treatment of bacterial infection. It has particular effectiveness against gram-positive, spore-forming bacilli, and there has been a resurgence of interest in its medical utility in recent years. That its development was an important chapter in American mycology and medicine, and not only in the fact of its discovery by Fleming, has been in a sense overlooked. The U.S. National Archives released the unpublished files of the USDA Northern Regional Research Lab in 1980. They remain as a permanent, public record on the heroic effort on research of a fungus that changed the course of history.

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