Goldenage of Medicine?

Penicillin: Pharmaceutical Companies: Oxford to America

For U.S. firms to commit to penicillin production, however, they needed to know if the tremendous financial investment would prove worthwhile. In other words, did penicillin's therapeutic action merit the heavy sunk costs that would be endured by pharmaceutical firms? The Oxford team's 1940 Lancet paper on the role of penicillin as a chemotherapeutic agent convinced Martin Henry Dawson, Karl Meyer, and Gladys Hobby, researchers at Columbia University's College of Physicians and Surgeons, to investigate penicillin further. In September-October1940, having contacted Ernst Chain and receiving cultures from Roger Reid, the Columbia group began producing penicillin and administering it to patients at New York's Presbyterian Hospital (Helfand, et al., 31). Their work continued into 1941, thereby initiating the earliest clinical trials of penicillin in the U.S., and it became clear "…that if properly purified and available in sufficient quantity, penicillin could be used parenterally and probably effectively in the treatment of infections due to susceptible microorganisms" (Hobby, 73). They presented these results to the Society for Clinical Investigation in May 1941. [Possible visuals include both Lancet articles published by the Oxford team as well as Fleming's 1928 paper-see attached primary bibliography for these sources. I have these articles in my possession.]

Pfizer subsequently learned of this paper, marking the link that existed between commerce and academic science. The company contacted Dawson to express its interest in assisting the Columbia group by producing increased penicillin quantities. In recommending itself, Pfizer emphasized its experience with mold fermentation in the production of citric, gluconic, lactic, tartaric, and fumaric acids (Hobby, 167). Pfizer was not the only drug company that was interested in research on antimicrobial organisms prior to Florey and Heatley's visit to the U.S. Selman Waksman's consulting work with Merck during the 1930s "…had sown the seeds for the company's subsequent interest in antimicrobial substances-an interest that spread easily to nearby E. R. Squibb and Sons [in New Jersey]" (Hobby, 175). In 1936, Squibb, in fact, already had begun investigating penicillin's potential for further experimentation and production, the company's interest arising after a 1932 study conducted by Clutterbuck, Lovell, and Raistrick. Likewise influenced by the 1932 study, Merck, with Waksman's help, began growing penicillin in 1940 and seeking its active principle. Lederle also had been working with penicillin for ten months prior to Florey and Heatley's arrival, while other firms, such as Winthrop Chemical Company, Inc., displayed a more casual interest (Helfand, et al., 32). [The 1932 study's full citation, taken from Helfand, et al., 31, note 1, is Clutterbuck, P. W., R. Lovell, and H. Raistrick, "The formation from glucose by members of the Penicillium chrysogenum series of a pigment, an alkali-soluble protein and penicillin-the antibacterial substance of Fleming," Biochem. J. 26 (1932): 1907-1918. A source that may reveal previous pharmaceutical company intent regarding penicillin is S. Waksman, Microbial Antagonisms and Antibiotics (New York: Commonwealth Fund, 1945)-cited in Hobby, 175, note 15.]

Moreover, in addition to the Columbia group, several other physicians and researchers associated with the College of Physicians and Surgeons devoted themselves to studying streptococcal and pneumococcal infections. These clinicians and scientists interacted not only with one another, but also with staff members at Merck, Squibb, and Lederle, while Meyer served as a consultant to Schering and Co. (Hobby, 174). Wallace Herrell, who had heard the Columbia group's presentation to the Society for Clinical Investigation, initiated tissue culture studies of penicillin at the Mayo Clinic with Dorothy Heilman. They reported their findings at the December 1941 meeting of the Society of American Bacteriologists; this "first [U.S.] symposium on antibiotics" received press coverage, heightening the interest of the scientific community and public alike (Hobby, 109). These projects, coupled with observations made by the Columbia group that substantiated the Oxford team's initial findings, thus further peaked commercial interest. [Hobby fails to cite the Society of American Bacteriologists' proceedings from December 1941.]
With Florey and Heatley's trip to the U.S. in June 1941, the U.S. government likewise entered into the task of penicillin investigation and production-an involvement that is discussed in The Federal Bureaucracy section. The Oxford scientists' visit, funded in part by the Rockefeller Foundation, brought them first to the National Research Council (NRC) in New Haven and subsequently to the U.S. Department of Agriculture (USDA) in Washington, D.C. Florey and Heatley met with Charles Thom, chief mycologist at the USDA's Bureau of Plant Industry, and then with Percy Wells, the director of the USDA's Eastern Regional Research Laboratory who was serving temporarily as the director for the four regional research laboratories (Hobby, 87). Wells, who had experience with mold fermentation, recognized that the Northern Regional Research Laboratory (NRRL), founded in late 1940 in Peoria, Illinois, was well suited to undertake Florey's goal of increasing penicillin supplies. Specifically, its researchers' experience with fermentation from earlier government projects prepared them for the work that Florey hoped to achieve. The NRRL's use of corn steep liquor, along with the development of higher-yield producing penicillin strains and submerged fermentation techniques, gave it a central role in the effort to mass-produce penicillin.

While the research on penicillin at the NRRL was underway by July 1941, Richards, who was impressed by Florey's presentation to him of the Oxford team's results, planned the first conference to stimulate extended penicillin research. Vannevar Bush, the director of the OSRD, presided over the conference, held on October 8, 1941. In addition to Richards and Bush, Lewis H. Weed, vice-chairman of the CMR, William Mansfield Clark, chairman of the NRC's Division of Chemistry, and Charles Thom attended the conference. Richards also contacted "…the four research directors of commercial firms thought to be capable of producing penicillin, namely, R. T. Major of Merck and Co., Inc.; George A. Harrop of E. R. Squibb and Sons; J. H. Kane of Charles Pfizer and Co.; [and] Y. SubbaRow of Lederle Laboratories" (Richards, 442). Florey already had approached Squibb, Lederle, and Merck regarding penicillin manufacture, and Richards invited Pfizer due to its experience with industrial-scale fermentation. [Neither Hobby nor Richards refers to biographical information on these directors, nor could I locate an image of the group at the conference.]

The objective of this first meeting was to encourage the drug industry to examine penicillin on a larger scale and to produce enough of the substance to allow additional clinical evaluations and chemical investigation. While a follow-up conference was held a month later, it was the third meeting that served as a turning point in the path towards production. As opposed to the earlier meetings, this third conference, held in New York on December 17, 1941, included not only the pharmaceutical companies' research directors, but also their chief executive officers. The CEOs expressed concern over the technological potential for producing mass quantities of penicillin. Yet upon hearing Robert D. Coghill, the head of the NRRL's Fermentation Division, report the 12 to 20 times increase in penicillin production during the previous two months alone, due in large part to the work of mycologist Andrew Moyer and Heatley, the corporate heads grew optimistic. For instance, George Merck, who had previously believed mass production impossible, emphasized, "…'if these results could be confirmed in [Merck's] laboratories, it was possible to produce the kilo of material for Florey, and industry would do it!' " (Neushul, 382). Highlighting the significance of this conference, specifically regarding commerce's integral role in penicillin production, Coghill "…later remarked that, as a result of the NRRL report, a new pharmaceutical industry was born" (Neushul, 382).

The December meeting marked the changing priorities of both the government and industry relative to penicillin production. The heightened interest in penicillin development evolved for several reasons. A prime factor was Florey and Heatley's journey to the U.S.-a visit strengthened by the Oxford team's initial findings, by their second Lancet article in August 1941, and perhaps by Heatley's work first at the NRRL and then for six months at Merck (Hobby, 90). Florey and Heatley's visit, coupled with the Columbia group's validating report in May 1941 and the advances at the NRRL in the fall 1941, revealed penicillin's astounding antimicrobal activity, thereby contributing to the government and industry's growing involvement in penicillin evaluation and production. The press may have played a crucial role as well, for its widespread coverage of penicillin developments from May 1941 until the end of WWII "…put strong pressure on the government and the pharmaceutical industry…" in addition to creating an insatiable public demand for penicillin (Hobby, 109). Finally, the U.S.'s entry into WWII with the December 1941 Pearl Harbor attack altered Richards's initial goal of finding at least one firm to produce enough penicillin to satisfy Florey's immediate need and examine penicillin's potential for mass production. U.S. wartime pressures now "…[demanded] that every possible means of combating infection in battle casualties be explored" and that production efforts be hastened, requiring the collaboration of research science, government, and industry (Hobby, 161).