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. 2013 Mar;103(3):426–434. doi: 10.2105/AJPH.2012.300693

Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative

Roswell Quinn 1,✉
PMCID: PMC3673487  PMID: 22698031

Abstract

Policy leaders and public health experts may be overlooking effective ways to stimulate innovative antibiotic research and development. I analyzed archival resources concerning the US government’s efforts to produce penicillin during World War II, which demonstrate how much science policy can differ from present approaches. By contrast to current attempts to invigorate commercial participation in antibiotic development, the effort to develop the first commercially produced antibiotic did not rely on economic enticements or the further privatization of scientific resources. Rather, this extremely successful scientific and, ultimately, commercial endeavor was rooted in government stewardship, intraindustry cooperation, and the open exchange of scientific information. For policymakers facing the problem of stimulating antibiotic research and development, the origins of the antibiotic era offer a template for effective policy solutions that concentrate primarily on scientific rather than commercial goals.

DURING THE LAST QUARTER of the 20th century, the antibiotic research and development pipeline was unable to address the increasing impact of antibiotic resistance. Instead of producing an array of novel compounds, the pipeline became less innovative and delivered fewer new drugs over time. For more than 30 years, the pharmaceutical industry failed to introduce a new class of antibiotics. Between the introduction of trimethoprim in 1968 and linezolid in 2000, all new antibiotics worked in ways similar to previous drugs, a factor in promoting drug resistance. In addition, the discovery rate for next-generation compounds declined 56% in the two decades leading up to 2003.1

As the need for novel antibiotics has continued to increase, the pharmaceutical industry has withdrawn from this area of development. Half of all pharmaceutical firms in the United States and Japan ceased their antibiotic activities in the late 1980s.2 This was most likely attributable to a market saturated by antibiotics with similar indications. Years later, when the biotechnology revolution failed to readily deliver new antibiotics, many pharmaceutical executives began to feel that antibiotic research and development was no longer “the best opportunity for success.”3 Between 1999 and 2003 pharmaceutical giants such as Aventis, Eli Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Procter and Gamble, Wyeth, Abbott, and Roche discontinued, downsized, or spun off efforts to produce novel antibiotics.4 By this time, antibacterials accounted for less than 1.6% of the industry’s overall research and development pipeline.5 Therefore, the crisis in antibiotic resistance is two dimensional: both the curative powers of antibiotics and the traditional forms of research and development are failing.

Many public health, scientific, and policy experts have identified decreasing corporate investments in antibiotic research and development as a key factor fueling the crisis in antibiotic resistance. New antibiotics are badly needed because antibiotic-resistant infections have rapidly become a leading cause of death in the United States and often double health care costs per patient.6

Moreover, the waning of research and development investments decreases the likelihood that novel antibiotics will enter clinical practice in a timely fashion. In response, proposals focus on economic incentives, mainly stronger intellectual property rights, to spur industrial participation in antibiotic research and development. Beyond industrial research and development, recommendations aimed at curbing antibiotic resistance include educational campaigns, increased disease surveillance, basic research, and public health training; however, these options are typically subordinate to expanding intellectual property rights. This economic approach has become so widely accepted as policy that one industry authority described the situation as “a problem that no longer requires further study.”7

The US pharmaceutical industry’s involvement in antibiotics originated in a government-sponsored project during World War II. A historical analysis of the broad wartime coalition that developed penicillin reveals important lessons for the present. The overwhelmingly successful effort that brought penicillin out of the laboratory and onto the market was not contingent on developing economic entitlements for corporations. Rather, wartime requirements induced scientific collaboration, dramatic acceleration of scientific innovation, and technical standardization. More importantly, this environment of exchange was profitable and conferred an array of noneconomic assets on industrial participants. Such scientific and technological assets propelled the US pharmaceutical industry beyond previous inefficiencies and transformed it into one of the country’s most successful sectors.

WORLD WAR II AND THE ADVENT OF PENICILLIN

At the onset of World War II, Penicillium notatum, the mold made famous by Alexander Fleming in 1928, was well recognized for its ability to inhibit the growth of certain bacteria in laboratory experiments. The pharmaceutical popularly known as penicillin, however, did not exist. Although several American pharmaceutical firms had examined Fleming’s widely distributed mold, none had continued to develop its potential, and it remained a curiosity.8 American officials only began to take the compound’s potential seriously in the summer of 1941, after a visit by Oxford scientists Howard Florey and Norman Heatley.

By sharing scientific information as well as mold cultures with US officials and scientists, Florey and Heatley sparked a unique collaborative effort. At Oxford they had produced preliminary data showing penicillin’s efficacy in humans, constructed makeshift production equipment, and isolated more productive strains of the penicillin-secreting mold. Imparting these resources to a range of academic, industrial, and governmental scientists led to an impressive scientific network seeking to provide the military with large quantities of highly refined, commercial-grade penicillin. In a matter of 5 years, this diverse group transformed the production of penicillin from a low-yielding, labor-intensive method of growing crude penicillin in bedpans and milk bottles to fermentation of highly refined penicillin in 10 000-gallon tanks. In this short time, a little-known, clinically insignificant, and unmanageable compound became a mass-produced miracle.

The advent of penicillin as a clinical and commercial reality depended on a wide range of biological, scientific, and human resources operating in an open network. Arguing that penicillin would play a critical role in the recovery of manpower, US military leaders mobilized these resources instead of prioritizing economic goals. Mold samples, top-secret reports, and scientists began flying all over the country and, in some cases, the world. This approach induced collaboration among the varied scientists involved with the wartime project, providing them access to a previously unfathomable network of scientific exchange.

Extensive coordination by government agencies made this collaboration possible. The Office of Scientific Research and Development initiated US involvement with penicillin and oversaw most of the scientific work prior to 1943. It coordinated a total of 57 research contracts covering the preliminary studies of penicillin, clinical trials by the Committee on Chemotherapies and Other Agents, and extensive research into the drug’s chemical synthesis.9 A second agency, the War Production Board (WPB), worked with 21 companies, 5 academic groups, and several government agencies, including the US Department of Agriculture (USDA), to establish large-scale production of penicillin by fermentation. These efforts created a unified scientific workforce comprising a range of mycologists, geneticists, clinicians, chemical engineers, pharmacologists, and chemists working across many sectors.

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This poster appeared on the walls of fermentation plants producing penicillin during World War II.

Source. Record Group 44, Records of the Office of Government Reports, 1932–1947, 44-PA-1505 “Penicillin Saves Soldiers' Lives! Every Minute Saved in Building This Plant Means a Life Saved on the Fighting Fronts. Give This Job Everything You’ve Got, 1941–1954,” National Archives, College Park, MD.

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Andrew Moyer, the Northern Regional Research Laboratory scientist who perfected the initial growth medium used for penicillin production during the war effort, points to the mycelium, or matt of mold growth, floating about the growth medium into which it secretes penicillin.

Source. Record Group 208, Records of the Office of War Information, 1926–1951, Still Pictures and Records Section, 208-SAI-1-55 Antibiotics, National Archives, College Park, MD.

The WPB worked vigorously to circulate new information among its participants, lifting restrictions on scientific exchange induced by property rights. In 1944, the director of the WPB, Albert Elders, implored project members to increase the exchange of information with each other: “[A]ttaining maximum production today depends upon the efficient harnessing of the ‘know-how’ recently developed.”10 To this end, the WPB encouraged the free exchange of technical information in its memorandums, press releases, plant tours, and routine meetings with industry representatives, as well as compiling and circulating technical reports. As A. N. Richards, head of the Committee of Medical

Research, noted, these efforts “obtained and distributed information that greatly increased production effectiveness,” ensuring an industry-wide adoption of the most valuable wartime developments in penicillin production.11

This heightened level of exchange required direct policy interventions by the WPB. By 1944, clinical trials had thoroughly proven penicillin’s usefulness in military medicine, and US strategic planning created heightened demand for the drug. With no foreseeable limit to demand and increasing calls for public and foreign distribution, the corporate leaders who composed the Penicillin Producers Industry Advisory Committee formulated a contract by which the WPB determined what aspects of research and development were most vital to the overall project and distributed this information accordingly. Continuing this effort, the WPB obtained exemptions from the Justice Department for companies after concerns arose that pooling technical information might violate antitrust laws.12 The following months saw a sharp increase in production, which continued until after the close of the war, as 21 factories individually commenced production, fully equipped with deep-tank fermentation and penicillin refinement capabilities. According to one government official’s count, production rates between May and June of 1944 saw “an increase in monthly production over 250 times attained in one year.”13

The WPB’s penicillin project began serendipitously and ended in triumph. Government stewardship facilitated industrial and nonindustrial groups in early-stage research and development: proving the compounds’ clinical utility, developing production technology, and recruiting further help. As a lead scientist for the project wrote, “Whatever course we were to take, we had to be sure of that D-Day supply.”14 At the project’s inception, laboratory scientists could ferment minimal amounts of crude, unstable penicillin, and by January 1945 US production, through commercial-scale fermentation, had soared to 4 million sterile packages of the drug per month. Heralding a new phase in the history of the pharmaceutical industry, the WPB released penicillin for commercial distribution to the public in March 1945.

STIMULATING RESEARCH AND DEVELOPMENT

Reviewing the origins of the antibiotic industry presents an opportunity to reflect on a time similar to the present, when various parties solicited commercial research and development. In fact, the 1940s and the early years of the 21st century have much in common: a heightened need for novel antibacterial drugs, corporate reluctance, and concern about overwhelming infections in the face of national security concerns.15 The two periods have obvious differences, especially regarding the complexities and costs of new drug development today. However, the World War II effort allows us to contemplate a different model of stimulating research and development, not to be precisely adopted, but to consider as a means of improving and diversifying current strategies. Recent examples of economic priorities deterring scientific practices, in particular the withholding of influenza samples from international public health collaborations out of patenting concerns, highlight the continued relevance of this comparison with the past.16

Companies in the 21st century use several features unique to antibiotics to paint a grim scientific and economic picture. These include dependence on past experience; challenges related to clinical trials; market assessments concerning size, value, and acceptable profit margins; and the inclination to aim scientific resources at the development of compounds perceived to have a lower scientific and financial risk.17 Moreover, an almost overwhelming number of corporate mergers have concentrated these administrative perspectives and decision-making processes, leaving few alternatives.18

Rather than focusing primarily on what economic logic might exist for corporate participation, the World War II penicillin project prioritized scientific attainment through extensive collaboration and exchange of scientific resources. For example, the Office of Scientific Research and Development’s Committee on Chemotherapeutics joined military and academic clinicians to create research protocols and conducted all initial clinical trials. Although the Food and Drug Administration did not modernize clinical trial requirements until 1962, these early trials established the drug’s efficacy and treatment guidelines. These cooperative clinical investigations yielded data about the drug’s use in humans, proving its therapeutic and commercial significance at a time when the director of such studies stated, “[T]here is a limit to which any firm can … venture capital without a reasonable chance of “return.”19 Moreover, prior to public sale of penicillin, the US government purchased $2 million worth from the drug manufacturers between 1943 and 1945 to conduct these investigations.20

Government-sponsored basic research was equally important, and the work of federal scientists was essential in recruiting pharmaceutical companies. Well versed in agricultural fermentation and mycology, the USDA’s Northern Regional Research Laboratory (NRRL) in Peoria, Illinois, was among the first groups to meet with the Oxford scientists, take a lead in the penicillin project, and ultimately solve the problem of how to produce penicillin.21 The NRRL’s scientists quickly refined the original mold species, developed an effective growth medium, and transferred the fermentation process from rudimentary surface culture techniques in flasks to submersion in tanks. Their initial efforts quadrupled penicillin production yields in a matter of months, convincing military and industry leaders of penicillin’s potential and setting the agenda for future research.22

In our time, advocates of antibiotic research and development have supported the broadening of patent rights as an organizing principle, establishing it as the key policy trope in the movement to revitalize industrial commitment to antibiotic research and development.23 Such incentives include restoration of patent time lost during the Food and Drug Administration’s review process; extended market exclusivity, as with orphan drugs; and wild-card patent extensions by which a company that provides a novel antibiotic gains additional years of patent exclusivity for an existing, more profitable drug. These proposals, however, do not guarantee that a proportional amount of funding will be reinvested in research and development aimed at needed public health interventions.24

Patents did not play a major role in the rapid development of penicillin. Many individuals filed patents covering various penicillin production processes; however, no single corporation had the opportunity to gain monopoly control, for two reasons. First, Alexander Fleming never sought a product patent on penicillin. Thus, no product patent on the drug itself existed. Second, the USDA obtained process patents for the most fundamental fermentation methods, a substantial block consisting of more than 32 process patents.25 In accordance with government policy, the agency licensed them to any interested party, without royalties. When these technologies proved successful, the pharmaceutical industry reorganized itself around a new form of drug discovery and production that lacked patent protection.26

For corporations, the absence of restrictive patents eliminated traditional barriers to sharing resources. As early as 1942, industrial groups entered into agreements to exchange information and specimens with one another. The first to do so were Merck and Squibb, joined a year later by Pfizer. Later, the Midwest group—Eli Lilly, Abbott Laboratories, Upjohn, and Parke, Davis—entered into a similar arrangement for information exchange and reciprocal licensing on all information pertaining to microbial cultures.27 Through such information-pooling agreements, these seven companies produced the largest share of penicillin during the war and maintained a successful market position and discovery rate thereafter.

Contemporary arguments for strengthening patents extend beyond economic rationale. Increased intellectual property rights, policy scholars argue, could delay the emergence of drug resistance by curbing antibiotic misuse in its various forms—agricultural uses, overprescribing, and drug-seeking behaviors—or by reserving the most efficacious drugs for dire circumstances.28 Policy scholars reason that this could be accomplished through longer patents, some even suggesting “patents of extraordinary duration,” essentially infinite in nature, to change consumption patterns through higher prices.29 Regardless of the validity of these arguments, patents also affect scientific practice. Intellectual property rights function by inducing scarcity where none truly exists; by conferring monopoly powers they limit the flow of information and other scientific resources.30

Access to biological specimens, often restricted today because of proprietary concerns, was central to the penicillin project’s success. According to NRRL mycologist Kenneth Raper, the agency’s collection housed more than 2000 species of fungi out of an estimated total of 3700 microorganisms, including 40 representatives of the genus containing P. notatum. Scientists reevaluated this collection and similar ones, including Yale University’s Osborn Botanical Laboratories, Harvard University’s Biological Laboratories, and the New York Botanical Gardens, for antibiotic-producing molds.31 From 1942 onward, the NRRL conducted an intensive search for high-yielding mold strains by collecting naturally occurring molds from both local and global locations. These collection activities involved everything from searching local markets for moldy fruits and vegetables to contracting the Army Transport Corps to collect and deliver soil samples “from wherever Army planes set down.”32

With this influx of microbes and with laboratory workers further characterizing penicillin-secreting molds, government scientists created an impressive network for classifying and trafficking these biological materials. George Beadle, then at Stanford University, was involved, along with scientists at Cold Spring Harbor and the University of Wisconsin. Improvements to production techniques often required different strains of mold more amenable to large-volume fermentation. The USDA scientists first identified a mold known as strain NRRL 1951.B25 as most suitable for fermentation in tanks. The WPB’s Office of Production Research and Development then contracted academic scientists to genetically manipulate this strain. Researchers at Cold Spring Harbor used x-rays to induce mutations and increased yields from 250 to 500 units of penicillin per milliliter of fermentation broth. Next, researchers at the University of Wisconsin improved the same strain with ultraviolet radiation, almost doubling its output.33

The NRRL acted as the hub for tracking these improvements. Thus, in addition to its collection efforts, the NRRL served as a central depot, cataloging and distributing the most productive mold strains to academic and later industry scientists. Between 1941 and 1946, USDA mycologists sent more than 1000 cultures of penicillin-producing molds to pharmaceutical firms, government and university investigators, and eventually official agencies from various allied nations.34

In our day, we do not lack large-scale scientific collaborations that employ similar exchanges. Examples include the National Cancer Institute’s Collaborative Research and Development Agreement, the Human Genome Project, and the military’s long-standing support of vaccine development by private companies.35 However, comparable models of collaboration have not been proposed for antibiotic research and development.

BEYOND A SINGLE DRUG

Current attempts to expand intellectual property rights could be detrimental not only to scientific productivity but also to industry. To improve antibiotic research and development and halt resistance, the 2007 publication Extending the Cure argues for extended patent rights, the granting of market exclusivity, and antitrust exemptions to bring entire classes of antibiotics under a single owner. For example, a single company would own all forms of penicillin and other drugs working the same way—nafcillin, ampicillin, piperacillin, and so forth. This effort would culminate in a sui generis right, or class of its own, adopted by Congress to create patents covering all compounds in a single class of antibiotics, even those off patent.36 These bundled rights would then be auctioned off in a way analogous to selling radio spectrum to the highest bidder, as endorsed by the Telecommunications Act of 1996.37 However, such policies simply confer monopoly control on those with economic power rather than encouraging scientific advancement, defeating the original purpose of intellectual property rights: spurring innovation and encouraging its dissemination.

The penicillin collaborative demonstrates how an absence of patents can actually increase scientific productivity and industrial growth simultaneously. By partaking in this unique scientific exchange, the pharmaceutical industry became, as one prominent American chemical engineer described it, “amazingly standard.”38 From sterilizing growth medium and aerating mold cultures at volumes exceeding 10 000 gallons to extracting and packaging refined penicillin, the equipment for commercial-scale antibiotic production quickly achieved a uniform character. According to the same chemical engineer, this occurred because “most major producers of antibiotics … got their start under the more or less cooperative arrangements of the government’s war-time penicillin program.”39 Rapid standardization is ultimately beneficial. As David Noble argues, it ensures large-scale production through the reproducibility of production equipment and guarantees consumption through quality control. This relationship between standardization and consumption, Noble writes, is “the sine qua non of corporate prosperity.”40

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This diagram depicts how government scientists, lacking commercial barriers, coordinated the selection, trafficking, and alteration of penicillin mold strains between multiple groups.

Source. William D. Gray, The Relations of Fungi to Human Affairs (New York: Henry Holt, 1959), 153.

Note. NRRL = Northern Regional Research Laboratory; UV = ultraviolet.

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Huge containers of mold and growth medium with submerged fermenters revolutionized penicillin production and enabled the pharmaceutical industry to produce large, refined quantities of complex biological materials.

Source. Record Group 208, Records of the Office of War Information, 1926—1951, Still Pictures and Records Section, 208-SAI-1-18 Antibiotics, National Archives, College Park, Md.

Moreover, the mass fermentation of penicillin was a radical departure from all previous means of pharmaceutical production. Until the Second World War, drug manufacturing consisted of either synthetic chemistry, as exemplified by the sulfa drugs, or the laborious and low-yielding extraction of naturally occurring components from large quantities of their parent compound. For example, the processes to extract certain hormones and vitamins required hundreds of kilograms of starting materials to produce only milligrams of the desired compound. Such extraction consisted of repetitive laboratory procedures rather than a codified technique for mass production. As a scientist at the Squibb Institute for Medical Research later remarked,

Before 1942 the basic manufacturing processes in pharmaceutical manufacturing plants in the United States produced vaccines and anti-sera, recovered biological products from plant and animal sources, and synthesized on a small scale. Except for the chemical techniques, which benefited by the experience of the chemical industry and by the attention of the chemical engineer, manufacturing processes were, for the most part, expanded laboratory techniques.41

In overcoming hurdles to industrial-scale aerobic fermentation and sterile product refinement, penicillin researchers revolutionized manufacturing processes for the entire pharmaceutical industry. With the cooperative efforts of microbiologists and chemical engineers, biological processes expanded in scale to encompass the needs of commercial distribution, and biology—rather than chemistry—became a platform for drug production and future corporate growth.

The dramatic postwar expansion of the medical profession’s arsenal was a direct outgrowth of the new production methods established by penicillin manufacturing. The shift from chemistry to microbiology as the basis of pharmaceutical manufacturing laid the groundwork for the commercialization of a multitude of future drugs. First, a parade of new and novel antibiotics marched through the early postwar period. Companies used penicillin technologies to discover and produce streptomycin, tetracycline, erythromycin, vancomycin, and others, including a plethora of semisynthetic antibiotics. Second, these production methods were not restricted to a single family of drugs. The same scientific and engineering know-how and infrastructure also made possible the mass production of steroid hormones such as cortisone and complex vitamins such as B12.42 Later, microbiology served as an engine for discovery and production of a diverse array of compounds produced by microorganisms, such as antineoplastic agents, immunosuppressives, and individual compounds that lower lipid, iron, and glucose levels.43

The experience and technology garnered from the government-coordinated development of penicillin were significant and vital predecessors to the biotechnology revolution. Decades later, biotechnology used these fermentation techniques to grow copious amounts of fungi and bacteria genetically engineered to produce human insulin, growth hormone, and other complex biologics. The penicillin collaborative unleashed the life sciences as a platform supporting corporate research and development both then and now.

CONCLUSIONS

This historical record points to alternative ways to stimulate biomedical innovation in general and antibiotic research and development in particular, and these alternatives primarily exist outside of economic contexts. The penicillin collaborative represents a period in which science operated under a different moral framework, focusing on civic duty.44 Instead of prioritizing economic goals, a diverse coterie of scientists from government, industry, and academia concentrated on a series of related scientific goals to swiftly meet wartime needs. As a result, penicillin transformed from a laboratory curiosity—simply a mold known to inhibit bacterial growth experimentally—into a mass-produced drug in a matter of years.

Current policy efforts concerning antibiotic research and development overlook the relationship between intellectual property rights and the equitable distribution of scientific resources. Economist Michael Perelman notes that the free flow of information has been the hallmark of scientific progress, yet in recent decades corporations have curbed this flow by obtaining expanded patent rights, thus introducing inefficiency into the nation’s system of scientific production.45 The history of penicillin demonstrates how the reverse can be true: by prioritizing scientific rather than economic goals, the penicillin collaborative spurred tremendous scientific innovation and industrial growth. [fx1]

Acknowledgments

A grant from the American Institute for the History of Pharmacy supported research essential to this article.

I thank Leslie Regan, Steven Doran, and the anonymous reviewers for their comments on earlier drafts of this article.

Endnotes

  • 1. Spellberg Brad, PowersJohn H, Pc BrassEric, Loren MillerG, and EdwardsJohn E Jr. “Trends in Antimicrobial Drug Development: Implications for the Future, ” Clinical Infectious Diseases 38, no. 9(2004): 1279–86. [DOI] [PubMed]
  • 2. ProjanSteven J, “Why is Big Pharma Getting Out of Antibacterial Drug Discovery?” Current Opinion in Microbiology 6, no. 5(2003): 428. [DOI] [PubMed]
  • 3. SellersL J, “Big Pharma Bails on Anti-infectives Research, ” Pharmaceutical Executive 23, no. 12(2003): 22.
  • 4. ShlaesDavid M, “The Abandonment of Antibacterials: Why and Wherefore?” Current Opinion in Pharmacology 3, no. 5(2003): 470–3; Projan, “Why is Pharma Getting Out?” 428; Infectious Diseases Society of America, Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates… A Public Health Crisis Brews (Alexandria, Va: ISDA, 2004)
  • 5. Spellberg et al., “Trends in Antimicrobial Drug Development, ” 1281.
  • 6. R. Monina Klevens, Melissa A. Morrison, Joelle Nadle, et al., “Invasive Methicillin-Resistant Staphylococcus aureus Infection in the United States, ” JAMA 298, no. 15 (2007): 1763–71; Gregory A. Filice, John A. Nyman, Catherine Lexau, et al., “Excess Costs and Utilization Associated with Methicillin Resistance for Patients with Staphylococcus aureus Infection, ” Infection Control and Hospital Epidemiology 31, no. 4(2010): 365–73. [DOI] [PubMed]
  • 7. Projan, “Why is Big Pharma Getting Out?” At present, this approach has remained essentially unchanged. See Andrew Polluck, “Antibiotic Subsidies Weighed by US, ” New York Times, November 6, 2010.
  • 8. As a scientist working in the public sphere Fleming received many requests from other scientists for samples of the mold following his serendipitous discovery, and he obliged. Several US collectionsalready contained samples of the mold prior to US involvement in World War II, 1959 already contained samples of the mold prior to US involvement in World War II. See for example, William D. Gray, The Relations of Fungi to Human Affairs (New York: Henry Holt, 1959), 152.
  • 9. See Jonathan P. Swann, “The Search for Synthetic Penicillin during World War II.” British Journal for the History of Science 16, no. 53, pt. 2 (1983): 154–90. The efforts to determine the exact chemical nature and synthesis of penicillin during the war produced close to 700 scientific reports, yet the goal of direct synthesis remained elusive until the late 1950s, long after the project had come to a close. These activities, however, provided the scientific foundation to develop second-generation beta-lactams such as methicillin. See also Hans T. Clarke, John R. Johnson, and Sir Robert Robinson, The Chemistry of Penicillin (Princeton, NJ: Princeton University Press, 1949). On clinical trials of penicillin during World War II, see David P. Adams, The Greatest Good to the Greatest Number: Penicillin Rationing on the American Home Front, 1940–1945 (New York: Peter Lang, 1991); Chester S. Keefer, “Penicillin: A Wartime Achievement, ” in Advances in Military Medicine, vol 2, ed. E. C. Andrus (Boston: Little, Brown, 1948) [DOI] [PubMed]
  • 10. As reprinted in Albert L. Elder, “The Role of Government in the Penicillin Program.” Chemical Engineering Progress Symposium Series 66, no. 100(1970): 3–11,11.
  • 11. RichardsAlfred N, “Forward, ” in Advances in Military Medicine, vol. 1, ed. E. C. Andrus . (Boston: Little, Brown and Company, 1948), lii.
  • 12. “Penicillin Data Exchange Exempted from Antitrust Laws, ” Oil, Paint, and Drug Reporter, December 20, 1943; “Penicillin Stride, ” Business Week, October 23, 1943. Copies on file, Kremer Reference Files, C39(g) Penicillin 1941–1944. A. L. Elder, American Institute for the History of Pharmacy, University of Wisconsin, Madison.
  • 13. StockFred J, “Penicillin Production and Distribution, ” Journal of the American Pharmaceutical Association 6 (1945): 110–14, 13.
  • 14. CoghillRobert, “The Development of Penicillin Strains, ” Chemical Engineering Progress Symposium Series 66, no. 100(1970): 19.
  • 15. In the years following 2001, experts and legislators campaigned simultaneously for research on biological weapons countermeasures and antibiotics. See Ari Schuler, “Billions for Biodefense: Federal Agency Biodefense Funding, FY2001–FY2005, ” Biosecurity and Bioterrorism 2, no. 2 (2004): 86–96; and Jill Wechsler, “Bioterrorism Shines Spotlight on Pharma.” Pharmaceutical Executive 21, no. 12(2001): 34–36. [DOI] [PubMed]
  • 16. David P. Fidler, “Influenza Virus Samples, International Law, and Global Health Diplomacy, ” Emerging Infectious Diseases 14, no. 1 (2008): 88–94. For a variety examples concerning the patenting of genes and its effects on biomedical research, see James P. Evans, “Putting Patients before Patents, ” Genetics in Medicine 12, no. 4(2010): S3–S4. [DOI] [PMC free article] [PubMed]
  • 17. See Randall Brenner, Evelyn J. Ellis-Grosse, and Roger Echols, “Moving Goalposts—Regulatory Oversight of Antibacterial Drugs, ” Nature Biotechnology 24, no. 12 (2006): 1515–20; Karen M. Overbye and John F. Barrett, “Antibiotics: Where Did We Go Wrong?” Drug Discovery Today 10, no. 1(2005): 45–52; Martin L. Katz et al., “Where have All the Antibiotic Patents Gone?” Nature Biotechnology 24, no. 12 (2006): 1529–31; Patrick G. P. Charles and M. Lindsay Grayson, “The Dearth of New Antibiotic Development: Why We Should Be Worried and What We Can Do about It, ” Medical Journal of Australia 181, no. 10 (2004): 549–53; and Thomas W. Croghan and Patricia M Pittman, “The Medicine Cabinet: What’s In It, Why, and Can We Change The Contents?” Health Affairs (Millwood) 23, no. 1 (2004): 23–33. [DOI] [PubMed]
  • 18. By 2003, five companies (Wyeth, Pfizer, Aventis, Novartis, Glaxo SmithKline, and Bristol-Myers Squibb) represented the consolidated outcome of 43 previously independent pharmaceutical companies that began merging in 1980, representing an 88% reduction in the number of traditional pharmaceutical companies. Steven J. Projan, “Antibiotic Drug Discovery in the 21st Century: The Best of Times and the Worst of Times” (paper presented at the University of Illinois Urbana–Champaign, August 26, 2004). In the following years, these megacompanies continued to merge. On the multiple megamergers since 2003, see James Quinn, “Drug Giants in $90bn Mergers, ” Daily Telegraph, March 10, 2009; Julie Schmit, “Pfizer to Pay $68 Billion to Buy Wyeth, ” USA Today, January 27, 2009; and Stephen Foley, “BMS Deal May Revive the Urge to Merge, ” Independent, January 31, 2007.
  • 19. Adams, The Greatest Good, 34.
  • 20. James Phinney Baxter, Scientists against the Time. (Boston: Little, Brown, 1946), 352.
  • 21. Percy Wells, “Penicillin Anecdotes, ” Kremer Reference Files, C39(g) Penicillin 1941–1944. See also Robert Bud, The Uses of Life: The History of Biotechnology (Cambridge, UK: Cambridge University Press, 1993)
  • 22. Coghill, “Development of Penicillin Strains, ” 20.
  • 23. See, for example, Interagency Task Force on Antimicrobial Resistance, “A Public Health Action Plan to Combat Antimicrobial Resistance, Part I, ” accessed May 11, 2010, http://www.cdc.gov/drugresistance/actionplan/action_plan.htmIDSA; Mark S. Smolinski, Margaret A. Hamburg, and Joshua Lederberg, eds. Microbial Threats to Health (Washington: National Academies Press, 2003); Infectious Disease Society of America, Bad Bugs, No Drugs; R. Finch and P. A. Hunter, “Antibiotic Resistance—Action to Promote New Technologies: Report of an EU Intergovernmental Conference Held in Birmingham, UK, 12–13 December 2005, ” Journal of Antimicrobials and Chemotherapy 58, no.1 (2006): i3–22.
  • 24. For a thorough critique of longer and enhanced patent rights, their costs, and relationship to antibiotic research and development, see Kevin Outterson, “The Vanishing Public Domain: Antibiotic Resistance, Pharmaceutical Innovation and Global Public Health, ” University of Pittsburg Law Review 67, no. 1 (2005): 67–123.
  • 25. To the distain of his colleagues, NRRL mycologist Andrew Moyer took out three foreign patents for advancements made in production processes. A group of industry producers (Commercial Solvent, Merck, Squibb) later purchased these foreign patents from the scientist. See US Federal Trade Commission, Economic Report on Antibiotics Manufacture (Washington: US Government Printing Office, 1958), 228 and 239. For a detailed description of patenting, especially in relation to the United Kingdom, see Robert Bud, “Upheaval in the Moral Economy of Science? Patenting, Teamwork and the World War II Experience of Penicillin, ” History and Technology 24, no. 2 (2008): 173.
  • 26. By contrast, in attempting to synthesize penicillin the Office of Scientific Research and Development entered into contracts with industrial groups for patent provision that both prioritized government access to relevant data and maintained private monopolies should a company prove successful in synthesizing penicillin. These efforts were ultimately unsuccessful.
  • 27. Federal Trade Commission, Economic Report, 237. This agreement covered all microbial cultures discovered until July 1952. Parke, Davis, however, withdrew from the agreement in 1947 just prior to marketing its broad-spectrum antibiotic chloramphenicol.
  • 28. Ramanan Laxminarayan, “How Broad Should the Scope of Antibiotic Patents Be?” American Journal of Agricultural Economics 84, no. 5 (2005): 1287–92; John B. Horowitz and H. quoted in Federal Trade Commission, Economic Report, 118.Brian Moehring, “How Property Rights and Patents Affect Antibiotic Resistance, ” Health Economics 12, no. 6(2004): 575–83; and Kevin Foster and Hajo Grundmann, “Do We Need to Put Society First? The Potential for Tragedy in Antimicrobial Resistance.” PLoS Medicine 3, no. 2 (2006): e29. [DOI] [PMC free article] [PubMed]
  • 29. Eric Kades, “Preserving a Precious Resource: Rationalizing the Use of Antibiotics, ” Northwestern University Law Review 99, no. 2 (2005): 672. These arguments include a secondary point that stronger patents would also generate incentive for private research and development.
  • 30. Christopher Mays and Susan K. Sell, Intellectual Property Rights: A Critical History. (Boulder, CO: Lynne Rienner, 2006)
  • 31. Northern Regional Research Laboratory, Peoria, Ill. Report of trip by Kenneth B. Raper, in Charge, Culture Collection Section, and Frank H. Stodola, in Charge, Chemistry Section, Fermentation Division, to attend Conference on Antibiotics, New York City, January 17–19, 1946. Kremer Reference Files, C39(g) Penicillin 1941–1944.
  • 32.Coghill, “Development of Penicillin, ” 18.
  • 33. RaperKenneth B, “A Decade of Antibiotics in America, ” Mycologia 44, no. 1(1952): 9.
  • 34. RaperKenneth B, “Research in the Development of Penicillin, ” in Advances in Military Medicine, ed. Andrus EC, et al. (Boston: Little-Brown, 1948), 723–45.
  • 35. GoodmanJordan and WalshVivien, The Story of Taxol: Nature and Politics in the Pursuit of an Anti-cancer Drug(Cambridge, UK: Cambridge University Press, 2001); and Kendal Hoyt, “The Role of Military-Industrial Relations in the History of Vaccine Innovation” (PhD diss., Massachusetts Institute of Technology, 2002)
  • 36. LaxminarayanRamanan, MalaniAnup, HowardDavid and SmithDavis L, Extending the Cure: Policy Responses to the Growing Threat of Antibiotic Resistance (Washington: Resources for the Future, 2007). The report proposes creating “functional resistance groups” that cover cross-resistance between classes and therefore would include a series of compounds for exclusive ownership.
  • 37.Purchased rights would last for a set duration similar to that established by the Orphan Drug Act, which permits seven years of exclusivity for off-patent compounds (whose patents have expired or are not patentable) developed for use in populations smaller than 200,000.
  • 38. GadenElmer, “Fermentation, ” Chemical Engineering (April 1956), as quoted in Federal Trade Commission, Economic Report, 118.
  • 39.Ibid., 118.
  • 40. NobleDavid, American by Design: Science, Technology, and the Rise of Corporate Capitalism (New York: Alfred A. Knopf, 1977), 70. As Nicolas Rasmussan points out, such production processes created financial barriers not only for patients but also for scientists desiring to work with these compounds. See Nicolas Rasmussen, “The Moral Economy of the Drug Company—Medical Scientists Collaboration in Interwar America, ” Social Studies of Science 34 (April 2004): 179. [DOI] [PubMed]
  • 41. LanglykkeAsgar F. “The Engineer and the Biologist, ” Chemical Engineering Progress Symposium Series 66, no. 100(1970): 91.
  • 42. Our Smallest Servants: The Story of Fermentation. New York: Chas. Pfizer, 1955.
  • 43. SneaderWalter S, Drug Discovery: A History(West Sussex, UK: John Wiley & Sons, 2005)
  • 44. Interestingly, in certain circumstances contemporary biotechnology and the pharmaceutical industry have adopted a sense of civics and national identity with regard to genetics and genomics. See Marina Levina, “Regulation and Discipline in the Genomic Age: A Consideration of Differences Between Genetic Engineering and Genomics, ” in A Foucault for the 21st Century: Governmentality, Biopolitics and Discipline in the New Millennium(Newcastle Upon Tyne, UK: Cambridge Scholars Publishing, 2009)
  • 45. PerelmanMichael, Steal This Idea: Intellectual Property Rights and the Corporate Confiscation of Creativity (New York: Palgrave, 2002), 103.

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