Miracle Cure

by William Rosen

  Fleming’s boss and mentor, who remained one of Britain’s most famous physicians, had spoken. Within hours, Fleet Street emptied out and headed to Paddington to find Fleming and Wright. An interview with Fleming appeared in the Evening Standard of August 31. On September 1, half a dozen other papers reported on Fleming’s discovery. Fleming was named the “Man of the Week” by the News Chronicle. Some stories actually had the lab at St. Mary’s producing the samples used at Oxford. In the Daily Mail, Fleming even gave the very strong impression that St. Mary’s, which had last investigated the properties of penicillin seven years before, was the place where a breakthrough could be expected, saying, “the production of the drug is very complicated and the difficulties are great but they are being overcome.”

  The obvious implication—that St. Mary’s was the center of penicillin research—didn’t go uncommented. English organic chemist and Nobel laureate Sir Robert Robinson had already replied to Almroth Wright with his letter to the Times, which appeared on September 1 and which read, in part, that if Fleming should wear the laurel wreath, then “a bouquet, at least, and a handsome one, should be presented to Professor H. W. Florey . . . he, and his team of collaborators, assisted by the Medical Research Council, have shown that penicillin is a practical proposition.”

  Florey was glad of Robinson’s support, but angry nonetheless. On December 11, 1942, he wrote to Henry Dale, president of the Royal Society, “I have now quite good evidence, from the director-general of the BBC in fact . . . that Fleming is doing his best to see the whole subject is presented as having been foreseen and worked out by Fleming and that we in this department just did a few final flourishes.”

  Public confusion about the discovery of penicillin goes on. Recreations in a BBC documentary from the 1970s include a dramatized Fleming preparing the compound to treat Albert Alexander, and even got the year wrong. W. Howard Hughes’s biography of Fleming, Alexander Fleming and Penicillin, claimed that St. Mary’s technicians had been making penicillin every week since its discovery in 1928. The durability of the resentments expressed by the Dunn School team are, in their way, enlightening: a window onto the motivations of research scientists, where careers can literally rise and fall over a few days difference in announcing even a minor discovery to other professionals. Scientists are human beings, after all, and their reasons for spending thousands of hours in poorly ventilated laboratories for poverty wages are complicated: the thrill of solving difficult puzzles; the joy of exercising their talents cultivated over a lifetime; and, of course, the pride and adulation that are the reward of first discovery.

  There are practical consequences to primacy of discovery. As Almroth Wright no doubt realized, the institution that could claim penicillin for its own would be a repository of both public acclaim, and a greater share of the financial resources of philanthropies and government agencies. The ways in which a legitimate claim to discovery profited the discoverers of penicillin—like the discovery of Salvarsan or Prontosil before—remain huge, even without calculating the benefits to society at large.

  But those ways pale in comparison to the very tangible profits that would be generated by the discoveries that followed.

  FIVE

  “To See the Problem Clearly”

  The battles over credit for the discovery of penicillin were still a year in the future when Howard Florey left Peoria in the summer of 1941. He left Heatley behind to work with Moyer and the rest of the Northern Lab team, while he transformed himself into North America’s most prominent penicillin evangelist. Florey had already spread the gospel to the National Research Council in New Haven, and to the USDA in both Washington and Peoria. On August 7, he arrived in Philadelphia for what would be his most consequential meeting of all, with Alfred Newton Richards of the University of Pennsylvania. Florey had met and worked with Richards as a junior researcher during his first Rockefeller Foundation–funded trip to the United States in 1925; he now had the most exciting discovery in all of medicine, and A. N. Richards was precisely the man who could translate that excitement into action on a national scale. The previous year, he had become chairman of the Committee on Medical Research for the U.S. government’s newly created Office of Scientific Research and Development. This made him, to Florey, the most important person in the country.

  By some measures, in fact, the OSRD would be the most important strategic asset of the United States in the coming war. When Florey and Richards met, it was, technically, only a week old, the creation of President Roosevelt’s Executive Order 8807, which had established it to guarantee “adequate provision for research on scientific and medical problems relating to the national defense,” though it had replaced an earlier version, the National Defense Research Committee, created the previous year. In both incarnations, it was run by an electrical engineer named Vannevar Bush. When Roosevelt tapped him to lead the country’s defense-related research, Bush had already made his name as a successful inventor of some of the basic components of what would become both digital and analog computers, as dean of MIT’s School of Engineering, president of the Carnegie Institution, and the founder of the company that was then known as the American Appliance Company (but would evolve into the electronics giant Raytheon). As the first and only head of the National Defense Research Committee, he was, in effect, the first presidential science advisor; as head of the OSRD, he gave strategic direction to the most consequential wartime research projects in history, most notably, the Manhattan Project, which would usher the world into the atomic age.

  It’s a close call, though, whether the long-term consequences of nuclear power would be more significant than those of the antibiotic revolution that was ignited by the OSRD’s Committee on Medical Research in 1941. The committee was explicitly not set up to initiate original research, but rather to oversee existing programs and to set up protocols for funding through its six divisions: medicine, surgery, aviation medicine, physiology, chemistry, and malaria. Nonetheless, Florey emerged from his August 7 meeting with Richards, agreement in hand guaranteeing the CMR would recommend a government grant for the production of penicillin.

  Medical research paid for, and managed by, federal agencies wasn’t a completely novel concept, even then. Well before the 1940s, the U.S. government had directly sponsored significant research on disease treatment and prevention; in 1887, Dr. Joseph J. Kinyoun of the Marine Hospital Service established a bacteriological laboratory in the Marine Hospital in Staten Island. In 1891, it was moved to Washington, DC, and renamed the Hygienic Laboratory. In 1902, Congress passed the Biologics Control Act largely to regulate the vaccines sold across state lines, but the same act also authorized the Hygienic Laboratory to test and improve such products as vaccines and sera—and added divisions in chemistry, pharmacology, and zoology. By 1912, the Marine Hospital Service had been transformed into the U.S. Public Health Service; in 1930, the Hygienic Laboratory had been renamed the National Institutes of Health, and seven years later moved to Bethesda, Maryland.

  But previous investments in research had funded institutions administered by the federal government: the USDA’s laboratories, or—a very different kind of research—Massachusetts’s Springfield Armory. No governmental-business alliance like the penicillin project had ever been contemplated. On October 8, 1941, Richards and Bush called a conference to be held in Washington. Among the invitees were a number of OSRD department heads: Lewis H. Weed, the vice chairman of Richards’s Committee on Medical Research; William Mansfield Clark, the chairman of the Division of Chemistry; and Charles Thom from the Department of Agriculture. More remarkably, the meeting, at which Bush presided, also included George A. Harrop of Squibb’s Institute for Medical Research, Jasper Kane of Pfizer, Yellapragada Subbarao of Lederle, and Randolph Major, the research director of Merck & Co.*

  The ad hoc committee would meet again on December 17, in New York. This time, the drug companies were represented not just by their heads of research, but by their president
s. George Merck, the president of his family company, presciently observed, “If these results could be confirmed . . . it was possible to produce the kilo of material for Florey. . . .” But by that time, ten days after Pearl Harbor, the nation had considerably more ambitious goals. Richards was no longer looking for a kilo of material from a single interested corporation. Now, “every possible means of combating infection in battle casualties [must] be explored.” Robert Coghill of the Northern Lab, who was also present at the meeting, would later confirm: “A new pharmaceutical industry was born.”

  With the birth of that new industry came a raft of other issues. Despite the patriotic enthusiasm with which the companies embarked on the first stages of penicillin manufacture, they were still, after all, commercial entities. And, although the commercial potential of penicillin was more than alluring to them, they soon realized that the lasting value of this project was knowledge. At the very least, some mechanism was needed to resolve disputes about the ownership of that knowledge: a patent.

  The historian of science Derek de Solla Price is generally credited with the observation that patents are to technology what scholarly papers are to science: the key method of allocating credit and disseminating knowledge. But while a system of patents had been a much-lauded feature of American society virtually since the country’s founding—Article I, Section 8 of the U.S. Constitution explicitly empowered the federal government to provide limited patents “to promote the progress of science and useful arts”—they had never been entirely free from controversy. Thomas Jefferson was, at least initially, hostile to the very notion of patenting ideas, writing, “If nature has made any one thing less susceptible than all others of exclusive property, it is the action of the thinking power called an idea. . . . Inventions cannot, in nature, be a subject of property.” As they were applied to medical innovations, patents were even more controversial. While mechanical inventors were unapologetically commercial in their goals, medicine—in theory, at least—was subject to a higher law, one that required that its work be performed for the greater good. Patenting of medicines, in consequence, had been forbidden in France from the time of Napoleon forward, and in Germany the nation’s first patent law, which was passed shortly after the modern state appeared in the 1880s, prohibited them for decades.

  American medical researchers had a very specific objection to medical patents, dating from 1923, when Harry Steenbock, a professor of biochemistry at the University of Wisconsin, discovered that exposing the sterols in fatty foods like milk to ultraviolet light enriched them with vitamin D, and therefore made milk into a defense against the then-widespread deficiency disease, rickets.* Although Steenbock, who had patented the process in his own name, reportedly turned down a million dollars from the Quaker Oats Company for its use, he did transfer the patent rights to a newly established nonprofit organization, the Wisconsin Alumni Research Foundation (WARF). By 1940, WARF was charging milk manufacturers for the use of the technology, and had pocketed royalties well in excess of $7.5 million (the number today is well in excess of $1 billion).*

  To the surprise of exactly no one, this was a source of resentment, followed by reaction. Dozens of research institutions, including Harvard, the University of Pennsylvania, Johns Hopkins University, and the California Institute of Technology, either forbade or severely restricted the ability of researchers to seek patents. By 1937, the American Chemical Society was hosting a conference entitled “Are Patents on Medicinal Discoveries and on Foods in the Public Interest?”

  On the other hand—when it comes to intellectual property, there is always at least one other hand—Ernst Chain had proposed patenting the Dunn School compound from the time it had been successfully extracted. By March 1941, he was lobbying Dr. J. W. Trevan, then the director of the Wellcome Research Laboratories, to support a patent application. He had considerable support from his boss; Florey shared Chain’s eagerness to secure a patent, less as a way to enrich the Dunn researchers than to enlist an entity like the Medical Research Council to whom such patents could be assigned.

  Unfortunately, though, the Medical Research Council wanted nothing to do with it. Its director, Edward Mellanby, the discoverer of vitamin D, had led the fight to invalidate Steenbock’s patent in Britain, and regarded patents with the sort of distaste that wealthy aristocrats generally hold for parvenu tradesmen. It would be a long-standing point of contention between Mellanby and Chain, who saw the development of antibiotics as “a whole tremendous virgin field [in which] we were the leaders and would remain so if we got enough money” [emphasis added]. He later said that it was unethical “not to take out patents protecting the people in this country against exploitation by foreign commercial organizations. . . .”

  In the event, he didn’t persuade Mellanby, who rebuked Chain for his stubbornness about patenting, telling him that if he “persisted in his ‘money grubbing’ he would have no scientific future in Britain.” In this, he was allied with the Rockefeller Foundation, which had a policy that discoveries generated on their dime ought to be free of patent . . . and they had been bankrolling Florey and the Dunn since 1939.

  But by the end of 1941, both the Rockefeller Foundation and the Medical Research Council had lost control over the penicillin project, which was now largely controlled by the OSRD, American pharmaceutical companies, and the United States Department of Agriculture, all of whom were enthusiastic about patents, less as a financial incentive than as a way of managing the diffusion of new knowledge in a systematic way. The enthusiasm had a strong historical foundation: Henry Leavitt Ellsworth—the “Father of the USDA”—had established the ancestor of the USDA as the Patent Office’s Agriculture Division in 1839.

  Small surprise, then, that in the fall of 1941, all the parties working at the Northern Lab, including Norman Heatley, signed a letter of agreement that assigned any subsequent patents to the United States Secretary of Agriculture. No doubt it seemed noncontroversial at the time.

  Heatley stayed at Peoria until June 1942, working with his American counterpart, the mycologist Andrew Moyer. Despite Heatley’s naturally genial disposition (and his practice dealing with the extraordinarily difficult Ernst Chain), the relationship was the opposite of amicable. In Heatley’s recollection, Moyer was a loud and obnoxious isolationist convinced Britain was pulling the United States into a mistaken war, one that would inevitably demand “gutters overrunning with [presumably American] blood.”

  Even more troubling in the long term, Moyer applied for and received a patent not only for the deep fermentation methods that he had developed jointly with Heatley—the patent itself reads: “a new and useful method for producing penicillin by the cultivation of molds, whereby the yield of penicillin is substantially increased above that previously obtained”—but for using the corn steep liquor. The names on the patent were Robert Coghill and Andrew Moyer: no mention of anyone from the Dunn School. In fact, though Heatley and Moyer had collaborated on a paper summarizing their joint research at Peoria, Moyer never submitted it for publication. It appears neither in his personal bibliography nor the patent application itself. And, while the underlying patent was assigned to the U.S. Secretary of Agriculture, allowing use without payment by all American users, it said nothing about the ability of the patent holders to sue for compensation in countries that were signatories to patent treaties with the United States. One such country was the United Kingdom, which allowed Moyer to secure British patent rights for his method of production.

  The members of the Oxford team were furious. Chain, in particular, spent the rest of his life feeling wronged over the patent issue. He had some justice on his side, but not much. The fact was that patenting penicillin itself was highly problematic, since the original discovery, of course, dated from 1928. The elapsed time meant that a patented process for manufacturing it was far more valuable than the substance itself. Chain’s grievances were emotional, not legal. The true innovations in manufacturing the substance had been
developed in Peoria, not Oxford. The key Coghill-Moyer patent, for example, was for adding phenylacetic acid to the penicillin broth, which increased yields by two-thirds. This isn’t to excuse Moyer’s actions, which were duplicitous, at best. But since the patents in question were for the procedures developed in 1941 at the Northern Lab, Heatley was the one with a reason for feeling wronged, not Chain.

  If Heatley had any complaints about the loss of credit, he had little time to share them. Even before the patent had been granted, Florey sent Heatley a cable reading, “WHY NOT GO MERCK SIX MONTHS IF THEY WILL PAY YOU. MORE USEFUL THAN COMING BACK HERE.”

  —

  When Norman Heatley left Peoria for Rahway, New Jersey, in 1942, Merck was the oldest continuously operating drug firm in the world; though as we have seen, this may be damning with faint praise. The company had been producing and selling medicinal compounds since 1668, when Friedrich Jacob Merck acquired the Engel-Apotheke, an apothecary in the Landgraviate of Hesse-Darmstadt, one of the dizzying number of German-speaking principalities that made up the seventeenth-century Holy Roman Empire.

  The business of selling medicine to consumers and physicians remained for nearly two centuries the Engel-Apotheke’s sole business, though one with limited potential before Pasteur and Koch established the microbial causes of infectious disease. In 1816, one of Friedrich Jacob’s descendants, Heinrich Emanuel, became proprietor of the family business, changed the name to E. Merck, and put the company into a different business altogether. An ambitious and, for his day, scientific druggist, Emanuel Merck sensed that the chemicals known as alkaloids were components of a large number of powerful plant-based extracts—examples include belladonna and caffeine—that could be purified and standardized. The most powerful of these extracts was the one derived from P. somniferum, the opium poppy, and in 1827 Merck bought from a Prussian apothecary named Friedrich Serturner the process by which opium could be transformed into a compound he called morphine, taking the name from the god of dreams in Ovid’s Metamorphoses.