By the middle of 1943, Feldman and Hinshaw had performed experiments testing a variety of compounds, including several of the sulfa drugs, and a related class of drug known as the sulfones on tuberculosis in guinea pigs. Sulfones had shown some promise in treating another mycobacterium-caused disease—leprosy—and the Mayo team reasoned, eo ipso, that they might be effective against tuberculosis. They were to be disappointed; the curative powers of antileprosy medications—Promin (from Abbott Laboratories) and Promizole (from Parke-Davis)—against M. tuberculosis weren’t completely absent, but nearly so.
Far more encouraging was Selman Waksman’s work with actinomycetes. After reading his papers on streptothricin, Feldman visited Rutgers in November 1943, and encouraged Waksman to keep the Mayo team in mind for anything that showed streptothricin’s antibacterial effectiveness without its very high cost in toxic side effects.
In February 1944, Feldman and Hinshaw received an advance copy of Schatz’s first streptomycin paper. Though the paper listed twenty-two different bacteria that were either killed or inhibited in vitro by the newly discovered compound, they saw only one: M. tuberculosis. The following month, Waksman wrote a letter to Feldman asking whether he and Hinshaw would be able to perform clinical tests in vivo on the drug.
It took Schatz five weeks to distill the 10 grams that the Mayo team requested, but by the end of April, a batch of streptomycin was on its way from New Brunswick to Rochester. On April 27, Hinshaw and Feldman began testing it on a dozen different pathogens they successively injected into four very unlucky guinea pigs.
The results were more than encouraging. Streptomycin was effective against nearly all of them: bubonic plague, tularemia, even the intestinal disease known as shigellosis. Most important: By the time the tests were completed on June 20, the preliminary results were almost too good to be true. Streptomycin cured tuberculosis.
At least, it cured the disease in four rodents. To know the compound’s real effectiveness, the test would need to be replicated as a proper experiment, with more subjects and a like number of controls: guinea pigs who would be given the disease, but not the treatment. For that second, crucial bit, considerably more streptomycin was needed than Schatz and his Heatley-like factory could dream of producing. On July 9, Hinshaw and Feldman arrived in New Jersey, this time so that Selman Waksman could introduce them to his patrons from Merck at their Rahway lab.
Feldman and Hinshaw had, perhaps overoptimistically, already selected and infected twenty-five guinea pigs before leaving Rochester, but their arguments failed to persuade Merck’s team. The pharmaceutical company’s chemists and pharmacologists were extremely dubious about their ability to produce the quantities needed for a proper trial. And even if they could, they questioned the wisdom of allocating resources to an unproven drug when the need for more and better penicillin production was clearly a greater national priority. Merck—along with the other sixteen companies that the War Department had enlisted in the penicillin project—was fully committed to the Florey-Chain-Heatley process. Its manufacturing facilities (and, particularly, its fermentation vats, which would be essential for producing large quantities of either penicillin or streptomycin) were working three shifts a day to produce the penicillin demanded by the war effort. This was only sensible, since the most common infections resulting from the wounds to American soldiers, sailors, and airmen were caused by Gram-positive bacteria: staphylococci, streptococci, enterococci, and especially clostridia: C. tetani, the vector for tetanus toxemia, and C. perfringens, which caused gas gangrene. Penicillin killed them. Streptomycin—even if it worked—wouldn’t.
At the moment it must have seemed to Waksman, Feldman, and Hinshaw (and even the absent Schatz) that their research was being sidetracked just when they were tantalizingly close to a breakthrough. George Merck joined the meeting. Merck’s chief executive knew, better than anyone in the room, the importance of the penicillin project to both the company and the war effort. He also possessed, more than anyone in the room, a vision of the future of drug development. And he alone had the executive authority to decide which was more important. Merck overruled his scientific staff and agreed to invest in a production line for streptomycin in the plant in Rahway; a month later, the company broke ground on a brand-new $3.5 million facility in Elkton, Virginia.
Even better: He directed Randolph Major, Merck’s research director, to assign fifty researchers to the project. Major knew precisely who he wanted to head the team. Ten years before, he had hired two Ivy League–trained chemists, Max Tishler and Karl Folkers. He assigned Tishler to work on a series of challenging problems in chemical synthesis—vitamin B2, cortisone, and ascorbic acid—while Folkers spent two years studying the poisonous alkaloids collectively known as curare as a possible anesthetic.* Both were put on the penicillin project in 1943, and were working on it seven days a week when Major reassigned them to streptomycin. Folkers became the company’s head of research, Tishler its head of development.
Tishler and Folkers were both children of immigrant families who received the most prestigious and rigorous graduate education available in the United States—Tishler was awarded his PhD from Harvard’s chemistry department, where he studied under the soon-to-be president of the university James Bryant Conant; Folkers did his postdoctoral work at Yale. Both joined Merck in the 1930s precisely because the company’s brand-new research lab promised the kind of support available nowhere else. Folkers, in particular, chose Merck over a higher-paying job working for General Electric because his “lab” at GE was more like a storeroom “with some chicken wire to separate it from the rest of the area.”
Working together as a team for the first time on streptomycin, Tishler and Folkers got on brilliantly, both with one another and with Waksman, whom Tishler remembered forty years later as an “extremely imaginative, able, wonderful scientist, and a very dedicated and prolific writer. . . . He was probably the best living scientist of the soil; no one has approached his expertise since then.” No one was better suited by training and temperament to get a sufficient quantity of streptomycin from New Jersey to the eagerly awaiting Hinshaw and Feldman.
By mid-July 1944, they had received enough streptomycin to begin their world-changing experiment. The twenty-five infected guinea pigs were injected with streptomycin every six hours for sixty-one days. Twenty-four control animals were not. The results, even now, are startlingly obvious. After forty-nine days, eighteen of the control animals showed tubercular nodes in their lungs; only one of the treatment animals did. Eight control animals had tuberculosis in their livers; none of the treatment animals did. And seventeen of the untreated animals—71 percent—had died. Of the twenty-five guinea pigs given streptomycin, twenty-three had survived to the end of the experiment.*
Waksman, Schatz, Hinshaw, Feldman, Folkers, and Tishler had their answer. Another wonder drug, one that seemed to be in every way as transformative as penicillin, had been identified, isolated, and tested.
Who would get to tell the world?
Streptomycin, like penicillin before, and tetracycline and others after, was the work of dozens of highly trained and ambitious professionals, and their motivations aren’t easily categorized. For some, it’s all about the pleasures of puzzle solving: Howard Florey famously said, “People sometimes think that I and the others worked on penicillin because we were interested in suffering humanity. I don’t think it ever crossed our minds about suffering humanity. This was an interesting scientific exercise, and because it was of some use in medicine is very gratifying, but this was not the reason that we started working on it. . . .” For others, though, Florey included, recognition was the thing. Scientists dream of the undying fame that comes with Copley Medals and Nobel Prizes, but even at more modest levels, authoring a major paper is the key to academic status and even employment. This was true even outside of universities; out of a shared conviction, promoted by Major, that Merck needed to be preserved as an attractive place f
or academics to work, Tishler and Folkers developed a protocol whereby Merck scientists were allowed—even encouraged—to publish results any time after a patent was filed, rather than waiting for the patent to be issued. And, let it not be said that scientists, even those not employed by profit-making enterprises like Merck, are immune to financial attractions, both from grants and the patent revenues whose loss had so enraged Ernst Chain.
What all these forms of compensation share, though, is the premium they place on priority: Recognition, prizes, grants, and patents are rewards only for first-place finishers. The problem with the news about streptomycin was that there were two important discoveries: first, the Rutgers discovery that the compound produced by S. griseus was effective against Gram-negative bacteria in vitro; and second, the Mayo results that it worked just as well in vivo. Complicating matters was the fact that Feldman and Hinshaw, because of their affiliation, were able to guarantee that their own paper could appear in the Proceedings of the Mayo Clinic—a prestigious, peer-reviewed journal—within weeks of submission, while Schatz and Waksman were still awaiting a date from the Proceedings of the Society for Experimental and Biological Medicine.
It was a polite disagreement, but a nontrivial one, and it required a third party to adjudicate it. Waksman persuaded Randolph Major to—politely—dissuade the Mayo team from publishing until the Rutgers streptomycin paper could appear. Since Merck had a long-standing relationship with Waksman (to say nothing of an interest in controlling the public release of information about a potential new miracle drug before it was closer to being produced in quantity), Major was happy to tell Feldman that while he “quite understood” his eagerness to publish, “You might care to wait until the publication of [Waksman’s] initial in vitro results.”
Major—and, presumably, his boss, George Merck—didn’t care about publishing priority. But he did have a powerful regard for the company’s relationship with Selman Waksman’s lab, which was starting to look like one of the most important research investments the company had ever made. Waksman knew this, and made his case to his corporate patrons accordingly: He needed to publish first.
It was at roughly the same time that Waksman performed an even more unlikely act of salesmanship: persuading George Merck to give up the patent on streptomycin.
Because of the 1939 agreement, Merck & Co. owned the patent on a potential super antibiotic, while penicillin could be produced by anyone as a generic drug. So the fact that Merck did, in fact, transfer ownership of the patent to the Rutgers Endowment Foundation seems, on the face of it, mystifying. Though George Merck famously, and sincerely, believed that people came before profits, he was also the CEO of a for-profit company that was certainly capable of providing streptomycin to millions of people; and since someone was going to own the patent, why not Merck?
The best guess is that, like penicillin (and so much else), the fate of streptomycin was intimately tied up with the overarching strategic objective of the time: winning the Second World War.
Even before it had become a shooting war, the nations that would become the Allied powers had been worrying—probably excessively—about the potential development of biological weapons by the Axis. It was widely believed in London and Washington that Japanese agents had tried to buy yellow fever virus as early as 1939. Other intelligence reports suggested that German biologists were secretly teaching their Japanese partners how to use anthrax and typhus militarily. The Swiss had reportedly told the United Kingdom that Nazi Germany had plans to use “bacteria of every description” in any coming war.
The identities of everyone in the United States who was privy to this intelligence aren’t known, but one was certainly George Merck, the head of the War Research Service.
As documented by the journalist and author Peter Pringle, and substantiated by the National Academy of Sciences committee on biological warfare, and the War Research Service, Merck had met with the Office of Strategic Services, a wartime intelligence agency, in 1943 in response to a request that he recommend biological weapons for use in covert operations behind enemy lines. But his more important duty was to protect the Allies against any likely biological attack; and it seems at least plausible that he decided that his responsibility to his nation trumped the one he had as the head of his family corporation. If streptomycin was a potential defense against German or Japanese biological warfare, it was imperative that production be scaled up immediately.* By the end of 1944, he agreed to forgo the monopoly granted by the 1939 agreement with Selman Waksman; within two years, six companies—Abbott, Lilly, Merck, Pfizer, Squibb, and Upjohn—were all manufacturing streptomycin.
Whatever Merck’s motives, his decision freed Waksman to secure the patent rights on behalf of Rutgers, and, on February 9, 1945, Schatz and Waksman jointly applied for a patent on streptomycin, swearing under oath that they were codiscoverers of the new drug. Three months before, Merck-manufactured streptomycin had been used, for the first time, on a human being: Patricia Thomas.
Thomas had spent more than a year at Mineral Springs, her symptoms gradually worsening, especially in her right lung. In October 1944, her physician, Dr. Karl H. Pfuetze, sent her to the Mayo Clinic for a consultation and examination by Corwin Hinshaw, who immediately started her on the course of streptomycin that would save her life. Over the next five months, she received five courses comprising multiple doses . . . doses that, in the absence of any prior human testing, were best-guess estimates by her physicians. Mayo Clinic surgeons operated on her nearly useless right lung, excising the diseased section and returning most of its function. In the summer of 1945, she returned home, where she would marry and have three children. Streptomycin saved her life, but she was still permanently weakened by the disease, and would die in June 1966, at only forty-two years old.
For Waksman, 1946 was an annus triumphalis, the first of many. He traveled to Europe, where he was presented with the first of what would become twenty-two honorary doctoral degrees and sixty-seven prizes and awards, including the Lasker Award, the Trudeau Prize, and the Nobel Prize in Physiology or Medicine. Also, in 1946, on May 3, Waksman and Schatz both assigned their pending patent* to the Rutgers Foundation (by then the Rutgers Research and Endowment Foundation) in return for one dollar apiece.
Schatz, who had by now completed his PhD dissertation, watched from the sidelines as Selman Waksman became a national hero. In 1948, a dozen newspapers hailed Waksman as the discoverer of the new wonder drug; in April 1949, Time profiled him as the model of a humble scientist in an article entitled “Man of the Soil.” In November, it put him on the magazine’s cover, accompanied by the folksy reminder that “the remedies are in our own backyards.” Schatz was unmentioned in either article. He registered his concern in a letter to his onetime boss. Waksman’s reply deserves quoting in detail:
You know quite well that we gave you all the credit that any student can ever hope to obtain for the contribution that you have made to the discovery of streptomycin. You know quite well that the methods for the isolation of streptomycin had been worked out in our laboratory completely long before your return from the army, namely for streptothricin.
Unsurprisingly, this failed to mollify Schatz. Nor did a subsequent letter in which Waksman told his onetime grad student and co-patent holder:
You must, therefore, be fully aware of the fact that your own share in the solution of the streptomycin problem was only a small one. You were one of many cogs in a great wheel in the study of antibiotics in this laboratory. There were a large number of graduate students and assistants who helped me in this work; they were my tools, my hands, if you please.
The “man of the soil” had dug one shovel too deep. In March 1950, Schatz filed suit in federal court.
More than reputation was at stake. In the intervening years, Schatz had learned—it’s unclear how—that the 1946 assignment of patent rights to the Rutgers Foundation, for which both Schatz and Waksman agreed to accept a
single dollar in compensation, wasn’t the only document signed by Waksman that month. He had, in addition, signed an agreement with the foundation that provided him with 20 percent of the royalties they would henceforth receive for licensing the rights to manufacture streptomycin. Even better (or worse), Schatz discovered that the agreement between Waksman and the foundation was contingent on Waksman persuading Schatz to sign away his rights. For a dollar.
By 1950, Waksman’s 20 percent had paid him approximately $350,000.
Though Waksman attempted a defense against the suit, he was severely handicapped by the documents he had himself signed—not merely the patent application, with its solemn oaths that he and Schatz were codiscoverers, but the original papers in which the discovery of streptomycin was described. Back in 1944, two articles had appeared in The Proceedings of the Society for Experimental and Biological Medicine entitled, respectively, “Streptomycin: A Substance Exhibiting Antibiotic Activity Against Gram-Positive and Gram-Negative Bacteria” and “Effect of Streptomycin and Other Antibiotic Substances upon Mycobacterium tuberculosis and Related Organisms.” The authors were Albert Schatz, Elizabeth Bugie (another of Waksman’s graduate students), and Selman Waksman . . . in that order. And while Waksman later asserted that it was his policy to give students first position on papers to help their careers, he did so only twice in his entire publishing life. Both were the streptomycin papers he had coauthored with Schatz.
In December, the case was settled without trial. Schatz was granted 3 percent of the foundation’s streptomycin royalties, which would amount to about $12,000 a year, and a one-time payment of $125,000 for foreign patent rights. Waksman was granted 10 percent (and 7 percent was granted to everyone else who had worked in the lab during the key months of 1943, up to and including the dishwasher).
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