Experiment Eleven

by Peter Pringle

  THAT EVENING AT the Mayo Clinic, Waksman left a manuscript of Schatz’s in vitro paper with Feldman, who, again prodded by Hinshaw, asked for at least a footnote on their own work to be included. “It would very properly give you the credit for recognizing the importance of the in vivo studies before speculating as to possible chemotherapeutic efficacy,” he said. Such a footnote, he continued, might read, “At the suggestion of the authors the effect of in vivo tests of streptomycin on M. tuberculosis is now being studied by Feldman, Hinshaw and Heilman, Mayo Foundation, Rochester, Minnesota. The results of their study will be the subject of an early report.” The footnote was printed in the paper, but without the last sentence. Waksman had successfully concluded his first move to control the story of the discovery of streptomycin.

  7 • A Conflict of Interest

  BY THE SPRING OF 1944, THE American companies producing penicillin were making enough to meet Allied demand. From D-day, June 6, 1944, onward, the death rate from infected wounds was reduced dramatically, and by 1945 penicillin was available for civilians. As streptomycin continued to show promise during the summer of 1944, Dr. Waksman was rarely seen in the “salt mines,” as Doris Jones had christened the laboratories where the graduate students toiled, poring over their petri dishes for zones of antagonism. Waksman’s onetime fascination with new species of mold, with watching them grow and perform weird tasks against their cousins, had long since faded. He was now preoccupied with turning streptomycin into a new wonder drug. In an astonishing move, Merck would give up its exclusive right to produce streptomycin—the right that Waksman had negotiated in return for Merck’s giving three hundred dollars a month to his department. Under a new arrangement, the patent rights would be owned by the nonprofit Rutgers Endowment Foundation, which would license companies to produce the drug, paying the foundation a 2.5 percent royalty. Waksman would be in charge of arranging those licenses. He would become the overlord of streptomycin.

  Any thoughts he might have had about leaving Rutgers for a better job at a bigger university, or even giving up academic life altogether and going into industry, quickly disappeared. He would stay at Rutgers, despite the tiny size of his department, despite Rutgers’s lower academic standing when compared with larger “aggie” colleges such as Cornell or Wisconsin, and despite the school’s meager level of funding. At fifty-six, Waksman was about to have his world transformed—and so were the drug companies.

  The official reason for Merck giving up the patent was that Merck and Rutgers, realizing how significant the new drug could be, had agreed that no one company should have a monopoly. Streptomycin should be produced by as many companies as possible, just like penicillin. More would be produced at a cheaper price because of the competition. Merck was seen as magnanimous in relinquishing what was about to be a grand money-spinner, and Waksman was seen as a great humanitarian for persuading the company to take this extraordinary path. While there was some truth in these official explanations, the reality, as with so many things unfolding in the streptomycin story, was somewhat different.

  SINCE THE BEGINNING of the war, the Allies had become increasingly concerned about the enemy’s possible use of biological weapons. Among the secret reports was one concerning a bizarre prewar operation in February 1939. Japanese agents tried to buy yellow fever virus at the Rockefeller Institute, in New York, but the plot was uncovered by the Federal Bureau of Investigations. In October 1941, the secretary of state for war, Henry Stimson, had called on the National Academy of Sciences to form a committee to assess the current state of knowledge about biological warfare. A “war bureau of consultants,” a dozen scientists led by Dr. Edwin Fred, professor of bacteriology at the University of Wisconsin, assessed the enemy’s possible offensive and defensive arsenals. In May 1942, President Roosevelt authorized Secretary Stimson to establish a secret civilian agency, the War Research Service, to develop biological weapons, which the United States would keep in reserve and never be the first to use. A site was chosen at Fort Detrick, in Maryland, an old army base. The War Research Service was made part of the Federal Security Agency to obscure its existence, and George Merck, who had proved his patriotism with his “Command me” remark to Vannevar Bush, was named director.

  In 1942, intelligence reports on enemy development of biological weapons escalated. An FBI informant in Tokyo had overheard drunken German doctors saying they were teaching the Japanese about biological weapons, including anthrax and typhus. Another informant, in Los Angeles, warned that Japanese saboteurs had cans of a jellylike substance containing typhus and bubonic plague. No such containers were ever found. A Swiss report said that the Germans would use “bacteria of every description” on Allied forces. Yet another said that Germans were making biological weapons in laboratories in Brazil. In March 1943, a memo from the War Department on the enemy’s “resort” to biological weapons talked about possible contamination of the U.S. domestic food supply.

  Although U.S. policy on biological weapons was strictly defensive, that did not prohibit the Office of Strategic Services, the forerunner of the Central Intelligence Agency, from asking Merck’s War Research Service to recommend “three or more” of its “most potent organisms” for use in covert operations, with directions on how to use them. At a special meeting chaired by George Merck to deal with the OSS request, the experts, led by Dr. Fred, suggested “two types” of organisms—“those extremely pathogenic and those that reduce the efficiency, but may not be fatal.” The “most promising” were “B. anthrax and Cl. botulinum,” and “perhaps a dysentery organism of the Shiga type, the plague organism [and] brucellosis of the Suis strain should be studied.” Streptomycin had shown promise against the plague and brucellosis. Later the OSS would ask for pellets or capsules of Staphylococcus aureus for “definite war use.” Albert Schatz had used S. aureus as one of his test organisms in his hunt for streptomycin.

  GEORGE MERCK HAD a clear conflict of interest. Under the deal with Waksman, his company would have monopoly control over streptomycin, which, he knew, had already proved itself to be effective in fighting the kinds of diseases that might be spread by the enemy in a biological weapons attack. And he was the chairman of the president’s committee charged with finding such a drug and producing it as quickly and as cheaply as possible. In addition, Merck was under constant pressure to increase supplies of streptomycin, and it had experienced production problems. At one point, they lost the entire contents of three of the big thirty-thousand-gallon fermentation tanks producing streptomycin because of a virus invasion that killed the culture. George Merck took the only path open to him: He gave up the company’s monopoly rights—but on his terms. Dr. Waksman understood Merck’s position very well. Since 1942, he had been advising Merck’s committee on how to deal with fungus infestations of clothing in the tropical climates where U.S. forces were fighting. And he was prepared for this moment.

  In October 1943, after Schatz became convinced of his discovery of streptomycin, Waksman had informed Merck’s Randolph Major that he had received a dramatic British report about the treatment of burns. “We can keep most of the burns uninfected for the first 10 days or so (by the use of sulphonamides and penicillin),” the report said, but to defeat subsequent infections, it continued, the British doctors needed a new antibiotic active against Gram-negative organisms.

  At the time, Waksman still hoped Merck would be able to turn streptothricin, discovered by Waksman and Boyd Woodruff in 1942, into that much-needed drug. Under his contract with Merck, Waksman had agreed not to give out samples of streptothricin to any other companies for testing. But he asked Merck to waive this rule.

  “It is hardly fair on my part not to place a material that we have isolated and that proved to be active against Gram-negative bacteria, especially a non-toxic preparation, in the hands of those that need it,” Waksman wrote. He still hoped that somehow it could be detoxified.

  Major “quite understood” Waksman’s position. He agreed to release the cultures “if you find i
t necessary.” The only reason Merck had felt justified in asking Waksman to withhold these cultures, he said, “was that I understood that you did not object to doing this.”

  This was evidently the beginning of several conversations and letters between Waksman and Merck during which Waksman told the company of his “feeling” that he should be “free to make available for development by other organizations antibiotic agents which may be of value to the armed forces in the present emergency.”

  By the end of 1943, the OSS had reported again that the Germans might be planning a biological weapons attack. While the evidence was still inconclusive, secret defensive work on biological weapons in the United States, Britain, and Canada was producing “concrete information” that such an attack “was feasible.” In the New Year, “all work in this field” was stepped up, so that by the summer of 1944 a large part of the program had been handed over to the War Department. President Roosevelt established a new overall manager, the U.S. Biological Warfare Committee. Merck was appointed chairman. His conflict of interest remained and, if anything, was heightened.

  As “consultant to the secretary of war,” Merck was personally receiving intelligence reports on enemy biological warfare. One such OSS report in August 1944 claimed that the German army had a “special service” in occupied France that was sending vials of cattle plague to England to be used for spreading epidemics among British livestock. The German agents in Britain were supposedly to infect the cattle when they were brought to market. In planning how to retaliate “in kind” if necessary, a “wide variety of agents pathogenic to men, animals and plants was considered.” This included many bacterial agents, such as bubonic plague and tularemia, against which streptomycin was the latest, and most effective, drug.

  The War Production Board, now in control of U.S. industry, considered bringing streptomycin production under government control, as had been done with penicillin. But such a move would have required a special act of Congress. Unlike with penicillin, no government research funds had been allocated to the acquisition or distribution of streptomycin. Thus the government owned no rights to it. The drug had not even been cleared or approved by the Food and Drug Administration and therefore could not be sold publicly for therapeutic purposes, “except to the federal services”—i.e., the military, including the biological weapons program, or government agencies performing clinical trials.

  In June 1944, Waksman formally asked Merck for the agreement of November 8, 1940, giving exclusive drug-development rights to Merck to be “abrogated.” As Feldman and Hinshaw at the Mayo Clinic announced the first successful guinea pig trials, George Merck ordered his legal staff to draw up a letter to Waksman ending their deal. The draft referred to unspecified “correspondence and conversations” with Waksman.

  On August 17, 1944, this draft became a formal letter and was signed by Waksman and William Martin, dean of the College of Agriculture, and eventually by Rutgers president Robert Clothier. The final letter kept the same wording: “You have advised us of your feeling that you should be free to make available by [sic] other organizations antibiotic agents which may be of value to the armed forces in the present emergency.”

  Later the agreement would be attributed by Rutgers to the fact that Merck and Waksman had realized that their cooperative enterprise had resulted in a great humanitarian discovery which should not be subject to an exclusive license. Accordingly, Merck & Co. Inc. had “voluntarily abandoned” its patent.

  The return of the patent did not come free, as the fine print revealed. The company only agreed providing it could have a nonexclusive license and a new agreement “satisfactory to us.” In the new agreement, Merck demanded repayment of the estimated $750,000 worth of research it claimed to have carried out for Waksman on development work on streptothricin and streptomycin. This was mostly work done by the company’s chemists in extracting and purifying the drugs. Rutgers eventually agreed to $500,000, which would be paid back to the company from Rutgers’ future royalty earnings. Also, as part of the new deal, Merck agreed to continue to use its legal staff to make the patent application.

  ON AUGUST 14, 1944, Waksman and Schatz filled out a standard memorandum of invention titled “Streptomycin and process for producing.” The date of the “conception” of the discovery was listed as August 23, 1943, the date of Experiment 11 on page 32 of Schatz’s notebook. The first verbal disclosure was on September 10, 1943, when Schatz told Waksman’s assistant, Robert Starkey. Waksman was apparently away. The first written description was recorded as October 8, 1943, and in Waksman’s notebook as his Experiment 59.

  The date of “reduction to practice” was put as November 22, 1943, corresponding to Experiment 72, on December 30, 1943, in Waksman’s lab notebook. That experiment was titled “Influence of treatment on the extraction of streptomycin.” On the opposite page, Waksman wrote in later, “First time method of extraction of streptomycin is described in detail.” Thus, according to the patent application, Waksman and Schatz were officially “co-discoverers.”

  The form was signed at Rutgers with Merck lawyers present. For the first time in their close relationship, Schatz questioned Waksman. He asked why they had to have a patent and why they had to use Merck lawyers. The university was an independent institution; why did they have to be involved with a commercial concern? For the first time, Schatz stood his ground with Waksman. “Streptomycin was the fruit of my labors. I felt that anything pertaining to human health and human life should be made available as quickly and as cheaply as possible to all people ... I didn’t want to have anything to do with Merck, whose interests were profits,” he recalled telling Waksman.

  Waksman replied that they had to go ahead with the patent to protect streptomycin. Without a patent, a company like Merck, Squibb, or Pfizer might produce a derivative of the drug, take out a patent, and control production and prices. Merck had patent lawyers who were able to help Waksman and Schatz with the application, a service that would otherwise have been expensive and was something Rutgers could not afford. Schatz would later remark, “Until then, the thought of patenting had never entered my head.”

  BEFORE THE YEAR was out, the first publicly recorded tests on human patients were carried out in New York and at the Mayo Clinic. Both tests were successful.

  On September 21, 1944, a two-week-old infant arrived at Columbia University Babies Hospital, in New York, suffering from a bacterial infection that had caused meningitis, septicemia, and a “heavy urinary tract infection.” The infant was deeply jaundiced, and his liver and gallbladder were enlarged. The doctors gave him a sulfa drug, sulfadiazine, combined with penicillin, but the infant’s fever remained high, and he was clearly dying.

  In desperation, but with no clinical data to support their decision, the doctors switched to streptomycin, administering it every three hours for five days, then doubling the dose on the last, the sixth, day. The infant’s temperature suddenly dropped, and he recovered. A memo of the event stamped “Secret: not to be disclosed without special permission” appears in Dr. Waksman’s archives. One of the doctors wrote, “The medical staff at Babies Hospital are naturally very much interested and excited about this case. They have no doubt that streptomycin produced the favorable change in the clinical procedure.” There is no record of whether Waksman was involved or who had provided the streptomycin. It could have come directly from Merck and Waksman may not have been involved. Merck was testing streptomycin on mice, rats, guinea pigs—and humans. Merck had also tested streptomycin on six patients suffering from Gram-negative bacterial infections. The results were mixed. An adult woman with endocarditis—infection of the heart lining—and an infant with sepsis died after treatment. The antibiotic had no effect on a child with tuberculosis and meningitis, or on another with brucellosis. An adult with typhoid fever recovered. The drug had promising results on a patient with pneumonia.

  On November 20, 1944, Patricia, a twenty-two-year-old farmer’s daughter, lay dying in a hospital bed at the Mineral
Springs Sanatorium, in Cannon Falls, Minnesota. She was suffering from advanced and spreading pulmonary tuberculosis, the most common kind. Patricia had been in the sanatorium for more than a year under the care of Dr. Karl Pfuetze, the medical superintendent of the sanatorium, and his assistant Dr. Marjorie Pyle. They had treated Patricia with the conventional forced bed rest. After initial improvement, she had deteriorated. Her right lung was badly diseased, and she suffered from alternating chills and high fever, sweating, and a worsening cough. The doctors considered her to be near death, and recommended that she be transferred to the Mayo Clinic for an assessment by Dr. Hinshaw.

  With Patricia’s consent, Hinshaw immediately started a course of streptomycin injections, using his limited and impure supply. He could only guess at the proper dose, and he was cautious at first, steadily increasing the dose until Patricia showed signs of improvement. The infection, which had spread to her left lung, gradually disappeared. Eventually, the doctors were able to operate on the right lung, removing the diseased section. Patricia made a remarkable recovery and was released from the sanatorium. She eventually married and had three children.

  Within a week, in collaboration with Pfuetze, Hinshaw started to give streptomycin to twenty-two patients from the Mineral Springs Sanatorium; eighteen improved. These were Hinshaw’s “scouting phases,” and he played down the results. He emphasized that many forms of TB “tend to improve spontaneously without treatment,” and that no single drug was likely to have “a rapidly curative effect” in a disease with the clinical pathology of TB. He did “not expect improvement” in less than a few weeks, nor did he expect clinical arrest of the infection in less than a few months. He pleaded for “extreme conservatism” in judging clinical results regarding chemotherapy and TB.