In another overstatement, Wallgren said that at the time that Waksman had begun his research, “the word antibiotic had not been coined,” and Waksman had “introduced” the word as representing an antibacterial substance. Waksman did not “coin” or “introduce” the word “antibiotic,” although he was always happy to have the story repeated. Waksman was certainly the first to use “antibiotic” as a noun in a published context, in his 1945 book on microbial antagonism. That is different from coining the word, however.
To put the Schatz affair to rest—at least for the ceremony—Wallgren deliberately mentioned Schatz by name as “one of those” who had worked with Waksman on the team. He also credited Schatz with the isolation of two strains of actinomycetes that produced streptomycin. But Wallgren stressed that the strains were “identical” to the strain of S. griseus “discovered by Dr. Waksman in 1915.” The difference was that the “rediscovered” microbe “was shown to have antibiotic activity.” The suggestion was that Schatz had only “rediscovered” Waksman’s original microbe, when in reality he had found an entirely new strain of griseus that produced streptomycin.
Waksman must have been pleased with Wallgren’s introduction. In his own acceptance speech he avoided the delicate matter of the discovery altogether. The word “discovery” was not even in the title of his lecture, “Streptomycin: Background, Isolation, Properties and Utilization.”
And his description of the discovery was “summarized briefly.” In a 6,113-word lecture, he never mentioned Schatz’s isolation of the two strains 18-16 and D-1, nor did he mention Schatz’s experiments to test the antibiotics from those strains against the virulent H37Rv tuberculosis germ. Instead, he devoted most of his lecture to the chemical nature of streptomycin, its antibacterial properties, its toxicity, its effect on infections and diseases, and the resistance of bacteria to streptomycin. The name Albert Schatz appeared only in an appendix, as number twelve in a list of nineteen assistants who had helped Waksman in his research over the years. Half of them had not even been at Rutgers when Schatz had discovered streptomycin. That is how Waksman wanted the world to see Albert Schatz.
IN JANUARY, A month after the award ceremony, Schatz received a reply from the Swedish royal court, not from the king himself, of course, but from his private secretary. It read,
Having made Himself acquainted with the contents of your letter as well as of its appendixes, His Majesty has commanded me to bring the following facts to your attention. The Nobel Foundation is a free and independent institution which by no means is submitted to directions from state authorities. The decisions taken by the different organs of the Foundation regarding the award of the Nobel Prizes—in this case by the Council of the Caroline Medico-Surgical Institute—are, according to express instructions, final and thus not liable to alterations by any superior instances.
The preceding will, I trust, have convinced you that your appeal is not of a nature to call for action on the part of His Majesty.
21 • The Drug Harvest
BY 1953, THE ANTIBIOTIC REVOLUTION WAS the driving force behind a rapidly changing pharmaceutical industry. Besides the “miracle cures” and “wonder drugs” like penicillin and streptomycin, a wide range of new medicines flowed from the expanding drug companies—vitamins, hormones, antihistamines, blood plasma extenders, antimalarials, drugs for hypertension. But antibiotics led the way in the industry’s transformation. As American companies screened hundreds of thousands of microbes, a Parke, Davis researcher would famously say that they were finding so many candidate antibiotics that they had to install “an IBM machine” (a computer) to keep track of them. In addition to eight American corporations, companies in other countries began harvesting wonder drugs from the soil—three in France, two in England, two in Italy, one in Sweden, and four in Japan. At the Rutgers Department of Soil Microbiology, Waksman and his students found more than a dozen antibiotics, although only two—neomycin and candicidin—would find widespread practical use.
On his world tours, Waksman was honored and feted by those who had experienced relief from meningitis and TB, and he kept a scrapbook at Rutgers on his “Streptomycin Babies,” the children who had survived tuberculosis. In addition to the piles of letters thanking Waksman, and rarely Schatz, for the discovery, however, there were also letters of complaint from those who had experienced toxic side effects.
In reality, the sheen had come off streptomycin. The gray-green culture of S. griseus, produced by companies in huge steel vats, was susceptible to a virus, an “actinophage,” capable of infecting and destroying the streptomycin-producing mold. This problem was quickly solved, but negative clinical effects were a more enduring issue. Although the drug was nontoxic at low dose levels, the higher doses needed to cure tuberculosis continued to cause the side effects first noticed by William Feldman and Corwin Hinshaw in 1945 and then publicized by British researchers. The Mayo team considered toxicity as one of several “limitations” of streptomycin. Tests showed that streptomycin, and its derivative, dihydrostreptomycin, which had reduced toxicity, could attack nerves responsible for hearing and balance. Among the symptoms were a ringing sound in the ears, vertigo, nausea, rash, fever, and nystagmus—a rapid involuntary movement of the eyeballs. In most cases, however, the symptoms “largely disappeared” within sixty to ninety days after the treatment had been stopped, the Mayo team reported.
A group of tuberculous Italian children pose with Dr. Waksman and his wife at the Children’s Hospital in Ostia. The children were being treated with streptomycin in 1950. (Special Collections and University Archives, Rutgers University Libraries)
Eventually, one of the “most serious obstacles” for streptomycin—as with other antibiotics—was the emergence of drug-resistant strains of the disease bacteria. In some cases, doctors had to increase the initial dose by one thousand times to stop the growth of the TB germ.
The solution came from the synthetic drugs. In the early 1940s, Jörgen Lehmann, a Danish scientist living in Sweden, had been working on an idea to stop TB that was, in fact, considerably more elegant than Waksman’s plodding method of screening hundreds of cultures from the soil.
Around the same time that Albert Schatz had isolated A. griseus, Lehmann had been inspired by a 1940 paper in the journal Science reporting that the TB germ seemed to grow at a rapid rate in the presence of the main ingredient of ordinary aspirin, salicylic acid. Lehmann thought that if he could make “a look-alike chemical”—a derivative of aspirin—that had the opposite effect, inhibiting the growth of the TB germ, he might have an agent against TB. The new chemical was para-aminosalicylic acid, known as PAS. But the Swedish medical establishment was skeptical. PAS was indeed capable of inhibiting the TB germ, but it was not as effective as streptomycin.
While Waksman found ready American sponsors in Merck, the Mayo Clinic, and the Commonwealth Fund, Lehmann, in war-torn Europe, could barely find funds for clinical trials. The German doctor Gerhard Domagk, who had isolated prontosil, found a new class of compounds, known as thiosemicarbazones, that also seemed to arrest the growth of tuberculosis. Despite wartime difficulties, Domagk tested derivatives of these compounds and found one, named isoniazid, that was a potent anti-TB agent. By 1949, however, Lehmann had discovered that a combination of streptomycin and PAS worked much better than one drug on its own. In the end, all three drugs, streptomycin, PAS, and isoniazid, would be needed to defeat the TB germ.
One of the first patients to receive this sort of combination therapy was William Feldman. At the end of 1948, after many years of work with H37Rv, he contracted pulmonary tuberculosis and was treated by Corwin Hinshaw with promin, one of the sulfa drugs; streptomycin; and PAS. He made a complete recovery from the “damnable disease” after a year.
THE DRUG COMPANIES now turned their attention to the new so-called broad spectrum antibiotics, which covered a wider range of diseases. The first was chloramphenicol, found by Paul Burkholder, a Yale microbiologist. Searching for microbes beyond America’s
farmland, Burkholder called his colleagues around the world and asked them to send him a pot of their local soil, and he subsequently isolated around seven thousand actinomycetes, of which nearly two thousand produced effective drugs. From these he chose four that showed an ability to destroy a wide spectrum of germs—Gram-positive and Gram-negative. Burkholder’s champion was Streptomyces venezuelae, which he had received from a colleague in Venezuela. It proved its worth during a typhus epidemic on the Peru-Bolivia border in 1947.
With the new antibiotics, the drug companies sought exclusive patents. The thirteen companies producing penicillin, for which there was no patent, had made competition so keen that the price had dropped from twenty dollars for one hundred thousand units in 1943 to four and a half cents in 1950. The downward trend was similar for the eleven companies producing streptomycin. In March 1950, John McKeen, the president of Pfizer, observed, “If you want to lose your shirt in a hurry start making penicillin and streptomycin.” Streptomycin was characterized as “distress-merchandise,” with production running at 200 to 300 percent above domestic demand.
But the antibiotic hunters, dazzled by the success of streptomycin—the royalties kept rolling into Rutgers’s coffers at more than half a million dollars a year—couldn’t bear to give up the chase. Business Week summarized the position: “The trouble is—from the competitive point of view—that nobody goes out of business. And that is partly because nobody knows what’s going to happen tomorrow. A company which is struggling along now in penicillin may come up with a better way of administering it, or a new way of making it. But there is a bigger reason for everyone wanting to hang on. That is the hope that the scores of researchers working in every company’s laboratory can come up with an antibiotic it can patent as its own.”
The companies sought the much-envied product patent, successfully argued by Waksman and Merck. Product patents were becoming more important than process patents because they gave the company the right to exclude the competition, even in derivatives. In the case of streptomycin, the product patent turned out to cover four chemically different compounds, and even covered dihydrostreptomycin, because to make the new drug you had to start with the old one.
At the beginning of the 1950s, hundreds of antibiotic patent applications were sailing through the Patent Office. (More than six hundred antibiotic patents were issued through 1956.) This flurry would lead to new patent law. The large-scale industrial screening of microbes was adding pressure on the Patent Office to change its original standard for an invention. The courts had previously required inventions to show a “flash of genius”—something inspired and out of the ordinary—in order for a patent to be granted. The essential distinction made was between a traditional inventor and a “skillful mechanic.” In the antibiotic revolution, Fleming had certainly had a flash of genius when he had discovered penicillin, and the discovery of streptomycin had been made in the old-fashioned way—by one indefatigable researcher in a basement lab.
Now the big companies engaged in massive screenings of tens of thousands of cultures involving millions in industrial investment. The company researchers could hardly be viewed as genius inventors in the old sense, but they were certainly “skillful mechanics.” As William Kingston, of the School of Business at Trinity College Dublin, has written, “a new law which would frankly recognize the change from individuals to investment as the source of what is to be protected, would have needed an amendment to the Constitution. Since this was out of the question, change could only be made in a way that forced the reality of invention by investment into the pretence of invention by individuals.”
To accommodate this need, the U.S. 1952 Patent Act provided that “patentability shall not be denied because of the way in which the invention was made.” No more flash of genius. That key phrase was replaced with the “inventive step” or “non-obviousness test.” A patent was now be granted for something that was new and was “not obvious to one skilled in the relevant art.”
In the case of antibiotics, if a company tested a wide variety of microbes from different samples of soil for long enough, it was almost certain to find something patentable. But it would not be “obvious” where to start this treasure hunt. Should it begin, as with Albert Schatz’s streptomycin, among the microbes living in a manure pile or on Doris Jones’s swab of a chicken’s throat? Or in soils on the other side of the world, like Donald Johnstone’s coral soils on the Bikini Atoll? At the time, neither of these was an obvious source for medicine. The new “non-obvious” standard was soon adopted internationally and gave the pharmaceutical industry yet another boost.
THE RATE AT which new patents were being granted for substances that were similar in their chemical makeup, and also in their effects, led to another, quite separate trend: companies that sought to keep drug prices high by restricting licenses for their patented products. The result was an antibiotic oligopoly.
Benjamin Duggar, a seventy-two-year-old former professor of botany at the University of Wisconsin and the head of the research department of Lederle Laboratories (American Cyanamid Company), had like Burkholder also been collecting soils from all over the world. He had screened around seven thousand actinomycetes before finding a golden culture, Streptomyces aureofaciens, named for its color (after the Latin for “gold”). It produced an antibiotic with a broad spectrum of activity, but it came from a soil sample found relatively close to home—in Columbus, Missouri. He called the drug aureomycin.
Pfizer was also looking for a broad-spectrum antibiotic when it found terramycin. It turned out to be chemically similar to Duggar’s aureomycin. The Pfizer chemists fiddled with the structure and produced a more effective product, which the company marketed under a different name, tetracycline. Lederle also discovered tetracycline by the same method and filed its own patent application. Three other companies—Bristol, Squibb, and Upjohn—found tetracycline by another route and filed their patent applications—a total of five.
The Patent Office declared “interference,” which usually means a long, hard-fought battle to establish which applicant discovered the new invention first and therefore has “priority” and the right to a patent. Instead of fighting it out in court, however, Pfizer and Lederle got together and settled the matter in a backroom deal in which Lederle conceded priority to Pfizer, which then licensed the drug to Lederle and the three other companies, thus cornering the market for tetracycline for the five companies at a fixed price. Tetracycline would soon become the nation’s best-selling antibiotic, with sales topping one hundred million dollars. The maneuver did not go unnoticed by the federal government, however.
THE SECOND GENERATION of anti-infective drugs reached the market in the early 1950s, during the Korean War, when the U.S. military became the primary consumer of such drugs. Congress and the federal government started to take notice of the price of drugs produced in America and, if it was too high, looked elsewhere, importing generics from abroad. The “tetracycline five” attracted a U.S. Senate inquiry, and the government brought a criminal antitrust case against the five companies under the Sherman Act. They were found innocent of collusion, but a damning Senate report concluded that the oligopoly had arisen from three factors: patents; the large sums spent on promotion; and “the well-entrenched practice of physicians of dealing with pharmaceuticals by their brand names rather than their generic categorization.” Half a century later, drug industry observers would look back at the Senate report and remark how little had changed.
By the end of the 1950s, some companies would be screening fifty thousand cultures a year. The companies began investing in research and development, and would eventually spend more than 50 percent of their recorded profits on R&D. In 1956, eleven principal drug companies owned 500 antibiotic patents, led by Merck with 111. Fifty percent of all antibiotic patents were for penicillin, 100 patents were for streptomycin and dihydrostreptomycin, and 69 were for broad-spectrum antibiotics.
As the search for antibiotics reached a peak in the mid-19
60s, researchers had fun with finding new names. A Greek researcher named one zorbamycin, after the book and movie Zorba the Greek, and another melinacidin, after Melina Mercouri, the star of Never on Sunday. One isolated by an Italian researcher on February 29 was christened lipiarmycin (“leap-year-mycin” with an Italian accent). By the end of the 1970s, the rate of discovery had fallen off, but more than five thousand potential antibiotics had been found, half of them from the Streptomyces genus of the actinomycetes.
Under the new rules of the Food and Drug Administration, the drugs were available only with a doctor’s prescription, so the companies soon began to target doctors, who did not pay for the drugs they ordered and often did not know how much the drugs cost the patient. Companies such as Merck and Pfizer began combining discovery, patenting, packaging, and selling, creating the new so-called integrated drug company. When introducing aureomycin, American Cyanamid shipped samples to physicians worth about two million dollars. The sudden increase in the number of advertisement pages in the Journal of the American Medical Association told the story. In 1949, there were 32 pages; in 1951, 157 pages; and in 1957, 534. Big Pharma was on its way.
22 • The Master’s Memoir
BASKING IN HIS INTERNATIONAL fame, Waksman continued his foreign tours and, in Japan and France, announced that streptomycin patent royalties would be used to set up Waksman Foundations, to give local students fellowships. In 1954, he also published his memoir.
Experiment Eleven Page 21