Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (13 page)

Waksman had established himself as the world authority in his science in 1927 with a 900-page textbook,
Principles of Soil Microbiology,
which gave the field the stature of a scientific discipline. He attracted dozens of graduate students to his department to work and study under him, helping to transform Rutgers from a small agricultural college into a world-class institution.

Soil microbiology—the study of its microscopic inhabitants—had been a passion of Waksman's for many years. A Russian Jew who had emigrated to the United States from the Ukraine in 1910 and earned a Ph.D. in biochemistry from the University of California at Berkeley in 1918, he would later recall the “earthy” fragrance of his rich native dirt. He came to understand that the smell was not of the earth itself but rather of a group of harmless funguslike bacteria called actinomycetes. Waksman's aim was to find practical applications of
his science, particularly in improving soil fertility and crop production, and he knew that the organic chemical content of soil was a crucial factor. He analyzed soil, humus, clay, loam, and sand for their microbes to see how they grew, how they multiplied, what nutrients they took in, and what waste products they exuded. Such microbes exist through a delicate ecological competition, some producing chemicals to kill others. But still unknown was their potential value to modern medicine.

Waksman missed several opportunities to make the great discovery earlier in his career, but his single-mindedness did not allow for, in Salvador Luria's phrase, “the chance observation falling on the receptive eye.” In 1975 Waksman recalled that he first brushed past an antibiotic as early as 1923 when he observed that “certain actinomycetes produce substances toxic to bacteria” since it can be noted at times that “around an actinomycetes colony upon a plate a zone is formed free from fungous and bacterial growth.”
¹
In 1935 Chester Rhines, a graduate student of Waksman's, noticed that tubercle bacilli would not grow in the presence of a soil organism, but Waksman did not think that this lead was worth pursuing: “In the scientific climate of the time, the result did not suggest any practical application for treatment of tuberculosis.”
²
The same year, Waksman's friend Fred Beau-dette, the poultry pathologist at Rutgers, brought him an agar tube with a culture of tubercle bacilli killed by a contaminant fungus growing on top of them. Again, Waksman was not interested: “I was not moved to jump to the logical conclusion and direct my efforts accordingly…. My major interest at that time was the subject of organic matter decomposition and the interrelationships among soil micro-organisms responsible for this process.”
³

Although Waksman knew that tubercle bacilli are rapidly destroyed in soil, his fixed paradigm of thinking simply kept him from carrying the problem to a practical conclusion. From that same year onward, Merck made grants to Waksman for research into antibiotics. In 1942 he was urged by his son, then a medical student, to isolate strains of actinomycetes active against human tubercle bacilli, but he replied that the time had not come yet. The general lack of interest in antibiotics at this time was no doubt discouraging, but it did not
stop a former pupil of Waksman's, René Dubos, who was working at the Rockefeller Institute in New York.

In 1939 Dubos, a tall Frenchman with a robust personality and piercing intelligence, isolated a crystalline antibiotic, tyrothricin, from a harmless soil organism. It proved active against a range of disease-causing bacteria but was too toxic for use in humans. Several years earlier, working with Oswald T. Avery at the Rockefeller Institute, he had found that pneumonia microbes could be killed by dissolution of their protective capsules by other microorganisms. With the success of the sulfa drugs, however, this line of research had been abandoned. Now Dubos tried to interest other researchers in tyrothricin's promising properties, but the response from most researchers was lukewarm. Waksman was the exception. Inspired by Dubos's achievements, he began a dedicated screening of microbes. Meanwhile, also in 1939 came news from the other side of the Atlantic that Florey and his team of researchers at Oxford University were feverishly pursuing the antibiotic properties not of a bacterium but of a mold.

Over the next four years, Waksman's intensive research program involved isolating some ten thousand different microbes from soil and other natural materials, such as dung, and methodically screening them for their killing abilities. To cultivate them on various media and test their ability to inhibit the growth of pathogenic bacteria was a painstaking process. Waksman's main focus was on actinomycetes.
⁴

Only about a thousand of the cultures had antibiotic properties, and only a hundred excreted the antibiotic to the growth medium. (Antibiotic potential is not enough. The microbe has to yield something like “penicillin juice.”) Of these, ten were studied in detail, and by 1942 Waksman had isolated two different antibiotics: actinomycin and streptothricin.
⁵
They turned out not to be clinically useful because they were too toxic. But he knew he was on the right trail.

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Among Waksman's graduate students was twenty-three-year-old Albert Schatz. He had been discharged early from army service because of a back problem and sought to complete his Ph.D. at Rutgers. Waksman
regarded him as unusually bright—a “star” among his student researchers. For more than three months, Schatz analyzed soil samples from the multitudes collected until, on October 19, 1943, in the words of fellow student Doris Jones, “Al hit paydirt!”
⁶

The throat swab taken from the wheezing chicken's throat had by now made its way to Schatz. It grew greenish gray colonies of an actinomycete on an agar plate. Because of their color they were called
Streptomyces griseus.
By a remarkable twist of fate, this same organism had been found by Waksman himself twenty-eight years earlier while he was working on his doctorate, but he had not pursued it.

Tests quickly showed that the organism not only was active against staphylococci but, most exciting, also had dramatic killing effects on the gram-negatives, bacteria that cause a variety of diseases that had been unaffected by penicillin, such as typhoid, bacillary dysentery, bubonic plague, brucellosis, and tularemia. Clearly, the organism generated a powerful antibiotic. On Waksman's instruction, Doris Jones tested it against salmonella infections in chick embryos and confirmed its ability to cure. Furthermore, she found it had no toxicity in laboratory animals.

At this point, Schatz took it upon himself to move to the next stage of research on the potential of the antibiotic now called
Streptomyces griseus.
It had been a fundamental aim of his research to seek an antibiotic that would cure tuberculosis. At the time, the only treatments for TB were prolonged bed rest and nutritious food. He had almost a religious zeal in this pursuit and could not be dissuaded by his colleagues’ insistence that the heavy wax capsule of the bacilli would resist drug action. Penicillin was useless against it, but Schatz held to the premise that if nutrients could enter the cell and waste products leave, so could antibiotics pass through the capsule. With great purpose, he tested streptomycin against tuberculosis and patiently waited several weeks for the slow-growing colonies to appear on the culture medium. The results were clear. Where streptomycin was added, not a single colony appeared, whereas in the controls dense growths were apparent. Schatz had shown that the new antibiotic was dramatically effective in inhibiting the growth of tuberculosis germs.

A short report published by Schatz, Bugie, and Waksman in January 1944 emphasized the antibiotic activity of streptomycin against gram-positive and gram-negative bacteria, but curiously included only marginal notation regarding its effectiveness in tuberculosis. Nevertheless, researchers at the Mayo Clinic, long interested in the treatment of the disease, committed to undertaking animal experiments and then human trials. Schatz spent eighteen-hour days working in his small basement laboratory to concentrate the antibiotic for the Mayo Clinic trials, sleeping with two old, torn blankets on the floor to monitor the continuous running of laboratory apparatus.

Later in the year, a second paper by Schatz and Waksman based on test tube work announced the effectiveness of streptomycin against tuberculosis.
⁸
By April, Schatz was able to provide a meager supply of impure streptomycin to be used at the Mayo Clinic.

Favorable results in guinea pigs led eight pharmaceutical companies to provide an estimated $1 million worth of streptomycin for the largest clinical study of a drug ever undertaken, involving several thousand tuberculosis patients. This constituted the first privately financed, nationally coordinated clinical drug evaluation in history. Medicine had taken a giant step in embracing the value of controlled experiments repeated thousands of times in the evaluation of a new drug. Once again, the drug worked wonders. Side effects, including impairment of the sense of balance and deafness, proved to be transitory and could be minimized by controlling the dosage. The drug's use was also limited by its tendency to produce resistant strains of the tubercle bacillus. In 1947 streptomycin was released to the public.

The Scourge of TB

Tuberculosis is one of the oldest infectious diseases, having afflicted humans since Neolithic times. In the previous century and a half, it claimed an estimated billion lives worldwide. The “white plague of Europe” that raged in the seventeenth century was due to growing urban populations.

Mycobacterium tuberculosis
was identified by Robert Koch in
1882. Because it has the ability to enclose itself in nodules in the body, the tubercle bacillus can remain dormant for years, then strike any part of the body with deadly results, although it most commonly affects the lungs. For centuries, “consumption,” as it was called, was believed to physically stimulate intellectual and artistic genius. (Some of the greats who were so afflicted include Molière, Voltaire, Spinoza, Schiller, Goethe, Kafka, Gorki, Chekhov, Paganini, Chopin, Dr. Johnson, Scott, Keats, the Brontë sisters, D. H. Lawrence, Thoreau, Emerson, Poe, and O'Neill.) The pasteurization of milk, establishment of sanitariums, and posting of “No Spitting” signs were all public health measures that were eventually taken to control tuberculosis.

Waksman was hailed as a medical hero—the discoverer of the world's newest “miracle drug”—whose victory over TB resonated with symbolic value in the wake of World War II. In the resulting avalanche of public acclaim, he toured the world, gave lectures, and took tours of medical facilities. Although Schatz, the graduate student, had actually made the discovery, Waksman, as head of the department, was in a position to arrange for commercial development and get the glory. He won the highly prestigious Albert Lasker Award, often a presager of the Nobel Prize in Medicine, and was featured on the cover of the November 7, 1949, issue of
Time
magazine.

Other “Down and Dirty” Drugs

With the success of streptomycin, the pharmaceutical industry embarked upon a massive program of screening soil samples from every corner of the globe. Other soil microorganisms soon yielded their secrets, and it was the actinomycetes that generated a cornucopia of new antibiotics.
⁹

Chloramphenicol (chloromycetin)—so named because it contains chlorine—was isolated in 1947 from a strain found in a
sample of Venezuelan soil. The tetracyclines came from various streptomyces and proved of great benefit as broad-spectrum antibiotics, useful against a wide array of infections: Aureomycin was introduced in 1948; Terramycin, so named because it was cultured from soil samples collected near Pfizer's Terre Haute factory, in 1950; tetracycline (Achromycin) in 1952; and Declomycin in 1959. Erythromycin was cultured in 1952 from a soil sample collected in the Philippines. And vancomycin, one of the most potent antibiotics ever found, comes from an actinomycete isolated in 1956 from a clump of Indonesian mud.
¹⁰

But the success of streptomycin also brought problems in its wake, involving who was to reap the rewards of its discovery. Rutgers was able to maintain the patent and the royalties from the drug's sales, based on nonexclusive licensing, yielding a huge financial windfall for the university and Waksman personally. Rutgers was then receiving two cents for each gram of the drug sold, and by 1950 its royalties amounted to almost $2.5 million. Waksman received some $350,000 in royalties.

Then something happened that thoroughly rocked the scientific community. Albert Schatz filed a legal claim demanding formal recognition as codiscoverer of streptomycin and a share of the royalties. This widely publicized lawsuit by a former doctoral student against a distinguished, internationally recognized professor was unprecedented.

Schatz's name had been listed first on the journal articles announcing streptomycin to the medical world, in accord with Waksman's policy of encouraging discoveries by his students or assistants. Furthermore, Schatz as well as Waksman was listed on the patent application filed by Rutgers in January 1945. Streptomycin was the subject of Schatz's Ph.D. thesis, which he defended in 1945. Waksman had always considered Schatz a brilliant star among his students, but the twenty-six-year-old, feeling that he was unfairly being shut out by his mentor, who was now enjoying worldwide acclaim over streptomycin, left Rutgers resentfully in 1946.

A Rutgers lawyer dismissed Schatz as “a carefully supervised laboratory assistant,” and “a small cog in a large wheel.”
¹¹
Waksman felt that the discovery of streptomycin was the last inevitable step in a path he had personally paved, with the prior discoveries of actinomycin and streptothricin, and that Schatz was lucky to be “in at the finish.” It was Waksman, after all, who had established the entire program of antibiotic research.