Selman Abraham Waksman, who coined the word “antibiotic,” searched for antibacterial substances in soil microorganisms, discovering eighteen antibiotics, including streptomycin, the first drug effective against tuberculosis.
The discovery of streptomycin was not a matter of chance as was penicillin; it was the result of a well-planned program of research. Some microbiologists in the late nineteenth century believed in a struggle for existence in the microbial world, and in 1889 Paul Vuillemin used the word “antibiosis” in reference to this natural antagonism between species. Some microbiologists also believed microbes contained substances that inhibited the growth of other microbes. There were attempts to isolate chemotherapeutic agents from molds and bacteria, but the field was abandoned in the early twentieth century as barren until the reawakening of interest in such agents by René Dubos in the 1930’s.
Dubos was a student of Selman Abraham Waksman. Both men emigrated to the United States in their twenties. Waksman spent his entire career at Rutgers University, becoming the leading figure in soil microbiology in the United States. He was extraordinarily prolific, producing more than five hundred articles and twenty-eight books. His expertise was the population of microorganisms that inhabit the soil. He elaborated the ecology, taxonomy, and physiology of thousands of species. He specialized in one type of soil microbe, the actinomycetes, organisms intermediate between bacteria and fungi. His research included a study funded by the National Tuberculosis Association
Dubos obtained his doctorate under Waksman in 1927 and then worked at the Rockefeller Institute in New York. He came to wonder what would happen if soil were enriched with pathogenic germs. He pondered if perhaps their introduction would encourage soil microbes antagonistic to them to flourish. In February, 1939, Dubos announced that he had tracked down such an antagonistic microorganism, Bacillus brevis, and from it isolated two antibacterial substances, tyrocidine and gramicidin
Dubos’s discovery alerted scientists to the possibility of finding other powerful drugs in microorganisms. When Baron Florey
The central figure in exploiting this field, however, was Waksman. He seized on Dubos’s work and converted his research on soil actinomycetes into a search for antibacterial substances in them. The actinomycetes proved to be the most fertile source for antibiotics. Waksman coined and defined the word “antibiotic” in 1941 for the novel drugs found in microbes. He developed soil enrichment methods and discovered eighteen antibiotics between 1940 and 1958. He cultured thousands of soil microbes in artificial media and screened them for activity. The promising ones were then chemically processed to isolate antibiotics.
Streptomycin was the most important of Waksman’s discoveries. In September, 1943, with his students Elizabeth Bugie
Selman Abraham Waksman.
Waksman wondered if streptomycin would be active against laboratory cultures of pathogenic germs, as well as in living animals. He established an arrangement with the drug manufacturer Merck
In the 1940’s, tuberculosis had not been fully under control. There had been no cure, only prolonged bed rest and a regimen of nutritious food. The tubercle germ could invade any organ of the body, and in its various forms, the disease took a horrifying toll. A diagnosis of tuberculosis entailed lifelong disability, and patients died because the available treatment was so limited.
The medical world took notice of the clinical tests conducted by William Hugh Feldman and H. Corwin Hinshaw at the Mayo Clinic. The two researchers had been investigating the chemotherapy of tuberculosis in the 1930’s. Many scientists believed that such therapy was unattainable, but they refused to accept this verdict. They worked with sulfa drugs and sulfones and found some effect in suppressing the growth of tubercle bacilli, but not their eradication. Feldman visited Waksman before Waksman’s discovery of streptomycin and indicated his desire to try any promising antibiotics.
When Waksman found antitubercular effects in 1944, he wrote at once to Feldman to offer streptomycin for his studies. Feldman and Hinshaw had developed a practical system to determine the ability of a drug to slow the course of tuberculosis in guinea pigs. They used streptomycin on guinea pigs inoculated with the tubercle germ. In December, 1944, they issued their first report. The tests revealed streptomycin’s ability to reverse the lethal course of the inoculations, and they concluded that it was highly effective in inhibiting the germ, exerting a striking suppressive effect, and was well tolerated by the animals.
Feldman and Hinshaw were now ready to test human patients. Merck agreed to supply the streptomycin for the tests. Hinshaw enlisted two physicians from a nearby sanitarium. On November 20, 1944, and for the next six months, a twenty-one-year-old woman with far-advanced pulmonary tuberculosis (one of her lungs already subjected to surgery, the other being eaten away) received streptomycin. In June of 1945, she was discharged, her tuberculosis arrested; she married eventually and had three children. This happy ending was followed by many more. Hinshaw and his associates made a preliminary report on thirty-four patients in 1945 and a fuller evaluation of one hundred cases in 1946. Streptomycin succeeded in the treatment of tuberculosis of the lungs, skin, bones, joints, meninges, and genito-urinary organs. The antibiotic brought humans back from the edge of death.
Toxic effects also emerged in the form of injury to the organ of equilibrium in the ear and deafness in some cases. These were sometimes transitory, sometimes permanent, and related to the dose and duration of therapy. By carefully using streptomycin between a range of too little and too much of the drug, the damage and injury could be minimized.
Feldman and Hinshaw deserve the credit for the revelation of the efficacy of streptomycin against tuberculosis. They demonstrated its value in carefully constructed trials. Some observers believe that they should have shared the 1952 Nobel Prize
With the realization that streptomycin was the first effective chemotherapeutic remedy for tuberculosis, Waksman and Merck agreed that no company should have a monopoly on its commercial production. Merck agreed to transfer its rights to Rutgers, which would license companies to produce it. By 1948, eight firms were manufacturers. With the increased availability of the drug, the most extensive study of a single drug ever undertaken took place as the manufacturers donated streptomycin at an estimated value of $1 million for a large-scale cooperative series of clinical trials involving several thousand tubercular patients. Major testing took place at the Cornell Medical School, which studied the most acute forms of tuberculosis—tubercular meningitis and miliary tuberculosis—hitherto 100 percent fatal. The most chronic form was pulmonary, and the National Tuberculosis Association sponsored studies of this form.
The Veterans Administration organized a third major trial at its hospitals to test thousands of World War II veterans discharged with tuberculosis. The Public Health Service sponsored another clinical trial. These trials established streptomycin’s effectiveness. One result was a remarkable decline in tuberculosis mortality, especially among children. By 1950, streptomycin found use against seventy different germs against which penicillin was useless. In addition to tuberculosis, these included several gram-negative infections of the abdomen, pelvis, urinary tract, and meninges.
Waksman did more than discover a major antibiotic; his work encouraged others to attempt to isolate them by means of screening programs similar to those he devised. The 1950’s witnessed a large increase in the number of antibiotics, and antibiotics became a large industry with total production of more than 9 million pounds in 1955.
Streptomycin was not perfect. As early as 1946, reports appeared on the resistance of bacilli. Such resistant strains could be responsible for the failure of therapy. New drugs came to the rescue of streptomycin. In the 1940’s, Swedish investigators found para-aminosalicylic acid to inhibit the tubercle bacillus, although not as effectively as streptomycin. In 1949, the Veterans Administration combined the two drugs.
Combination therapy proved the key to the future of chemotherapy, as the combination delayed the appearance of resistant strains. Better drugs soon appeared, the most potent being isoniazid. Known to chemists since 1912 but of no value until 1952, three pharmaceutical companies independently found isoniazid to be as effective as streptomycin. The two drugs in combination became the standard initial therapy against tuberculosis. By 1970, there were eleven drugs in all, and by the judicious use of combinations, physicians could achieve recovery in nearly all cases of pulmonary tuberculosis.
By the end of the 1950’s, new cases of tuberculosis had diminished to the extent that the disease seemed on the way to extinction, at least in the developed countries of the world. The enthusiasm for the chemotherapy of tuberculosis, however, was not always matched by the recipients. A combination of indifference, refusal of treatment, and lack of access to adequate medical care, especially among lower socioeconomic groups, kept tuberculosis alive.
In the United States, tuberculosis strikes those who are homeless or live in crowded, unsanitary conditions; have inadequate diets; or are drug addicts, alcoholics, or living with AIDS (acquired immune deficiency syndrome), whose immune system has been weakened. Drug therapy can control and cure tuberculosis, but the patient must continue a medication of two or more drugs daily from a minimum of nine months to two years or more. Once a patient feels well again, he or she often abandons the treatment before completion. By stopping before completion, a person is not cured, the disease returns, and he or she can infect others, thereby producing new cases. Tuberculosis remains the leading cause of death in the world among infectious diseases.
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Dowling, Harry F. Fighting Infection: Conquests of the Twentieth Century. Cambridge, Mass.: Harvard University Press, 1977. Dowling considers the antibiotics, sulfa drugs, vaccines, and serums that have played a noteworthy role in combating and preventing infectious disease. This is one of the best books on the control of diseases in the twentieth century and includes an expert account of streptomycin and its clinical trials. -
Epstein, Samuel, and Beryl Williams. Miracles from Microbes: The Road to Streptomycin. New Brunswick, N.J.: Rutgers University Press, 1946. This is a straightforward record of Waksman’s research that produced streptomycin. The authors include a chapter on Dubos and his discovery of gramicidin. -
Lappé, Marc. Germs That Won’t Die. Garden City, N.Y.: Doubleday, 1982. Important for the documentation and discussion of the overuse and misuse of antibiotics, the rise of antibiotic-resistant microorganisms, and the danger they represent to human health. -
Lechevalier, Hubert A., and Morris Solotorovsky. Three Centuries of Microbiology. 1965. Corrected reprint. New York: Dover, 1974. The authors reconstruct the main lines of development of microbiology. The longest section is on chemotherapy with a fine narrative on Waksman and on the work of Feldman and Hinshaw at the Mayo Clinic. -
Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers. Cambridge, Mass.: Perseus, 2001. A leading researcher in molecular biology explores a modern-day evolutionary change in bacteria because of misuse of antibiotics. -
Sneader, Walter. Drug Discovery: A History. Hoboken, N.J.: Wiley, 2005. More than a compilation of drugs, this work provides an interesting narrative of the origins, development, and history of drugs with especially significant social and medical import. Includes discussion of antibiotics. -
Straus, Eugene W., and Alex Straus. Medical Marvels: The One Hundred Greatest Advances in Medicine. Amherst, N.Y.: Prometheus Books, 2006. A history of medicine and medical discoveries with chapters on streptomycin and penicillin. -
Waksman, Selman A. The Conquest of Tuberculosis. Berkeley: University of California Press, 1964. Discusses tuberculosis, including its long history, spread, diagnosis, discovery of the tubercle microbe, treatments, tests, preventive measures, and the development of the chemotherapy of tuberculosis. For a wide audience. -
_______. My Life with the Microbes. New Brunswick, N.J.: Rutgers University Press, 1954. A solid, straightforward, and accessible narrative of Waksman’s life and work. Provides details of Waksman’s career, his relations with other scientists, and the public’s response to his antibiotic discoveries.
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