Ann Thorac Surg 2012;93:1753-1760. doi:10.1016/j.athoracsur.2011.11.079
© 2012 The Society of Thoracic Surgeons
Our Surgical Heritage
How an Aspirin, a Throat Swab From a Chicken, and Four Guinea Pigs Changed Thoracic Surgery
John A. Odell, MB ChB*
Division of Cardiovascular and Thoracic Surgery, Mayo Clinic, Jacksonville, Florida
* Address correspondence to Dr Odell, Division of Cardiovascular and Thoracic Surgery, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (Email: odell.john{at}mayo.edu).
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Abstract
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The development of antituberculous drugs changed thoracic surgery and also markedly lowered the morbidity and mortality of a disease that had epidemic proportions. This article summarizes aspects from 3 important articles that led to the discovery of these drugs.
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Introduction
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Important discoveries that followed 3 articles published during the war years are the subject of this article. They changed dramatically and forever the type of chest operations performed. Procedures such as thoracoplasty became obsolete, sanatoriums closed, and the specialty of pulmonary medicine was taken up by those who had previously scrutinized chest roentgenograms for signs of progress in their patients with tuberculosis. The 3 articles that changed thoracic surgery had 6 authors or coauthors, but only 1 author was a physician. The authors of 2 of the articles did not initially recognize the significance of their discovery. The other study, based on experiments in only 4 guinea pigs, prompted the building of manufacturing plants by Merck in the middle of wartime. If one considers the time and millions of dollars spent in the current era on the development of new drugs, this commitment, is truly remarkable. One of the authors was awarded the Nobel Prize; the lack of acknowledgement of the others involved led, in some, to rancor and bitterness [1].
For those with an interest in medical history and the history of tuberculosis the excellent book written by Frank Ryan [2], The Forgotten Plague, How the Battle Against Tuberculosis Was Won and Lost, which documents in more detail these discoveries, will be of intense interest. Other articles have covered the same subject [3, 4]; the reiteration and intent of this article is to stress how important these discoveries were for the practice of thoracic surgery.
Before about 1920, pulmonary tuberculosis was the leading cause of death in the United States and was probably the leading cause of death worldwide. The Industrial Revolution and the population shift to cities and overcrowding contributed to spread of the disease. It was suspected that the disease was communicable, but medical proof had to await Koch's presentation entitled "Die Tuberculose" (On Tuberculosis) to the Berlin Physiological Society, on March 24, 1882. An electrifying atmosphere developed as the presentation was given [2]. Present in the crowded room was Virchow, Loeffler, and Ehrlich—the latter described "that evening to be the most important experience of my scientific life." Three weeks after the presentation, the lecture was published [5]. Twelve days later an English summary was published in the London Times and a few weeks later on May 3, 1882 it was published in the New York Times. The rapidity of the spread of the news and its publication in the professional and lay press is testament to how pervasive and threatening tuberculosis was and the effect it had on society at the time.
At the time of publication of the 3 articles to be discussed, the treatment options for tuberculosis were rest and collapse therapy in its various guises. John Alexander, the 17th president of the American Association for Thoracic Surgeons, wrote 2 books while he was bedbound with the disease himself and recovering from a thoracoplasty on the surgical treatment of tuberculosis; 1 of the books was 700 pages and devoted to collapse therapy [6, 7].
It is not difficult to imagine why thoracoplasty found popularity. The operation involved the chest wall, and efforts were concentrated on keeping the procedure extrapleural. Many operations were performed using local anesthesia. Operations for resection within the chest were difficult because extensive adhesions were generally present. In the first 4 decades of the 20th century when thoracoplasty was a predominant operation for tuberculosis, there were no antibiotics, no blood banks, no double-lumen endotracheal tubes, and no accurate monitoring of oxygen saturation or arterial blood pressure. A thoracoplasty was obviously a safer procedure for the vast majority of surgeons and their patients.
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Aspirin—Not Just for Headaches
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In August of 1940, an article written by Frederick Bernheim, which was less than a page in length, was published in the journal Science [8]. Bernheim, of Duke University, became a pharmacology scientist almost by accident. He is better known for discovering the importance of histamine in the allergic response and the development of antihistamines.
His approach to tuberculosis was that of a scientist. He endeavored to determine the metabolic requirements of the organism that caused tuberculosis. Using a bovine attenuated strain of tuberculosis placed in a Warburg apparatus, he measured the uptake of oxygen and carbon dioxide production. The assumption was that if oxygen uptake (use) increased and carbon dioxide production increased, the organism was using that substance for metabolism. Standard nutritional substances such as amino acids and carbohydrates had no effect on the tubercle bacillus. He then repeated the experiment but added a small quantity of aspirin. Aspirin was commonly available; whether he used it because it was lying around to deal with headaches or because he wished to try it on a whim is unknown. He noted a remarkable change. The oxygen uptake by the bacteria doubled (Fig 1).
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Fig 1. The figure that occupied almost half the article of Bernheim's experiment. Notice the increased uptake of oxygen when salicylate was added.
(Reprinted from Bernheim F, Science 1940;92:204 [8] with permission from AAAS.)
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Bernheim mailed a copy of the 1-page article to his friend Jorgen Lehmann in Gothenburg, Sweden. Lehmann was Chief of Chemical Pathology at Sahlgrenska University Hospital. They had met while Lehmann was working at the Rockefeller Institute. While working in Gothenburg, Lehmann had discovered—at the same time as Link in Madison, Wisconsin—that coumarin, an aromatic substance in sweet clover, was similar in chemical structure to vitamin K and that its anticoagulant properties were due to competitive inhibition [9, 10]. The article sent by Bernheim crossed the Atlantic Ocean unscathed without being sunk by a German U-boat. Ryan [2] describes Lehmann's reaction when he received it: "Immediately, I saw the significance. I remember I sat on my couch in my study with my spine erect and read the article over and over again." Lehmann however did not do anything at this stage; he was involved with research into dicoumarol [10].
Back on the other side of the Atlantic, Bernheim was also fascinated by the aspirin finding. He continued further similar experiments. Subsequent experiments [11], reported a year later, demonstrated that acetylsalicylic acid when compared with sodium salicylate had an effect only after a latent period, which he explained by hydrolysis of the acetyl group.
He also found that a derivative of benzoic acid, 2,3,5-triiodobenzoate, inhibited oxygen uptake and growth of the tubercle bacillus [12]. Meanwhile in London, Fildes [13] determined that sulfanilamide, the active ingredient of Prontosil, the only substance moderately effective against infections until the discovery of penicillin, worked because its chemical structure was similar to para-aminobenzoic acid. Para-aminobenzoic acid is an essential part of the metabolic pathway of certain bacteria, and sulfanilamide worked also by competitive inhibition. Lehmann, on reading the article concerning triiodobenzoate, recognized similarity between the chemical structure of this substance and para-aminobenzoic acid. In 1943, he wrote a remarkable letter to a small pharmaceutical company Ferrosan, with whom he had previously worked, asking them to make the 4-amino salt of salicylic acid, or para-aminosalicylic acid (PAS) [14]. He predicted that the substance would likely work in patients with tuberculosis.
Ferrosan initially had great difficulties in formulating the drug. Eventually 13 g were produced. In the laboratory Lehmann, using the live attenuated Bacillus Calmette-Guerín bacteria and increasing dilutions of the drug, noted that the organisms failed to grow. Similar dramatic experiments in infected laboratory animals followed; the organism did not grow and no ill effect to the animal was noted. Lehmann then tried the drug on himself; also without ill effect. He then recruited the assistance of the head of the local tuberculosis sanatorium. Initially the drug was used cautiously in a topical fashion for patients with tuberculosis with bone involvement and tuberculous sinuses. It was then injected into empyema cavities after removal of pus and was later used orally in more advanced cases; all treatments produced dramatic improvement. A preliminary report was published in the journal Lancet [15]; a more public presentation was to take place at the Nordic Physicians Meeting, but the embargoed press report of the announcement was published prematurely, with considerable publicity, to an astonished Swedish population. To the more conservative medical establishment, the publicity associated with the news leak caused a rift among the investigators, their colleagues, and also the pharmaceutical company Ferrosan [2].
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A Throat Swab From a Chicken
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The principal player in this story is Selman Waksman, who was born in the Ukraine and immigrated to the United States in 1910. He enrolled at Rutgers College, an agricultural college, and obtained bachelor's and a master's degrees. A PhD in biochemistry at Berkeley followed and he returned to Rutgers as a lecturer in soil microbiology, where he became a world authority. He discovered Actinomyces. His 900 page textbook, Principles of Soil Microbiology, became the authoritarian text.
Many students flocked to Waksman to study under him. One of Waksman's students was Rene Dubos from France. Rene Dubos obtained his PhD with a thesis on the decomposition of cellulose by aerobic and anaerobic bacteria while working with Waksman [16]. After completing his PhD, Rene Dubos traveled to the Rockefeller Institute to meet a fellow Frenchman, Alexis Carrel. There he met Oswald Avery, the discoverer of DNA (Watson and Crick discovered the chemical structure), who was very interested in his work with cellulose. Oswald Avery recruited Dubos and assigned him the project of finding something that would decompose type 3 polysaccharide, the capsule that surrounds the pneumococcus; Avery's attempts had been unsuccessful. Dubos' attitude was that if a microbial organism did not exist to break down the capsule, polysaccharides would cover the earth. He was determined to find that organism. He created a culture medium in which the only source of carbon was the pneumococcus polysaccharide and incubated the culture medium under different conditions with hundreds of different samples taken from different soils, manure heaps, and so on. Eventually he found an organism that had been retrieved from a cranberry bog, the cranberry bog bacillus, which thrived in the polysaccharide medium. He created an extract from the organism, which seemed to have an effect on infected laboratory animals: The polysaccharide protective layer of the pneumococcus was destroyed and the remainder of the organism was phagocytosed [17]. They were ready to try the extract on humans, but the development of a better and safer agent, Prontosil, developed by Domagk working at Bayer, Germany foreshadowed their intentions.
Dubos later continued work in another direction. He now concentrated on Staphylococcus, creating media of pure staphylococci and adding different soil samples. Eventually a bacillus, Bacillus brevis, was found that destroyed staphylococci. An extract diluted to a thousandth of a gram destroyed a billion staphylococci in an hour. He called the substance tyrothrycin. This crude antibiotic was further refined and an active component called gramicidin was produced. Hopes of using it systemically were dashed when it was found that it caused hemolysis and kidney damage; it was however able to used as a cream applied to wounds.
Tuberculosis, as mentioned, was rife and Dubos' wife unfortunately succumbed to this disease and he was devastated. He continued to devote his life thereafter to the study of tuberculosis. He developed an effective culture medium [18], for growth of the tubercle bacillus, but it was left for the former teacher Waksman to find the answer Dubos had been searching for.
Waksman, as mentioned, was a soil scientist and was somewhat out of the mainstream of medicine. However he knew of his former pupil Dubos' work and had met Florey and Fleming. One of Waksman's assistants had done a study in which mycobacteria in sterile soil had thrived in the presence of aerobic and anaerobic bacteria but appeared to die in the presence of fungi. However the significance of this study was not appreciated [19]. He decided that the solution to bacterial infections lay in his beloved soil, and his research efforts became devoted to finding organisms with antimicrobial activity. The pupil had stimulated the teacher. The baton had been returned.
Waksman concentrated his effort on the species Actinomyces, which he later renamed Streptomyces. The first antibiotic discovered was actinomycin, which was very effective in vitro but killed the laboratory animals. The next discovery was streptothricin, which was effective against both gram-positive and gram-negative organisms but caused delayed renal failure. Waksman coined the term antibiotic for these new substances. A relationship developed between Waksman's laboratory and the pharmaceutical company Merck, which were geographically close. Woodruff, Waksman's assistant, left to work for Merck and his place was taken by Albert Schatz, a student working on his PhD thesis. Schatz reviewed thousands of Streptomyces strains, obtained from diverse areas, looking for a zone of inhibition surrounding a culture of streptococcus on an agar plate. Eventually after months of work, Streptomyces griseus, which had come from a throat swab of a sick chicken provided by Beaudette the poultry pathologist [3, 20], was found to dramatically inhibit the streptococcus organism. From this organism, the active ingredient was isolated and purified. It was called streptomycin and an article on its antibacterial effects was published in January 1944 [20]. As emphasized by Comroe [3], M. tuberculosis was used only within the table (Fig 2). There is no mention of tuberculosis anywhere else, neither within the article nor in a subsequent article published in August of the same year. The discovery had been made but not initially recognized.
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Fig 2. Table 3 from Schatz and colleagues [20]. The only mention of tuberculosis in the article is on the 10th line of the table.
(Reprinted from Schatz A, et al, Proc Soc Exp Biol Med 1944;55:66-9 [20] with permission from the Proceedings of the Society for Experimental Biology and Medicine.)
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Four Guinea Pigs
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William Feldman was a veterinarian working at the Mayo Clinic. He and H. Corwin Hinshaw, a physician with a PhD in microbiology, had a special interest in tuberculosis and were investigating potential drugs that could have an impact on the disease. The 2 of them had looked at a variation of the sulfonamide molecule Promin for treatment of tuberculosis [21], but this drug caused hemolytic anemia. Feldman visited Waksman soon after the discovery of streptomycin but before publication of the article and offered the expertise of the Mayo Clinic in evaluating any potential new antibiotic. It is not known whether he was informed of the discovery of streptomycin [22].
After the publication of Waksman's article and recognition of the implications, Waksman was pressed to supply the drug for evaluation. Ten grams arrived in April 1944. The 10 g was divided into 4 lots so that 4 guinea pigs could be treated. The cartoon of the guinea pig model and the results are noted in Fig 3
. The site of inoculation and the involvement of lymph nodes and organs (lungs, liver, and spleen) are diagrammatically drawn. A solid bar indicated the day that the animal died of the disease or was sacrificed. As indicated, the results were dramatic. Unfortunately the supply of the drug had run out and no further studies were possible. Hinshaw and Feldman traveled to New Brunswick to meet with Waksman to discuss further supplies and intended experiments. Before leaving they infected a large group of guinea pigs, with the presumption that further supplies of the drug would be forthcoming. When they met Waksman, it was obvious that his laboratory was unable to supply the amount of the drug requested and that a pharmaceutical company would need to be involved. Waksman arranged a meeting with Merck and Co, but the company was committed to producing penicillin for the war effort and was hesitant to proceed. When Hinshaw stressed that during World War I more people had died of tuberculosis than had been killed in military action, the company director and owner George Merck made the decision to proceed with production [2].
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Fig 3. Diagrammatic representation of the 4 guinea pigs treated with streptomycin compared with controls. The arrow indicates the site of inoculation and presence of disease at this site. Further shading indicates either mediastinal node involvement or lung, liver, or spleen disease. Solid bar indicates date of death or sacrifice. Feldman and Hinshaw also had a numeric grading system of severity of disease.
(Reprinted from Feldman WH, et al, Am Rev Tuberc 1945;52:269-88 [34].)
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The original experiment was repeated for Merck and terminated at 61 days, with similar impressive results. Those guinea pigs that had been inoculated before Feldman and Hinshaw traveled to visit Waksman, had liver biopsies done on day 49 to confirm infection and then were treated for 166 days [23], mimicking more closely the clinical situation in which the patient presents with overt disease. These guinea pigs also showed a dramatic response to the drug.
Hinshaw started to treat patients. The first patient with meningeal involvement died. The second patient had miliary tuberculosis with meningeal, renal, and bladder tuberculosis and died of a pulmonary embolus. No evidence of tuberculosis was noted at postmortem examination. The roentgenographs of the first patient to be treated successfully with streptomycin (the third patient) are shown in Fig 4
A–C. She was 21 years of age and had extensive disease in her right upper lobe as well as a cavity in the superior segment of the left lower lobe. O.T. Clagett did a thoracoplasty on the right side, but she continued to deteriorate. Streptomycin was given in divided doses over 5 months, with resulting recovery. She later married and had 3 children.
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Fig 4. (A–C) The roentgenograms of the first patient successfully treated for pulmonary tuberculosis with streptomycin. The initial roentgenogram demonstrates extensive right apical disease. The second roentgenogram is after her thoracoplasty. There is a thin-walled cavity in the superior segment of the left lower lobe. The last roentgenogram is a few years after treatment.
(From Mayo Clinic archives.)
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As the news of the drug reached the public, Hinshaw and Waksman were inundated by requests from desperate patients with the disease. Initially the drug was rationed to selected patients by a central government committee until production increased, with Hinshaw empowered as the person making the decisions. Within 5 years more than a thousand articles were published on streptomycin.
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Other Drugs
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Chemists working in very difficult wartime conditions under the direction of Domagk at the Bayer laboratories in Germany developed a new family of drugs effective against tuberculosis, the thiosemicarbazones. The most effective drug was initially called Tibione and then Conteben. The Allies refused to allow Bayer to patent Conteben. Although this drug was effective, a better drug, isoniazid (INH), was on the horizon.
By coincidence, INH was found simultaneously by Bayer (Domagk again), by Hoffman La Roche, and by Squibb. The drug was created by replacing the benzene ring in the thiosemicarbazone molecule by a pyridine ring. All 3 companies were conducting trials at the same time without the other companies being aware. The pharmaceutical companies' work was based on an article by French researcher Chorine [24] reporting that infected guinea pigs who also received nicotinamide, a chemical derived from one of the B group vitamins, had a response to treatment. Conteben and PAS contain a benzene ring, where 6 carbon atoms exist. The pyridine ring has a nitrogen atom displacing 1 of the carbon atoms and this was present in nicotinamide. None of the companies could patent the discovery of INH because Prague chemists had previously synthesized the drug in 1912 as a requirement for their doctorates in chemistry. A large international lawsuit was thus avoided.
Rifampicin [25] was discovered by the Lepetit pharmaceutical company and is derived from Streptomyces mediterranei, now reclassified as Nocardia mediterranei. It is named after a French gangster movie called Rififi.
Pyrazinamide [26], ethambutal [27], ethionamide, and cycloserine are other drugs that were found by manipulation of the chemical structure of existing drugs and used in tuberculosis treatment.
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The Players
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Domagk was awarded the Nobel Prize for Medicine in 1939 for his work on Prontosil but was prohibited by Hitler from accepting it. After the war he traveled to Sweden and received the prize but was not given the monetary portion, which is allocated only in the year assigned.
Jorgen Lehmann was honored by awards and gold medals from every corner of the world, but strangely his achievement was not honored by his colleagues.
Rene Dubos became a social scientist and an environmentalist and wrote widely about tuberculosis and other societal issues, for which he was awarded 2 Pulitzer Prizes. The slogan "Think globally, act locally," was coined by him. He and his second wife also contracted tuberculosis but were able to be treated medically.
Selman Waksman was awarded the Nobel Prize in 1952. No one doubted that Waksman deserved the prize, but the lack of inclusion of others such as Feldman, Hinshaw, Lehmann, and Schatz was contentious.
William Feldman was infected with tuberculosis in 1948, with the same strain he worked with in the laboratory, and was treated with streptomycin and PAS.
Corwin Hinshaw left the Mayo Clinic in 1949 for California. He traveled widely and later became president of the Trudeau Society.
Albert Schatz left Rutgers, as he felt his part in the discovery of streptomycin had been undermined by Waksman. The differences resulted in a lawsuit over the distribution of royalties. He also challenged the sole awarding of the Nobel Prize to Waksman [2].
George Merck was extremely generous with respect to streptomycin. Although originally the sole manufacturer, Merck relinquished the exclusive rights because worldwide demand exceeded expectations. He also donated to the American Medical Research Council a million dollars worth of streptomycin.
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Conclusion
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The exact dosage of the drugs and how long they needed to be given was determined by trial and error. It soon became apparent that the tubercle bacillus rapidly developed resistance to the different medications. The British Medical Council trial of 1948 [28] and the studies of Crofton [29] confirmed that combination therapy was necessary. The Madras experiment demonstrated that supervised home therapy was as effective as treatment in a sanatorium [30]. Bacille Calmette-Guerín vaccination (not adopted in the United States) and mass screening miniature chest roentgenograms further contributed to control of the disease.
Changes in the management of tuberculosis occurred at a rapid pace. Tuberculosis is now primarily a medical condition. Within about 10 years the sanatoriums became redundant. The most famous sanatorium—in Davos, Switzerland, which is the highest town in Europe—is where Robert Louis Stevenson was treated; it was also the setting for Thomas Mann's book the Magic Mountain [31] and was where Sauerbruch did many of his thoracoplasties. It is now better known for the World Economic Summit and winter sports than for tuberculosis. The sanatoriums there have been turned into hotels, the rooms once occupied by patients now accommodate politicians and economists, and the spittoons lining the hallways have been replaced by flowerpots.
In the United States in 1945, the year effective antituberculosis drugs were first used, 115,000 new cases of tuberculosis were diagnosed and 63,000 persons died [32]. The rate of tuberculosis then was 87 per 100,000 persons [32]; currently it is 3.6 per 100,000 persons [33]. In 1945 the United States had 450 tuberculosis hospitals with 79,000 beds but only 86,000 admissions, indicating the long hospital stay [32]. Figures 5 and 6
reflect the dramatic effect that antituberculosis drugs had on the disease [32]. Currently only 1 of the original sanatoriums exists, the AG Holley Hospital in Lantana, Florida, which has 50 beds for complicated patients with multiple-drug–resistant tuberculosis.
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Fig 5. The annual reported cases of tuberculosis per 100,000 persons in the United States, 1930 to 1992. Arrows mark 1944 and 1954, the years in which streptomycin and INH were introduced. The increase in rates between 1941 and 1954 probably represent an increased burden of cases in armed forces personnel and immigrants related to World War II.
(Reprinted from Snider GL, Ann Intern Med 1997;126:237-43 [32] with permission from the American College of Physicians.)
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Fig 6. Tuberculosis hospitals and beds in the United States from 1945 to 1992. The rapid decline in hospital beds and hospitals coincided with the use of antituberculous chemotherapy. Surgical procedures for tuberculosis rapidly declined in similar fashion.
(Reprinted from Snider GL, Ann Intern Med 1997;126:237-43 [32] with permission from the American College of Physicians.)
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Surgical management of tuberculosis changed dramatically as the incidence of the disease and hospital admissions fell; surgical procedures today have only a limited role in management. Today surgical procedures are undertaken in assisting to make a diagnosis, in dealing with complications that have resulted from the disease, and occasionally as resection therapy in patients with multiple-drug–resistant tuberculosis. Collapse therapy is redundant. Alexander's reference book on collapse therapy is no longer present on thoracic surgeons' shelves; it now belongs to collectors of medical antiquarian books.
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References
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- Feldman WH. Streptomycin: some historical aspects of its development as a therapeutic agent in tuberculosis Am Rev Tuberc 1954;69:859-868.
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- Chorine V. Action de l'amide nicotinique sur les bacilles du genre Mycobacterium Compt Rendu Acad Sci 1945;229:150-152.
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- Malone L, Schurr A, Lindh H, McKenzie D, Kiser JS, Williams JH. The effect of pyrazinamide (aldinamide) on experimental tuberculosis in mice Am Rev Tuberc 1952;65:511-518.[Medline]
- Thomas JP, Baughn CO, Wilkinson RG, Shepherd RG. A new synthetic compound with antituberculous activity in mice: ethambutol (dextro-2,2'-(ethylenediimino)-di-l-butanol) Am Rev Respir Dis 1961;83:891-893.[Medline]
- A Medical Research Council Investigation. Streptomycin treatment of pulmonary tuberculosis. Br Med J 1948;ii:762-782.
- Crofton J. Tuberculosis undefeated Br Med J 1960;2:679-687.[Free Full Text]
- Fox W. The chemotherapy and epidemiology of tuberculosis some findings of general applicability from the Tuberculosis Chemotherapy Centre, Madras Lancet 1962;280:473-478.
- Carter R. The mask of Thomas Mann (1875–1955): medical insights and last illness Ann Thorac Surg 1998;65:578-585.[Free Full Text]
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- Centers for Disease Control and Prevention Trends in tuberculosis—United States, 2010 MMWR Morb Mortal Wkly Rep 2011;60:333-337.[Medline]
- Feldman WH, Hinshaw HC, Mann FC. Streptomycin in experimental tuberculosis Am Rev Tuberc 1945;52:269-288.
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Abstract
Introduction
