Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (46 page)

3. Clifford Dobell,
Antony van Leeuwenhoek and His “Little Animals”
(New York: Harcourt, Brace, 1932), 245.

4. Leeuwenhoek's unquenchable drive to peer into the microscopic world and his unshakable faith in his observations can be likened to Galileo's exploration of the heavens with his telescope earlier in the century. In 1632, at the University of Padua, Galileo defended the heliocentric Copernican system in disregard of the Church's admonition. He was finally tried by the Inquisition and under threat of torture recanted. Legend has it that as he left the tribunal, he murmured under his breath, “Eppur si muove!” (And yet it moves). The sentence passed on Galileo by the Inquisition was formally retracted by Pope John Paul II on October 31, 1992. Leeuwenhoek shared a similar resolute certitude in his findings. During his lifetime, his observations became widely known and excited wonderment. The highest-born and most powerful people in Europe—Frederick the Great of Prussia, James II of England, and Peter the Great of Russia—came to his home in Delft to peer through his microscope and see for themselves. Some of his discoveries were doubted, in part because of the imperfect optical instruments used by others. However, any skepticism he faced, as he wrote in a letter to Herman Boerhaave in 1717, “does not bother me. I know I am in the right.” William Bulloch,
The History of Bacteriology
(London: Oxford University Press, 1938), 29.

C
HAPTER
2: The New Science of Bacteriology

1. Robert Koch,
Untersuchungen über die Aetiologie der Wundinfectionskrankheiten
(Leipzig: F. C. W. Vogel, 1878).

2. R. Koch, “Die aetiologie der Tuberkulose,”
Berl Klin Wschr
19 (1882): 221–30 (reprinted with translation in
Medical Classics
2 [1938]: 821–80).

C
HAPTER
3: Good Chemistry

1. Until the middle of the nineteenth century, only natural dyestuffs were generally employed. Their production was a huge industry, involving millions of acres of land and hundreds of thousands of persons. This was supplanted by coal-tar dyes which were less costly, frequently more brilliant, and usually simpler to use.

2. Georg Meyer-Thurow, “The Industrialization of Invention: A Case Study from the Germany Chemical Industry,”
Isis
73 (1982): 363–81.

3. Quoted in W. D. Foster,
A History of Medical Bacteriology and Immunology
(London: Heinemann Medical, 1970).

4. The principle relating biological activity to molecular chemical substances was not established until the late 1860s, by Alexander Crum Brown, professor of chemistry, and Thomas Fraser, professor of pharmacology, at the University of Edinburgh. They determined that certain arrangements of atoms could confer specific types of biological activity upon molecules. A. Crum Brown and T. R. Fraser, “On the physiological action of the ammonium bases derived from atropia and conia,”
Trans Roy Soc Edin
25 (1868): 693–739.

5. Paul Ehrlich and S. Hata,
Die experimentelle Chemotherapie der Spirillosen: Syphilis, Rückfallfieber, Hühnerspillose, Frambösie
(Berlin: J. Springer, 1910).

6. Martha Marquardt, “Paul Ehrlich: Some Reminiscences,”
British Medical Journal
1 (1954): 665–66.

7. W. I. B. Beveridge,
The Art of Scientific Investigation
(New York: Vintage, 1950), 61.

8. Quoted in Iago Galdston,
Behind the Sulfa Drugs
(New York: D. Appleton–Century, 1943), 127.

C
HAPTER
4: The Art of Dyeing

1. Author interview with Ernõ Mako, M.D., Ph.D., Semmelweis University of Medical Sciences, Budapest, Hungary, September 14, 2003.

2. Years earlier, the need for the body to alter a chemical drug to render it effective had been come across by Ehrlich. To his surprise, Ehrlich found that the arsenic-containing compound Atoxyl didn't work in his cultures of trypanosomes but was converted into an active form by the infected animal. Was Domagk's team aware of this precedent?

3. Quoted in Frank Ryan,
The Forgotten Plague
(Boston: Little, Brown, 1992), 97.

4. G. Domagk, “Ein Beitrag zur Chemotherapie der bakteriellen Infektionen,”
Dtsch Med Wschr
61 (1935): 250–53.

5. Daniel Bovet,
Une chimie qui guérit: Histoire de la découverte des sulfamides
(Paris: Payot, 1988), 42–43.

6. J. Tréfouël, T. Tréfouël, F. Nitti, and D. Bovet, “Chimiothérapie des infections streptococciques par les dérivés du
p
-aminophénylsulfamide,”
Ann Inst Pasteur
58 (1937): 30–47.

7. Bovet,
Une chimie qui guérit.

8. By the late 1930s IG Farben's successful diversification into strategic raw materials, such as synthetic rubber and oil, proved of great use to the Nazi war machine. As an unrivaled chemical syndicate, it came to employ 120,000 people, including a thousand chemists. Peter Hayes,
Industry and Ideology: IG Farben in the Nazi Era
(Cambridge: Cambridge University Press, 1987).

The chillingly deceptive phrase “Arbeit macht frei” (Work makes you free) mounted in time above the gates to the concentration camps originated from posters against trade unionism at IG Farben's factories for making Buna rubber. In 1941 the slave labor camp Monowitz-Buna was established as an outstation only a few miles from the main camp, Auschwitz, using about 40,000 of its prisoners, mostly Jews. One of these was Primo Levi, a skilled chemist. After liberation, resuming his life and career in Turin, Italy, Levi experienced a grim incident related in his 1975 book
The Periodic Table
(trans. Raymond Rosenthal; New York: Schocken, 1984). Recognizing an idiosyncratic phrase in a business correspondence with a chemical distributor in Germany, he realized that this was the same individual who was the chief of the laboratory in which he himself had worked as a starved and abused prisoner. In a written exchange, the German declared that he and Levi were both victims who should collaborate on “overcoming the past.” Levi found the invitation to admit his own share in responsibility for Auschwitz puzzling.

IG Farben's notoriety did not end here. One of its subsidiaries, Degesch, manufactured Zyklon B, the poisonous gas initially marketed as an insecticide, used at Auschwitz and other camps for the mass murdering of Europe's Jews. IG Farben was dismantled by the allies in 1952—its factories split up among Bayer, BASF, and other German chemical companies and its chief scientist condemned as a mass murderer by the Nuremberg war crimes tribunal.

9. Despite this ill-fated history, some have questioned why only Domagk was the recipient of the Nobel Prize. Of the two IG Farben chemists intimately involved in the synthesis of azo dyes for this type of drug research, one in particular expressed bitter dissatisfaction at his exclusion. Others thought that the director of Farben's medical division, as team organizer, should have been honored. And, most notably, it was the investigators at the Pasteur Institute who had determined that the metabolism in the body broke down Prontosil and unleashed its active ingredient, sulfanilamide. (In 1937 Domagk had been deceptive in explicitly dismissing the possibility of metabolic breakdown in the body even as IG Farben had synthesized the active constituent, sulfanilamide, under the trade name Prontosil Album.) Nevertheless, since Alfred Nobel's will stipulated that the original discoverer be recognized, the prize was given to Gerhard Domagk, “for the discovery of the antibacterial effects of Prontosil.”

10. Quoted in Ryan,
The Forgotten Plague,
119.

11. J. E. Lesch, “The Discovery of M & B 693 (sulfapyridine),”
American Institute of the History of Pharmacy
16 (1997): 106.

12. One reason was the development, particularly in the United States, of a number of well-equipped university hospitals with full-time teachers and investigators and sophisticated laboratories for clinical research. Close relationships between clinical and basic science departments were established, and research by even junior staff was encouraged and facilitated. This was in distinct contrast to the rigid hierarchal system in Germany, where the professor dictated to his staff the type of clinical research to be done on his patients; there, the science departments remained compartmentalized as separate institutes. In France, Great Britain, Switzerland, and the United States, pharmaceutical companies developed and heavily invested in their own research and development activities.

13. Richard Lovell,
Churchill's Doctor: A Biography of Lord Moran
(London: Royal Society of Medicine, 1992), 228–35.

14. Sulfanilamide and the family of sulfa drugs work by preventing bacteria from utilizing an essential growth requirement called paraaminobenzoic acid, but generally known by its acronym PABA. (Many people are familiar with PABA as an active ingredient in sunscreen products. It absorbs ultraviolet light at the very wavelengths that have been found to be most damaging to skin cells). PABA is a component of the vitamin folic acid and is chemically similar to sulfanilamide and the family of sulfa drugs. These drugs function as antimetabolites, competitively inhibiting the uptake of PABA for the synthesis of folic acid, causing the bacteria to die. D. D. Woods, “The relation of p-amino benzoic acid to the mechanism of the action of sulphonamide,”
Brit J Exp Pathol
21 (1940): 74–90.

Humans, relying on folic acid absorbed from our food, are not negatively affected by the action of sulfanilamide. Researchers in other fields subsequently seized upon this new concept. Reasoning that since folic acid is needed for the production of blood cells and its action might be blocked by means of a “folic acid antagonist,” Dr. Sidney Farber of the Children's Hospital in Boston put it to work in treating children with leukemia. The concept of antimetabolites provided a springboard in the search for other chemotherapeutic agents, psychotropic drugs, antihista-mines, and antihypertensives. It also led to the discovery of PAS, paraaminosalicylic acid, a drug effective against tuberculosis. The tubercle bacillus depends upon salicylates, a substance similar to ordinary aspirin, for growth and nutrition. Over a period of six years in the 1940s, a Swedish investigator tested a large number of derivatives of salicylates before coming upon PAS as an effective competitive inhibitor. Another major drug unanticipated as a spinoff from the sulfa drugs was chlorothiazide. It forces the kidneys to eliminate salt resulting in diuresis, or an increased secretion of urine. Marketed as Diuril in January 1958 and still widely used, it revolutionized the treatment of heart disease and high blood pressure. K. H. Beyer Jr., “Discovery of the Thiazides: Where Biology and Chemistry Meet,”
Perspectives in Biology and Chemistry
20 (1977): 410–20.

C
HAPTER
5: Mold, Glorious Mold

1. In addition to his scientific background, Wright was a brilliant linguist and was prone to quote sections from the Bible, Milton, Dante, Goethe, Browning, and Kipling. George Bernard Shaw used Wright as the model for his main character, Sir Colenso Ridgeon, in
The Doctor's Dilemma,
a brilliant satire on the medical profession but also one introducing the necessity of ethical choices engendered by limited resources. Little wonder that the doctor's detractors took delight in calling him “Almost Wright.”

2. The outcome of this tragedy was that by the time World War I broke out in 1914, medical authorities bowed to the inevitable. For the first time, the whole of the British army and navy were vaccinated against typhoid.

3. André Maurois,
The Life of Sir Alexander Fleming, Discoverer of Penicillin,
trans. Gerard Hopkins (New York: E. P. Dutton, 1959), 97, 93.

4. V. D. Allison, “Personal Recollections of Sir Almroth Wright and Alexander Fleming,”
Ulster Medical Journal
43 (1974): 89–98.

5. Gwyn Macfarlane,
Alexander Fleming: The Man and the Myth
(Cambridge, Mass.: Harvard University Press, 1984), 103.

6. Hare convincingly dispels the myth concerning an open window by Fleming's bench. Besides the difficulty of reaching the window to open it, with the risk of flasks and dishes kept on the windowsill clattering down on the heads of passing pedestrians, only to admit the unbearable roar of traffic, Fleming was too skilled to run the high risk of contamination of his cultures. Contamination is the bane of bacteriologic work, spoiling a crop of colonies. Bacteriologists must then just throw the cultures down the drain.

7. Alexander Fleming, “History and Development of Penicillin,” in
Penicillin, Its Practical Application
(London: Butterworth, 1946).

8. Allison, “Personal Recollections,” 89.

9. Macfarlane,
Alexander Fleming,
116, 248.