The Demon Under the Microscope, page 34
Luckily, by the war’s end, penicillin was available to help treat sulfa-resistant infections. Researchers quickly discovered how the bacteria became resistant—there were several biochemical mechanisms employed by different strains. But regardless of how it was done, sulfa researchers realized, misuse of the medicine worsened the problem, most likely by clearing out the bacteria that were sensitive to it, leaving resistant strains to live and take their place. It is likely that the low doses of sulfa given over a period of weeks or months during mass army tests against meningitis, gonorrhea, and strep contributed to the problem of resistance. Despite the problem, sulfadiazine was used for twenty years after the war to treat meningitis in army camps—until, in the early 1960s, sulfa-resistant strains started spreading so rapidly that the fear of a massive outbreak of sulfa-resistant meningitis caused at least one training center to temporarily close. By 1974, a study found that nearly a quarter of all the meningococcus sampled in army trainees was resistant to sulfa.
Sulfa was quickly embraced by the public, used in massive amounts, and often obtained and administered in the early years without any medical supervision. The result was an orgy of misuse, people buying it for the wrong diseases, or using it just long enough to clear up symptoms. Unfortunately, the lessons learned with sulfa did not stop the same thing happening with almost every other antibiotic that followed. The past fifty years have seen a dramatic increase in antibiotic-resistant bacteria of all sorts. Bacteria, it has been discovered, can be promiscuous in the ways they share their DNA with other bacteria and viruses. A gene conferring resistance to one strain of germ can be quickly passed on to other strains, the resistant bacteria surviving the antibiotics used to get rid of them, thriving, and passing the genes on to others. Sometimes the resistant genes for different antibiotics, including sulfa, get packaged together and passed along as a group. Luckily, there are proven ways to stop the spread of resistant bacteria, and physicians are beginning to employ them widely. The most important is simply using antibiotics more carefully, making certain that patients strictly adhere to the dosing schedule, ensuring that the body has a chance to kill off the last resistant bacteria. Regardless, the number of antibiotics on the market, the extent of their use (more than 50 million pounds of antibiotics are produced each year in the United States alone), and their ubiquitous presence (a glass of milk, according to one recent study, can contain minute amounts of up to eighty different antibiotics) have kept the problem of resistance very much alive. The World Health Organization lists antibiotic resistance as one of the three most important public health threats of the twenty-first century.
In the first blush of the sulfa boom in the late 1930s, and again in the first flush of confidence following the fuller introduction of new antibiotics in the 1950s, people got carried away with wonder drugs. They used these unprecedentedly powerful medicines too freely, too carelessly, and too often. Many physicians and patients still do. Sulfa and its children are remarkably seductive drugs.
This new power in medicine led to another effect that seems, at least to many patients, unfortunate. Physicians have changed. Before sulfa, physicians learned their craft in a miscellany of schools, employed a number of approaches, and used techniques developed by a variety of practitioners. In the early 1930s, a quarter of all healers in the United States were homeopaths, osteopaths, chiropractors, Christian scientists, or other “irregular” medical practitioners. They, and the majority of “mainstream” medical practitioners, did what they could with a grab bag of generally weak medicines often made by patent-drug firms or local pharmacists in corner drugstores. Americans had the opportunity to choose from an array of medical approaches, just as they chose from an array of over-the-counter medicines. In both cases quality could vary tremendously—it was an open market, and let the buyer beware. The one thing all physicians had in common, and had held in common since antiquity, was their powerlessness, their inability to fundamentally change the course of most infectious disease. Before sulfa, physicians were by default observers and diagnosers, more able to predict the course of a disease than to do anything about it. Their incomes were, for the most part, modest. Their ambitions were, for the most part, limited. Their goal was often to comfort as much as it was to cure.
Much has changed. Ever-more-powerful drugs, starting with sulfa, led to ever-more-centralized control and oversight of medical care. Physicians accrued increasing power to decide who got what medicine. With burgeoning numbers of new drugs deemed too strong, too potentially toxic, or too easy to abuse to be sold directly to consumers, physicians took an increasing role as gatekeepers. The prescription pad became a forceful tool for determining which medication would be taken by a patient. The right to self-medication, the battle cry of the patent-medicine makers, became more or less a thing of the past. These more powerful physicians were trained in new ways, with a growing emphasis in medical school curricula on the newest, most “scientific” research in molecular biology, physiochemistry, microbiology, and pharmacology. Those physicians who did not master the new methods were gradually marginalized. Homeopathy nearly disappeared in the United States, although a resurgence of interest since the 1960s has kept the study alive, with naturopathy, as “alternative” forms of health care. Where there were once several competing approaches to medicine, there is now only one that matters to most hospitals, insurers, and the vast majority of the public, one that has been shaped to a great degree by the successful development of potent cures that followed the discovery of sulfa drugs. Aspiring caregivers today are chosen as much (or more) for their scientific abilities, their talent for mastering these manifold technological and pharmaceutical advances, as for their interpersonal skills. A century ago most physicians were careful, conservative observers who provided comfort to patients and their families. Today they act: They prescribe, they treat, they cure. They routinely perform what were once considered miracles. The result, in the view of some, has been a shift in the profession from caregiver to technician.
The powerful new drugs changed how care was given as well as who gave it. Antibiotics made hospitals safer for patients, and alliances were made between mainstream medical schools and hospitals to bring together the strongest medicines with the most skilled practitioners in the most advanced and hygienic care-giving environments. In the 1930s, historian of medicine Paul Starr points out, most medical care took place in patients’ homes. Only one physician in sixteen worked at a hospital full-time. Half of all births were home births. The average private physician in 1930 saw about fifty patients each week. By 1950, armed with faster, stronger tools, the average physician was seeing twice that many per week, a rate that has continued to rise. House calls today are almost extinct. More than 90 percent of births take place in hospitals, and it is in hospitals and hospital-associated offices that most physicians do much more of their work. In general, compared to practitioners before the 1930s, physicians today are better trained, better equipped, better able to control the types of medicines that their patients take, much more effective in saving lives, far more harried—and far wealthier.
Finally, the advent of sulfa and the antibiotics that followed changed the way nations approach the control of disease. The period between 1890 and 1930—just after Pasteur and Koch and just before sulfa—is sometimes called “the Golden Era” of public health. This was a time when health professionals understood that germs caused disease but were unable to do anything once patients were infected. The only answer was to prevent the infection. Very effective programs were developed and employed to improve the quality of water, food, and sewage systems; to enhance basic hygiene; and to vaccinate against disease. These programs did wonders to lower disease rates before sulfa. Since 1930, limited health-care funds have increasingly moved away from public health measures toward new drugs and new medical technologies.
Whether these changes prove, in the long term, to be for good or ill remains to be seen. For now, the drugs and techniques are working. We live in a blessed, perhaps all-too-temporary, era in which the invisible predators of the past have been beaten away from our campfires. With yesterday’s common killers now relegated to little more than bogeymen in the stories of grandparents and great-grandparents, we suffer instead from diseases of the long-lived conditions that were once considered perquisites of the rich: cancer, obesity, rheumatism, heart disease. Our numbers have risen enormously. The problem now is not staying alive but keeping the earth alive as we overrun it.
If sulfa, the first miracle medicine, shows anything, it is that there is really no such thing as a “miracle” in science. Every great drug discovery (and every modern technological advance) carries with it, like the blood of the Gorgon mentioned in the epigraph that begins this book, two opposing qualities: one positive, healing, and helpful; one negative, often unintended, sometimes deadly. The ancient Greeks understood that. We must remember it, too.
ACKNOWLEDGMENTS
SPECIAL THANKS GO TO Corporate Historian Ruediger Borstel, M.A., whose help at the Bayer Archive in Leverkusen was vital to the success of this work. Michael Frings at Bayer searched out and made available scores of valuable photographs. The Bayer Corporation itself provided travel support for my research in Leverkusen, for which I thank the company in general and Thomas Reinert in particular. At the Pasteur Archives, Stéphane Kraxner provided very able and courteous assistance. At the Wellcome Library in London, I received welcome help from Helen Wakely, archivist. I relied as well on the able reference staff at the University of Oregon’s Knight Library and the Oregon Health and Sciences University. Clifford Mead, head of special collections at Oregon State University, provided insightful and intelligent advice throughout the project.
This book would not have been possible without my agent, Nat Sobel, who put me together with the editors at Harmony. Special thanks here to my editor, Julia Pastore. Maureen Sugden was an exceptional copy editor. Translators were essential for understanding works in French and German, and I was assisted capably by Geraldine Poizat-Newcomb, Yasmin Staunau, Matthias Vogel, and Gerhard Spitteler, as well as my German-savvy son, Jackson Hager. Other scholars who provided support and advice included Suzanne White Junod; John H. Mather, M.D.; Ute Deichmann; Kees Gispen; Brian J. Ford; Frank Ryan; Mary Jo Nye; Charles C. Mann; and Mark L. Plummer.
As every author knows, writing a book can make you temporarily crazy. Thanks to my family—especially my patient and loving partner in life and writing, Lauren Kessler—for putting up with this one.
Tom Hager
Eugene, Oregon
SOURCE NOTES
Rather than extensive footnoting, I have chosen to provide a brief outline of source materials for interested readers. All references refer to entries in the bibliography.
Some sources were tapped for material fairly consistently throughout the book, and rather than repeat them separately under the individual chapter headings below, I have chosen to highlight them once, here, at the beginning.
Wherever possible, I default to primary sources, the raw material of history, original letters, lab notes, diaries, and memoranda. The three major sources for primary papers related to the discovery of the sulfa drugs are the extensive Bayer Archive at Leverkusen, the archive of the Pasteur Institute in Paris, and the Wellcome Library for the History and Understanding of Medicine in London. The Bayer holdings constitute one of the world’s richest corporate archives. Here are housed Domagk’s laboratory notes, Klarer and Mietzsch’s monthly reports, a trove of internal company memos and reports, and the single most important source of information about Domagk’s private life: the typescript manuscript of Lebenserrinnerverrungen, a long, somewhat eccentric memoir he wrote late in life that remains unpublished. Unfortunately this otherwise superb archive does not offer for public viewing Bayer’s top-level administrative records, a corporate policy that limits the chance to completely piece together some puzzles, notably why Bayer hesitated so long before publicly announcing what seemed to be, by most measures, the world’s greatest miracle drug. The Pasteur Institute archives are the repository for much firsthand information on the Fourneau laboratory, its workers, and their achievements. Especially important is the Daniel Bovet collection, which includes documents he collected while investigating the Prontosil discovery many years after the fact (Bovet [1988], the result of his labor, is a colorful and useful source to which I returned often). The Wellcome Library’s holdings include Leonard Colebrook’s papers, a small but valuable source of primary documents that includes his original lab notes and correspondence related to the London Prontosil tests on childbed fever.
The only full-length adult biography of Gerhard Domagk is an admiring study by a former colleague, Ekkehard Grundmann, published in Germany in 2001 and translated into English in 2004. A brief young person’s biography, Bankston (2003), offers basic information. Ryan (1993) includes valuable details on Domagk’s research and his private life, with a focus on his tuberculosis work. Ryan is especially valuable because it includes very readable translations of many passages from the Lebenserrinnerverrungen. Following Domagk’s death, significant obituaries were written by Colebrook (1964) and Posner (1971).
The best historical analysis of the scientific work of Domagk, Klarer, and the Bayer research operation, as well as the subsequent research on M&B 693, is the work of science historian John Lesch (see all entries under his name, esp. 1993). Robert Behnisch worked with Domagk at Bayer and describes the laboratory, its scientific approach, and its personalities; Behnisch’s recollections (1986) were vital in helping me to re-create the atmosphere and research approach within the company. Bayer’s corporate history is recounted in a large, wonderfully illustrated book, Verg (1988), published to celebrate the company’s 125th anniversary.
In addition to these often-used sources:
PROLOGUE
A number of books describe the attack on Pearl Harbor, including material about the medical response. I relied on Condon-Rall (1998) for many facts and figures, supplemented by Clarke (2001) and contemporary news sources. The story of John Moorhead can be found on the Web site of the Mamiya Medical Heritage Center (http://hml.org/mmhc); his report for the American Medical Association is published as Moorhead (1942).
CHAPTER ONE
The sense of what it was like in a World War I battlefield hospital is drawn primarily from Domagk’s memoir, with additional details from Church (1918), Hutchinson (1918), Shay (2002), Higonnet (2001), and MacDonald (1980).
CHAPTER TWO
Information on wound occurrence and methods of treatment during World War I can be found in Hutchinson (1918), Church (1918), Mitchell (1931), MacDonald (1980), Gordon (1993), Higonnet (2001), and Shay (2002). Additional facts about gas gangrene are found in Gordon (1993) and Bhushan (2002). More specific background on Sir Almroth Wright, his research before and during World War I, and his laboratory in the Boulogne Hospital can be found in Dunnill (2000), Colebrook (1954), Cope (1966), Noble (1974), and Heidelberger (1977). The development of antiseptics and the nature of surgery prior to sulfa are described variously in the sources above as well as in Taylor (1942), Galdston (1943), Sokoloff (1949), Hare (1970), Koop (1997), and Zimmerman (2003).
CHAPTER THREE
Basic information on van Leeuwenhoek, Koch, and the other early researchers mentioned in this chapter can be found in a variety of scientific biographical encyclopedias (see, for example, Asimov, 1982); van Leeuwenhoek wrote many fascinating letters, collected and published by the Committee of Dutch Scientists (1939). Louis Pasteur has been the subject of numerous biographies (see Dubos, 1976); the importance of his work and Koch’s research as steps toward the discovery of sulfa is also recounted in Taylor (1942) and Galdston (1943). The importance of early discoveries in bacteriology to medicine is highlighted in Williams (1982) and Warner (1986). Further information on the changing attitude of physicians toward bacteriology and drug therapy in the decades prior to the 1930s can be found in Hare (1970), Foster (1970), Lesch (1997), Thomas (1983), Balis (2000), Young (1967), Le Fanu (1999), and Zimmerman (2003).
CHAPTER FOUR
The history of Lister and Listerism as it relates to the development of chemotherapy is recounted in Taylor (1942), Galdston (1943), Sokoloff (1949), and Gordon (1993); a number of biographies of Lister are available as well.
CHAPTER FIVE
Details of Carl Duisberg’s career and the development of the Bayer firm are found in Augustine (1994), Mann and Plummer (1991), and Stokes (1988). More general information on synthetic dyes, the German dye firms, and the formation of IG Farben can be found in Aftalion (1991), Travis (1993), Hayes (2000 and 2001), Lesch (2000), and Higby and Stroud (1997). Further information on the Council of the Gods was obtained from the Bayer Archive; a striking painting of the meeting with Duisberg as its primary focus hangs in the Bayer Kasino at Leverkusen.
