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Self-experimenters in medicine: heroes or fools? Part II. Anesthesia, surgery, therapeutics, vaccinations, and vitamin C
Clinics in Dermatology (2008) 26, 657–661
DERMATOLOGIC DISQUISITIONS AND OTHER ESSAYS Edited by Philip R. Cohen, MD
Self-experimenters in medicine: heroes or fools? Part II. Anesthesia, surgery, therapeutics, vaccinations, and vitamin C Paul T. Martinelli, MD a,⁎, Adam Czelusta, MD b , S. Ray Peterson, MD c a
Charles D. Kennard, MD, PA, Arlington, TX 76017, USA Katy Dermatology, PA, Katy, TX 77450, USA c Mohs Surgery Unit Director, Central Utah Clinic, Provo, UT 84604, USA b
Introduction Self-experimentation has helped to transform various medical fields. The first part of this 2-part series examined how various physicians and scientists, in their willingness to experiment on themselves, contributed to the knowledge of various pathogenic microorganisms and hence to the expansion of the field of infectious disease.1 This second and concluding essay will focus on how other self-experimenters would forever change and advance the realms of anesthesia, surgery, therapeutics, vaccinations, and vitamin C.
Anesthesia Procedure-oriented medical specialties such as anesthesiology, surgery, and cardiology have also benefited from those researchers who chose to use themselves as their first human subjects. For centuries, physicians have striven for the development of painless surgery. Although largely taken for granted today, the development of proper and effective anesthetics was very elusive. There are anecdotes, some humorous and others frightening, of doctors using a variety of techniques to sedate, subdue, or somehow render unconscious
⁎ Corresponding author. Tel.: +1 817 460 4444; fax: +1 817 460 8844. E-mail addresses: [email protected] (P.T. Martinelli). 0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.07.006
a patient awaiting a procedure. Dilute narcotics, brandy, and even blows to the head with a hammer are all recorded.2
Horace Wells: nitrous oxide It was no small feat that Dr Horace Wells, a dentist from Hartford, Conn, helped develop surgical anesthesia. His introduction to anesthesia first came at the age of 26, when, on December 10, 1844, a traveling entrepreneur named Gardner Colton performed a demonstration in which young men volunteered to inhale a gas called nitrous oxide. After a drugstore clerk inhaled the gas, he became combative and, while running across the stage, he fell and severely cut his leg. To Wells's amazement, the man apparently did not feel the pain from his injury until the effects of the gas had worn away. Inspired, Wells wondered if the gas could be given to patients during dental extractions, which had been almost prohibitively painful up to that point. He decided to test his theory on himself by having one of his own teeth extracted while under the influence of the experimental gas. The next day, Wells convinced one of his colleagues, Dr John M. Riggs to perform the procedure. According to Wells, the experiment was a resounding success, and after he woke up to the discovery of his extracted tooth said he “didn't feel as much the prick of a pin.”2 In the weeks that followed, Wells worked rapidly, trying to learn about the properties of his newly tested anesthetic agent. During this time, he used
658 nitrous oxide in his own practice, reportedly extracting teeth painlessly from about 15 patients.2,3 Wells confided in his former partner, Dr William T.G. Morton, who was then a medical student at Harvard. To his surprise and dismay, the medical community in Boston regarded his experiment as “humbug.”3 Morton, however, eventually continued research into anesthesia using ether and eventually found acceptance during a demonstration at Harvard in 1846. Wells supposedly became depressed in the years that followed and became estranged from his wife and family during that time. Sadly, in 1848, while under the influence of a new substance he was testing, chloroform, Horace Wells took his own life by slashing his femoral artery. Ironically, it would not be until after his death that the Parisian Medical Society officially awarded Wells with the discovery of anesthesia.3
Surgery Not all self-experimenters inoculated themselves with a potentially pathogenic substance or inhaled unstudied gases. Some performed surgical procedures on themselves to advance knowledge in their field.
Werner Forssmann: cardiac catheterization Dr Werner Forssmann was one such individual. Forssmann grew up and worked in Nazi Germany during the 1920s. After studying sketches of the catheterization of a horse's heart in his physiology text, Forssmann became interested in performing the same experiment on a human. He rejected the proposal of his mentor, Dr Richard Schneider, to attempt the procedure on animals first, stating that the French physiologists had already determined its safety in animal models. Therefore, he decided to attempt it on himself first. After prepping his left antecubital area with iodine and injecting novocaine locally, he made his incision. Finding a large vein, he passed a hollow needle into the vessel to hold it open and then gently pushed a sterile 65-cm rubber ureteral catheter through the vein and toward his heart. Standing behind a fluoroscopic screen, he documented the rubber catheter tip entering the right atrium. Forssmann acknowledged that the “method opens up numerous prospects… in the investigation of…cardiac function,”2 and, as history would prove, the procedure had tremendous implications on the diagnosis and management of cardiac disease. Forssmann would go on to catheterize his own heart a total of 9 times without complications.4 With the aid of hindsight, it may be said that Forssmann was very fortunate not to have suffered from any cardiac dysrythmias as the rubber tube contacted the endocardium. Expressing the sentiment of many self-experimenters, however, he said that “when the problems in an experiment are not very clear, you should do it on yourself and not on another person.”2
P.T. Martinelli et al. Dr Werner Forssmann shared the 1956 Nobel Prize in Physiology or Medicine with Drs Cournand and Richards, who performed a heart catheterization on a patient in 1940.
Therapeutics Gerhard Domagk: sulfonamides The pioneering work of self-experimenters extends beyond the discovery of an etiologic basis of disease. With the advent and development of microbiology in the second half of the 19th century, a logical next step would be the development of therapeutic techniques to combat the newly recognized pathogens. By and large, before the early 20th century, the concept of a chemical acting internally against a specific microorganism without causing significant toxicity was not widely accepted, and some researchers focused their efforts on developing appropriate chemotherapeutic agents. Early chemicals used consisted largely of azo dyes, arsenicals, and other heavy metal compounds. Although the first generation of antimalarials would ultimately arise from these chemical classes, the drugs proved ineffective in treating bacterial infections. In 1932, German pathologist Gerhard Domagk was experimenting with a chemical called Prontosil, a synthetic azo dye, which contained an attached sulfonamido group. He noted that Prontosil, although inactive in vitro, had a pronounced in vivo effect in mice infected with human Streptococcus hemolyticus. Although the drug was in clinical trials for only approximately 2 years, the most famous experiment with Prontosil was soon to come. Domagk injected his own daughter with the new drug, which reportedly saved her “from the threatening consequences of septicemia.”5 Although there are no reports of Domagk ever using the agent on himself, its use in a loved one may be considered just as, if not more, daring. Ultimately, sulfanilamide was determined to be the active metabolite of Prontosil, and within the decade a new class of antimicrobial agents, the sulfonamides, was introduced into the therapeutic arsenal for previously untreatable bacterial pathogens.
Beppino Giovanella: thymidine Self-experimentation with potential therapeutic agents has continued to nearly the present day. In the late 1970s, Dr Beppino Giovanella was the senior scientist on the thymidine project at the Stehlin Research Foundation in Houston, Tex. Encouraged by initial results that thymidine shrank certain cancers in mice with minimal toxicity, Dr Giovanella attempted to persuade the Food and Drug Administration to allow thymidine, a well-studied substance with no known side effects, to proceed straight to human clinical trials without the lengthy toxicity and safety testing that is normally required. When the FDA refused, Dr Giovanella reportedly consumed thymidine himself, at first orally and then
Self-experimenters-Part II-Essay and Commentary intravenously, in an attempt to prove its low risk of adverse effects.3 With the exception of some abdominal cramping and diarrhea, Giovanella reported no other adverse reactions, even as his serum concentration reached a point when needlelike crystals composed of a thymidine metabolite supposedly appeared in his urine samples. When presented with this information, the FDA reversed its decision and allowed thymidine to proceed to human trials, where, unfortunately, it did not prove to be an effective cancer therapy. In this case, the efforts and risks taken by Giovanella to have his drug approved were more remarkable and historically noteworthy than the merits of the drug itself.
Vaccinations As is the case with the development of new medications, the history of the evolution of vaccines is also rife with stories of scientists who chose to self-experiment. There is no question as to the enormous impact that vaccinations have had during the last century. As stated by Altman, “disease prevention by inoculation has become the underpinning of modern medicine…(and)…is the main reason that…life expectancies have expanded not just by years but by decades.”2 There are numerous stories of scientists and physicians who selfexperimented while developing various vaccines.
Waldemar Mordecai Haffkine: cholera Dr Waldemar Mordecai Haffkine, a Russian emigrant and colleague of Pasteur in Paris, set about to find a vaccine for cholera. In 1892, he attenuated the cholera bacterium by “passing” it numerous times through guinea pigs, and he noted that the experimental vaccine offered protection against the disease in guinea pigs. To determine whether it would be safe in humans, Haffkine had one of his friends inject him in the flank with a weak dose of the preparation on July 18 of the same year. Six days after his initial injection, he was injected with a stronger version of the vaccine. His only symptoms included low-grade fevers and local tenderness. After testing the vaccine on only 3 of his Russian friends, none of whom developed any adverse effects, he was sent to India in an attempt to combat the cholera epidemic there at the time. Compared with the modern cholera vaccine, Haffkine's was weaker and not totally effective.2 His experimentation, however, represented a significant advancement in the immunotherapy of cholera.
Almoth E. Wright: typhoid Similar work was progressing during that same time toward the development of a vaccine against typhoid. Dr Almoth E. Wright developed a killed typhoid vaccine, which he then injected into himself in 1897 in England. After he avoided serious ill effects, the vaccine was tested in larger groups over
659 the next 5 years, with mostly favorable results. It was also offered to British troops engaged in the South African Boer War, although it is estimated that only about 4% consented to take it.2 Wright's work and his self-experiment not only helped provide protection against typhoid, it also established the feasibility of using a killed vaccine preparation.
Brodie, Park, and Kolmer: polio The search for vaccinations carried over into the next century, beginning with Dr Maurice Brodie in Montreal and Dr William H. Park in New York City, who were engaged in the development of a killed polio vaccine. On September 3, 1934, after initial testing on monkeys was completed, the Brodie-Park vaccine, as it came to be called, was administered to the 2 scientists as well as to 4 other colleagues in the New York City Health Department. No systemic reactions resulted from the injections, and there was evidence of antibody production. Given these results, the vaccine was then given to children. Unfortunately, the vaccine was not as effective as originally touted, and although it is difficult to say how many of the thousands of children who received this vaccine actually developed poliomyelitis, it does appear that there were at least several.2 During the same time, Dr John A. Kolmer of Philadelphia was developing a live attenuated variant of the polio vaccine. After similar experimentation on monkeys, Kolmer injected himself and his laboratory assistant. Encouraged by his production of antibodies and his lack of adverse reaction to the vaccine, Kolmer then vaccinated his own 2 sons, as well as 23 other children before it was administered to more than 10,000 children across the country. Like the Brodie-Park vaccine, however, Kolmer's was not entirely protective either. It is reported that at least 12 children who were vaccinated became paralyzed and 5 died.2 In retrospect, the clinical pilot studies that both groups of experimenters performed were simply too small to assess the relative benefits of the vaccine's use. The efficacy and safety trials of the following Sabin and Salk vaccines were much more rigorous.
Kaplan and Koprowski: rabies Dr Martin M. Kaplan and Dr Hilary Koprowski developed an attenuated rabies vaccine by passing the virus through chick embryos. In 1955, the 2 men injected an impure preparation of this vaccine into their skin and found that it did stimulate antibody production without severe adverse sequellae. Their vaccine represented a significant advancement since Pasteur's earlier preparation because it had a much reduced risk of adverse neurologic reactions. According to Koprowski, “it was incumbent on us to show our own confidence in it by injecting it into ourselves first. It was only fair that we do it on ourselves.”2 His eloquent statement probably captures the sentiment and motivation of many scientists who chose to self-experiment.
660
Vitamin C John Crandon: vitamin C deficiency, scurvy, and wound healing In 1939, Dr John H. Crandon, a second-year surgical resident at Boston City Hospital, experimented with selfdeprivation rather than inoculation or catheterization.6–8 To investigate the effects of vitamin C deficiency, particularly on wound healing, Crandon placed himself on a diet “containing no milk and no fruits or vegetables of any kind.”7 Although the 2 teenage volunteers he paid to join him in his diet were caught drinking orange juice and thus excluded, Crandon persisted on his diet. He ate only in the hospital cafeteria and nearby delicatessen and his sustenance consisted of “cheese, bread, crackers, eggs, beer, coffee, and chocolate, supplemented by riboflavin, niacin, yeast tablets, and wheat-germ oil.”8 He used a newly available test to measure the levels of vitamin C and noted that it was absent from the plasma in 41 days and could not be detected in white blood cells by day 82. On day 90, Crandon underwent a 6-cm transverse incision in his back with the removal of a small amount of muscle. A biopsy of the site was performed 10 days later and revealed normal wound healing. Within several months, fatigue developed and he noted hyperkeratotic sandpaper-like papules on his buttock and calves by day 134. Perifollicular hemorrhages appeared on his lower legs by day 162, and while performing an exercise test on day 180, Crandon became tachycardic and briefly lost consciousness. Despite these developments, Crandon pressed on. Soon after his exercise test, an appendectomy scar present since age 15 began to disintegrate. On day 182, a second incision was made, and this time a biopsy confirmed no wound healing at the site. At this time, he received daily intravenous infusions of vitamin C, and a repeat biopsy 10 days later confirmed normal healing. Crandon succeeded in giving himself scurvy over the course of his 6-month experiment on himself and, in so doing, dramatically proved that vitamin C deficiency does impair wound healing.
P.T. Martinelli et al. performed and with an appreciation for the relatively limited knowledge available at the time. The reasons to self-experiment are as varied as the experimenters themselves. Pride, nationalism, altruism, and stubborn arrogance were all present in some degree. The following statement, however, seems to capture the sentiment of those who chose to use themselves first: “Why do we do it? Because we are cheaper, and more representative of human beings, than a hundred laboratory rats; because we are better informed of the risks and possible benefits than probably anyone else in the world; because we are impatient of bureaucratic delays and burning with our need to know the answer; because we believe that the potential benefits to mankind are great— and perhaps also out of a zest for adventure, not necessarily a shameful motive.”10 Heroic or foolish, these individuals deserve recognition.
References 1. Martinelli PT, Czelusta A, Peterson SR. Self-experimenters in medicine: heroes or fools? Part I: Pathogens. Clin Dermatol 2008;26:570-3. 2. Altman LK. Who goes first? The story of self-experimentation in medicine. New York: Random House, Inc; 1987. 3. Franklin J, Sutherland J. Guinea pig doctors: the drama of medical research through self-experimentation. New York: William Morrow & Co., Inc; 1984. 4. Fontenot C, O'Leary JP. Vignettes in medical history: Dr. Werner Forssman's self-experimentation. Am Surg 1996;62:514-5. 5. Bickel MH. The development of sulfonamides (1932-1938) as a focal point in the history of chemotherapy. Gesnerus 1988;45:67-86. 6. Crandon JH, Lund CC. Vitamin C deficiency in an otherwise normal adult. N Engl J Med 1940;222:748-52. 7. Crandon JH, Lund CC, Dill DB. Experimental human scurvy. N Engl J Med 1940;223:353-69. 8. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999;41:895-906. 9. van Everdingen JJE, Cohen AF. Self-experimentation by doctors. Lancet 1990;336:1448. 10. Freed DLJ. Self experimentation. Lancet 1987;2:746.
Commentary Conclusions The work of many self-experimenters helped transform various medical fields, from dermatology to infectious disease to cardiology and from nutrition to surgery. Although there is no accurate way of knowing just how many scientists have decided to use themselves as guinea pigs over the years, their number is probably underestimated. In fact, some studies suggest that a substantial fraction of researchers continue to experiment with themselves to this day.9 By modern standards, many of the experiments done seem foolish and hasty; others were clearly dangerous and ended tragically. These actions, however, should be judged in the context and medical climate in which they were
Commentary to Self-experimenters in medicine: heroes or fools? Martinelli et al highlight a sampling of situations in which the investigator serves as the volunteer subject.1,2 Several additional entertaining and intriguing reviews of selfexperimentation in medicine also summarize the accomplishments (or attempted accomplishments) of these adventurers in research.3-8 Some of the investigators experienced nearfatal sequellae5; however, others were less fortunate.3,6,9 The definition of self-experimentation has been expanded to not only include investigators who use
DERMATOLOGIC DISQUISITIONS AND OTHER ESSAYS Edited by Philip R. Cohen, MD
Self-experimenters in medicine: heroes or fools? Part II. Anesthesia, surgery, therapeutics, vaccinations, and vitamin C Paul T. Martinelli, MD a,⁎, Adam Czelusta, MD b , S. Ray Peterson, MD c a
Charles D. Kennard, MD, PA, Arlington, TX 76017, USA Katy Dermatology, PA, Katy, TX 77450, USA c Mohs Surgery Unit Director, Central Utah Clinic, Provo, UT 84604, USA b
Introduction Self-experimentation has helped to transform various medical fields. The first part of this 2-part series examined how various physicians and scientists, in their willingness to experiment on themselves, contributed to the knowledge of various pathogenic microorganisms and hence to the expansion of the field of infectious disease.1 This second and concluding essay will focus on how other self-experimenters would forever change and advance the realms of anesthesia, surgery, therapeutics, vaccinations, and vitamin C.
Anesthesia Procedure-oriented medical specialties such as anesthesiology, surgery, and cardiology have also benefited from those researchers who chose to use themselves as their first human subjects. For centuries, physicians have striven for the development of painless surgery. Although largely taken for granted today, the development of proper and effective anesthetics was very elusive. There are anecdotes, some humorous and others frightening, of doctors using a variety of techniques to sedate, subdue, or somehow render unconscious
⁎ Corresponding author. Tel.: +1 817 460 4444; fax: +1 817 460 8844. E-mail addresses: [email protected] (P.T. Martinelli). 0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.07.006
a patient awaiting a procedure. Dilute narcotics, brandy, and even blows to the head with a hammer are all recorded.2
Horace Wells: nitrous oxide It was no small feat that Dr Horace Wells, a dentist from Hartford, Conn, helped develop surgical anesthesia. His introduction to anesthesia first came at the age of 26, when, on December 10, 1844, a traveling entrepreneur named Gardner Colton performed a demonstration in which young men volunteered to inhale a gas called nitrous oxide. After a drugstore clerk inhaled the gas, he became combative and, while running across the stage, he fell and severely cut his leg. To Wells's amazement, the man apparently did not feel the pain from his injury until the effects of the gas had worn away. Inspired, Wells wondered if the gas could be given to patients during dental extractions, which had been almost prohibitively painful up to that point. He decided to test his theory on himself by having one of his own teeth extracted while under the influence of the experimental gas. The next day, Wells convinced one of his colleagues, Dr John M. Riggs to perform the procedure. According to Wells, the experiment was a resounding success, and after he woke up to the discovery of his extracted tooth said he “didn't feel as much the prick of a pin.”2 In the weeks that followed, Wells worked rapidly, trying to learn about the properties of his newly tested anesthetic agent. During this time, he used
658 nitrous oxide in his own practice, reportedly extracting teeth painlessly from about 15 patients.2,3 Wells confided in his former partner, Dr William T.G. Morton, who was then a medical student at Harvard. To his surprise and dismay, the medical community in Boston regarded his experiment as “humbug.”3 Morton, however, eventually continued research into anesthesia using ether and eventually found acceptance during a demonstration at Harvard in 1846. Wells supposedly became depressed in the years that followed and became estranged from his wife and family during that time. Sadly, in 1848, while under the influence of a new substance he was testing, chloroform, Horace Wells took his own life by slashing his femoral artery. Ironically, it would not be until after his death that the Parisian Medical Society officially awarded Wells with the discovery of anesthesia.3
Surgery Not all self-experimenters inoculated themselves with a potentially pathogenic substance or inhaled unstudied gases. Some performed surgical procedures on themselves to advance knowledge in their field.
Werner Forssmann: cardiac catheterization Dr Werner Forssmann was one such individual. Forssmann grew up and worked in Nazi Germany during the 1920s. After studying sketches of the catheterization of a horse's heart in his physiology text, Forssmann became interested in performing the same experiment on a human. He rejected the proposal of his mentor, Dr Richard Schneider, to attempt the procedure on animals first, stating that the French physiologists had already determined its safety in animal models. Therefore, he decided to attempt it on himself first. After prepping his left antecubital area with iodine and injecting novocaine locally, he made his incision. Finding a large vein, he passed a hollow needle into the vessel to hold it open and then gently pushed a sterile 65-cm rubber ureteral catheter through the vein and toward his heart. Standing behind a fluoroscopic screen, he documented the rubber catheter tip entering the right atrium. Forssmann acknowledged that the “method opens up numerous prospects… in the investigation of…cardiac function,”2 and, as history would prove, the procedure had tremendous implications on the diagnosis and management of cardiac disease. Forssmann would go on to catheterize his own heart a total of 9 times without complications.4 With the aid of hindsight, it may be said that Forssmann was very fortunate not to have suffered from any cardiac dysrythmias as the rubber tube contacted the endocardium. Expressing the sentiment of many self-experimenters, however, he said that “when the problems in an experiment are not very clear, you should do it on yourself and not on another person.”2
P.T. Martinelli et al. Dr Werner Forssmann shared the 1956 Nobel Prize in Physiology or Medicine with Drs Cournand and Richards, who performed a heart catheterization on a patient in 1940.
Therapeutics Gerhard Domagk: sulfonamides The pioneering work of self-experimenters extends beyond the discovery of an etiologic basis of disease. With the advent and development of microbiology in the second half of the 19th century, a logical next step would be the development of therapeutic techniques to combat the newly recognized pathogens. By and large, before the early 20th century, the concept of a chemical acting internally against a specific microorganism without causing significant toxicity was not widely accepted, and some researchers focused their efforts on developing appropriate chemotherapeutic agents. Early chemicals used consisted largely of azo dyes, arsenicals, and other heavy metal compounds. Although the first generation of antimalarials would ultimately arise from these chemical classes, the drugs proved ineffective in treating bacterial infections. In 1932, German pathologist Gerhard Domagk was experimenting with a chemical called Prontosil, a synthetic azo dye, which contained an attached sulfonamido group. He noted that Prontosil, although inactive in vitro, had a pronounced in vivo effect in mice infected with human Streptococcus hemolyticus. Although the drug was in clinical trials for only approximately 2 years, the most famous experiment with Prontosil was soon to come. Domagk injected his own daughter with the new drug, which reportedly saved her “from the threatening consequences of septicemia.”5 Although there are no reports of Domagk ever using the agent on himself, its use in a loved one may be considered just as, if not more, daring. Ultimately, sulfanilamide was determined to be the active metabolite of Prontosil, and within the decade a new class of antimicrobial agents, the sulfonamides, was introduced into the therapeutic arsenal for previously untreatable bacterial pathogens.
Beppino Giovanella: thymidine Self-experimentation with potential therapeutic agents has continued to nearly the present day. In the late 1970s, Dr Beppino Giovanella was the senior scientist on the thymidine project at the Stehlin Research Foundation in Houston, Tex. Encouraged by initial results that thymidine shrank certain cancers in mice with minimal toxicity, Dr Giovanella attempted to persuade the Food and Drug Administration to allow thymidine, a well-studied substance with no known side effects, to proceed straight to human clinical trials without the lengthy toxicity and safety testing that is normally required. When the FDA refused, Dr Giovanella reportedly consumed thymidine himself, at first orally and then
Self-experimenters-Part II-Essay and Commentary intravenously, in an attempt to prove its low risk of adverse effects.3 With the exception of some abdominal cramping and diarrhea, Giovanella reported no other adverse reactions, even as his serum concentration reached a point when needlelike crystals composed of a thymidine metabolite supposedly appeared in his urine samples. When presented with this information, the FDA reversed its decision and allowed thymidine to proceed to human trials, where, unfortunately, it did not prove to be an effective cancer therapy. In this case, the efforts and risks taken by Giovanella to have his drug approved were more remarkable and historically noteworthy than the merits of the drug itself.
Vaccinations As is the case with the development of new medications, the history of the evolution of vaccines is also rife with stories of scientists who chose to self-experiment. There is no question as to the enormous impact that vaccinations have had during the last century. As stated by Altman, “disease prevention by inoculation has become the underpinning of modern medicine…(and)…is the main reason that…life expectancies have expanded not just by years but by decades.”2 There are numerous stories of scientists and physicians who selfexperimented while developing various vaccines.
Waldemar Mordecai Haffkine: cholera Dr Waldemar Mordecai Haffkine, a Russian emigrant and colleague of Pasteur in Paris, set about to find a vaccine for cholera. In 1892, he attenuated the cholera bacterium by “passing” it numerous times through guinea pigs, and he noted that the experimental vaccine offered protection against the disease in guinea pigs. To determine whether it would be safe in humans, Haffkine had one of his friends inject him in the flank with a weak dose of the preparation on July 18 of the same year. Six days after his initial injection, he was injected with a stronger version of the vaccine. His only symptoms included low-grade fevers and local tenderness. After testing the vaccine on only 3 of his Russian friends, none of whom developed any adverse effects, he was sent to India in an attempt to combat the cholera epidemic there at the time. Compared with the modern cholera vaccine, Haffkine's was weaker and not totally effective.2 His experimentation, however, represented a significant advancement in the immunotherapy of cholera.
Almoth E. Wright: typhoid Similar work was progressing during that same time toward the development of a vaccine against typhoid. Dr Almoth E. Wright developed a killed typhoid vaccine, which he then injected into himself in 1897 in England. After he avoided serious ill effects, the vaccine was tested in larger groups over
659 the next 5 years, with mostly favorable results. It was also offered to British troops engaged in the South African Boer War, although it is estimated that only about 4% consented to take it.2 Wright's work and his self-experiment not only helped provide protection against typhoid, it also established the feasibility of using a killed vaccine preparation.
Brodie, Park, and Kolmer: polio The search for vaccinations carried over into the next century, beginning with Dr Maurice Brodie in Montreal and Dr William H. Park in New York City, who were engaged in the development of a killed polio vaccine. On September 3, 1934, after initial testing on monkeys was completed, the Brodie-Park vaccine, as it came to be called, was administered to the 2 scientists as well as to 4 other colleagues in the New York City Health Department. No systemic reactions resulted from the injections, and there was evidence of antibody production. Given these results, the vaccine was then given to children. Unfortunately, the vaccine was not as effective as originally touted, and although it is difficult to say how many of the thousands of children who received this vaccine actually developed poliomyelitis, it does appear that there were at least several.2 During the same time, Dr John A. Kolmer of Philadelphia was developing a live attenuated variant of the polio vaccine. After similar experimentation on monkeys, Kolmer injected himself and his laboratory assistant. Encouraged by his production of antibodies and his lack of adverse reaction to the vaccine, Kolmer then vaccinated his own 2 sons, as well as 23 other children before it was administered to more than 10,000 children across the country. Like the Brodie-Park vaccine, however, Kolmer's was not entirely protective either. It is reported that at least 12 children who were vaccinated became paralyzed and 5 died.2 In retrospect, the clinical pilot studies that both groups of experimenters performed were simply too small to assess the relative benefits of the vaccine's use. The efficacy and safety trials of the following Sabin and Salk vaccines were much more rigorous.
Kaplan and Koprowski: rabies Dr Martin M. Kaplan and Dr Hilary Koprowski developed an attenuated rabies vaccine by passing the virus through chick embryos. In 1955, the 2 men injected an impure preparation of this vaccine into their skin and found that it did stimulate antibody production without severe adverse sequellae. Their vaccine represented a significant advancement since Pasteur's earlier preparation because it had a much reduced risk of adverse neurologic reactions. According to Koprowski, “it was incumbent on us to show our own confidence in it by injecting it into ourselves first. It was only fair that we do it on ourselves.”2 His eloquent statement probably captures the sentiment and motivation of many scientists who chose to self-experiment.
660
Vitamin C John Crandon: vitamin C deficiency, scurvy, and wound healing In 1939, Dr John H. Crandon, a second-year surgical resident at Boston City Hospital, experimented with selfdeprivation rather than inoculation or catheterization.6–8 To investigate the effects of vitamin C deficiency, particularly on wound healing, Crandon placed himself on a diet “containing no milk and no fruits or vegetables of any kind.”7 Although the 2 teenage volunteers he paid to join him in his diet were caught drinking orange juice and thus excluded, Crandon persisted on his diet. He ate only in the hospital cafeteria and nearby delicatessen and his sustenance consisted of “cheese, bread, crackers, eggs, beer, coffee, and chocolate, supplemented by riboflavin, niacin, yeast tablets, and wheat-germ oil.”8 He used a newly available test to measure the levels of vitamin C and noted that it was absent from the plasma in 41 days and could not be detected in white blood cells by day 82. On day 90, Crandon underwent a 6-cm transverse incision in his back with the removal of a small amount of muscle. A biopsy of the site was performed 10 days later and revealed normal wound healing. Within several months, fatigue developed and he noted hyperkeratotic sandpaper-like papules on his buttock and calves by day 134. Perifollicular hemorrhages appeared on his lower legs by day 162, and while performing an exercise test on day 180, Crandon became tachycardic and briefly lost consciousness. Despite these developments, Crandon pressed on. Soon after his exercise test, an appendectomy scar present since age 15 began to disintegrate. On day 182, a second incision was made, and this time a biopsy confirmed no wound healing at the site. At this time, he received daily intravenous infusions of vitamin C, and a repeat biopsy 10 days later confirmed normal healing. Crandon succeeded in giving himself scurvy over the course of his 6-month experiment on himself and, in so doing, dramatically proved that vitamin C deficiency does impair wound healing.
P.T. Martinelli et al. performed and with an appreciation for the relatively limited knowledge available at the time. The reasons to self-experiment are as varied as the experimenters themselves. Pride, nationalism, altruism, and stubborn arrogance were all present in some degree. The following statement, however, seems to capture the sentiment of those who chose to use themselves first: “Why do we do it? Because we are cheaper, and more representative of human beings, than a hundred laboratory rats; because we are better informed of the risks and possible benefits than probably anyone else in the world; because we are impatient of bureaucratic delays and burning with our need to know the answer; because we believe that the potential benefits to mankind are great— and perhaps also out of a zest for adventure, not necessarily a shameful motive.”10 Heroic or foolish, these individuals deserve recognition.
References 1. Martinelli PT, Czelusta A, Peterson SR. Self-experimenters in medicine: heroes or fools? Part I: Pathogens. Clin Dermatol 2008;26:570-3. 2. Altman LK. Who goes first? The story of self-experimentation in medicine. New York: Random House, Inc; 1987. 3. Franklin J, Sutherland J. Guinea pig doctors: the drama of medical research through self-experimentation. New York: William Morrow & Co., Inc; 1984. 4. Fontenot C, O'Leary JP. Vignettes in medical history: Dr. Werner Forssman's self-experimentation. Am Surg 1996;62:514-5. 5. Bickel MH. The development of sulfonamides (1932-1938) as a focal point in the history of chemotherapy. Gesnerus 1988;45:67-86. 6. Crandon JH, Lund CC. Vitamin C deficiency in an otherwise normal adult. N Engl J Med 1940;222:748-52. 7. Crandon JH, Lund CC, Dill DB. Experimental human scurvy. N Engl J Med 1940;223:353-69. 8. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999;41:895-906. 9. van Everdingen JJE, Cohen AF. Self-experimentation by doctors. Lancet 1990;336:1448. 10. Freed DLJ. Self experimentation. Lancet 1987;2:746.
Commentary Conclusions The work of many self-experimenters helped transform various medical fields, from dermatology to infectious disease to cardiology and from nutrition to surgery. Although there is no accurate way of knowing just how many scientists have decided to use themselves as guinea pigs over the years, their number is probably underestimated. In fact, some studies suggest that a substantial fraction of researchers continue to experiment with themselves to this day.9 By modern standards, many of the experiments done seem foolish and hasty; others were clearly dangerous and ended tragically. These actions, however, should be judged in the context and medical climate in which they were
Commentary to Self-experimenters in medicine: heroes or fools? Martinelli et al highlight a sampling of situations in which the investigator serves as the volunteer subject.1,2 Several additional entertaining and intriguing reviews of selfexperimentation in medicine also summarize the accomplishments (or attempted accomplishments) of these adventurers in research.3-8 Some of the investigators experienced nearfatal sequellae5; however, others were less fortunate.3,6,9 The definition of self-experimentation has been expanded to not only include investigators who use