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, MDa,⁎, Adam Czelusta, MDb, S. Ray Peterson, MDc aCharles D. Kennard, MD, PA, Arlington, TX 76017, USA bKaty Dermatology, PA, Katy, TX 77450, USA cMohs Surgery Unit Director, Central Utah Clinic, Provo, UT 84604, USA

Introduction a patient awaiting a procedure. Dilute narcotics, brandy, and even blows to the head with a hammer are all recorded.2 Self-experimentation has helped to transform various medical fields. The first part of this 2-part series examined Horace Wells: nitrous oxide how various physicians and scientists, in their willingness to experiment on themselves, contributed to the knowledge of It was no small feat that Dr Horace Wells, a dentist from various pathogenic microorganisms and hence to the expan- Hartford, Conn, helped develop surgical anesthesia. His sion of the field of infectious disease.1 This second and introduction to anesthesia first came at the age of 26, when, concluding essay will focus on how other self-experimenters on December 10, 1844, a traveling entrepreneur named would forever change and advance the realms of anesthesia, Gardner Colton performed a demonstration in which young surgery, therapeutics, vaccinations, and vitamin C. 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 Anesthesia leg. To Wells's amazement, the man apparently did not feel the pain from his injury until the effects of the gas had Procedure-oriented medical specialties such as anesthe- worn away. siology, surgery, and cardiology have also benefited from Inspired, Wells wondered if the gas could be given to those researchers who chose to use themselves as their first patients during dental extractions, which had been almost human subjects. For centuries, physicians have striven for the prohibitively painful up to that point. He decided to test his development of painless surgery. Although largely taken for theory on himself by having one of his own teeth extracted granted today, the development of proper and effective while under the influence of the experimental gas. The next anesthetics was very elusive. There are anecdotes, some day, Wells convinced one of his colleagues, Dr John M. humorous and others frightening, of doctors using a variety of Riggs to perform the procedure. According to Wells, the techniques to sedate, subdue, or somehow render unconscious 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 ⁎ Corresponding author. Tel.: +1 817 460 4444; fax: +1 817 460 8844. worked rapidly, trying to learn about the properties of his E-mail addresses: [email protected] (P.T. Martinelli). newly tested anesthetic agent. During this time, he used

0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.07.006 658 P.T. Martinelli et al. nitrous oxide in his own practice, reportedly extracting teeth Dr Werner Forssmann shared the 1956 Nobel Prize in painlessly from about 15 patients.2,3 Physiology or Medicine with Drs Cournand and Richards, Wells confided in his former partner, Dr William T.G. who performed a heart catheterization on a patient in 1940. Morton, who was then a medical student at Harvard. To his surprise and dismay, the medical community in Boston “ ”3 regarded his experiment as humbug. Morton, however, Therapeutics eventually continued research into anesthesia using ether and eventually found acceptance during a demonstration at Harvard in 1846. Gerhard Domagk: sulfonamides Wells supposedly became depressed in the years that followed and became estranged from his wife and family du- The pioneering work of self-experimenters extends beyond ring that time. Sadly, in 1848, while under the influence of a the discovery of an etiologic basis of disease. With the advent new substance he was testing, chloroform, Horace Wells took and development of microbiology in the second half of the his own life by slashing his femoral artery. Ironically, it would 19th century, a logical next step would be the development of not be until after his death that the Parisian Medical Society therapeutic techniques to combat the newly recognized officially awarded Wells with the discovery of anesthesia.3 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 Surgery developing appropriate chemotherapeutic agents. Early chemicals used consisted largely of azo dyes, Not all self-experimenters inoculated themselves with a arsenicals, and other heavy metal compounds. Although the potentially pathogenic substance or inhaled unstudied gases. first generation of antimalarials would ultimately arise from Some performed surgical procedures on themselves to these chemical classes, the drugs proved ineffective in advance knowledge in their field. treating bacterial infections. In 1932, German pathologist Gerhard Domagk was experimenting with a chemical called Werner Forssmann: cardiac catheterization Prontosil, a synthetic azo dye, which contained an attached sulfonamido group. He noted that Prontosil, although inactive Dr Werner Forssmann was one such individual. in vitro, had a pronounced in vivo effect in mice infected with Forssmann grew up and worked in Nazi Germany during human Streptococcus hemolyticus. Although the drug was in the 1920s. After studying sketches of the catheterization of a clinical trials for only approximately 2 years, the most famous horse's heart in his physiology text, Forssmann became experiment with Prontosil was soon to come. Domagk interested in performing the same experiment on a human. He injected his own daughter with the new drug, which “ rejected the proposal of his mentor, Dr Richard Schneider, to reportedly saved her from the threatening consequences of ”5 attempt the procedure on animals first, stating that the French septicemia. Although there are no reports of Domagk ever physiologists had already determined its safety in animal using the agent on himself, its use in a loved one may be models. Therefore, he decided to attempt it on himself first. considered just as, if not more, daring. Ultimately, sulfani- After prepping his left antecubital area with iodine and lamide was determined to be the active metabolite of injecting novocaine locally, he made his incision. Finding a Prontosil, and within the decade a new class of antimicrobial large vein, he passed a hollow needle into the vessel to hold it agents, the sulfonamides, was introduced into the therapeutic open and then gently pushed a sterile 65-cm rubber ureteral arsenal for previously untreatable bacterial pathogens. catheter through the vein and toward his heart. Standing behind a fluoroscopic screen, he documented the rubber Beppino Giovanella: thymidine catheter tip entering the right atrium. Forssmann acknowl- edged that the “method opens up numerous prospects… in the Self-experimentation with potential therapeutic agents investigation of…cardiac function,”2 and, as history would has continued to nearly the present day. In the late 1970s, prove, the procedure had tremendous implications on the Dr Beppino Giovanella was the senior scientist on the diagnosis and management of cardiac disease. thymidine project at the Stehlin Research Foundation in Forssmann would go on to catheterize his own heart a Houston, Tex. Encouraged by initial results that thymidine total of 9 times without complications.4 With the aid of shrank certain cancers in mice with minimal toxicity, hindsight, it may be said that Forssmann was very fortunate Dr Giovanella attempted to persuade the Food and Drug not to have suffered from any cardiac dysrythmias as the Administration to allow thymidine, a well-studied substance rubber tube contacted the endocardium. Expressing the with no known side effects, to proceed straight to human sentiment of many self-experimenters, however, he said that clinical trials without the lengthy toxicity and safety testing that “when the problems in an experiment are not very clear, is normally required. When the FDA refused, Dr Giovanella you should do it on yourself and not on another person.”2 reportedly consumed thymidine himself, at first orally and then Self-experimenters-Part II-Essay and Commentary 659 intravenously, in an attempt to prove its low risk of adverse the next 5 years, with mostly favorable results. It was also effects.3 With the exception of some abdominal cramping and offered to British troops engaged in the South African Boer diarrhea, Giovanella reported no other adverse reactions, even War, although it is estimated that only about 4% consented to as his serum concentration reached a point when needlelike take it.2 Wright's work and his self-experiment not only helped crystals composed of a thymidine metabolite supposedly provide protection against typhoid, it also established the appeared in his urine samples. When presented with this feasibility of using a killed vaccine preparation. information, the FDA reversed its decision and allowed thymidine to proceed to human trials, where, unfortunately, it Brodie, Park, and Kolmer: polio did not prove to be an effective cancer therapy. In this case, the efforts and risks taken by Giovanella to have his drug approved The search for vaccinations carried over into the next were more remarkable and historically noteworthy than the century, beginning with Dr Maurice Brodie in Montreal and merits of the drug itself. 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 Vaccinations Brodie-Park vaccine, as it came to be called, was adminis- tered to the 2 scientists as well as to 4 other colleagues in the As is the case with the development of new medications, the New York City Health Department. No systemic reactions history of the evolution of vaccines is also rife with stories of resulted from the injections, and there was evidence of scientists who chose to self-experiment. There is no question as antibody production. Given these results, the vaccine was to the enormous impact that vaccinations have had during the then given to children. Unfortunately, the vaccine was not as last century. As stated by Altman, “disease prevention by effective as originally touted, and although it is difficult to say inoculation has become the underpinning of modern medi- how many of the thousands of children who received this cine…(and)…is the main reason that…life expectancies have vaccine actually developed poliomyelitis, it does appear that expanded not just by years but by decades.”2 There are there were at least several.2 numerous stories of scientists and physicians who self- During the same time, Dr John A. Kolmer of Philadelphia experimented while developing various vaccines. was developing a live attenuated variant of the polio vaccine. After similar experimentation on monkeys, Kolmer injected Waldemar Mordecai Haffkine: cholera himself and his laboratory assistant. Encouraged by his production of antibodies and his lack of adverse reaction to Dr Waldemar Mordecai Haffkine, a Russian emigrant and the vaccine, Kolmer then vaccinated his own 2 sons, as well as colleague of Pasteur in Paris, set about to find a vaccine for 23 other children before it was administered to more than cholera. In 1892, he attenuated the cholera bacterium by 10,000 children across the country. Like the Brodie-Park “passing” it numerous times through guinea pigs, and he vaccine, however, Kolmer's was not entirely protective either. noted that the experimental vaccine offered protection It is reported that at least 12 children who were vaccinated 2 against the disease in guinea pigs. To determine whether it became paralyzed and 5 died. In retrospect, the clinical pilot would be safe in humans, Haffkine had one of his friends studies that both groups of experimenters performed were inject him in the flank with a weak dose of the preparation on simply too small to assess the relative benefits of the vaccine's July 18 of the same year. Six days after his initial injection, use. The efficacy and safety trials of the following Sabin and he was injected with a stronger version of the vaccine. His Salk vaccines were much more rigorous. only symptoms included low-grade fevers and local tender- ness. After testing the vaccine on only 3 of his Russian Kaplan and Koprowski: rabies friends, none of whom developed any adverse effects, he was sent to India in an attempt to combat the cholera epidemic Dr Martin M. Kaplan and Dr Hilary Koprowski there at the time. Compared with the modern cholera vaccine, developed an attenuated rabies vaccine by passing the Haffkine's was weaker and not totally effective.2 His virus through chick embryos. In 1955, the 2 men injected an experimentation, however, represented a significant impure preparation of this vaccine into their skin and found advancement in the immunotherapy of cholera. that it did stimulate antibody production without severe adverse sequellae. Their vaccine represented a significant Almoth E. Wright: typhoid advancement since Pasteur's earlier preparation because it had a much reduced risk of adverse neurologic reactions. Similar work was progressing during that same time toward According to Koprowski, “it was incumbent on us to show the development of a vaccine against typhoid. Dr Almoth E. our own confidence in it by injecting it into ourselves first. It Wright developed a killed typhoid vaccine, which he then was only fair that we do it on ourselves.”2 His eloquent injected into himself in 1897 in England. After he avoided statement probably captures the sentiment and motivation of serious ill effects, the vaccine was tested in larger groups over many scientists who chose to self-experiment. 660 P.T. Martinelli et al.

Vitamin C performed and with an appreciation for the relatively limited knowledge available at the time. John Crandon: vitamin C deficiency, scurvy, and The reasons to self-experiment are as varied as the wound healing experimenters themselves. Pride, nationalism, altruism, and stubborn arrogance were all present in some degree. The In 1939, Dr John H. Crandon, a second-year surgical following statement, however, seems to capture the resident at Boston City Hospital, experimented with self- sentiment of those who chose to use themselves first: “ deprivation rather than inoculation or catheterization.6–8 To Whydowedoit?Becausewearecheaper,andmore investigate the effects of vitamin C deficiency, particularly representative of human beings, than a hundred laboratory on wound healing, Crandon placed himself on a diet rats; because we are better informed of the risks and “containing no milk and no fruits or vegetables of any possible benefits than probably anyone else in the world; kind.”7 Although the 2 teenage volunteers he paid to join him because we are impatient of bureaucratic delays and in his diet were caught drinking orange juice and thus burning with our need to know the answer; because we — excluded, Crandon persisted on his diet. He ate only in the believe that the potential benefits to mankind are great hospital cafeteria and nearby delicatessen and his sustenance and perhaps also out of a zest for adventure, not necessarily ”10 consisted of “cheese, bread, crackers, eggs, beer, coffee, and ashamefulmotive. Heroic or foolish, these individuals chocolate, supplemented by riboflavin, niacin, yeast tablets, deserve recognition. 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 References white blood cells by day 82. On day 90, Crandon underwent a 6-cm transverse incision in his back with the removal of a 1. Martinelli PT, Czelusta A, Peterson SR. Self-experimenters in medicine: small amount of muscle. A biopsy of the site was performed heroes or fools? Part I: Pathogens. Clin Dermatol 2008;26:570-3. 10 days later and revealed normal wound healing. 2. Altman LK. Who goes first? The story of self-experimentation in Within several months, fatigue developed and he noted medicine. New York: Random House, Inc; 1987. 3. Franklin J, Sutherland J. Guinea pig doctors: the drama of medical hyperkeratotic sandpaper-like papules on his buttock and calves research through self-experimentation. New York: William Morrow & by day 134. Perifollicular hemorrhages appeared on his lower Co., Inc; 1984. legs by day 162, and while performing an exercise test on day 4. Fontenot C, O'Leary JP. Vignettes in medical history: Dr. Werner 180, Crandon became tachycardic and briefly lost conscious- Forssman's self-experimentation. Am Surg 1996;62:514-5. ness. Despite these developments, Crandon pressed on. 5. Bickel MH. The development of sulfonamides (1932-1938) as a focal point in the history of chemotherapy. Gesnerus 1988;45:67-86. Soon after his exercise test, an appendectomy scar present 6. Crandon JH, Lund CC. Vitamin C deficiency in an otherwise normal since age 15 began to disintegrate. On day 182, a second adult. N Engl J Med 1940;222:748-52. incision was made, and this time a biopsy confirmed no 7. Crandon JH, Lund CC, Dill DB. Experimental human scurvy. N Engl J wound healing at the site. At this time, he received daily Med 1940;223:353-69. intravenous infusions of vitamin C, and a repeat biopsy 8. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999;41:895-906. 10 days later confirmed normal healing. Crandon succeeded 9. van Everdingen JJE, Cohen AF. Self-experimentation by doctors. in giving himself scurvy over the course of his 6-month Lancet 1990;336:1448. experiment on himself and, in so doing, dramatically proved 10. Freed DLJ. Self experimentation. Lancet 1987;2:746. that vitamin C deficiency does impair wound healing. Commentary Conclusions

The work of many self-experimenters helped transform Commentary to Self-experimenters in medicine: heroes various medical fields, from dermatology to infectious or fools? disease to cardiology and from nutrition to surgery. Although there is no accurate way of knowing just how many scientists Martinelli et al highlight a sampling of situations in which have decided to use themselves as guinea pigs over the years, the investigator serves as the volunteer subject.1,2 Several their number is probably underestimated. In fact, some additional entertaining and intriguing reviews of self- studies suggest that a substantial fraction of researchers experimentation in medicine also summarize the accomplish- continue to experiment with themselves to this day.9 ments (or attempted accomplishments) of these adventurers By modern standards, many of the experiments done in research.3-8 Some of the investigators experienced near- seem foolish and hasty; others were clearly dangerous and fatal sequellae5; however, others were less fortunate.3,6,9 ended tragically. These actions, however, should be judged The definition of self-experimentation has been in the context and medical climate in which they were expanded to not only include investigators who use