Abstract Heparin, insulin, the sinoatrial node and ether anaesthesia are just some of the major discoveries made by medical students, all of which have had a huge impact on the practice of surgery. This paper explores the breadth and depth of some of these talented individuals and their extraordinary contributions to medicine. While some continued to enjoy brilliant careers, others became embroiled in damaging disputes about priority or were overtaken by illness or personal problems. Regardless of their fate, their contributions are a potent reminder of what can be achieved by gifted and determined medical students undertaking a period of basic scientific or clinical research. Introduction Who, today, would credit the discovery of heparin, insulin, the sinoatrial node, pancreaticobiliary sphincter and ether anaesthesia to medical students? Who were these gifted students and what became of them? This paper highlights the breadth and depth of some of these talented individuals and their extraordinary contributions to surgery and medicine. While some progressed to brilliant careers, others became embroiled in damaging disputes about priority or were overtaken by illness or personal problems. But regardless of their fate, their contributions are a potent reminder of what can be achieved by able and hard working medical students undertaking basic scientific or clinical research. Anticoagulants and arteries The discovery of heparin, a natural anticoagulant, revolutionized the management of thromboembolic disorders and cardiac surgery after its introduction into clinical practice in the 1940s. Its discovery is commonly attributed to Jay Mclean (1890–1957). McLean had a difficult start in life. His father died when he was only 4 years old and the San Francisco earthquake and fire of 1906 destroyed his stepfather's business and family home. To complete his medical studies, McLean took on various jobs including scrubbing ferry boat decks. In 1916, as a second-year medical student at Johns Hopkins University in Baltimore (Fig. 1), he began researching in the coagulation laboratory of the physiologist William Henry Howell. He was assigned to investigate procoagulants and reported his findings later that year.1 During this research, he identified a phosphatide anticoagulant in canine liver tissue, but this substance received little attention in his paper because Howell considered that its anticoagulant activity should be investigated further.2,3 McLean then moved to the University of Pennsylvania, where he published a second paper on procoagulants. It would be 24 years before he published again. Meanwhile, Howell continued to research the anticoagulant that McLean had discovered, and in 1918, together with another medical student, named it heparin (from hepar, Greek for liver). Over the next 40 years, priority for the discovery of heparin was to become the subject of dispute.3 Figure 1. Jay McLean as a surgical resident. Courtesy of the Alan Mason Chesney Medical Archives of the Johns Hopkins Medical Institutions. After a brief spell in the American Ambulance Corps in France, in 1917, McLean returned to Baltimore and graduated in 1919. During his surgical training, he worked for William Stewart Halsted and Alan Whipple, among others. In 1925, he entered private practice but his surgical career never thrived. He moved into radiotherapy and oncology, returning intermittently to his research on heparin. His attempts to write a definitive monograph on the compound failed. Much of his energy – lectures, correspondence and even a radio interview – was expended on his claim to priority in the discovery of heparin. His unfinished autobiographical sketch published in 1959 was devoted to this topic. He considered that the discovery of heparin was a result of his determination to accomplish something by his own ability borne out of the hardship he had endured.4 McLean died of ischaemic heart disease at the age of 67 years. An attempt to nominate him posthumously for a Nobel Prize failed.2 Dr Thomas J Fogarty is today an award-winning Californian vintner,5 but he is best known for his invention of the balloon embolectomy catheter. Born in 1934, he too had a hard childhood. After losing his father at the age of 8, he sought part-time employment in the sterile supply department of a local hospital in Cincinnati to help his widowed mother make ends meet.6 As a teenager, he began working as a surgical scrub technician when he witnessed long and difficult operations undertaken to remove blood clots from arteries. This inspired him to think of a new approach that he perfected as a medical student at the University of Cincinnati. He took a latex glove, cut off the fingertip and attached it to a plastic catheter, using fly-tying techniques he learned as a fisherman. Fogarty recounts how news of the unconventional device was received by the surgical community – rejected by three mainstream surgical journals and publicly criticized as being dangerous.7 He could not get manufacturers interested in the balloon catheter. Undaunted, he made the catheters by hand for himself and other vascular surgeons during his fellowship training in 1961 and 1962. The balloon catheter was finally patented in 1963, the same year that he published an account of its use in nine patients (Fig. 2).8 Two years later, Fogarty and colleagues were able to report their experience of its use in treating 50 patients with femoral or aortoiliac emboli; 80% of the patients survived and only two required an amputation.9 Today, more than half a million Fogarty catheters are sold annually (Edwards Lifesciences, CA, USA, pers. comm., 2008). Figure 2. Illustration of the original Fogarty embolectomy catheter.8 Reproduced with kind permission of the Journal of the American College of Surgeons. Fogarty was also a member of Dr Norman Shumway's team that performed the first heart transplant in the USA. Later, he became Director of Cardiovascular Surgery and Professor of Surgery at Stanford University School of Medicine. He maintained his passion for invention and minimally invasive techniques, acquiring over 110 surgical patents (T. Fogarty, pers. comm., 2008). According to Fogarty, the key to his success has been persistence to the point of obnoxiousness and an unwillingness to give up. Another important vascular discovery by a medical student was made by Auguste-Maurice Raynaud (1834–1881). The thesis for his medical doctorate in 1862 was entitled Local Asphyxia and Symmetrical Gangrene of the Extremities.10 In his thesis, he modestly described 25 patients, mostly women, with episodic vasoconstriction of the digits causing classical colour changes (white, blue and vermilion) associated with loss of sensation, pain and localized gangrene. Raynaud recognized that exposure to cold was a precipitant but mistakenly rejected occupational factors. During the next 30 years, he expanded and updated his observations.11Today, Raynaud's disease or phenomenon is recognized as a manifestation of a wide spectrum of clinical disorders. The son of a university professor, Raynaud studied medicine in Paris, where he also excelled in the arts, gaining a doctorate in literature in the same year as his medical degree. As an intern, he won numerous medals.12 After Raynaud reached the position of associate professor in 1866, his academic future looked bright but he never progressed to a senior position. He was turned down for both the anatomy and pathology chairs in Paris.11 Whether this was connected to his fervent Catholicism or public criticism of the Faculty Of Medicine is uncertain. He was eventually elected to the Academy of Medicine in 1879, having published more than 50 clinical papers. He died from ischaemic heart disease at the age of 47 years. Islets and Insulin The son of a successful physician, Paul Langerhans (1847–1888) was born in Berlin (Fig. 3). His mother died of tuberculosis when he was just 6, but he enjoyed a good relationship with his stepmother and half brothers (Hausen 1987). He studied medicine at the University of Berlin, where he was taught by the famous pathologist, Rudolf Virchow (1821–1902). During this period, Langerhans made not just one but two major discoveries. The first was the description of dendritic cells in the skin (now known as Langerhans cells). The second was the pancreatic islets. Figure 3. Paul Langerhans in 1873. © Bildarchiv Preußischer Kulturbesitz, Berlin, 1873, Photographer: Ruf und Dilger. The pancreas had been studied since the 16th century, but only the secretory acini and ductal system were known about, and the organ was classified anatomically as a salivary gland.13Langerhans began his research on the microscopic anatomy of the pancreas in the summer of 1867 but interrupted this in order to compete for and win the Berlin University medicine prize. He resumed his studies on the pancreas in October 1868 and completed the work in 6 months.14,15 Using pancreatic tissue from the salamander, rabbit and human, Langerhans recognized clusters of small ‘irregularly polygonal’ cells with clear cytoplasm diffusely scattered throughout the gland, each measuring 0.1–0.24 mm in diameter.16,17 He did not speculate on the function of these cells and was rather apologetic about his findings, stating, ‘With regret, I must begin my communication with the declaration that I cannot in any way put forth the conclusive results of a completed investigation. I can describe, at most, a few isolated observations which suggest a much more complicated structure of the organ (pancreas) than hitherto accepted’.13 It was not until 24 years later that the French histopathologist Edouard Laguesse (1861–1927) suggested that the ‘islets of Langerhans’ were the site of an internal secretion of the pancreas later named insulin. At the age of 27 years, Langerhans was appointed full professor at the University of Freiburg, but later the same month he was diagnosed with pulmonary tuberculosis, which forced him to eventually give up this position.15 After seeking treatment in Switzerland, Italy and Germany, he settled in Madeira. Here, he described more than 50 new species of marine worms, wrote a famous Handbuch für Madeira and practised medicine. In 1885, Langerhans married a widow, Margarethe Ebart; together with her daughter, they shared ‘three indescribably happy years’.18In July 1888, just days before his 41st birthday, he died from uraemia secondary to renal tuberculosis. He is buried in the British cemetery at Funchal, capital of Madeira. Insulin was discovered by Charles Herbert Best (1899–1978) and Frederick Grant Banting (1891–1941) in Toronto during the sweltering summer of 1921. In 1916, Best enrolled in a liberal arts programme at the University of Toronto, but his studies were interrupted by military service in World War I. Returning to Toronto in 1919, he switched courses to study physiology and biochemistry in preparation for a medical degree. In the autumn of 1920, Best's physiology professor, John JR Macleod, introduced him to Banting, a 28-year-old medical practitioner from Ontario. Banting had persuaded Macleod (with some difficulty) to let him use his laboratory for a research project over the summer of 1921. Banting was convinced that the crucial substance preventing diabetes mellitus would be found in the islets of Langerhans. These cells could be isolated in the dog after ligating the pancreatic duct, which caused the exocrine pancreas to atrophy. Banting suggested that injecting an extract of the islets into a diabetic dog would relieve the symptoms of diabetes. He would do the surgery but he needed an assistant to help with the animals' blood and urine tests. Another of Macleod's students was also interested in the job and the position was decided by the toss of a coin. Banting and Best first tested their pancreatic extract in a diabetic dog in July 1921 (Fig. 4). Within months they had confirmed its efficacy in treating diabetes. Banting and Best worked hard, eating and sleeping in the laboratory. Banting sold his car to raise money for their research. Macleod, who had been on holiday in Scotland during the summer, returned in September and advised further work to confirm the results. He also hired James Collip, a biochemist, to help purify the active component of the extract. By the time their paper was published in February 1922, Banting and Best had already treated a diabetic patient with the extract.19 Fourteen-year-old Leonard Thompson was expected to live for just a few more weeks. Before administering insulin to the boy, Banting and Best injected each other with their extract. There seemed to be no major side effects, and so, in January 1922, they went ahead and treated the boy. Thompson lived another 13 years, dying from complications of a road traffic accident. Banting and Best sold the rights to insulin to the University of Toronto for one dollar, stipulating that royalties would not be charged.20 Figure 4. Banting (right) and Best (left) standing on the roof of the Medical School Building, University of Toronto, with one of the diabetic dogs used in experiments with insulin. University of Toronto Archives, Frederick Grant Banting and Charles H. Best, 1921. A1978-0041/001(53), Acc IB001. The 1923 Nobel Prize in physiology and medicine was awarded to Banting and Macleod for the discovery of insulin. Banting was furious that Best had been left out and immediately decided to share the prize money with Best. Macleod divided his portion of the prize with Collip. Only later did the Nobel Foundation acknowledge that Best should have shared the award.21 But this was only part of a brewing controversy. A personal feud erupted between Banting and Macleod over the latter's role in the discovery22,23; later, this extended to disagreements between Banting and Best.23 Best continued his studies, receiving his MD in 1924. After a period of research in England, he returned to Toronto and, when Macleod retired, took over the chair of physiology. He was just 30 years old. After Banting's death in a plane crash in 1941, Best became Director of the Department of Medical Research at the University of Toronto. During his career, he received scores of medals, awards and honorary degrees. He was honoured by the Queen of England, the Pope and other heads of state. Charles Best died in 1978 from a ruptured abdominal aortic aneurysm. A personal biography was published by one of his sons in 2003.24
A pacemaker, a plexus and a sphincter Another hot summer's day, this time in 1906, was the setting for another major discovery. Dr Arthur Keith (1866–1955), an anatomy lecturer at the London Hospital, had just returned to his holiday cottage from a cycle ride when Martin William Flack (1882–1931) (Fig. 5), a medical student at the same hospital, excitedly showed him the ‘wonderful structure he had discovered in the right auricle of the mole’.25 Keith had persuaded Flack to spend the summer holidays studying the hearts of trapped moles, mice and frogs. Keith quickly recognized that Flack's findings closely resembled the atrioventricular node, which had been identified the year before by Sunao Tawara, a Japanese anatomist, and confirmed by Flack and Keith in an earlier study.26They rapidly established the presence of a ‘sino-auricular node’ in other vertebrate hearts and in so doing discovered the origin of ‘the dominating rhythm of the heart’ (Fig. 6).27 Figure 5. Portrait of Group Captain Martin William Flack. With kind permission of the Wellcome Trust, London. Figure 6. Coronal section of the mole's heart (figure 8, p. 184).27‘At the sino-auricular junction is a mass of tissue (A,E) totally different from surrounding musculature, lying in intimate contact with nerves’.With permission of Wiley-Blackwell Publishing. Arthur Keith subsequently enjoyed a career as a feted anatomist and expert on human evolution, but what became of Martin Flack? After graduating in 1908, he took up a travelling scholarship to Europe before returning to the London Hospital as lecturer in physiology. Here, he researched the invigorating effects of oxygen in athletes28 and continued his studies on the sinoatrial node. During the First World War, he worked for the Medical Research Council and, in 1919, was appointed as the first Director of Medical Research for the Royal Air Force. He continued to investigate cardiorespiratory physiology and developed techniques for assessing the physical fitness of prospective pilots.28,29 Flack died in 1931 from bacterial endocarditis,25 a complication of his childhood rheumatic heart disease. Augusta Klumpke (1859–1927) famously championed the rights of women doctors, but she is best known for her description of inferior brachial plexus injuries as a medical student in 1885 (Fig. 7). She was born in San Francisco, the second of four daughters. Her older sister, Anna, fractured her femur in early childhood, and when osteomyelitis set in, Augusta's mother took her daughters to Europe to seek medical advice. Two years later, they returned to San Francisco, but after two more children, Augusta's parents separated. In 1871, Augusta's mother took all six children back to Europe, determined to raise her daughters to be independent.30 Figure 7. Augusta Klumpke (left), at the age of 30 years, with the wife of Dr Paul Dubois, a Swiss psychiatrist and close friend of Jules Déjerine. With kind permission of the author Dr J. Bogousslavsky and European Neurology 2005; 53: 113–120 published by S. Karger AG, Basel. Augusta was destined to become a teacher until she read an article in a fashion magazine about a woman who had recently graduated in medicine in Paris. Augusta was excited by the prospect of medicine and so the family moved to Paris, where, in 1877, she was admitted to the Faculty Of Medicine.31 Here she excelled, studying under such notable figures as Ranvier (histology), Charcot (neurology) and Fournier (dermatology). Her fluency in French, German and English proved invaluable in understanding the contemporary literature. While working at the Hôtel-Dieu, she diagnosed a brachial plexus palsy associated with Horner's syndrome. This, together with experimental work, formed the basis of her undergraduate thesis and her eponymous description of lesions of the inferior roots of the brachial plexus.32 Her research won an Academy of Medicine prize but was not enough to secure her an internship in the exclusively male medical hierarchy. After repeated unsuccessful attempts and much lobbying, Augusta was finally allowed to compete for an internship and, in 1886, she became the first female full intern in a Parisian hospital. In 1888, she married Jules Déjerine, a distinguished neurologist. Together they collaborated on numerous neurology and neuroanatomy texts, many of which were skillfully illustrated by Augusta. Her doctoral thesis on polyneuritis, lead toxicity and neuromuscular atrophies (1889) received much acclaim. During World War I, she made important contributions to the care of soldiers with spinal cord injury. She later became the first woman president of the French Society of Neurology and was awarded the French Legion of Honour.33 She died at the age of 68 years, survived by her only daughter. She attributed her professional success (and that of her sisters) to her mother about whom she said, ‘She taught us not to give up when faced with difficulties, to persevere and to succeed’.30 The setting for the next famous discovery is late nineteenth century Italy. As a 23-year-old, fourth-year medical student at the University of Perugia, Ruggero Oddi (1864–1913) studied the actions of the sphincter at the distal end of the common bile duct (Fig. 8).34,35 He concluded that the sphincter controlled the intermittent flow of bile from the liver to the duodenum. He also suggested that dysfunction of the sphincter might cause biliary tract disease. The University of Perugia could not at that time award a medical degree, so Oddi continued his studies first at the University of Bologna, where he measured pressure changes across the sphincter,36 and subsequently in Florence, where he gained his degree in medicine and surgery in 1889. Two years later, Oddi married 23-year-old Teresa Bresciani Bartoli several months after their first child was born.37 In 1894, at just 29 years of age, he moved from Florence to Genoa to become Director of the Physiology Institute. During his 7 years in Genoa, he gained substantial academic recognition, but then for reasons that may have been related to family, drug addiction or illness, Oddi's career went into freefall, resulting in him leaving both his job and Italy. Figure 8. Ruggero Oddi. Courtesy of the National Library of Medicine. The photograph probably dates to 1906, when Oddi was 42 years old. In Genoa, Oddi had become friends with an influential aristocrat, Stefano Capranica, who owned the laboratory that Oddi used for his research. After the death of his mistress, Capranica became addicted to morphine and experienced a spiritual crisis that probably deeply affected Oddi. Before his death in 1899, Capranica donated all his property to the Genovese Curia, which duly confiscated Oddi's laboratory, uncovering financial irregularities and exposing Oddi's probable drug abuse in the process. Oddi either resigned or was dismissed.38 In parallel with these events, Oddi had needed surgery for appendicitis in 1898 and, 2 years later, for bowel obstruction. To escape the scandal, he moved to Brussels (where he was treated for depression) and thence to the Belgian Congo, where he worked as a doctor. Ill health, mental instability and narcotic abuse forced him to return to Belgium 6 months later.37 In 1905, he returned to Perugia, where he practised medicine, widely advocating the administration of Vitaline (a compound of glycerine, sodium borate, ammonium chloride and alcohol) for infectious and malignant diseases. After the death of one of his patients, he was accused of manslaughter and charged with ‘abusive commerce of medicinal products’.38 He became a broken man and left Perugia for Tunisia in 1911 where he died 2 years later at the age of 48.37 Penicillin and Ether This section consists of two discoveries by medical students that were both overlooked and later credited to others. The first of these was penicillin. In his 1897 graduation thesis entitled ‘Contribution to the study of vital competition between microorganisms: antagonism between moulds and microbes’, Ernest Duchesne (1874–1912), a 23-year-old medical student at l'École du Service de Santé Militaire in Lyon (Fig. 9), France, demonstrated the ability of the fungus Penicillium glaucum to treat pathogenic bacterial infections caused by Escherichia coli or Salmonella typhi.39 His studies included in vivo experiments in guinea pigs. Duchesne attributed this property to the existence of a toxin (an antibiotic) produced by the fungus. He also predicted its therapeutic potential. Unfortunately, Duchesne did not continue his research and never saw his work confirmed by Chain, Florey and Jennings in 1942 or the benefits of his discovery. It appears that he never came to terms with his wife's death from tuberculosis in 1903. He too contracted pulmonary tuberculosis and by 1907 was on permanent sick leave. He died at the age of 37. His work was only rediscovered in 194538 and was commemorated in a postage stamp issued in Monaco in 1974 on the centenary of his birth. Figure 9. Ernest Duchesne (1874–1912). With kind permission of l'École du Service de Santé Militaire de Lyon. According to Lyman,40 a medical student by the name of William E. Clarke was the first to administer ether anaesthesia for surgery. This event took place in Rochester, New York, in January 1842, enabling a dentist to perform a painless tooth extraction. Priority for the use of ether anaesthesia is usually given to others including Crawford Williamson Long (1815–1878), who, as a young country doctor in Georgia in March 1842, administered ether to a young man from whom he painlessly excised a small cyst from his neck.41,42 Although Long performed several further operative procedures under ether anaesthesia, he did not publish an account of his activities until 1849, several years after Horace Wells' personal experiment with nitrous oxide (1844) and William Morton's public demonstration of ether anaesthesia (1846). Spermatozoa We end this review at the beginning of life. Spermatozoa were first discovered in 1677 by Johan Ham (1651–1723), a medical student from Leiden who brought Antoni van Lewenhoeck (alt.Leeuwenhoek) (1632–1723), a specimen of urethral discharge from a man with gonorrhoea in which Ham had found small living ‘animalcules’ with tails.43 Lewenhoeck was a poorly educated Dutchman whose passion for making lenses and studying biological tissues and microorganisms later earned him a place in history as the father of microscopy.44,45 According to one source, Ham may have first identified spermatozoa in the semen of a rooster.43 He also noted the absence of spermatozoa in the semen of sterile men43 and the fact that they did not survive beyond 24 hours.46 After Ham's visit, Lewenhoeck studied his own semen (obtained by ‘conjugal coitus’ and not from ‘sinfully defiling’ himself) and confirmed the presence of motile animalcules, less than a millionth the size of a coarse grain of sand, with blunt round bodies and thin, undulating transparent tails. A month later, Lewenhoeck reported these findings in a letter to the Royal Society in London in which he credited Johan Ham with the discovery (Fig. 10).46,47 The letter was in Latin because of the delicate nature of its content. The impact of Ham's discovery and Lewenhoeck's observations on the theory of generation was immense. Although Ham may have first suspected the relevance of spermatozoa to reproduction, it was Lewenhoeck who proposed that fertilization followed the penetration of the ovum by the sperm, although he mistakenly believed that the spermatozoon contained a preformed individual.43 Figure 10. Lewenhoeck's drawings of spermatozoa,46 reproduced with permission of The Royal Society. Figure 1 depicts a living rabbit spermatozoon, while figures 2–4 are dead. Comment This account of famous discoveries by medical students is neither comprehensive, nor are the biographies exhaustive. Figures such as Galileo and Keats who never completed their medical studies but made such profound ‘discoveries’ in other walks of life have been overlooked. So too have some notable other discoveries by medical students such as the roller pump invented by Michael DeBakey (1908–2008), which subsequently became an essential component of the heart lung machine.48 However, from the selected biographical sketches, a few common themes emerge. All of these achievements have impacted on the practice of surgery. They were the result of intense effort. To quote the great inventor Thomas Edison (1847–1931), ‘Success is ten percent inspiration and ninety percent perspiration.’ Several of these students suffered loss of a parent and/or particular hardship in childhood, which undoubtedly strengthened their resolve to succeed. This is well demonstrated by Klumpke and Fogarty. Another thread that binds many of these discoveries together is the opportunity for research by medical students. In the latter half of the 19th century, European medical students had to write and defend a research thesis for their doctorate in medicine. This was the platform on which the discoveries of Raynaud, Langerhans, Klumpke, Oddi and Duchesne were built. In England and North America, summer research projects seem to have been particularly fruitful for Flack, McLean and Best. Opportunities for research by medical students in an increasingly crowded undergraduate curriculum need to be preserved. Although some of the spontaneity and freedom of research are restricted by today's bureaucracy, the opportunity for discovery is still there. In a world overwhelmed with biomedical publications, modern medical students might wonder if there is anything left to discover. A quick search on the Internet is usually enough to suggest that any idea has already been exhaustively explored or that new discoveries are only possible in molecular biology. But students and teachers must not be discouraged. The most naive questions are often the best. John Shaw Billings (1838–1913), founder of the National Library of Medicine, vowed to establish the world's greatest medical library when he was a medical student. He said, ‘There is nothing really difficult if you only begin. Some people contemplate a task until it looms so big it seems impossible. But I just begin and it gets done somehow. There would be no coral islands if the first bug sat down and began to wonder how the job was to be done’.49 Acknowledgements We wish to thank Dr Thomas J Fogarty for kindly commenting on his biographical details; Jonathan Evans, Trust Archivist, Royal London Hospital Archives and Museum, for biographical information on Martin Flack; Rachael Cross, Picture Researcher, The Wellcome Trust, London, for her help with the portrait photograph of Flack; Eva Galamand, librarian at the Ecole du Service de Santé des Armées, Bron, France for the photograph of Ernest Duchesne; and Dr K John Dennison for kindly translating parts of van Lewenhoeck's Latin manuscript. Source
