Maxwell Wintrobe, in his own words
2003; Wiley; Volume: 121; Issue: 2 Linguagem: Inglês
10.1046/j.1365-2141.2003.04188.x
ISSN1365-2141
Autores Tópico(s)Empathy and Medical Education
ResumoWhat follows is a story rich in irony that illustrates the influence of chance in human affairs. It is a story about a man without specific career objectives who founded a Department of Medicine and was instrumental in the development of a medical school: a man without formal scientific training who was the recipient of the first research grant awarded by the National Institutes of Health and was elected to the National Academy of Sciences; a man without formal training in haematology who wrote the most authoritative textbook on the subject; a man who had no mentors but trained 110 postdoctoral fellows; a man who believed that internal medicine should be an indivisible entity but whose work was responsible for establishing haematology as a distinct subspecialty; a man who experienced discrimination but who always made others feel welcome; a man who, by his own efforts, achieved international renown but whose autobiography includes the biographies of all his colleagues and contemporaries. Finally, it is a story demonstrating that what is important is the journey, not the destination. ‘We lived on what we had and tried to do the best with that’ (Wintrobe, 1985). Maxwell Myer Wintrobe was born on 27 October 1901. His childhood was spent in Halifax, Nova Scotia where his parents, both from Tarnopol in Austrian-ruled Galicia, had emigrated to join his mother Ethel's family. Lacking a formal education, Wintrobe's father tried many jobs to make ends meet, an accomplishment achieved only by dint of extreme frugality on the family's part. This situation not only left a deep impression on Maxwell but was also one from which he would not escape for many years. Indeed, in his autobiography, when using the careers of contemporaries to illustrate the status of haematology in the 1930s, it was probably not coincidental that Wintrobe's choices were two physicians, Claude Forkner and William Moloney, who themselves had experienced severe financial hardship during their early years (Wintrobe, 1985). In 1912, in search of better employment opportunities, Wintrobe's father moved the family to the cold, wind-swept province of Manitoba, far from the warmth of their extended family in Halifax. Ironically, although he could not know it then, this was not to be Wintrobe's last journey to a far-flung Western outpost. Wintrobe's situation, however, was mitigated by being an only child with a doting mother, who encouraged him not only to excel at school but also to participate in other activities, including playing the violin. One suspects her admonitions to study reflected the attitude of Maxwell's teachers as class work came easily to him and he would only study as hard as was necessary to keep up. Even this effort, however, was sufficient for Wintrobe to complete 8 years of grade school in 6 years and to enter the University of Manitoba at age 15 years. At the same time, he held a variety of jobs: selling and delivering newspapers, collecting bills, teaching art, working in a vinegar factory, selling used books, teaching the violin and cooking for farm workers as his contribution to the war effort. Although the Canadian educational approach required only 1 year of college before matriculation in medicine, because of his age and a desire for a complete general education, Wintrobe chose to enroll in the 4-year curriculum, a choice made possible by the award of two scholarships. Interestingly, Wintrobe's premedical interests did not include science, though he took the required courses, but rather English, Latin, history, French and political economics; for the latter two, he was awarded gold medals and he also excelled in composition (Wintrobe, 1985). Given the eloquence of his prose and the breadth of his literary allusions, Wintrobe obviously made the most of his liberal arts exposure. ‘I do not recall why I chose medicine except perhaps for the fact that it was a respectable and rewarding occupation’ (Wintrobe, 1985). Wintrobe found his medical courses, with the exception of Pathology, more interesting than his teachers and even inquired about transferring to Johns Hopkins during his third year. Nevertheless, he excelled at every level, standing first in his class and receiving scholarships for his efforts. Yet at graduation, he felt less than well educated and was not interested in following his classmates into private practice or to England for further study, even if the latter was an attainable proposition. It was at this point that a postgraduate fellowship, newly created for the medical school's retiring Dean, Gordon Bell, was offered to Wintrobe. ‘Having no other interesting or promising alternatives…’ (Wintrobe, 1985), he accepted. The fellowship provided Maxwell with his first stipend and gave him the opportunity to participate in both an epidemiological and a basic research project involving pernicious anaemia. This was the exciting topic of the day as Minot and Murphy had just published their report on the success of liver therapy in this previously fatal disorder (Minot & Murphy, 1926), a report that had a profound influence on Wintrobe. Little came of Wintrobe's survey of the gastric contents of residents in several Manitoba towns; his attempt to create achylia gastrica in dogs using steam was also a failure, but this did not diminish his interest in research or in the pathogenesis of pernicious anaemia (Wintrobe, 1928). More importantly, the fellowship gave him the opportunity to read, think about his future and search for a job. At the point of decision, he was left with three choices: a fellowship at the Mayo Clinic, a position as a physician for a Chicago plumbing company or as an Assistant in Medicine at Tulane. The only opening at Mayo was in paediatrics not surgery and Wintrobe decided on New Orleans rather than Chicago; after all, the salary was such that he could now afford to marry (Wintrobe, 1985). ‘That I chose to go to New Orleans was without doubt the most fortunate decision that I ever made in my life’ (Wintrobe, 1985). With respect to what follows, it is worth remembering that Wintrobe was only a 26-year-old when he began his first faculty position. New Orleans and Tulane could not have been a more different experience for Maxwell and his bride, Becky. The semitropical climate was a far cry from the −50°F environment of Winnipeg and Southern racial segregation came as an unpleasant surprise, but the couple was warmly welcomed into the Tulane medical community. Wintrobe was enthralled with the academic environment. Here there were full time physicians engaged in both clinical care and laboratory research while Charity Hospital provided the full spectrum of medical illness. Furthermore, the scenario of a wise Dean with an interest in laboratory medicine recruiting a promising young physician would become a familiar one in Wintrobe's career. His first research project, concerning a method for measuring renal function, also had a theme that would become familiar: the development of a simple laboratory test that would be useful to clinicians (Wintrobe, 1929a). The resulting publication also demonstrated a meticulous and thorough approach to laboratory research on the part of its author. Based on Wintrobe's fellowship projects, John Musser, Tulane's chief of Medicine suggested that he determine whether the so-called ‘anaemia of the South’ was a true clinical entity. What would appear today as a rather pedestrian assignment of no academic merit was then a formidable task. Clinical medicine at the time was more art than science, largely because of lack of adequate technology and, with respect to the study of blood in particular, the technical problems involved in counting blood cells or measuring their haemoglobin content were substantial (Gray, 1921). Haemoglobinometers were difficult to use, inaccurate, not standardized and only gave results in proportion to a ‘normalized’ value, although no one had ever adequately established what ‘normal’ was, or even whether it was influenced by age or sex. Furthermore, the methods that existed for the measurement of red cell number, packed cell volume and red cell size were also technically demanding, in addition to a paucity of up-to-date data on what constituted normal and continued reliance on values obtained a half-century earlier using crude techniques. However, as early as 1903, Capps had described the volume index, a means of using the red cell volume to distinguish primary (macrocytic) anaemias from secondary (microcytic) anaemias. This approach had considerable value in identifying patients with pernicious anaemia, which was the principal focus of attention in that era, and when Wintrobe began his studies at Tulane, prominent investigators such as Edward Osgood in Portland (Osgood & Haskins, 1927), Russell Haden in Kansas City (Haden, 1923), William Murphy of (pernicious anaemia fame) in Boston (Murphy & Fitzhugh, 1930) and Hans Christian Gram in Copenhagen, known more widely for his bacterial stain (Gram & Norgaard, 1923), were actively examining the relationship between red cell volume and haemoglobin content in normal and anaemic individuals. Initially, for comparative purposes, Wintrobe chose to use the methodology adopted by his American colleagues and demonstrated that blood values in normal individuals residing in the South were not different from individuals in other areas of the country (Wintrobe & Miller, 1929). However, recognizing the inadequacy of the existing technology and of the interpretation of the data obtained, Wintrobe set out to rectify the situation. He developed an improved device for measuring haemoglobin: the Hellige–Wintrobe Haemometer but, more importantly, recognizing that the packed red cell volume offered the most rapid and accurate method for identifying anaemia, he developed an improved haematocrit for this purpose (Wintrobe, 1929b). The device was so simple that it did not occur to either Wintrobe or Tulane to patent it nor did he subsequently accept royalties when offered, which was remarkably admirable conduct considering his financial situation. The ‘Wintrobe’ haematocrit proved useful not only for measuring the volume of packed red cells for which it became eponymous but also for determining the erythrocyte sedimentation rate (Wintrobe & Landsberg, 1935) and for macroscopic evaluation of the blood (Wintrobe, 1933). Indeed, it was in the course of examining a spun blood specimen in this fashion that Wintrobe discovered the first monoclonal cryoglobulin (Wintrobe & Buell, 1933). Having developed satisfactory methods for packed cell volume and haemoglobin measurements, Wintrobe turned his attention to the expression of red cell volume and haemoglobin content. As indicated above, he was not the first to address this issue but his approach would provide the foundation upon which modern haematology practice is based. Dissatisfied with the indirect expression of these measurements using the currently accepted colour, volume and saturation indexes that relied on poorly defined norms as standards, Wintrobe decided to calculate red cell volume and haemoglobin content directly as mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC) (Wintrobe, 1929c, 1930a). In his own words: ‘The idea of calculating the average size and haemoglobin content of the red corpuscules in this way came to me in the middle of the night after I had been puzzling for some time about how one could improve and make more understandable what had been attempted by the introduction of the indexes but required artificially chosen percentages and was expressed in terms that were indirect’ (Wintrobe, 1985). This simple, direct approach enabled Wintrobe to quantitatively classify the anaemias in a logical manner not previously contemplated. In a 1934 landmark article, involving the analysis of more than 1000 patients and normal control subjects, Wintrobe firmly established that anaemias could be subdivided into four categories on the basis of MCV and MCHC that not only reflected differences in their pathophysiology but also their expected response to treatment (Wintrobe, 1934). To appreciate the significance of this 28-year-old physician's intellectual achievement, it is necessary to understand the conception of anaemia at that time. This is best illustrated by the classification proposed by Russell Haden, one of the foremost haematologists of that era (Haden, 1932) (Fig 1). Russell Haden's classification of anaemia based on red cell number, volume and haemoglobin content. (Haden, R. Arch Intern Medical 1932, 49: 1039). Copyrighted (1932), American Medical Association. Although Wintrobe's classification system put the practice of haematology on a quantitative basis, it was not immediately embraced; it is likely that the subsequent publication of his haematology textbook had more to do with its acceptance than the logical nature of his classification system. In 1928, Musser invited Wintrobe to join him as co-author of the ‘Diseases of the Blood’ section of Tice's Practice of Medicine, a popular 10-volume, loose-leaf text. Wintrobe agreed, but Musser's other obligations prevented him from participating except in name only, and Wintrobe (without any haematology training) was left to his own devices. His response was to carefully document every statement with the result that the section's bibliography was copious, a departure from the usual practice at that time (Wintrobe, 1985). The final product, however, was truly outstanding and one that is still fascinating to read even if only as medical history. It is an irony that when Wintrobe decided to expand this section into a freestanding book, Tice's publishers declined the opportunity to publish it. One further episode in Wintrobe's Tulane sojourn illustrates his exceptional energy and organizational skills. Recognizing that his research would be acceptable for a doctoral degree, he enrolled in Tulane's Ph.D. programme with the thesis topic ‘The Erythrocyte in Man’. This remarkable decision had more far reaching consequences as it resulted in Wintrobe's recruitment to Johns Hopkins. During the course of his research, Wintrobe had sought statistical advice from Raymond Pearl, a professor in Hopkins' School of Hygiene and Public Health. Pearl invited him to Baltimore to review his data and Dean Bass agreed to underwrite the visit. During the visit, Wintrobe was introduced to Hopkins' Dean, Alan Chesney. Chesney was also the editor of the journal Medicine and in charge of the medical school's Division of Clinical Microscopy. When Wintrobe decided to submit his thesis to Medicine for publication, there happened to be a faculty opening in Chesney's Division. Not only was his manuscript accepted for publication (Wintrobe, 1930b) but Wintrobe was also offered this position, fulfilling his longtime wish to work at the institution that William Osler had helped to found. It is interesting to tabulate Wintrobe's productivity during his tenure at Tulane. Within 3 years, and before his thirtieth birthday, he had published 11 papers including a doctoral thesis and a 157-page book section (not counting its bibliography). This alone would be a remarkable intellectual accomplishment but it must be coupled with the fact that he had created a classification of anaemia using quantitative and reproducible methods that would become the standard of practice in haematology; in essence, he had established haematology as a scientific discipline. ‘A rude shock awaited us’ (Wintrobe, 1985). Neither Cushing's Life of Osler nor 3 years in New Orleans prepared Maxwell & Becky Wintrobe for Baltimore in 1930. Segregation in this city encompassed ethnicity as well as race, and restrictive covenants prevented the Wintrobes from residing in or even visiting certain neighbourhoods such as the bucolic urban enclaves of Roland Park or Guilford where many of the Hopkins' faculty lived. Indeed, when the Wintrobes dined at my home 50 years later, it was their first visit to Roland Park and one that would not have been possible for either family a few years earlier. While the friendly and gregarious couple developed a close circle of friends outside the Hopkins community, the situation left an indelible impression on them and was partly responsible for their move to Utah in 1943. Professionally, however, Hopkins was all that Wintrobe could have wished for (Fig 2). A talented faculty with a gift for assistance and collaboration, students and residents interested in research and a wealth of clinical material for study. In a familiar refrain, because of Chesney's obligations as Dean, the responsibility for the Division of Clinical Microscopy fell to Wintrobe. In typical fashion, he reorganized the teaching of third year student laboratory skills by involving patients and developed a laboratory manual that served as a guide for the haematology section of the second year pathophysiology course until the 1970s, when the introduction of automated cell counters eliminated the practice of near patient testing. By bringing a microscope and a technician to the outpatient clinic, he made blood smears as available to physicians as their patients' radiographs and electrocardiograms, a practice that continues to this day in the Hematology clinic at Hopkins. With respect to research, Wintrobe continued to accumulate data, substantiating his classification of anaemia and his results on normal blood values and, as mentioned above, also expanded the use of the Wintrobe tube. One important result of his studies was the recognition that so-called idiopathic hypochromic anaemia was iron-responsive (Wintrobe & Beebe, 1933). Unfortunately, as a result of his interest in pernicious anaemia, his focus on the achlorhydria seen in this situation apparently obscured the recognition that iron loss was the cause of the anaemia, an observation that was left for William Castle and colleagues to make (Heath et al, 1932). Maxwell Wintrobe at Johns Hopkins in 1940. Printed with permission from The Alan Mason Chesney Medical Archives of the Johns Hopkins Medical Institutions. Lacking funds to pay for technical help, Wintrobe sought out individuals willing to work for nothing, including Saturdays, for a set time period. In exchange, Wintrobe trained them and promised full-time employment if funds became available. This approach was extremely successful, yielding a stream of talented individuals with whom he developed long and productive professional relationships. One of these was Regina Weistock, a part-time college student who was pursuing studies in chemistry and biology at Hopkins (Fig 3). Weistock proved to be so talented that she was offered a salaried technician's position within 6 months and remained as loyal employee of the institution for over 50 years, teaching generations of students, residents and fellows the art of preparing and interpreting blood smears. Ms Weistock is worth mentioning, not just because she was Wintrobe's first technician but also because she was instrumental in the recognition of the thalassaemia trait in the USA. A half-century of haematology at Johns Hopkins. From the left: C. L. Conley, M. M. Wintrobe, Regina Weistock and the author in 1982. (From the author's collection.) Observing many stippled red cells on the blood smear of a patient of Italian extraction and suspecting lead poisoning, Weistock, on her own initiative, performed an osmotic fragility test. However, the cells were osmotically resistant and the blood lead level was normal. A repeat osmotic fragility test gave the same result. A month later, she recognized similar abnormalities on a blood smear and once again repeated testing of that patient's blood yielded the same results. When Wintrobe was informed of these observations, he suggested that a mistake must have been made but Ms. Weistock was adamant that she would not make the same mistake four times in a row (Harvey, 1976)! Two years later, a patient with Cooley's anaemia was admitted to the medical service and Wintrobe decided to examine the blood of the family, which had never been done before. Upon examining the blood smears, Ms. Weistock recalled the previous two patients who had the same red cell abnormalities. Wintrobe immediately recognized that they were dealing with a ‘benign’ form of thalassaemia and his publication about these patients established the hereditary basis of this disease (Wintrobe et al, 1940). Wintrobe's studies of the blood during this period were wide ranging. Most notably, in collaboration with Arnold Rich, he was able to distinguish between leukaemic myeloblasts and lymphoblasts on the basis of their locomotion, providing the first description of the ‘hand mirror’ configuration of the latter (Rich et al, 1939). They also described the response of lymphocytes to foreign proteins, anticipating future discoveries about lymphocyte function. The quantitative analysis of red cell size and haemoglobin concentration led to his recognition of the macrocytic anaemia associated with liver disease (Wintrobe & Schumacker, 1933; Wintrobe, 1936); a series of studies in dogs trying to create an animal model followed. His intellectual curiosity also extended to comparative haematology. With the assistance of his wife, whom he trained, he studied the blood of a variety of fishes during summers at the Marine Biological Laboratory in Woods Hole Massachusetts, various mammals at the Washington Zoo, observing that regardless of size, red cells from all species had a comparable haemoglobin content (Wintrobe, 1930b). He also encouraged medical student research and it was in his laboratory that Irving Sherman discovered the birefringence that occurred with red cell sickling (Sherman, 1940), an observation that led to Linus Pauling's epochal studies. However, his greatest effort was directed at establishing the aetiology of pernicious anaemia by applying Koch's postulates to Castle's hypothesis. Impressed with Ehrlich's observation that fetal haematopoiesis shared many morphological similarities with that of pernicious anaemia, he sought to develop an experimental model using newborn animals. Initially, the opossum seemed promising, because the offspring could be returned to the mother's pouch after study, but was abandoned when the mother devoured the experimental subject and the rest of her litter. Newborn pigs, whose diet is similar to humans and whose stomach contained intrinsic factor, proved to be more pliable (Wintrobe, 1985). However, there was no published information on the nutritional needs of the pig, and this had to be defined before Wintrobe and his collaborators could test the hypothesis. Considering what is known today about the pathogenesis of pernicious anaemia, Wintrobe's quest seems quixotic unless the one considers the profound impact that Minot and Murphy's discovery had on Wintrobe at a seminal stage in his career. ‘As an intern, in 1925–26, I was confronted with the usual medical dilemmas, one of which was our ineffectiveness in the treatment of many diseases. Tonics, carminatives, and a few other similar concoctions for easing our patients’ symptoms were listed in the Hospital Formulary we carried, but specific therapeutic agents such as digitalis were few… Except for conditions that could be treated surgically, our patients either recovered as a result of their own resources or succumbed to their illnesses. The report in 1926 that liver was effective in the treatment of an invariably fatal disease, pernicious anaemia, came as a bright ray of sunshine on this dismal landscape’ (Wintrobe, 1985). Not surprisingly, based on what we know today, Wintrobe failed to define the pathogenesis of pernicious anaemia. However, 14 years of studying the effect of nutritional deficiencies on porcine haematopoiesis yielded valuable but unexpected biological insights, and had additional collateral benefits and consequences. First, these studies, begun with George Cartwright, a Hopkins medical student, initiated a life-long collaboration between the two men. Second, as the University had never received funding from a commercial source, Wintrobe's funding for the project from the pharmaceutical manufacturer Parke Davis led to the development of an institutional policy that today would be deemed unusually restrictive but is very refreshing (Wintrobe, 1985). In essence, Parke Davis' support would be acknowledged in publications but they were denied prior access or any other privileges regarding the data obtained. From a scientific perspective, by defining the pig's nutritional requirements, Wintrobe and his collaborators discovered the biological consequences of pyridoxine deficiency before this deficiency state was recognized in humans, and the obligatory role of pyridoxine in haem synthesis. They also described the haematological consequences of copper deficiency and the importance of this heavy metal in iron metabolism, anticipating the subsequent recognition of ceruloplasmin as a ferroxidase (Wintrobe, 1967). Megaloblastic anaemia was eventually induced in the pig but it proved to require both vitamin B12 and folic acid for its correction, and no neurological deficits occurred. However, the course of these experiments had an unusual twist and, although it brought Wintrobe national attention, would probably be viewed with disfavour by an institutional review board today. Lacking a suitable bioassay for the extrinsic factor activity of a non-autolysed yeast preparation that was to be used as a nutritional supplement in his pigs, Wintrobe decided to test the preparation by feeding it to pernicious anaemia patients. To his surprise, large amounts of the yeast produced a salutary haematological response. Expanding these studies despite the disapproval of his department chairman, Warfield Longcope, Wintrobe demonstrated that brewers' yeast was as effective as liver therapy but not did not contain the same active factor (Wintrobe, 1939). He had discovered folic acid though he could not have known it at the time. Nor could Wintrobe have been aware that the use of folic acid in the treatment of pernicious anaemia led to irreversible neurological deficits, although subsequently he would show that the antipernicious anaemia factor in liver could not correct folic acid deficiency (Cartwright et al, 1948). Presented at the spring clinical meetings in Atlantic City in 1938, the study attracted national attention (Anonymous, 1938); it also attracted the gratitude of a brewery, which sent Maxwell a case of beer (Wintrobe, 1985). Wintrobe's attempt to create an animal model for pernicious anaemia, albeit unsuccessful, not only demonstrated his tremendous fascination with this disease, it also demonstrated his tenacity of purpose and meticulous approach to a research problem. However, even he recognized that his quest might seem unimportant to some and his answer was as follows: ‘Those who have experience in research will answer that never has painstaking observation been made that it did not bear fruit, even though the result may not have been of the nature or even the direction expected’ (Wintrobe, 1957). In essence, in science, as in life, it is still the journey that is important. In a familiar refrain, during his tenure at Hopkins, a kindly Dean once again allowed Wintrobe to travel. In this instance it was to Europe to consult with a German scientist about fetal haematopoiesis. Although this did not prove useful to his research, Wintrobe also used his sabbatical time to visit the important medical institutions and over 40 influential haematologists and blood researchers in seven countries, including Janet Vaughan, A. E. Boycott, Price-Jones, Parkes-Weber, Joseph Barcroft and Robb-Smith in England, H. C. Gram and E. Meulengracht in Denmark, Paul Morawitz in Austria, and Otto Naegeli in Switzerland. At home, although promotion was slow, Wintrobe's responsibilities grew, and he was appointed Chief of the Clinic for Nutritional, Gastrointestinal and Hematological Disorders, succeeding Thomas Brown who had trained with Osler. By now Becky Wintrobe had joined her husband at Hopkins as the technician for the hospital's Diagnostic Clinic. In 1937, after 10 years of marriage, their first child, Susan Hope, was born; the delay in this event dictated by financial considerations, including the need to support Maxwell's parents (Wintrobe, 1985). The onset of World War II coincided with the completion of the manuscript for the first edition of Clinical Hematology, a textbook unusual for the degree of bibliographic documentation and thereby not attractive to some publishers at the time. However, it was to become the most influential text of its kind ever published and, true to Wintrobe's scholarly habits, the book included a fully referenced section on comparative haematology. Wintrobe's assignment during the war effort was to study chemical warfare agents, an assignment that would subsequently lead to a landmark publication with Louis Goodman and others on the beneficial effects of the nitrogen mustards when used as chemotherapeutic agents (Goodman et al, 1946). In 1943, Wintrobe was offered the opportunity to be the first chairman of the Department of Medicine at the University of Utah Medicine School, which was converting from a 2-year to a 4-year programme. The invitation was unexpected and the prospects were uncertain to a Canadian, who, although raised in western Canada and who had been a United States resident for 16 years, knew nothing about Utah. At the time, Wintrobe's research was going well and, overall, he and his wife, who was expecting their second child, Paul, were ‘not unhappy’ (Wintrobe, 1985). On the other hand, promotion opportunities at Hopkins were limited and Wintrobe felt that there was no prospect for any one from his background to become a department chairman. Furthermore, both Allen Gregg, vice president of the
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