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About heparin, or … Whatever happened to Jay McLean?

1989; Elsevier BV; Volume: 10; Issue: 1 Linguagem: Inglês

10.1016/0741-5214(89)90277-2

1097-6809

Nathan P. Couch,

History of Medical Practice

When I began work on this address several months ago, I could not easily decide on a topic. My first impulse was to speculate about the future. Where will our subspecialty be in only 12 years at the double turn of century and millenium? Will it exist? What about all of the changes that have already happened in the treatment of vascular disease: enzymatic thrombolysis; balloon, laser, and radiofrequency angioplasty; antismoking campaigns; triglyceride and cholesterol control by drugs, fish, bran, or oats? What about better control of hypertension and compulsive exercise or other disturbing news? Is there any hope for our youthful, prematurely aging, subspecialty? After considerable thought I decided not to trust my crystal ball, especially when most vascular surgeons, including some of the bigwigs, were predicting doomsday. The last time we approached a millenium many people expected a terminal cataclysm. They were disappointed when it did not happen. Especially disappointed were those who borrowed large sums of money expecting no need to repay it. Clairvoyance seemed risky so I considered a look backward. What about an overview of the origins and evolution of vascular surgery? It would be a much less busy specialty if people had not begun to live longer in the last half of the nineteenth century because of better understanding and prevention of infectious diseases, a benefit only partly nullified by more deadly weaponry such as the breech-loading rifle, the machine gun, poison gas, and the cigarette machine. What if the average life span in this country were only about 38 years, as it was in the eighteenth century? Most of us would not be around, planning our futures. This speech would include the usual homage to nineteenth century surgical worthies like William S. Halsted and all of his pioneering surgical brethren and students, and the generations of professional descendants whose labors brought major advances to surgical art and science. But you already know about that. I decided to talk about heparin and its history because of its great clinical importance and a history that became ever more intriguing as I dug around in its archives, and because knowledge gained just in the past 15 years had shown us what a complex and multifunctional agent it really is. The story of heparin began about 20 years before the last century ended. As so often happened in the recent origins of medical and other modern technology, Germany was a leader. The first solid evidence that mammals harbor indigenous anticoagulants came with the work of Schmidt-Mulheim,1Schmidt-Mulheim A Beitrage zur Kenntniss des Peptons und seiner physiogische Bedeutung.Arch Physiol. 1880; 33Google Scholar cited by Best,2Best CH. Preparation of heparin and its use in the first clinical cases.Circulation. 1959; 19: 79-86Crossref PubMed Scopus (65) Google Scholar which shows that Witte's "peptone," a kind of polypeptide stew, produced shock and incoagulability of blood when injected into dogs. In 1905 Morawitz reviewed peptone shock research and concluded that it "is the most thoroughly investigated field of blood coagulation,"3Jaques LB. Addendum: the discovery of heparin.Semin Thromb Hemost. 1978; 4: 350-353PubMed Google Scholar but the analytic methods of the time did not enable very precise characterization of the anticoagulant. Additional progress awaited the work of two of our protagonists: Howell and McLean. William Henry Howell was born in Baltimore in 1860 and was educated in local schools where he became interested in chemistry and medicine. During his third year in high school (Baltimore City College), he accepted a paid appointment as an assistant to a natural science teacher, which gave him the opportunity to perform experiments. In 1879 he entered Johns Hopkins University, and 2 years later he obtained an AB degree. He joined the faculty and fulfilled the requirements for a PhD in biology in 1884. The title of his dissertation was "Experiments upon the Blood and Lymph of the Terrapin, and the Origin of the Fibrin Formed in the Coagulation of the Blood." He continued on the Johns Hopkins faculty until 1889 when he accepted an appointment at the University of Michigan as chairman of the Department of Physiology, where he succeeded Henry Sewall, who had tuberculosis. In that same year, at age 29 years, he became a charter member, with 27 others, of the American Physiological Society. The group included such worthies as S. Weir Mitchell of Philadelphia, H. Newell Martin of Baltimore, and Henry Bowditch of Boston. 4Fye WB. Heparin: the contributions of William Henry Howell.Circulation. 1984; 69: 1198-1203Crossref PubMed Scopus (11) Google Scholar, 5Chesney AH Holt Jr, LE Baetjer AM. An anniversary tribute to the memory of the late William Henry Howell.Bull Johns Hopkins Hosp. 1961; 109: 1-19Google Scholar, 6Erlanger J. Biographical memoir of William Henry Howell (1860–1945).in: National Academy of Sciences of the United States of America Biographical Memoirs. 26. 1950: 153-180Google Scholar Howell left Michigan after only 3 years because he found that many of his students were unruly,4Fye WB. Heparin: the contributions of William Henry Howell.Circulation. 1984; 69: 1198-1203Crossref PubMed Scopus (11) Google Scholar and he moved to the refined environment of Harvard, where he became an associate professor in Bowditch's department. Howell lasted only 1 year there because he accepted the chairmanship of the Department of Physiology in the new Johns Hopkins medical school in 1893 when he was 33 years old. He gained a reputation as an outstanding lecturer, laboratory instructor, and administrator, and he was known for a host of other virtues including courtesy, fairness, and eloquence. In 1899 he became dean of the medical school and remained in that post until 1911 when he resigned because of ill health—he had a duodenal ulcer. (It was probably a coincidence that his deanship was synchronous with Harvey Cushing's presence at Johns Hopkins. Cushing left for Boston in 1913 to become the first surgeon-in-chief at the New Peter Bent Brigham Hospital, where he was to spend a few years sparring with another dean, David Linn Edsall, over turf and territory.7Aub JC Hapgood RK. Pioneer in modern medicine: David Linn Edsall of Harvard.in: Harvard Medical Alumni Association, Boston1970: 228-229Google Scholar) Howell's best known academic contribution during the same decade was his Textbook of Physiology (1905), which eventually went through 14 editions. Although he gave up the deanship, he continued to work in his laboratory where he studied blood components, the cardiac effects of electrolytes, and nerve function. In 1910 he found a way to isolate thrombin, just 5 years before Jay McLean entered the medical school. Who was McLean? He was born in San Francisco in 1890.8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar In 1906 his family was ruined by the earthquake and fire, but he managed to obtain his Bachelor of Science degree in 1914 at the University of California when he was 24 years old. He entered Johns Hopkins University in 1915 and met Howell, who was trying to determine which tissues and organs contained clot-promoting agents. As McLean said in his landmark paper of 1916,9McLean J. The thromboplastic action of cephalin.Am J Physiol. 1916; 41: 250-257Crossref Google Scholar his task was to "determine if possible whether the thromboplastic effect may be attributed to an impurity, or is a property of cephalin itself, and also to determine in how far [sic] a similar property is exhibited by other related phosphatids. …" Further, "The cuorin [from ox heart] on the contrary when purified by repeated precipitation in alcohol at 60 degrees, has no thromboplastic effect—indeed it possesses an anticoagulating power … the heparphosphatid on the other hand when purified by many precipitations in alcohol at 60 degrees has no thromboplastic action and in fact shows a marked power to inhibit coagulation." Strangely, the title and the four points made in the conclusions only refer to the thromboplastic effects of the brain, heart, and liver extracts and not to the anticoagulant effects. McLean did no further work at the time, probably because he was busy completing medical school. Howell, who had let McLean be the sole author of the 1916 paper, continued the work, with the help of T. Emmett Holt, analyzing the anticoagulant heparphosphatid, which he named heparin in a paper published in 1918.10Howell WH Holt LE. Two new factors in blood coagulation—heparin and pro-antithrombin.Am J Physiol. 1918; 47: 328-341Crossref Google Scholar One year later McLean was graduated from Johns Hopkins and began an internship at the Johns Hopkins Hospital. For Howell the same year was less happy: He was operated on for his refractory duodenal ulcer by the celebrated J. M. T. Finney, Sr., who could only do a gastroenterostomy. Gastrectomy was impossible because of advanced duodenal scarring. Howell recovered smoothly and continued his research career with the publication of five more papers on heparin from 1923 through 1928 (Fig. 1).One of the most important papers described a method for the purification of heparin and was published in 1925.11Howell WH. The purification of heparin and its presence in blood.Am J Physiol. 1925; 71: 553-562Google Scholar During his surgical residency McLean rotated through the Hunterian Laboratory (Fig. 2), which had been founded and named by Cushing in 1905.In 1920 Cushing wrote a long letter to McLean describing the history of the Hunterian, which McLean treasured for the rest of his life. It is extensively quoted in Fulton's biography of Cushing. While McLean was at the Hunterian, work seemingly unrelated to heparin was beginning about 350 miles due north of Baltimore, in Toronto. The year 1921 was a very auspicious one for that city, for two young medical research workers, for the University of Toronto and its medical school, and above all for the diabetics of the world … and even for our knowledge of heparin. Charles Herbert Best was born in West Pembroke, Maine, in 1899, the son of a Nova Scotian doctor who conducted a country practice on both sides of a 40-mile section of the Canadian-U.S. border. He soaked up medical lore from his father during vacations on the family orchards in Nova Scotia, while apples were being loaded for shipment to England.12Young F Hales CN. Charles Herbert Best, biographical memoirs of fellows of the Royal Society. vol 28. 1982: 1-25Google Scholar At the age of 12 years he gave emergency anesthetic to his father's patients. In 1916 he moved to Toronto to prepare for entry at the university the next year. His father's sister Anna, a nurse trained at the Massachusetts General Hospital when Elliott Joslin was also there, and a diabetic under Joslin's care, received the only accepted method of treatment of the time: semistarvation. In 1918 she died in a coma in her early thirties, weighing 80 pounds. Her death had a lasting impact on Best and led to his deep interest in the disease. After briefly serving in the Canadian field artillery in the summer of 1918, he returned to the University of Toronto where he received his BA degree in 1921 after an honors course in physiology and biochemistry. After graduation he continued to study biochemistry, physiology, and "chemical pathology." He and another student worked with Professor J. J. R. MacLeod on the influence of the medulla oblongata on liberation of glucose from the liver. It was this experience that prepared him for the collaboration with Frederick G. Banting (Fig. 3) that began on May 17, 1921, when Best was 22 years old and Banting was 29 years old. The story of the discovery of insulin and its prompt clinical application seems incredible today.12Young F Hales CN. Charles Herbert Best, biographical memoirs of fellows of the Royal Society. vol 28. 1982: 1-25Google Scholar It also had a decisive effect on heparin research. The idea of defunctioning the enzymatic acinar portions of the pancreas by duct ligation to spare the islets of Langerhans and the suspected agent that controlled glucose levels came to Banting while he was lying awake one night in October 1920. (The notebook in which he recorded the idea survives.) All previous attempts to extract the agent had failed. Banting presented his plan to MacLeod who skeptically allowed Banting to use his laboratory for 8 weeks in the summer of 1921 when MacLeod would be in Europe. After receiving his undergraduate degree Best wanted to do more biologic research and was hired by Banting. With about $100 of support and 10 dogs, they began as Banting commented, "Let's get started, Mr. Best. We don't have much time." Their first few attempts at ligating pancreatic ducts were "learning experiences" as they perfected their surgical techniques, but by late July they were able to extract the elusive agent from a pancreas with sufficient acinar atrophy. After intravenous injection in dogs with surgically removed pancreases the blood sugar level dropped markedly. When MacLeod returned from Europe in September, the observation had been solidly confirmed, and only 3 months later Banting, with MacLeod and Best as coauthors, delivered his paper at the annual meeting of the American Physiological Society at Yale in late December 1921. At the end of the discussion period MacLeod made the closing remarks, leaving the impression that he was a coworker in the discovery. That was resented by Banting, especially when MacLeod was awarded the Nobel prize with Banting in 1923. Progress continued to be smooth and rapid as the animal work expanded and advanced to clinical trials at the Toronto General Hospital in January 1922, only 8 months since the work's beginning and less than 1 month from presentation of the paper. Not only were these two neophytes lucky to have triumphed so early in life, but they were also lucky to work before our era of regulation, litigation, animal rights movements, and grantsmanship. It was particularly important that their success solidified Best's decision to devote his life to biologic research. In turn, this led to his prominent role in the story of heparin. After receiving his medical degree in 1925 from the University of Toronto, he was granted a traveling fellowship by the Rockefeller Foundation and toured European laboratories. Although when he returned he continued research on insulin and glucose metabolism, he also began studies of histamine in lung tissue and of choline metabolism. The histamine studies required continuous blood pressure measurement by arterial cannulas, which often clotted. He promoted work by David A. Scott and Arthur F. Charles, who devised a way to purify heparin to a high level of potency at the Connaught Laboratories in Toronto.13Charles AF Scott DA. CCLXX. Studies on heparin. IV. Observations on the chemistry of heparin.Biochem J. 1936; 30: 1927-1933Crossref PubMed Google Scholar The method required about 66 separate steps to completion, but it led to a commercially practical method, which used ox lung as a source. By 1937 heparin was available for use on a small scale. While all of this was happening in the 1920s and 1930s, where was Jay McLean? For a better understanding we turn to McLean's comment to J. McGehee Harvey, quoted by Lam,8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar "The discovery of heparin came as a result of my determination to accomplish something by my own ability. It was this determination to become a physiology-based surgeon, rather than an anatomy-based surgeon, that led to the discovery of heparin." In his article Lam wondered why McLean nevertheless chose to train in the Hunterian, which was fundamentally an incubator for surgical craftsmen, not basic scientists. Lam also guessed that McLean found, perhaps too late, that he lacked aptitude for operative surgery.8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar In any event, in 1924 McLean returned to the University of California to become an instructor in surgery. Only 3 years later, in 1927, he joined Dr. James Ewing in the Department of Pathology at Cornell, where he remained until 1939. Although he was apparently uninvolved in the great progress of heparin research since he left Baltimore, he must have followed the developments with a blend of pride and regret. By the early 1930s practical methods of purification and the inevitable clinical applications arrived in Toronto, Denmark, and Sweden. Certainly Howell, in his seventies and still working in his laboratory in Baltimore, must have been pleased to see heparin become clinically useful. One of the more colorful clinicians in Toronto at the time was Dr. D. W. Gordon Murray, a surgeon who collaborated with Best in very early studies of heparin's use in venous thrombosis14Murray DWG Jaques LB Perrett TS Best CH. Heparin and the thrombosis of veins following injury.Surgery. 1937; 2: 163-187Google Scholar; this work was done simultaneously with similar work by Crafoord and Jorpes in Sweden.15Crafoord C. Preliminary report on post-operative treatment with heparin as a preventive of thrombosis.Acta Chir Scand. 1937; 79: 407-425Google Scholar In May 1935 when he was 41 years old, Murray began clinical trials with the crystalline sodium salt of heparin prepared by the Charles and Scott method. The paper reporting this work entitled "Heparin and the Thrombosis of Veins Following Injury" (1937)14Murray DWG Jaques LB Perrett TS Best CH. Heparin and the thrombosis of veins following injury.Surgery. 1937; 2: 163-187Google Scholar included Charles Best as one of the coauthors. It described very extensive studies on dog veins injured mechanically and chemically in vivo and the efficacy of heparin in preventing thrombosis. Additional studies in humans began on April 16, 1935, when a cutdown approach to a patient's left brachial artery was made and a needle was inserted. (There was no mention of the patient's diagnosis, consent, or objection.) Heparin powder of high potency was dissolved in saline and sterilized by passage through a Berkefeld filter. While the heparin solution was infused, blood was sampled at 6-minute intervals from the veins of the upper arm, and clotting times were determined. As expected, the latter rose steeply from 6 to 18 minutes, whereas the clotting times did not change in samples from remote sites. Murray referred to this as "regional heparinization." He also noted that after cessation of the infusion there was no decrease in coagulation time below normal, or "heparin rebound." Of great importance was the fact that the purified heparin did not cause the toxic reactions (weakness, headache, and chills) that characterized the cruder preparations. Because of the obvious need to develop a nontoxic heparin, Clarence Crafoord in Stockholm, who was in his middle thirties, performed clinical trials in the prevention of thrombosis contemporaneously with those of Murray; he had equally promising results. His paper entitled "Preliminary Report on Postoperative Treatment with Heparin as a Preventive of Thrombosis" was also published in 1937.15Crafoord C. Preliminary report on post-operative treatment with heparin as a preventive of thrombosis.Acta Chir Scand. 1937; 79: 407-425Google Scholar It reported the use of heparin in 12 patients for prophylaxis of deep venous thrombosis and provided considerably more detail about these human subjects than did the Murray paper. His first patient was given heparin intravenously just before a prostatectomy. The "unusually strong and profuse bleeding from the prostatic bed" and "the almost complete absence of coagulations of the blood" encouraged Crafoord to change to a completely postoperative schedule. The next patient was given heparin immediately after a cholecystectomy and by continuous infusion through the first night. By the next afternoon, after a slow decline, her blood pressure sank to 65/30 mm Hg and her pulse rose to 120 to 130 beats/min. She responsed well to a transfusion and the heparin was discontinued. The next patient, a young man who also was given immediate postoperative heparin after a vein stripping, fared somewhat better, although his wounds grew large hematomas. The fourth and fifth patients also had heparin immediately after operation. The former did fairly well after his appendectomy but dislodged his heparin needle, and the infusion was not restarted. The latter had a blood pressure drop to 83 mm Hg at 6½ hours after her cholecystectomy. She too did well after cessation of the heparin and a 400 ml transfusion. For all of the remaining seven patients the first heparin was given at least 3 hours after their operations, and there were no further bleeding problems. When the Murray and Crafoord studies were carried out, protamine was unavailable, but by 1937 its ability to reverse the anticoagulant action of heparin was reported by Chargaff and Olson16Chargaff E Olson K. Studies on the chemistry of blood coagulation, studies on the action of heparin and other anticoagulants. The influence of protamine on the anticoagulant effect in vivo.J Biol Chem. 1937; 122: 153-167Abstract Full Text PDF Google Scholar in New York. They were helped by another insulin "connection." It was known that protamine (or salmine as it was known at the time because of its source in salmon roe) prolonged the effect of insulin. They thought they might see the same effect with heparin. Although they were disappointed, the discovery that protamine is a powerful heparin antagonist proved to be much more useful than the one they predicted. Less than 10 years later Murray built and used the first practical dialysis apparatus originating in North America. Heparin was essential to his success. In the meantime, Best had also conducted experiments in animals, showing that heparin could prevent coronary arterial thrombosis or endocardial thrombi. This work was interrupted by World War II. Best stated, "Problems of military medicine diverted our attention in 1939." There things stood at the outbreak of the war: Howell was still doing research in Baltimore in what could have been emeritus years of retirement; Best, already venerable at age 40 years, was working in Toronto along with Murray and his collaborators; McLean was in New York in a pathology department; and Crafoord was in Sweden. Heparin, the central hero, was poised to play a central role after the war in medical and surgical practice, not only with the arrival of hemodialysis, which of course made the first organ transplants possible, but also with the arrival of peripheral vascular and open-heart surgery, to name just a few of the pending advances. What happened to our understanding of heparin as it developed in recent years? And what happened to Jay McLean? To Howell, Best, Murray, and Crafoord? We have learned that the heparin molecule is much more than a simple anticoagulant. It has several other functions in promoting blood flow, including effects on endothelial and vascular smooth muscle proliferation after injury,17Castellot Jr, JJ Wright TC Karnovsky MJ. Regulation of vascular smooth muscle cell growth by heparin and heparan sulfates.Semin Thromb Hemost. 1987; 13: 489-503Crossref PubMed Scopus (93) Google Scholar and the proliferation or arrest of neovasculature in the support of tumor growth.18Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue?.Cancer Res. 1986; 46: 467-473PubMed Google Scholar Much has been learned about the functions of heparin molecular fragments (ranging from 1600 to 60,000 MW) in the past several years, and far more remains to be discovered. (Those interested in a lucid and thorough discussion of the chemistry and pharmacology of heparin are referred to Rosenberg.19Rosenberg R. The molecular basis of blood diseases. WB Saunders, Philadelphia1987: 549-556Google Scholar) The story of heparin has been full of surprises, beginning with the McLean paper of 1916, and there are more to come as further questions are answered as the research advances. It is rather fitting that the course of heparin research has been as varied as the lives of its early investigators. Howell continued his career in blood research. He had an enduring interest in heparin and its growing clinical promise. He revised the fourteenth edition of his Textbook of Physiology in 1940 at age 80 years, just as he had every 3 years since 1905. He was extracting thromboplastin from lung on the day before he died of a myocardial infarction, Feb. 6, 1945. Charles Best, who had become head of the Department of Physiology at Toronto at the age of 30 years, continued with many research efforts in addition to those concerning heparin; they included studies on prevention of fatty liver by choline, the functions of folic acid and vitamin B12, and exercise physiology.23Murray G Delorme E Thomas N. Development of an artificial kidney. Experimental and clinical experiences.AMA Arch Surg. 1947; 55: 505-522Crossref Scopus (28) Google Scholar Like Howell, he and Norman Taylor edited a highly regarded, multiple edition (10) textbook of physiology. During World War II he served in the Division of Naval Medical Research of the Royal Canadian Navy, studying night vision. He and his group discovered that red lighting in otherwise dark surroundings improved night vision.11Howell WH. The purification of heparin and its presence in blood.Am J Physiol. 1925; 71: 553-562Google Scholar The finding was so valuable that red lighting was adopted by the Royal Navy, the Royal Canadian Navy, and the U.S. Navy, which gave an important advantage to the Allies and even to radiologic fluoroscopists until image intensifiers arrived in x-ray departments. He also devised improved treatment for seasickness. After the war, in the mid-1950s, he conducted important studies of glucagon, extending his primordial interest in the pancreas and its role in sugar metabolism.11Howell WH. The purification of heparin and its presence in blood.Am J Physiol. 1925; 71: 553-562Google Scholar He was especially proud of his achievement as a codiscoverer of insulin, and in 1972 he estimated that during the previous 50 years about 130 million people had taken insulin and avoided early death.11Howell WH. The purification of heparin and its presence in blood.Am J Physiol. 1925; 71: 553-562Google Scholar One of his biographers described him as "balding, heavy-set" and "with a pleasant sense of humor, who exudes quiet and modest self-confidence." Late in life he still enjoyed oil painting, golfing, horseback riding, and watching baseball.24Ulin AW Gollub S Posthumous award commemorating the discovery of heparin.N Engl J Med. 1964; 270: 466Crossref Google Scholar Best died of a ruptured abdominal aortic aneurysm on March 31, 1978, about one month after his seventy-ninth birthday. At about the same time in the 1930s that he was doing clinical studies with heparin, Gordon Murray also began research with kidney transplants and with an artificial kidney.25 In 1947 he published experimental results of hemodialysis in dogs with surgically removed kidneys and a strikingly successful case report of a 26-year-old woman who had become anuric after an induced abortion. She was given dialysis 3 times in December of 1946; she emerged from a coma and completely recovered.26 At the same time he learned that Willem Kolff had been doing the same kind of dialysis research in Holland during the war. Murray gained renown as a cardiac surgeon with pioneering work in patent duct closures, coarctation repairs, repairs of tetralogy of Fallot, and closed corrections of stenotic valves.25 Unfortunately, he had many critics because of his unconventional ideas. As one of his biographers said, "Murray was a charming mentor, full of new and often unorthodox thoughts and questions."25 Unhappily, he became controversial to a pathetic degree when in 1967 at the age of 73 years (Fig. 4) he announced that he had devised an operation for the relief of spinal cord injury.It was his last "breakthrough." He died in 1976 at 82 years of age. Crafoord also became a distinguished cardiac surgeon and died in 1984 at 85 years of age. But what about Jay McLean? After 12 years with Ewing, between 1939 and 1941, he moved to Columbus, Ohio, where he was in private surgical practice with an older surgeon.8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar However, Dr. Conrad Lam, an acquaintance, biographer, and surgeon at the Henry Ford Hospital, received from McLean a request for a reprint reporting some of Lam's work with heparin.8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar Lam had recently placed an exhibit at the annual AMA meeting that had been visited by both Howell and Best. McLean resented Howell's advice in 1931 to Dr. Roy McClure, first surgeon-in-chief at the Henry Ford Hospital, not to use heparin clinically in patients after surgery because of the bleeding risk. McLean thought the advice was misguided and said in a letter to McClure, "What a shame the idea could not have been developed by you instead of the Toronto and Stockholm schools." McClure replied that he obtained some heparin anyway, "made, supposedly, as you have made it. This was used on two patients with very severe reactions so, of course, I never repeated it, especially in view of Dr. Howell's opposition." Lam also corresponded with L. B. Jaques, a Toronto biochemist, who had assisted in the heparin work in the early 1930s. Jaques said that McLean came to Toronto in 1939 to meet Best and Murray, but both arranged to be away, leaving the job of lunch with McLean to Jaques and Arthur Charles. They heard a "sad and boring" story that included a divorce. In 1943 McLean was appointed an associate professor of Surgery at Ohio State Medical School in Columbus and was involved with building a "clone" of the Hunterian Laboratory, while at the same time his private practice and his finances were languishing. Lam's paper8Lam CR. The strange story of Jay McLean, the discoverer of heparin.Henry Ford Hosp Med J. 1985; 33: 18-23PubMed Google Scholar includes other interesting correspondence with McLean, but the sad point is clear: McLean never established a durable career either in research or in clinical surgery in Columbus or anywhere else. His last years continued to be unsettled. In 1947, at age 57 years, he was director of the Bureau of Cancer Control of the District of Columbia, but in 1949 he went to Savannah to become director of Radiation Therapy and Consultant in Malignant Diseases, where he remained until his death in 1957 at age 67 years. In his article Lam hoped that "the last 7 years of his life were happier than those spent north of the Mason and Dixon Line." He also regretted that McLean never received any major honors while alive, but he did receive one 6 years after he died. A memorial plaque, along with a $6000 gift from the Upjohn Company to his widow, was presented to the Johns Hopkins University School of Medicine by the New York Academy of Sciences at a conference on "Bleeding in the Surgical Patient."27 The inscription read, "In recognition of his major contribution to the discovery of heparin in 1916 as a second year medical student in collaboration with Professor William H. Howell, this plaque is presented to the Johns Hopkins Medical School at the Conference on Bleeding in the Surgical Patient held by the New York Academy of Sciences, May 3, 1963." At the end that is all there was; that is all that happened to Jay McLean. I am grateful for material on Howell and McLean provided by Lynn McLea Chambers, of the Office of Medical Affairs, and Gerard J. Shorb, of the Alan Chesney Martin Medical Archives, both of the Johns Hopkins University School of Medicine. I am also grateful to Drs. Conrad Lam (for his letter and his published paper on McLean), William T. W. Clarke and Wilfred G. Bigelow of the University of Toronto (for their letters and material on heparin and Murray), E. Wood, also of the University of Toronto (for information about Best), and finally to our reference librarian at the West Roxbury Veterans Administration Medical Center, Mrs. Mary Abram, for her indispensable reference retrieval.