John James Rickard Macleod

British physiologist John James Rickard Macleod (1876–1935) shared the 1923 Nobel Prize in Medicine for the discovery of insulin and the studies of its use in treating diabetes. A pioneer in the area of carbohydrate metabolism, Macleod's major published works include Diabetes: Its Physiological Pathology (1913) and Carbohydrate Metabolism and Insulin (1926). A member of many major professional scientific associations, he served as president of the American Physiological Society from 1921 to 1923.

Macleod was born in Cluny, Scotland, on September 6, 1876, the first child of Robert and Jane (McWalter) Macleod. Due to his father's calling as a minister, the Maclead family eventually moved to Aberdeen, where Macleod received his education. Macleod proved himself to be an excellent student. After attending Aberdeen Grammar School, he went on to Marishchal College of Aberdeen University, where he began the study of medicine. In his first year Macleod won first prize in all his subjects and, in 1898 he graduated with honorable distinction, earning an M.B. and Ch.B. In 1899, thanks to a traveling scholarship, he attended the Physiological Institute in Leipzig, Germany, where he studied physiological chemistry for a year. While at the institute, he published his first scientific paper.

Entered Academia

In 1900 Macleod joined the faculty at the London Hospital Medical School as demonstrator in physiology, serving under noted physiologist Sir Leonard Hill, who headed the department. Macleod collaborated with Hill to study caisson sickness, a condition that affected laborers who worked in the high atmospheric pressure of the submerged caissons used when building underwater tunnels or sinking bridge pylons. If the workers emerged from the water too quickly, without gradual decompression, they suffered the "bends," a problem also frequently experienced by deep-sea divers who rose too rapidly to the surface. The pain that causes the body to bend over in pain is a result of the sudden bubbling up of nitrogen in the blood and tissues as a result of liquid's inability to absorb gas at reduced pressure; the condition can cause agonizing pain and even death. Macleod and Hill collected data on cases of the sickness and then experimented with mice, subjecting the animals to different pressure levels to determine the effects on their physiology. Their work resulted in a series of articles published in 1903.

In 1902 Macleod was appointed lecturer in biochemistry at the London Hospital Medica School. He also earned a diploma in public health from Cambridge University. That same year he received the McKinnon research studentship of the Royal Society of Medicine. In 1903 the 27-year-old Macleod married Mary McWalter and in August the couple traveled to the United States. Macleod's work and reputation had attracted the notice of officials at Western Reserve University in Cleveland, Ohio, and they offered him the position of chair of their Physiology Department. Macleod continued studying caisson sickness at Western Reserve and he created a compression chamber for laboratory experiments. But, more significantly, he also became interested in carbohydrate metabolism, particularly in relation to diabetes. He built his reputation on this interest, and it would eventually result in a Nobel Prize.

Also in 1903, Macleod was elected a member of the American Physiological Society (APS) and went on to become an important figure in the organization. In 1915 he was first elected to the APS Council and in 1920 he was named to the board of editors of the organization's publication, Physiological Reviews. In 1921 Macleod was appointed president of the APS.

Meanwhile, from 1907 to 1910, Macleod wrote and delivered important articles and lectures about diabetes, and in 1913 published Diabetes: Its Physiological Pathology. Works such as this established his reputation as an authority on carbohydrate metabolism. Also during this period, Macleod became a member of several other prominent professional organizations and served on the editorial boards of both the Journal of Biological Chemistry and the Journal of Laboratory and Clinical Medicine. In addition, during World War I, he was kept busy with various war-related duties and, for part of the winter session of 1916, served as a professor of physiology at McGill University in Montreal, Quebec, Canada.

In 1918 Macleod was elected professor of physiology at the University of Toronto, where he also directed the school's physiological laboratory and served as associate dean of the faculty of medicine. He had first been offered the position two years before, in 1916, but had been unable to accept it, and university officials were so eager to obtain his services that they left the position open until Macleod felt confident that he could dedicate sufficient time to his professorial duties. In that same year he published a textbook titled Physiology and Biochemistry in Modern Medicine that placed increased emphasis on the importance of chemistry in physiology and eventually became a classroom standard. In addition, under Macleod's direction, members of his department at the University of Toronto researched the behavior of blood sugar in turtles. Macleod further cemented his reputation when he delivered an important paper, "Methods of Study of Early Diabetes," to a diabetes symposium at the May 1921 meeting of the Ontario Medical Association. He soon began receiving job offers from leading medical institutions in the United States and Great Britain, and he was being considered for election to the Royal Academy of Medicine.

Started Collaboration with Bunting

In 1920 when he was 42 years old, Macleod first met the man who with whom he would share his Nobel Prize. Encouraged by Professor F. R. Miller from the Department of Physiology at Western University Medical School in London, Ontario, Fred G. Banting approached Macleod in his office and related his idea about isolating the internal secretion of the pancreas. Macleod was not overly impressed with Banting's presentation. Still, in 1921, he arranged for Banting to come to the University of Toronto. Banting's idea interested Macleod because he had come to believe that the pancreas was involved in diabetes, but he had been unable to determine its exact role. Previously, it had been suggested by other scientists that the organ produced an internal secretion that controlled the metabolism of sugar. In 1916 the research team of Sharpey-Schafer had named this hypothetical substance "insuline," but nobody could prove its existence. Macleod hoped that Banting's ideas would lead to that proof. Macleod provided Banting with laboratory space and dogs, as well as the services of his two of his best students, C. H. Best and E. Clark Noble. Macleod then instructed Banting in the Hodon method of performing a two-stage pancreatectomy on a dog. Then he went home to Scotland for the summer.

When he returned to Toronto in September, Macleod found that Banting and Best had made significant progress. They had managed to isolate the secretion, and Macleod suggested they call it "insulin." After Banting and Best presented their early findings to the Journal Club of the Physiological Society of the University of Toronto in November 1921, they were joined in their experiments by J. B. Collip. After more work, and before the end of the year, the four researchers present their findings at the annual meeting of the American Physiological Society.

Manufacture of Insulin Started

Despite the initial skepticism of fellow scientists, in January 1922, the researchers initiated the first clinical trials involving insulin at the Toronto General Hospital. When word about the studies got out, the press prematurely reported news about a diabetic cure. Macleod became besieged with questions about this "cure." By the end of the month, the research team began conducting research on the manufacture and physiology of insulin, and it grew to include Noble, J. Hepburn, J. K. Latchford, and the Connaught Anti-Toxin Laboratories under the direction of J. G. FitzGerald and R. D. Defries.

In March George H. A. Clowes, director of research at Eli Lilly and Company, a large pharmaceutical manufacturer based in Indianapolis, Indiana, approached Macleod with a proposal. Clowes suggested that Eli Lilly help the researchers develop a method of large-scale insulin production. Macleod first rejected the offer; he wanted his team to do it on its own. However, the researchers made little progress in developing a way to mass-produce insulin, and Macleod recontacted Clowes. In May of 1922, the University of Toronto entered into an agreement with Eli Lilly and Company. By the summer, thanks to the increased amount of insulin now available, more extensive clinical trials involving insulin could be conducted.

This increased activity added to Macleod's administrative responsibilities. From August 1922 to May 1923, Macleod served as official secretary of the insulin committee created by the board of governors of the University of Toronto to deal with patenting and licensing issues. He was also responsible for coordinating the patenting of insulin in Great Britain and the United States, and he was the main contact for both Clowes and Eli Lilly. Proceeds from the patent were given to the British Medical Research Council for the Encouragement of Research. The four researchers gained no profit from their discovery. In 1926 insulin was isolated in pure form by John Jacob Abel, and it eventually it became available as a manufactured product.

Despite what the press had earlier reported, insulin does not cure diabetes. However, it has proved to be crucial in the treatment of the condition and has provided help where none was previously available. Because its use transforms severe cases of diabetes into milder ones and also improves management of the condition by preventing diabetic coma and death, it has been credited as one of the most important medical discoveries of the 20th century.

Awarded the Nobel Prize

In 1923 Macleod received widespread recognition for his work. Early in the year, he was awarded the Cameron Prize by the University of Edinburgh. In May he was elected a fellow of the Royal Society, the independent scientific academy of the United Kingdom dedicated to promoting excellence in science. The most significant recognition came in October, when Macleod and Banting were awarded a Nobel Prize in Medicine for their discovery of insulin. After the announcement, Macleod made a statement indicating he would share his half of the Nobel prize proceeds with Collip; Banting indicated he would do the same with Best.

Macleod spent the next five years at the University of Toronto experimenting on insulin, looking for alternative sources of the drug, and campaigning for the establishment of an international standard for insulin potency. As a member of the League of Nations health committee, he helped establish a biological standard in 1926.

Returned to Scotland due to Failing
Health

In 1926 Macleod published a book on diabetes and insulin titled Carbohydrate Metabolism and Insulin. The following year, he accepted an position at his alma mater, the University of Aberdeen, as Regius Professor of Physiology. In 1928 Macleod and his wife sailed to Scotland. Back at Aberdeen, he continued to be active in research and experiments. His subsequent work and publications involved a variety of physiological and biochemical topics, including diabetes, carbamates, purine metabolism, the breakdown of liver glycogen, intracranial circulation, ventilation, and surgical shock. That same year he wrote The Fuel of Life: Experimental Studies in Normal and Diabetic Animals. In addition, he held the post of consultant physiologist to the Rowett Institute for Animal Nutrition, and he served as the British representative for the APS.

During the 1930s Macleod suffered declining health. Afflicted with severe arthritis, his movements became more painful and limited. Despite his progressive physical debilitation, his mind remained active and he continued many of his editorial duties. In 1932 he returned to conducting experiments on the role of the central nervous system in the causation of hyperglycemia, something he had first become involved in 1908. Through experiments done on rabbits, he concluded that stimulation of gluconeogenesis in the liver occurred by way of the parasympathetic nervous system. In early 1935 Macleod's health worsened to the point where he was finally admitted to a nursing home. Spending two months there, he returned home to Aberdeen shortly before he died, on March 16, 1935.

During his career Macleod produced 11 books and monographs. He was a member of the Royal Societies of Canada, Edinburgh, and London, as well as London's Royal College of Physicians. He served as president of the APS from 1921 to 1923 and of the Royal Canadian Institute from 1925 to 1926. He received honorary doctorates from the universities of Toronto, Cambridge, Aberdeen, and Pennsylvania, as well as from Western Reserve University and the Jefferson Medical College. He was an honorary fellow of the Academia Medica, Rome, and a corresponding member of the Medical and Surgical Society, Bologna, the Societé Medica Chirurgica, Rome, and the Deutsche Akademie der Naturforscher Leopoldina, as well as foreign associate fellow of the College of Physicians, Philadelphia.

Macleod's interests included golf, gardening, and the arts. As an educator, he was described as sympathetic, stimulating, and humble, but also as demanding. As a man, he was described as loyal, engaging, affectionate, and serene.

Online

"Biography of John James Rickard Macleod," University of Toronto Libraries Web site,http://eir.library.utoronto.ca/insulin/application/about.cfm?page=macleod (December 19, 2003).

"John James Rickard Macleod," American Physiological Society Web site,http://www.the-aps.org/about/pres/introjjm.htm (December 19, 2003).

"Macleod's Compression Chamber," Dittrick Medical History Center,http://www.cwru.edu/artsci/dittrick/artifactspages/b6chamber.htm (December 19, 2003).

Nobel e-Museum,http://www.nobel.se/medicine/laureates/1923/ (December 19, 2003).

Macleod, John James Rickard

(b. Cluny, near Dunkeld, Perthshire, Scotland, 6 September 1876; d. Aberdeen, Scotland, 16 March 1935)

physiology.

Macleod was a distinguished teacher, author, investigator, and administrator. He was the son of Rev. Robert Macleod, who shortly after the boy’s birth was called to Aberdeen; Macleod received his education at the Aberdeen Grammar School and Aberdeen University. He studied medicine at Marischal College, and graduated with distinction as M.B., Ch.B in 1898, winning the Matthews Duncan and Fife Jamieson medals; he was also awarded the Anderson traveling scholarship and spent a year in the Physiology Institute at Leipzig, where he studied biochemistry under Siegfried and Burian. In 1900 Macleod joined the London Hospital Medical College as demonstrator in physiology under Sir Leonard Hill. He became lecturer in biochemistry at the school in 1902 and was also selected as Mackinnon research scholar of the Royal Society. He married Mary Watson McWalter in 1903; there were no children.

During his short stay in London Macleod published an account of experiments on intracranial circulation and on caisson disease, carried out in conjunction with Hill; he retained his interest in the problems of respiration throughout his life, publishing many papers on the control of respiration between 1902 and 1922. In the early years of the twentieth century Macleod continued his postgraduate studies at Cambridge, where he took his diploma in public health. In 1903 he published a text entitled Practical Physiology, and in the same year he was appointed professor of physiology at Western Reserve University, Cleveland (now Case Western Reserve University). Here he remained as a teacher and researcher for fifteen years, In 1918 he became professor of physiology at the University of Toronto and not long afterward published, with collaborators, a textbook of nearly 1,000 pages, Physiology and Biochemistry in Modern Medicine. This text, which reached its seventh edition the year before Maclcod’s death, was widely read and consulted. Its title reveals it as one of the last of such broad scope and, at the same time, as the precursor of other, more recent wide-ranging treatises appealing both to the special student and to the clinician.

In his first years at Western Reserve Macleod published a series of papers on the carbamates and one on purine metabolism. In 1907 there appeared the first of a long series of “Studies in Experimental Glycosuria” in the American Journal of Physiology, studies on the breakdown of liver glycogen, whether produced by piqftre, stimulation of the splanchnics, reflexly by asphyxia, or by injection of adrenaline. He conceived of the problem as one fundamentally involving the access of the diastatic enzyme to the stored glycogen. In 1913, nearly ten years before the discovery of insulin, Macleod wrote a book on diabetes and its pathological physiology, an expansion of lectures which he had delivered during the summer of 1912 at the University of London. Although he published on surgical shock (1918–1920) and other subjects, his first years in Toronto were devoted chiefly to studying the peculiarities of respiration in decerebrate animals and of the effects of anoxemia and of excess oxygen. Later, in 1921, he made a thorough examination of the control of the blood-sugar level in the normal and in the depancreatized animal and of the roles played by the liver, the muscles, and the pancreas in the metabolism of sugar.

His return to work on carbohydrate metabolism had been stimulated by the initial successes of Banting and Best. As J. B. Collip subsequently observed, Macleod had already attained, by the time of his arrival in Toronto (1918), “an outstanding position in the field of carbohydrate metabolism, and it was both appropriate and fortunate that the discovery of insulin should have been made in his laboratory.” It was early in 1921 that Macleod agreed to receive Frederick G. Banting, a young surgeon, into his department to carry out investigations aimed at determining the true function of the pancreatic islets; C. H. Best, a member of the professor’s senior class in physiology, was assigned to be Banting’s assistant. Banting and Best began their research on 16 May. The general pattern of their work, following Banting’s conception of how the islets might be freed from the acinar tissue of the gland and then extracted, was worked out with Macleod; but its first results were obtained in midsummer, when Macleod had gone to Scotland. On his return, he discontinued his work on anoxemia and turned all the resources of his laboratory to the new work. J. B. Collip joined the team; and usable preparations of insulin were ready, and were used with success, early in 1922.

Macleod was president of the American Physiological Society at the time of the discovery of insulin and had received many honors; now they multiplied. In 1923 Banting and Macleod shared the Nobel Prize; Banting divided his share with Best, and Macleod divided with Collip. Macleod became fellow of the Royal Society in 1923 and was awarded honorary degrees by Toronto, Western Reserve, Aberdeen, and other universities. In 1928 he returned to Scotland as regius professor of physiology at Aberdeen. Productive work there, and at the Rowett Institute, continued to add to knowledge of carbohydrate metabolism. The metabolism of the decerebrate eviscerated animal, with special reference to the respiratory quotient, occupied much of his time until crippling arthritis put an end to his laboratory work; even then he continued to direct the activities of his department. Macleod’s last important publication marked his return to an earlier problem, the nervous control of the glycogenic function of the liver.

BIBLIOGRAPHY

I. Original Works. Macleod’s writings include Practical Physiology (1903); “Studies in Experimental Glycosuria,“in American Journal of Physiology (1907); “Teaching and Research Positions in Medical Science,” in Western Reserve University Bulletin, 11, no. 6 (1908), 129–150; and Physiology and Biochemistry in Modern Medicine (St. Louis, 1918), written with Roy G. Pearce and others.

II. Secondary Literature. See C. H. Best, “The Late John James Rickard Macleod, M.B., Ch.B., LL.D., F.R.C.P.,“in Canadian Medical Association Journal,n.s. 32 (1935), 556; J. B. C[ollip], “John James Rickard Macleod (1876–1935),“in Biochemical Journal,29, no. 1 (1935), 1253–1256; “John J. R. Macleod, F.R.S., D.Sc, M.D. Aberd., F.R.C.P. Lond.,“in Lancet, no 228 (1935), 716–717; and L. G. Stevenson, Sir Frederick Banting, rev. ed. (Toronto, 1947).

Lloyd, G. Stevenson