John Macleod (physiologist)

John James Rickard Macleod (6 September 1876 – 16 March 1935), was a Scottish biochemist and physiologist. He devoted his career to diverse topics in physiology and biochemistry, but was chiefly interested in carbohydrate metabolism. He is noted for his role in the discovery and isolation of insulin during his tenure as a lecturer at the University of Toronto, for which he and Frederick Banting received the 1923 Nobel prize in Physiology or Medicine.

Biography
Macleod was born in Clunie, near Dunkeld in Perthshire. Soon after he was born, his father Robert Macleod, a minister of the Free Church, was transferred to Aberdeen, where John attended Aberdeen Grammar School and enrolled in the study of medicine at the University of Aberdeen. At the University of Aberdeen, one of Macleod's principal teachers was the young professor John Alexander MacWilliam. He was awarded his medical degree with honours in 1898 and then spent a year studying biochemistry at the University of Leipzig, Germany, on a travelling scholarship. He became a demonstrator at the London Hospital Medical School, where in 1902 he was appointed lecturer in biochemistry. In the same year, he was awarded a doctorate in public health from Cambridge University. Around that time he published his first research article, a paper on phosphorus content in muscles.

In 1903, Macleod became a lecturer in physiology at the Western Reserve University in Cleveland, Ohio, where he remained for 15 years. This was the period when he developed an interest in carbohydrate metabolism that was to last for the rest of his career.

In 1910, he delivered a lecture on various forms of experimental diabetes and their significance for diabetes mellitus at the joint meeting of the section on Pharmacology and Therapeutics and the section on Pathology and Physiology of the American Medical Association.

In 1916, he was a professor of physiology at McGill University in Montreal, Canada. After the First World War, he went on to teach physiology at the University of Toronto, where he became director of the physiology lab and an assistant to the dean of the medical faculty. He researched various topics in physiology and biochemistry, among which were the chemism of Mycobacterium tuberculosis, electroshocks, creatinine metabolism and blood circulation in the brain.

In 1905 he became interested in carbohydrate metabolism and diabetes, publishing a series of scientific papers and several monographs on the subject from then on. Additionally, Macleod was a popular lecturer and an influential contributor to the development of the six-year course in medicine at the University of Toronto.

Frederick Banting and the discovery of insulin
At the end of 1920, Macleod was approached by Frederick Banting, a young Canadian physician who had the idea of curing diabetes using an extract from a pancreas whose functioning had been disrupted. Macleod was not enthusiastic, because (unlike Banting) he knew about unsuccessful experiments in this direction by other researchers. He thought it more likely that the nervous system had a crucial role in regulating blood glucose concentration. Macleod was not initially impressed by his interview with Banting. However, he came to the conclusion that it was worth trying because the results may be of "great physiological value," and granted Banting laboratory space while Macleod himself would be away on holiday. In addition to the laboratory, Macleod provided experimental animals and his student Charles Best, who worked as a demonstrator. Macleod instructed Banting on the accepted method of pancreatectomy to be used on the experimental subjects. While he was of the opinion that the project would "go up in smoke," Macleod believed it would at least be good training for Best. While Macleod was away, Banting and Best achieved a breakthrough: They isolated an internal secretion of the pancreas and succeeded in reducing the blood sugar level of another dog, whose pancreas had been surgically removed. On his return, Macleod expressed doubt about the results, leading tensions between himself and Banting to mount. They argued bitterly over Banting's demands to Macleod, which included a salary for himself and Best, a private room to work in, an assistant to take care of the dogs, and repairs for the operating room. Macleod initially declined on the grounds that this would cause other research in the department to suffer, to which Banting remarked that he would take the research elsewhere if the University of Toronto did not see any value in it. Macleod relented, and for a while their relations improved. Further experiments were successful and the three started to present their work at meetings. Again worsening the relationship between the researchers was Macleod's tendency to speak on behalf of the team. This was exemplified by a December 1921 presentation to the American Physiological Society at Yale, where Banting and Best were due to present their findings. Banting felt he had not presented well but wanted to answer audience questions. However, it was Macleod who addressed the audience next, to which Banting took offense. After their return to Toronto, Macleod was persuaded by another professor to apologize to Banting, smoothing over the relationship once again.

Their discovery was first published in the February 1922 issue of The Journal of Laboratory and Clinical Medicine. Macleod declined co-authorship because he considered it Banting's and Best's work. Despite their success, there remained the issue of how to get enough pancreas extract to continue the experiments. Together, the three researchers developed alcohol extraction, which proved to be far more efficient than other methods. This convinced Macleod to divert the whole laboratory to insulin research and to bring in the biochemist James Collip to help with purifying the extract.

The first human clinical trial was unsuccessful. Towards the end of January 1922, there was an altercation between Banting and Collip, who refused to share details of his alcohol purification. Banting and Best viewed this as a violation of a verbal agreement to share their discoveries with each other. Collip threatened to leave because of the strained atmosphere but the encouragement of others who saw the potential of their research prevented escalation of the conflict. That same month, the team performed the first successful clinical trial, on 13-year-old Leonard Thompson, and it was soon followed by others.

Demonstrations of the method's efficiency drew huge public interest, because the effect on patients, especially children, who until then were bound to die, seemed almost miraculous. The pharmaceutical company Eli Lilly & Co. took over mass production, but without an exclusive license, as the patent was transferred to the Medical Research Council to prevent exploitation.

In the summer of 1923 Macleod resumed other research. He took interest in teleost fish, which have separate regions of islet and acinar tissue in their pancreas. Working at the Marine Biological Station in St. Andrews, New Brunswick, he made extracts from each of those parts separately and proved that insulin is derived from the insular and not the acinar tissue of the pancreas. Meanwhile, Banting remained in Toronto and relationships soon deteriorated again because of conflicting press accounts. Macleod wrote a report on the discovery in 1922, but otherwise refrained from active involvement in controversy about credit. Banting hated him passionately, believing Macleod had purposely overstated his and the University of Toronto's contributions to the discovery, and the two never spoke again. When Macleod left the University of Toronto in 1928, Banting harbored such enmity that he refused to attend the farewell dinner for Macleod.



Later years
Macleod returned to Scotland in 1928 to become Regius Professor of Physiology at the University of Aberdeen (in succession to his former teacher, John Alexander MacWilliam who retired in 1927) and later Dean of the University of Aberdeen Medical Faculty. Between 1929 and 1933 he was also a member of the Medical Research Council.

Macleod did not continue to work on insulin, but he remained active as a researcher, lecturer and author. His last major contribution was a proof that the central nervous system does have an important role in maintaining carbohydrate metabolism balance, as was his original hypothesis. His theory about conversion of fats into carbohydrates remained unproven, despite his provision of several indirect proofs. He devoted his spare time to golf, motorcycling and painting. He was married to Mary W. McWalter, but they never had children. He died in 1935 in Aberdeen after several years of suffering from arthritis, despite which he remained active almost until his death. In 1933 he made a lecture tour of the US, and in 1934 he published the 7th edition of his book Physiology and Biochemistry in Modern Medicine.

Works
Macleod was a prolific writer. His first academic article was a paper on phosphorus content in muscles published in 1899. During his career he authored or co-authored over 200 papers and eleven books. Among them are:


 * Practical Physiology (1903)
 * Recent Advances in Physiology (with Leonard E. Hill, 1905)
 * Diabetes: its Pathological Physiology (1913)
 * Physiology for dental students (with R. G. Pearce, 1915)
 * Physiology and Biochemistry in Modern Medicine (1st edition 1918)
 * Insulin and its Use in Diabetes (with W. R. Campbell, 1925)
 * Carbohydrate Metabolism and Insulin (1926)
 * The Fuel of life: Experimental Studies in Normal and Diabetic Animals (1928)

Awards and honours
John Macleod was a distinguished physiologist prior to the discovery of insulin. He was elected a member of the Royal Society of Canada in 1919 and president of American Physiological Society in 1921. In 1923, Macleod was awarded the Cameron Prize for Therapeutics of the University of Edinburgh. Among the recognitions he received after 1923 were memberships of the Royal Society and the Royal Society of Edinburgh, corresponding membership of the German Academy of Sciences Leopoldina and honorary membership of the Regia Accademia Medica.

Macleod's reputation in Canada was overshadowed by the contributions of Banting and Best. It was only in the 1980s that it became commonly accepted that Banting's and Best's story was distorted, since more documentation had been made publicly available, and it made a precise reconstruction of the events possible. Until Best died, this documentation had been kept confidntial for over 50 years by the University of Toronto, whose administration wanted to avoid fuelling the controversy. The auditorium of the Toronto University Medical Research Centre was named in his honour, as was Diabetes UK's award for patients who survive for 70 years with diabetes. In 2012, he was inducted into the Canadian Medical Hall of Fame.

Nobel Prize
The Nobel Committee reacted almost immediately to the first successful clinical trials. In the autumn of 1923, Banting and Macleod received the Nobel Prize in Physiology or Medicine, even though the long-term importance of the discovery was not yet apparent. They were nominated by the Danish physiologist and Nobel laureate August Krogh, who had a diabetic wife and had visited Macleod's laboratory and taken the method back to Denmark. The committee concluded that Macleod's work in interpreting the data, managing the clinical trials and providing a high level of public presentation were crucial for success, so they awarded the Nobel prize to both. Upon accepting, Banting gave half of his prize money to Best. Macleod in turn gave half of his to Collip. In 1972 the Nobel Foundation officially conceded that omitting Best was a mistake.

A second controversial aspect of the award was the fact that eight months before Banting's and Best's paper, the Romanian physiologist Nicolae Paulescu had reported the discovery of a pancreas extract that he dubbed pancrein, which lowered blood glucose concentration. Banting and Best cited him in their paper, but misinterpreted his findings, purportedly because of an error in translation from French. Best publicly apologized for that mistake many years later.