John James Rickard Macleod,FRS, FRSE[1] (6 September 1876 – 16 March 1935), was a Scottishbiochemist andphysiologist. He devoted his career to diverse topics in physiology and biochemistry, but was chiefly interested incarbohydrate metabolism. He is noted for his role in the discovery and isolation ofinsulin during his tenure as a lecturer at theUniversity of Toronto, for which he andFrederick Banting received the 1923Nobel prize in Physiology or Medicine.[2] Awarding the prize to Macleod wascontroversial at the time, because according to Banting's version of events, Macleod's role in the discovery was negligible. It was not until decades after the events that an independent review acknowledged a far greater role than was attributed to him at first.[3]
In 1903, Macleod became a lecturer in physiology at theWestern Reserve University inCleveland, Ohio, where he remained for 15 years. This was the period when he developed an interest incarbohydrate metabolism that was to last for the rest of his career.[5][7]
In 1910, he delivered a lecture on various forms of experimental diabetes and their significance fordiabetes mellitus at the joint meeting of the section on Pharmacology and Therapeutics and the section on Pathology and Physiology of theAmerican Medical Association.[8]
In 1905 he became interested in carbohydrate metabolism anddiabetes, publishing a series of scientific papers and several monographs on the subject from then on.[1][10] 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.[1][6][11]
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 apancreas 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 thenervous system had a crucial role in regulating bloodglucose concentration. Even though Banting had virtually no experience of physiology, he managed to convince Macleod to lend him laboratory space during a holiday in Scotland that summer.[3] In addition to the laboratory, Macleod provided experimental animals and his studentCharles Best, who worked as a demonstrator. Macleod also advised on project planning and the use of analytical techniques, and assisted with the operation on the first dog.[3][12] 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.[3]
On his return, Macleod was surprised and expressed doubt about the results. Banting took this as an attack on his integrity. They argued bitterly, but Banting finally accepted Macleod's instruction that further experiments were needed, and he even convinced Macleod to provide better working conditions and to give him and Best a salary. Further experiments were successful and the three started to present their work at meetings. Macleod was a far better orator, and Banting came to believe that he wanted to take all the credit.[3] This was exemplified by a December 1921 presentation to theAmerican Physiological Society atYale, which took a toll on Banting's nerves due to the "prestige of the audience" causing him to freeze up, and as a result the "audience was highly critical of the findings presented".[13] Macleod who was "desperate to snatch victory from the jaws of defeat" stepped in and finished the presentation. From Banting's viewpoint, "this was a brazen coup by Macleod to rob him of the credit for having discovered insulin – and to rub salt into the wound, it had been done in front of the most eminent doctors in the field".[14]
Their discovery was first published in the February 1922 issue ofThe Journal of Laboratory and Clinical Medicine.[15] 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 biochemistJames Collip to help with purifying the extract.[3][16]
The firsthuman clinical trial was unsuccessful. Banting was insufficiently qualified to participate and felt sidelined. By the winter of 1922, he was certain that all Macleod's colleagues were conspiring against him. There was a reported physical altercation between Banting and Collip, as Banting saw Collip's breakthrough on alcohol purification as a threat, while Collip was reluctant to share the details. 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.[3] In January 1922, the team performed the first successful clinical trial, on 13-year-oldLeonard Thompson, and it was soon followed by others.[14]
Although all the team members were listed as co-authors of their publications, Banting still felt overlooked, because Macleod took over the coordination of clinical trials and the acquisition of larger amounts of extract. Macleod's presentation at a meeting of theAssociation of American Physicians in Washington, D.C., on 3 May 1922 received a standing ovation, but Banting and Best refused to participate in protest. At that time, 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.[3] The pharmaceutical companyEli Lilly & Co. took over mass production, but without an exclusive license, as thepatent was transferred to theMedical Research Council to prevent exploitation.[1]
In the summer of 1923 Macleod resumed other research. He took interest inteleost fish, which have separate regions ofislet andacinar tissue in their pancreas. Working at theMarine Biological Station inSt. 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.[3] Meanwhile, Banting remained in Toronto and relationships soon deteriorated again because of conflicting press accounts. Banting eventually started to claim that he deserved all the credit and that Macleod had only hindered him the whole time and had made no contribution other than to leave the keys to the laboratory when he went on vacation.[3] MacLeod wrote a report on the discovery in 1922 to explain his side of the story, but otherwise refrained from active involvement in controversy about credit. Banting hated him passionately, and the two never spoke again.[3] When Macleod left the University of Toronto in 1928, Banting harbored such enmity that he refused to attend the farewell dinner for Macleod.[17]
Grave of Macleod and his wife at Aberdeen cemetery
Macleod returned to Scotland in 1928 to becomeRegius 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 thecentral nervous system does have an important role in maintaining carbohydrate metabolism balance, as was his original hypothesis. His theory about conversion offats into carbohydrates remained unproven, despite his provision of several indirect proofs.[12] He devoted his spare time to golf, motorcycling and painting.
He married Mary Watson McWalter (1876–1940) in 1903, but they never had children. He died in 1935 in Aberdeen after several years of suffering from arthritis,[18] 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 bookPhysiology and Biochemistry in Modern Medicine.[1]
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[6] and eleven books. Among them are:
After Banting's death in a plane crash in 1941, Best, with the help of his friends, continued to spread Banting's account of the discovery and tried to "write out" Macleod and Collip from the history books. Only in 1950 was the first independent revision of all sides of the story made, and it gave credit to all four members of the team.[3] However, Macleod's public image remained tainted for decades after that. The 1976ITV television dramaComets Among the Stars, withRalph Richardson in the Macleod role, portrayed him as dark and repulsive.[3] The second dramatization of the discovery,Glory Enough for All (1988), at last portrayed him more objectively.[12] By then it was 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 secret for over 50 years by the University of Toronto, whose administration wanted to avoid fueling the controversy.[3]
Macleod's reputation in Canada remained under the influence of Banting and Best's story for decades, so Macleod was not esteemed there.[20] His contribution to science is now recognized by the broad public, even in Canada. The auditorium of the Toronto University Medical Research Centre was named in his honour, as wasDiabetes UK's award for patients who survive for 70 years with diabetes.[21] In 2012, he was inducted into theCanadian Medical Hall of Fame.[22]
The Nobel Committee reacted almost immediately to the first successful clinical trials. In the autumn of 1923, Banting and Macleod received theNobel 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 laureateAugust Krogh, who had a diabetic wife and had visited Macleod's laboratory and taken the method back to Denmark.[3][12] Banting "had well-placed friends in Toronto" and "knowing that a Nobel Prize might well be awarded for insulin, they worked very hard to have Banting honoured, at home and abroad, as the discoverer of insulin". However, "among experienced scientists there was more support for the view that Banting and Best’s somewhat fumbling researches would not have reached the goal without the contributions of both Macleod and Collip". The committee judged that Macleod's work in interpreting the data, managing the clinical trials and providing a high level of public presentation were crucial for success, and "concluded that Banting would not have found the way to insulin without the guidance of Macleod", so they awarded the Nobel prize to both.[23] Banting was furious, as he was convinced that Best should have received the other half, and he even thought of rejecting the prize. He was finally persuaded to accept it but gave half of his prize money to Best. Macleod in turn gave half of his to Collip. In 1972 theNobel Foundation officially conceded that omitting Best was a mistake.[3]
A second controversial aspect of the award was that eight months before Banting's and Best's paper, the Romanian physiologistNicolae Paulescu had reported the discovery of a pancreas extract that he dubbedpancrein, which lowered blood glucose concentration. Banting and Best even cited him in their paper, but misinterpreted his findings, purportedly because of an error in translation from French.[24] Best publicly apologized for that mistake many years later.[citation needed]
^Banting, Frederick G.; Best, Charles H. (1922)."The Internal Secretion of the Pancreas"(PDF).The Journal of Laboratory and Clinical Medicine.7 (5). Archived fromthe original(PDF) on 26 November 2010. Retrieved18 October 2012.
^Murray, Ian (1971). "Paulesco and the Isolation of Insulin".Journal of the History of Medicine and Allied Sciences.26 (2):150–157.doi:10.1093/jhmas/XXVI.2.150.PMID4930788.
