In early 1922, in Toronto General Hospital, 14-year-old patient Leonard Thompson was drifting in and out of consciousness. Leonard had Type 1 diabetes, a devastating diagnosis at the time, and Leonard's father knew his son was unlikely to survive much longer. So he volunteered Leonard for a radical new treatment and, on 11 January 1922, the young boy became the first person in the world to be given the purified extract of what we now know as insulin.
Insulin would go on to transform diabetes from a rapidly fatal illness into a manageable chronic condition and it is still the main form of treatment for Type 1 diabetes (and for Type 2 diabetes not successfully controlled by diet and medication) 100 years later.
The road to the discovery of insulin began in 1920 when Canadian physician, Frederick Banting, read an article suggesting that insulin-producing cells in the pancreas are slower to deteriorate than other pancreas tissue. Banting wondered whether it might be possible to break down the pancreas in a way that would leave intact only the insulin-producing cells. And he knew that to explore this hypothesis further he would need help.
Professor John Macleod, a lecturer at the University of Toronto, had long been interested in carbohydrate metabolism and diabetes, and he offered his research lab to Banting, creating a partnership which would not only result in the two men being jointly awarded the Nobel Prize for Physiology or Medicine in 1923, but would also end in bitter personal rivalry, with Banting determined to denigrate Macleod's reputation, even after his death.
John James Rickard Macleod was born near Dunkeld in Perthshire on 6 September 1876. Not long after his birth, his father, a clergyman, was transferred to Aberdeen and John went to Aberdeen Grammar School before enrolling at the University of Aberdeen to study medicine. He was awarded his degree with honours in 1898 and, after a year studying biochemistry at the University of Leipzig, he went to work in London as a biochemistry lecturer, while also being awarded his doctorate in public health from Cambridge University.
In 1903, Macleod emigrated to the United States, becoming a lecturer in physiology at the Western Reserve University in Cleveland, Ohio, where he stayed for 15 years and began developing his interest in diabetes. In 1916, he was appointed professor of physiology at McGill University in Montreal, Canada, moving to the University of Toronto at the end of WWI, where he became director of the physiology lab and an assistant to the dean of the medical faculty.
In 1920, Banting, who had hardly any experience of physiology, managed to convince Macleod to let him use his laboratory, while Macleod was visiting Scotland. Macleod also provided Banting with experimental animals and an assistant, Charles Herbert Best, who worked with Macleod as a demonstrator. Macleod gave Banting and Best advice on project planning and the use of analytical techniques, and assisted with the operation on the first dog.
While Macleod was overseas, Banting and Best succeeded in reducing the blood sugar level of another dog, whose pancreas had been surgically removed. When Macleod returned, he was initially sceptical about the results – he knew that there had been many unsuccessful experiments in this done by other researchers – but Banting immediately took Macleod's cautious approach as a personal attack on his integrity.
The two men argued bitterly but Banting finally accepted Macleod's advice that other experiments were needed. Further experiments were successful and the three men started to present their results at meetings. Macleod was a much better speaker and Banting believed his speaking success was evidence that Macleod wanted to take all the credit.
Their discovery was first published in February 1922 in The Journal of Laboratory and Clinical Medicine
and, together, the three researchers developed a more efficient method of extracting insulin, which convinced Macleod to divert the work of his whole laboratory to insulin research and to bring in another assistant, biochemist James Collip.
But Banting's paranoia increased and he became certain that Macleod and all his colleagues were conspiring against him. Collip was so disheartened by the strained atmosphere that he threatened to quit. Fortunately, the encouragement of others who saw the potential of their research prevented an escalation of dissent.
The first successful clinical human clinical trial was performed on Leonard Thompson and this was soon followed by others. Macleod took over the organisation of clinical trials and Banting, once again, believed he had been overlooked.
In 1923, after pharmaceutical firm Eli Lilly and Co took over the mass-production of insulin, Macleod took the opportunity to resume other research, moving to New Brunswick to work at the Marine Biological Station. Banting remained in Toronto and continued to change the story to his own benefit, finally claiming that he deserved all the credit and Macleod had made no contribution other than to leave the keys to the laboratory when he went on holiday to Scotland.
In 1928, Macleod returned to Scotland to become regius professor of physiology at Aberdeen University and later dean of the University of Aberdeen Medical Faculty. Between 1929 and 1933, he was also a member of the Medical Research Council. He wrote a report on the discovery of insulin in 1922 to explain his side of the story but otherwise refrained from active involvement in the the controversy about credit. Banting hated him passionately and the two never spoke again, Macleod dying in Aberdeen on 16 March 1935, aged 58.
Over the years, Macleod's role in this medical breakthrough continued to be diminished and overshadowed, and it was even suggested that his Nobel Prize was undeserved. It wasn't until the late Canadian medical historian Professor Michael Bliss revisited the issue in 1982 that Macleod's vital role in the discovery of insulin has been accepted by the medical establishment worldwide. 'As a consequence of jealousies and academic rivlary, Macleod's rightful role in the discovery of insulin was discredited and his reputation deeply tarnished,' Prof Bliss said at the time. 'This version of history has now been corrected and his reputation restored but, tragically, not in his lifetime.'
'John Macleod directed and informed the research which led to the discovery of insulin. His expertise ensured that the laboratory findings of his team were rapidly translated into the clinical application of insulin in 1922 to treat Type 1 diabetes, one of the therapeutic landmarks of 20th century medicine, Professor Brian Frier, honorary professor of diabetes at the University of Edinburgh,' has added. 'Yet, for decades, Macleod was effectively airbrushed out of medical history. The importance of the research of this quiet and self-effacing Scottish scientist cannot be over-estimated. He deserves to be as well known to the public as is Sir Alexander Fleming for his discovery of penicillin.'
Millar is an adjudicator of the Young Programme