Realigning history: The Toronto Four insulin discovery team

Abstract

This article describes the discovery and deployment of the world’s first clinically useful insulin in Toronto more than 100 years ago. It addresses the propagation of a false account of how this breakthrough was achieved and the controversy that ensued leading to a diminution of the contribution of the Scottish academic leader of the discovery team. It describes how, despite the advent – some 60 years later – of a meticulously compiled and definitive history of what really happened in Toronto, the traditional account has proved resistant to correction. It concludes with a description of a spectacular memorial project in Aberdeen restoring the reputation of Professor JJR Macleod, and going on to respectfully reunite ‘the Toronto Four’.

Introduction

In September 2023, a special issue of the Canadian Journal of Health History was released. ¹ Freely accessible online, it had the intriguing title ‘Macleod Reconsidered’ and documented in detail a half-day workshop held by the Toronto Medical Historical Club (TMHC) in May 2022 as an add-on to its insulin centenary celebrations. One hundred years after the advent of insulin therapy, and 40 years after Michael Bliss laid bare how unfairly history had treated Macleod in his best-selling book, ‘The Discovery of Insulin’, ² a rising tide of veracity was washing away at the unjustly mired reputation of Scotland’s insulin Nobel laureate. The following month, on 12 October 2023, at a major event in Aberdeen’s Duthie Park, 300 invited guests saw the unveiling of the world’s first memorial statue to Professor Macleod. By September 2024, the rehabilitation of the insulin story took a further leap forward when a set of bronze plaques was added at the statue site acclaiming all four members of the original insulin discovery team. The following describes how a greatly deserved and quite magnificent tribute came into being and how it is continuing to promote the truth behind a major medical breakthrough in a spirit of respectful reconciliation. The selected references cited were chosen after years of being immersed in the subject matter as those considered most relevant to the manuscript and its overall purpose.

The impact of insulin on medical practice

Surely everyone involved in clinical practice has experienced the stark trauma of therapeutic impotence. As a diabetes doctor with a career starting in the late 1970s, I always had the privilege of ready access to insulin for my patients. It is hard to imagine the hopelessness of a diagnosis of early-onset diabetes barely two generations earlier – for practitioners, parents and most of all, patients.

When a research team in Toronto first gave clinically useful insulin to the world in early 1922, it must have seemed like a medical miracle giving immediate hope where before, there was none. We have all marvelled at the before-and-after images of children showing the wondrous transformation from moribund to healthy. Who, then, could imagine that such an unequivocally stunning medical success story could lead to such acrimony among the discovery team and such protracted misrepresentation of expressed opinion and documented fact? Toronto medical graduate and later Chief of Medicine at Johns Hopkins, Llewellys Barker, was a guest at the University of Toronto’s banquet in honour of the new Nobel laureates in November 1923. Speaking on behalf of Toronto graduates working in the United States, he must have had some awareness of the divisive disagreements over credit when he memorably said, ‘There is in insulin glory enough for all’. ³

The Toronto Four and their flawed story

It is neither necessary nor appropriate to retell and compare here all of the various versions of the insulin story that have appeared in print. Interested readers can be referred to Michael Bliss’s engaging and scholarly account in ‘The Discovery of Insulin’ first published in 1982. ² Using numerous previously untapped sources, the historical accuracy of this exquisitely assembled record of events – which is often at odds with the ‘standard’ tale – has not been seriously challenged in over four decades.

Bliss describes the assorted backgrounds and serendipitous coalescence of the Toronto Four when they met in May 1921 (Figure 1): Frederick Banting (29 years old; Canadian doctor with a big idea on diabetes; decorated war hero; surgical experience but none in research), Charles Best (21; New England son of a Canadian doctor; physiol/biochem student of Macleod so some laboratory expertise), James Bertram Collip (28; Ontarian; triple University of Toronto graduate; Assistant Professor of Biochemistry at University of Alberta; on Rockefeller travelling fellowship) and JJR Macleod (44; Scottish academic physiologist for more than 20 years; internationally recognised expert on carbohydrate metabolism; celebrated researcher, author and educator).

Figure 1.

The Toronto Four: FG Banting, CH Best, JB Collip, JJR Macleod – from around the time they worked together on insulin. Composite image reproduced with permission of Thomas Fisher Rare Book Library, University of Toronto.

In summarising his book, Bliss accords a share of the credit for insulin to each of the four for their individual contributions. He is quite clear, however, that Banting’s idea would have come to nothing had he not been advised to take it to Macleod in Toronto. He was similarly clear in asserting how unfairly history had treated Macleod by misrepresenting his insulin, and indeed, his career legacy.

Bliss’s book should have unequivocally given the lie to the traditional and perennially promoted ‘Banting and Best myth’ of how two inexperienced researchers made a wondrous scientific breakthrough against the odds – then had credit for their work misappropriated by a wicked and unhelpful professor. A widespread and persistent fondness for the ‘successful underdog mythology’ has proved remarkably resistant to correction. It is therefore pertinent to at least list a few counterpoints to the broad belief – probably firmly held by Banting himself from 1921 onwards – that he deserved the lion’s share of any credit for establishing insulin treatment.

First, when Banting and Best used a pancreatic extract to lower glucose in a depancreatised dog in late July 1921, they were not breaking new ground but had simply achieved the same as several prior research groups over, perhaps, 16 years; in fact, Zuelzer in Berlin had used such an extract and claimed transient benefit in human diabetes in 1908. ⁴ Also pancreatic duct ligation had been tried unsuccessfully before, ⁵ and there was even doubt about the logic of employing it since trypsin was already known to be inactive within pancreatic tissue. ⁶ None of the previous groups had made a sufficiently purified extract for repeat usage (n.b. this is still a requirement a century later!) and Banting’s extract produced a similar inflammatory reaction round the injection site when first used on Leonard Thompson on 11 January 1922. Perhaps most importantly of all, preparation of extracts from duct-ligated pancreas (i.e. the main core of Banting’s ‘big idea’) had been permanently abandoned in the weeks before Collip set about working on his effective, purified preparation. Collip’s extract, you see, which ultimately saved Leonard Thompson’s life following its first successful use on 23 January 1922, was made from whole bovine pancreas, easily obtained from the abattoir and purified by extraction in increasing concentrations of ethanol as recommended by Macleod. ⁷

What became of the Toronto Four in 1922 and afterwards?

It is telling that despite their sharing a monumental medical breakthrough, no photograph exists including all of Banting, Best, Collip and Macleod. Readers wishing more detail on the immediate and protracted consequences of the disputed credit due for insulin treatment should once more be referred to Bliss’s book. ² The determined and forthright Banting had had documented fall-outs with Best (summer 1921), Macleod (autumn 1921) and Collip (early 1922). Furthermore, he had felt severely put-out when Macleod intervened during question-time at the American Physiological Association (APA) session in which Banting gave his first important public exposition of the research (30 December 1921). Macleod, who was current President of APA, had been chairing the session; unfortunately, his attempts at rescuing Banting from searching questions that he was ill-equipped to answer, were perceived by the latter as undermining and even predatory. Matters really came to a head when in October 1923, the announcement came from Stockholm that the Nobel Prize for Physiology or Medicine was jointly awarded to Banting and Macleod (Figure 2). Banting, incensed that Macleod should get any credit at all, had to be talked out of refusing outright the award of Canada’s first Nobel Prize. In the end, he shared his prize money with Best while Macleod shared his with Collip.

Figure 2.

The 1923 Nobel Certificate awarded to Banting and Macleod. Macleod’s copy and Nobel medal were bequeathed to the University of Aberdeen. The medal is on long-term loan to Aberdeen City Council and on display in their Provost Skene House Museum. Certificate image courtesy of JJR Macleod Memorial Statue Society.

Banting, who had strong political backers, received much in terms of a non-teaching professorship, a generous salary with additional research funding, and even a research Institute in Toronto. He practised diabetes for about 2 years gaining much sound, early experience of insulin treatment as expounded in his Nobel acceptance lecture in 1925. ⁸ He then decided to give up diabetes and to turn to alternative research, imagining he could make another major breakthrough. However, despite all of the resources available to him, his research made little impact and one can only imagine how heavily his accolades as a pioneering medical researcher must have weighed on his ill-equipped shoulders. He never relented in terms of criticising Macleod and he died in a war-time plane crash aged 49 in 1941. The intriguing story of this complex character was told in Bliss’s follow-up volume, ‘Banting – a Biography’ published in 1984. ⁹

Best was somewhat variably credited in Banting’s serial accounts of the insulin discovery. He completed his medical studies in Toronto, undertook doctoral studies in England and succeeded Macleod as Chair of Physiology in Toronto. Best did useful research work on choline and heparin but despite several nominations, was never a Nobel laureate. In a further publication in 1994, Bliss challenged the extent to which Best had unashamedly tried to retrospectively reinforce his alleged contributions to the insulin discovery story. ¹⁰ It was following the 1978 passing of Best, that Bliss began his ‘Discovery of Insulin’ project.

Collip had a highly successful career in Canada as a scientist, administrator and educator of national importance. ¹¹ His research talents contributed to the discovery of several further hormones back in Alberta and later while Head of Biochemistry at McGill in Montreal. He subsequently became Dean of Medicine at the University of Western Ontario, retiring from this post 4 years before his death in 1965. It has often been said that Collip should have shared the insulin Nobel Prize, but he was not on the list of nominations and modestly reported that he had done ‘only that which any well-trained biochemist could be expected to contribute’. ¹²

Macleod, ground down by the ongoing grumblings of Banting and his supporters, nevertheless continued his great work in medical science and education in Toronto. However, it is likely that he would have been delighted to be offered the opportunity to return to his Alma Mater as Regius Professor of Physiology in 1928. Over the next 7 years, he undertook further original research, continued his scientific writing, served as Dean of the Medical Faculty and served on important national research committees. His ability to travel and work were progressively limited by rheumatoid arthritis and he died in post aged 58. His regret over the unpleasantness that had unfolded in Toronto meant that he rarely spoke about his Nobel award or the work leading up to it. The best descriptions of the character (and work) of this noble and self-effacing scientist and educator are found in the words of those who knew him and wrote obituaries that are, incidentally, uniformly at odds with Banting’s antipathy towards Macleod.^13–15

Restoring Macleod to his rightful place

For almost 50 years after his death Macleod was rarely given a mention in accounts of the Toronto insulin story; as our former College Vice-President, Professor Brian Frier remarked, ‘it was as if he had been airbrushed from history’. ¹⁶ Even following the publication of Bliss’s book in 1982, stemming the customary assertion that insulin was discovered by Banting and Best has been painfully slow. At the University of Toronto, an auditorium was named for Macleod in 1990, and he was granted entry to the Canadian Medical Hall of Fame in 2012. Diabetes UK named their award for those having lived with diabetes for 70 years, the Macleod Medal around the time that Aberdeen Diabetologist, Dr. Michael Williams produced a biography of Macleod which was published by RCPE as a stand-alone supplement to its Proceedings in 1993. ¹⁷

With his growing interest, Williams had photographs of Macleod and his Nobel Prize certificate mounted in the Aberdeen Diabetes Clinic where they were noticed, in due course, by local businessman John Otto who had developed diabetes as a child in 1973. He was shocked at the lack of recognition of the importance of Macleod in the history of diabetes – and resolved to put that right one day. John Otto’s ambitious project took off around the autumn of 2021 amidst talk of the centenary of the discovery of insulin – most of it still misguidedly credited to Banting and Best and misfocussed on the summer of 2021. John and his partner, Kimberlie Hamilton, a screenwriter and award-winning children’s author from California, formed the JJR Macleod Memorial Statue Society ¹⁸ with a view to raising support and funds to erect a permanent monument to Macleod’s memory.

With Macleod’s story attracting a great deal of interest, the project progressed rapidly on several fronts. Ayrshire-based sculptor John McKenna was soon engaged in developing designs for a seated figure on a park bench to be cast in bronze. Aberdeen City Council approved use of a site in Duthie Park just a short distance from Macleod’s burial place in Allenvale Cemetery. Sponsorship for the project – which cost around £0.25M – was addressed by a plan to mount the statue on a platform featuring a grey and pink granite mosaic on which sponsors’ names would be engraved. A low granite wall to the rear of the statue was further decorated with individually designed bronze plaques bearing the names of additional sponsors. Several local companies contributed greatly in kind by undertaking to provide input to building, granite cutting, path-laying and transporting the completed bronze, weighing around 1 tonne, to Aberdeen from a foundry in Wales. This monument was also to be Scotland’s first ‘storytelling statue’ via a smart phone app developed by Talking Statues™ in Denmark. Visitors who scan a QR code receive a 2-min ‘phone call’ purportedly from John Macleod himself. Scottish actor, David Rintoul, who was raised in Aberdeen where his father was a pioneering geriatrician, gave Jack Macleod his voice, reading a script prepared by Kimberlie.

In under 2 years, the JJR Macleod Memorial Statue Society, reached its primary goal when, on 12 October 2023 (13 days before the centenary of the Nobel Prize announcement), the statue (Figure 3) was officially unveiled before a private gathering of 300 invited guests including great-nephews and great-nieces of Professor Macleod and his wife. Television coverage of the event raised further the profile of Macleod’s story and the statue continues to be a popular attraction for visitors to the park. Its work in acclaiming the Toronto Four, however, was not yet complete.

Figure 3.

The statue of JJR Macleod on its grey and pink granite plinth in Aberdeen’s Duthie Park on 12 October 2023 – the day of its unveiling. Picture reproduced courtesy of aberdeeenphoto.com.

Reconciling the Toronto Four

Professor John Dirks, former Dean of Medicine at the University of Toronto and personal friend of the late Michael Bliss, addressed the company at the statue unveiling as representative of the TMHC. That institution was due to host an event at the University of Toronto in November 2023 marking the centenary of the insulin Nobel Prize announcement. ¹⁹ At the Toronto event, there was further discussion of the significance of the monument in Aberdeen which led to TMHC undertaking to sponsor the installation of additional bronze plaques reuniting the discoverers of insulin. Thus, at a further event on 6 September 2024 (JJR Macleod’s 148th birthday) plaques naming Banting, Best, Collip and Macleod were formally unveiled on the granite wall behind Macleod’s statue before several TMHC representatives and Professor Erling Norrby, a former member of the Nobel Prize committee and noted Nobel medical historian (Figures 4 and 5). Later that day, a workshop celebrating the contributions of the Toronto Four – and their symbolic and, in over 100 years unique, reconciliation for all to see in Aberdeen’s Duthie Park. Recordings of the ‘Toronto Four conference’ are available on the TMHC YouTube channel. ²⁰ I cannot objectively report that events of the day actually made the statue smile, but I should like to think that ‘Professor JJR Macleod of Aberdeen and Toronto: Nobel Laureate and Noble Scientist’ (the title of the conference presentation about him) would have thoroughly approved of this outcome that had been a century in the making.

Figure 4.

The Toronto Four reunited in bronze plaques unveiled on the parapet immediately behind Macleod’s statue on 6 September 2024. L to R linking hands between the national flags are Gary Goldberg (TMHC), Erling Norrby (Nobel Prize medical historian, Stockholm), John Otto (JJR Macleod Memorial Statue Society), John Dirks (TMHC), Ken McHardy and Peter Kopplin (TMHC). Picture reproduced courtesy of aberdeenphoto.com. TMHC: Toronto Medical Historical Club.

Figure 5.

Explanatory bronze plaque embedded in the path below the reunited Toronto Four. Picture reproduced courtesy of JJR Macleod Memorial Statue Society.