Celebration of the 90th birthday of the emergence of insulin was launched in Toronto on 25 October 2011. The event was organized and sponsored through a partnership of the University of Toronto (whose foresight, faculty, funds, and facilities provided the environment for the discovery of insulin) with The Gairdner Foundation (whose annual awards are Canada's most prestigious international recognition of scientific achievement worldwide). A key message of the celebration was to declare before a distinguished audience that the discovery of insulin was a joint effort of four people, Banting, Macleod, Collip, and Best, each of whom played an essential part in this monumental accomplishment, overturning in the process the established dogma that the team was only Banting and Best. A celebratory symposium further highlighted the advances to date in the functions of insulin and treatments for diabetes.
The celebratory dinner, held at the university's Massey College Upper Library, which upheld its reputation for outstanding cuisine and service, included four toasts by four leaders, one toast to each of the discoverers (Figures 1-4). Additional encomiums and comments followed the toasts (Table 1). The celebration continued with an all day symposium devoted to recent research on diabetes and metabolic disorders, culminating in late afternoon with the opening of the university's permanent monument to honor the discovery and the four discoverers (Figure 5) . A web version of the exhibit is currently under development. In addition to the informational video, an extended effort will be required to add material from Macleod and Collip to better balance the great mass of memorabilia from Banting and Best. The final piece in this celebration took place on 21 March 2012 at the Four Seasons Hotel in Toronto when J. J .R. Macleod was inducted into Canada's Medical Hall of Fame. The other three discoverers were in the first group of inductees in 1994. It remains a mystery why one of Canada's handful of Nobel laureates in medicine had his induction delayed for 18 years.
Table 1. Additional comments
Similar to the audience for a play by Sophocles or Euripedes, each guest at the dinner knew details of the events surrounding the discovery of insulin, the Nobel Prizes, and more. When the toastmasters briefly alluded to these events, they were confident that each member of the audience would fill in the rest. Here, we will swiftly retrace the essentials of the tale – political, medical, and scientific – so that the reader can appreciate better why this 90th year celebration is a landmark event.
Credit where credit is due
The 1923 Nobel Prize for the discovery of insulin was awarded by ‘the professorial staff of the Caroline Institute’  to Banting and Macleod. Banting quickly shared his prize money with Best, and Macleod with Collip. Despite the Nobel decision and the well-publicized splitting of the cash prizes, Banting and Best are often credited in the international arena with the discovery of insulin and its transformation into a life-sustaining therapy for diabetes. Everyone warmed to the Hollywood-like myth of two novices, a surgeon and a medical student, who came out of nowhere and during their first summer, while the professor who provided the lab was away on ‘vacation’, succeeded in a task that had stymied many professional researchers who came before them. Bliss estimated that 400 labs had attempted the feat. The two favorite sons' achievements led to many honors including Banting and/or Best professorial chairs, lectureships, named research prizes, departments, and institutes, funded by private and government bodies in Canada and worldwide. The only doubters out there in modern times were (i) some experienced laboratory researchers who were silently incredulous – the official narrative was beyond belief and (ii) a group of Romanian academics who maintained that Professor Nicolae Paulescu, their countryman, had made the discovery a year earlier [3, 4]. Of note, Bliss and Laron evaluated and denied the Paulescu claim [5, 6].
In 1982, Michael Bliss, now an emeritus professor of history at the University of Toronto and one of the evening's toasters, published an award-winning book, ‘The Discovery of Insulin’. In retrospect, the title probably should have been ‘The Discovery of the Discoverers of Insulin’. That book and Bliss' follow-up biography of Banting, along with numerous journal articles based on comprehensive and detailed searches of the documents and interviews with then-living survivors of the era , made clear that (i) insulin had been very nearly purified and isolated many times in many places in the decades between 1890 and 1920; (ii) the triumph in 1921–1922 was due to the collective efforts, stamina, and skills of the four researchers – Banting, Macleod, Collip, and Best – working at the University of Toronto, a highly supportive institution with a large endowment; (iii) that the 1923 Nobel Prize to Banting and to Macleod was appropriate; and that (iv) Banting and Best, in addition to promoting credit to themselves, were withholding or suppressing credit for Macleod and Collip . Bliss, in addition to the mass of evidence he marshals, has a captivating narrative style that carries over into his lectures on the topic, delivered over the last three decades at major meetings in North America and Europe. Yet, the myth persists.
Evidence that the myth persists comes from my own experience (J. Roth). I begin my visiting lectures at the announced time. Typically some attendees drift in after that. To start on time but not sabotage my own talk, I bring along a vignette or two – intellectual hors d'oeuvres – to stimulate the on-timers. In 2011, when I asked ‘Who discovered insulin?’ or ‘Who won the 1923 Nobel Prize for the discovery of insulin?’, Banting and Best, in secret ballots, won landslide victories. Also, recall that most of my talks are on diabetes-related topics so that even my diabetes-enriched audiences of MDs, PhDs, and graduate level trainees are still stuck in the past. Worst of all are the academic authors and editors who assign the discovery of insulin to Banting and Best and then reference the Bliss book as their source, despite Bliss' very clear commitment to the quartet, not the duo.
Insulin as treatment
Politics aside, let us recall the medicine and then the science. Juvenile-onset or type 1 diabetes was uniformly fatal within days or weeks of onset until the early 20th century; carefully constructed programs of starvation that were introduced at that time, when followed, could extend survival to a couple of years. Indeed, the miracle-like rescue by insulin of these starved youngsters at death's door in the summer of 1922 was a very dramatic and highly significant part of the discovery story. Elliott Joslin, a leader in use of the new treatment, commented ‘I had witnessed so many near resurrections that I realized I was seeing enacted before my very eyes Ezekiel's vision of the valley of dry bones’ [Ezekiel 37:2–10] [5, 9, 10] (Figure 6). The speed with which insulin spread is unimaginable today. In about 1 year, Joslin had treated 127 patients .
Joslin was prescient in warning that strict attention to diet was still essential. He also warned that ‘diabetes, though subdued, is not yet conquered’ . It was only decades later that it was widely appreciated that insulin was not fully restorative. Many patients on insulin suffer diabetic complications, typically one or more decades after onset of the illness and a shortened life span due to diabetes.
Ninety years later, insulin and its synthetically modified siblings remain the mainstay and sine qua non for treating type 1 diabetes. Insulin is now prescribed for an increasing fraction of patients with type 2 diabetes who are not achieving adequate control of glycemia with pills and other interventions. Insulin has a key role in the treatment of gestational diabetes, the disturbance in carbohydrate metabolism that first comes on with pregnancy to the potential detriment of the mother and offspring . It is also used to reduce the transient severe hyperglycemia that in nondiabetic patients can accompany acute medical situations (e.g. stroke, infection, and trauma), so-called stress hyperglycemia[12, 13].
Basic science origins
In the late 1880s, Josef von Mering, a researcher focused on the gastrointestinal tract, approached Oskar Minkowski (Figure 7), a colleague with training in surgery, to help him perform a total pancreatectomy. The dog recovered, but unexpectedly developed polyuria. Minkowski, a rising star in a leading diabetes laboratory, recognized the cause of the polyuria: hyperglycemia with glycosuria . When replacements of pancreas prevented or reversed these abnormalities, he concluded that the pancreas produced an internal secretion that promoted glucose metabolism [14, 15]. Soon after, multiple investigations and investigators suggested that the mysterious islets of Langerhans were the cells that produced the internal secretion. For the next three decades, many researchers in Europe and North America unsuccessfully pursued this hypothetical substance, named ‘insuline’ in French in 1909 and anglicized to ‘insulin’ a few years before the isolation.
Banting in Toronto
In 1920, Fred Banting, a Toronto-trained surgeon whose nascent practice in London, Ontario was slow in developing, came upon a publication, a review and report of a patient in whom blockage of the pancreatic duct by a stone led to atrophy of the exocrine pancreas but left intact the islets of Langerhans, by now believed to be the source of the internal secretion (Figure 8) . Banting immediately hatched the idea that duct ligation would allow the long sought ‘internal secretion’ of the pancreas to be isolated (by him), safe from proteolytic attack by the digestive enzymes of that organ. Luckily, he was referred to J. J. R. Macleod, a highly published internationally recognized authority on all aspects of carbohydrate metabolism who had recently been recruited as Chairman of the Department of Physiology at the University of Toronto, following a successful term as professor in Cleveland [17, 18]. The almost 1000 page, nearly solo-authored Macleod textbook, ‘Physiology and Biochemistry in Modern Medicine’, had just come out in its third edition (Figure 9) . His new laboratories were first rate, attracting on sabbatical J. B. Collip, a recently appointed faculty member in biochemistry at the University of Alberta and author of an impressive publication on internal secretions, a common synonym for hormones at that time (Figure 10) [20, 21].
When Banting presented his idea, Macleod hesitated . Among his concerns may have been some of the following: many excellent researchers had failed for over three decades; Banting had very modest research experience; and the duct ligation story was not new or unique. Macleod very likely knew that a simpler alternative could be found in some fish, whose islets of endocrine tissue are separate from their exocrine pancreas [15, 23].
In May 1921, after Macleod had transformed Banting's big but vague idea into a reasonably defined set of experiments, Banting started in Macleod's lab in Toronto. Macleod introduced Collip to Banting, helped Charles Best to become Banting's assistant, and schooled the pair in the techniques they would need – pancreatic surgery, glucose and ketone measurements, and methods for preparing tissue extracts [8, 24]. Macleod then left for the summer. From leafing through the Macleod textbook, one suspects that Macleod's ‘vacations’ were filled with writing.
The pair of laboratory rookies had a disastrous start: no significant results and many dead dogs, despite Banting's strong background in surgery [5, 25]. Late in July, they turned the corner – pancreatic extracts helped reduce the hyperglycemia of pancreatectomized dogs. It is noteworthy that bioactive extracts came from multiple preparations of pancreas, not solely from those whose pancreatic ducts had been ligated (which Banting had imagined was his own magic formula, the vision that drove Banting to Toronto). Bliss commented that ‘Banting and Best did not know that their results with their extracts were no more favorable than, say, Paulescu's results and were less favorable than Kleiner's. They did not read the literature carefully at the beginning of their work…’ . Banting and Best, after they had reviewed their own results with Macleod, began to write their first article (Figure 11) .
Given that Macleod had prepared the detailed research plan and methods that they followed and provided much other help, he was justified in being a co-author. Why was Macleod's name not on the article? We imagine that he judged the article to be okay for two beginners to publish but not suitable for a senior professor and lab chief with an international reputation. The positive results up to this point were roughly comparable to those obtained by many lab groups in the past. The reproducibility of their work had not yet been established, and failure to achieve a reasonable level of reproducibility was a recurrent problem for even excellent biochemists of that period (e.g. Zuelzer and Kleiner). For many years at the National Institutes of Health, I was part of the faculty for advanced courses in endocrinology. One format we used was to read 60 classic articles including the first article of Banting and Best. Recurrently, I decided that I would not have allowed my name to be on it and a majority of young researchers felt the same way – the data were too dicey.
Reproducibility was a recurrent problem. By reading the work of Bliss, one suspects that Banting and Best had lost the ability to make bioactive extracts in the weeks leading up to the first public presentation of this work by Banting at the American Physiological Society's annual meeting on 30 December 1921 in New Haven . It was about then that Collip was recruited to take over the tissue extraction research . With Collip's innovations, they recovered the ability to make insulin. The first successful injection of insulin to a patient, Leonard Thompson, took place at the Toronto General Hospital on 23 January 1922 , only seven months after the launch of their search for the pancreatic hormone. The ability to make insulin was lost once more in the weeks prior to the major presentation by Macleod announcing the discovery on 3 May 1922 at the annual meeting of the American Association of Physicians at the Willard Hotel in Washington D.C. . By the summer of 1922, with help from Eli Lilly and Connaught, a University of Toronto laboratory recruited to help produce insulin, the Torontonians were producing insulin and treating patients, many of whom were near death . Reproducibility of methods to produce insulin was an ongoing challenge. With the increasing number of patients now dependent on insulin, the intermittent shortages were nightmares.
War without end
At the University's dinner to honor its Nobel laureates, Lewellys Barker, University of Toronto alumnus and successor to William Osler as Physician-in-Chief at Johns Hopkins, proudly declared ‘There is in insulin, glory enough for all’ [5, 32]. In its truncated version, ‘Glory enough for all’ soon became the bitter ironic distillate of the strife-riven discovery. With Banting versus Macleod at the epicenter, the struggles also spread to adjacent players and to multiple constituencies. Banting's misbehavior repeatedly disrupted the work. He was recurrently angry at Macleod for giving what Banting thought was insufficient support for his work . A never-to-be-repaired rupture came at the 1921 Physiology meeting. When Banting presented their early results, the expert audience pressed for details and confirmations. Banting had vocal and intellectual difficulties in responding. Macleod stepped in to help him and used the term ‘We…’ That episode led Banting to the immutable conclusion that Macleod was trying to steal his discovery. From this time forward, Banting made private and public accusations that Macleod was lying, attempting to steal his discovery and take credit for his work.
Banting, in addition to physically attacking Collip, needed help from Best to deal with his recurrent bouts of depression, paranoia, alcohol excess, and absenteeism (as well as a threat of suicide – see later). The 1923 Nobel Prize (Figure. 12) awarded to Banting and Macleod, instead of cooling Banting's anger, seemed to act as fuel for further conflagrations. In a public display, he besmirched Macleod and gave half of the Nobel stipend to Best . That Macleod then shared his honorarium with Collip was of no avail. On 26 November 1923, Banting and Macleod were grandly feted and lauded by Toronto and the University for their achievements, their new honorary degrees conferred by the University, and their Nobel Prize. Banting's rage continued unabated.
Following the Nobel announcements, as expected, the world gave honors to Banting and Macleod. Banting waged a sustained campaign to credit himself by attacking Macleod in private and in public venues. Recent documents reinforce the earlier conclusion that a major force in this unbalanced apportioning of credit was Dr William G. Ross, a casual researcher and politically very well connected uncritical hero-worshiper of Banting. Ross was convinced that Banting alone deserved credit for the discovery and campaigned energetically on Banting's behalf. Ross was also responsible for denying credit to Best. Best believed that Ross was responsible for Best's exclusion from the celebration marking the tenth anniversary of the discovery .
Banting's unqualified kudos to Best at the time of the Nobel announcement was short lived. For the remaining two decades together in Toronto, Banting's pronouncements about Best and his role in the discovery were mixed and qualified. Meanwhile, Best and friends (including Nobel laureate Henry Dale) pushed ahead to support Best's role, which grew year by year in the retelling . In retrospect, the Canadians and then the rest of the scientific world were led astray by Banting and by Best, each with his energetic acolytes, into an extraordinarily unfair division of honor and funding.
Banting's interactions with patients appear to have been appropriate, and especially admirable at the war front and in Toronto giving insulin to youngsters near death from diabetes. Banting's attitudes with respect to cash and credit were unexpected and difficult for us to rationalize. For all of the pre-insulin years of Banting's life, his finances were very spare and weighed heavily in his planning of schooling, marriage, and private practice. Yet, he was against accepting any profits from the sale of insulin and initially opposed patenting it. Ultimately, the insulin patents were filed in the names of Banting, Best, and Collip, and immediately transferred to the Board of Governors of the University, which licensed manufacturers and collected royalties. The Nobel Prize money was a princely sum (the $40 000 is roughly equivalent to $1 000 000 today) but in his anti-Macleod furor, Banting instantly committed half to Best.
When it came to apportioning credit for the research work performed, Banting was shockingly miserly. His denial of credit to Macleod was outrageous but possibly could be explained by (i) his unshakable erroneous belief that his duct ligation idea was a unique essential to the success of the enterprise; (ii) the novice investigator's lack of appreciation of the resource-filled environment – intellectual, technical, and physical – that the lab chief and his deputies provided; and (iii) Banting's thoughts that one gets credit only for what your hands did. Macleod did none of the early experiments himself. But Collip did do many crucial experiments (though in another space at the University) and yet was denied credit along with Macleod. Banting's generosity to Best, although wholehearted when he was besmirching Macleod, was not always sustained.
Banting suffered post-traumatic stress
We raise the possibility that Banting was suffering from a post-traumatic stress disorder that contributed to his aberrant behavior (described previously) while in Macleod's department in Toronto. In 1918, he served 3 months immediately behind the front lines of allied trenches in France [35, 36]. Steady artillery fire, recurrent attacks and counter attacks, threats of poison gas, and the cavalcade of horrendously injured young men that came under Banting's care were surely sufficient trauma. He then suffered a major injury with shrapnel in his right (dominant) arm that led to infection and threats of amputation, a terrifying prospect, especially for a budding surgeon. Research has shown that physical injuries significantly increase the prevalence of traumatic stress disorder [37-39]. Another recent study found that US army veterans with the diagnosis of post-traumatic stress who returned to college, had a three-fold increase in the incidence of fist fights . Of note, our search of the literature came up with only one other group who inferred that Banting was suffering from post-traumatic stress disorder .
Summary and look to the future
In retrospect, it is clear that Banting and Best (with help from influential intimates) not only promoted themselves as discoverers but also actively sought to deny credit to their partners. The biomedical community of Canada and of the rest of the world bought into the distorted attribution of credit and in the creation of eponymous monuments (professorships, departments, prizes, and more). The 75th Anniversary in 1996 brought about the naming of the major Faculty of Medicine Auditorium as the J. J. R. Macleod Auditorium. The 90th anniversary celebration is refreshing with clear declarations of honor to the insulin quartet from the University of Toronto, host and partner in the discovery, and from the Gairdner Foundation, representative of the national and international bioscience community of Canada. The university's new exhibit and other monuments to the four are most appropriate. The sharing of honor will be clearer as the university and the world biomedical community are able to expand the number of memorial devices to honor Macleod and Collip along with Banting and Best. Finally, recognizing the courageous and eloquent detective who re-opened the cold case and led our way to true justice and understanding, let us now praise University of Toronto historian Michael Bliss for his 30-year successful effort. The rest is now up to all of us.
Macleod's legacy and a personal postscript
A legendary scholar explained to his most advanced class: the final grade will be on the basis of both the answers you give as well as on the questions you ask. The advent of insulin in 1922 led Macleod, the deeply rooted physiologist, to explore the biological effects of insulin, which took up the lion's share of his 26 May 1925 Nobel Lecture. He closed by stating ‘I have attempted to review but a small part of the work relating to insulin and have only cursorily referred to the perplexing problem of the mechanism of its action in the animal body.’ The latter problem – the mechanism of insulin action – remained unsolved for 50 years, despite efforts by legions of investigators including four Nobel laureates (Macleod, Gerty Cori, Carl Cori and Earl Sutherland) and other notables (e.g. Rachmiel Levine and William Stadie) (Figure 13). Our group at the National Institutes of Health (and our colleagues there) from the early 1960s to the late 1970s had the privilege of being pioneers in providing Macleod with the answer.
We were lucky. On the basis of then recent data from the newly introduced radioimmunoassay, we calculated that a cell could recognize insulin when insulin represented only one out of a million or more other molecules that it was being bathed in. Instead of asking ‘What is the mechanism of insulin action?’, we asked a simpler question, ‘How does the cell know that insulin is there?’ After introducing both the concepts and methods for cell surface receptors [42, 43] – which had not existed before – we were leaders in showing that the only action of insulin is to bind to and activate the insulin receptor [43-45]. The insulin receptor is the purveyor of all actions of insulin. Insulin without its receptor can do nothing. The receptor, when stimulated even without insulin (e.g. with an anti-receptor antibody), can activate all processes that we call insulin action [43, 45]. We tip our hats to the four discoverers of insulin, especially to Macleod, whose post-1921 work and thoughts were closest to our own work 50 years later.
Note added in proof
In retrospect, bottom line, we suspect that between May 1921 and January 1922, Banting and Best with input from Macleod were frequently but not always able to produce an insulin preparation that could lower the blood glucose in a depancreatized dog but was not suitable for use in humans – seemingly similar to what was achieved by earlier researchers, e.g. Zuelzer, Kleiner, and possibly others. Collip in January 1922 brought them to the next level – insulin suitable for treating patients. The next level required multiple inputs from the Toronto quartet and their pharmaceutical partners – reliably reproducible results.
Conflict of interest
The Gairdner Foundation happily followed Mladen Vranic's suggestion that the Foundation and its Canada Gairdner Award should enlist the University of Toronto into a partnership in celebrating the 90th anniversary of the discovery of insulin. The Foundation and the University thank the organizing committee of John H. Dirks, Daniel J. Drucker, Bernard Zinman, Amira Klip, and Mladen Vranic; the speakers including Catharine Whiteside, Robert Bell, Gary F. Lewis, Joe L. Goldstein, Jesse Roth, Jeffrey M. Friedman, Andrew T. Hattersley, Philip M. Sherman, Marc Y. Donath, C. Ronald Kahn, and I. George Fantus, as well as John H. Dirks, Mladen Vranic, Bernard Zinman, Amira Klip, and Daniel J. Drucker. The dinner and the symposium were generously supported by Novo Nordisk and Lilly and by the University of Toronto. All authors contributed to the conceptualization, writing, and design of the manuscript, as well as drafting the article and revising it critically for intellectual content. All authors approved the version to be published. We are indebted to John H. Dirks (Gairdner) for encouraging us to create this document; to Michael Bliss (University of Toronto) for many facts and insights related to multiple aspects of the article; to Catharine Whiteside (University of Toronto) for encouragement and support of the celebratory events; to Amira Klip (University of Toronto), Ann Danoff (New York University), Tom R. Coleman (Feinstein Institute of North Shore-LIJ), LaQueta K. Hudson (Feinstein), and Sergio I. Valdes-Ferrer (Feinstein) for critiques of the manuscript. Jesse Roth's academic program receives support from the Feinstein Institute for Medical Research, Manhasset, NY; the Russell Berrie Foundation, Teaneck, NJ; and the Alan and Tatyana Forman family. Jesse Roth dedicates this article to the memory of (i) Christopher D. Saudek MD of Johns Hopkins who devoted much of his professional life to improving methods for delivering insulin, and (ii) Arnold Horowitz, the best teacher at New Utrecht High School, whose lifespan was cut in half by the post-insulin complications of diabetes, reminding us that insulin at its best is not the full answer to the ravages of diabetes.