The criticism has been made that Banting and Best’s experiments in which simple extracts of duct-ligated pancreas were used formed no essential step in the investigations which have given us insulin. I need scarcely reply to these criticisms. They were apparently made without any appreciation of the real obstacle that stood in the way of development of the subject – namely, convincing evidence that an antidiabetic hormone does actually exist in the pancreas – and to Banting and Best is due the credit of furnishing this by experiments of a different type from those of their predecessors. We owe much to the initiative, skill and patience they displayed in completing this first essential step in the investigation.32
This was a revealing response. Instead of dealing with Roberts’ specific criticisms of Banting and Best’s hypothesis, experiments, and conclusions, Macleod was saying that these were all beside the point. Banting and Best’s work, Macleod stated, had provided “convincingevidence,” that there was an anti-diabetic hormone in the pancreas. That ended the “first essential step” in the investigation. Then, in this lecture and most of his other accounts of the discovery, Macleod went on to describe the rest of the steps, notably Collip’s isolation of the active principle and the investigation of its physiological effects by the team of workers at Toronto. In Macleod’s mind, the whole importance of Banting and Best’s experiments had been in convincing Macleod and the others of the team that the internal secretion was there to get. They then went and got it. If anything, Roberts’ criticisms reinforced Macleod’s view that Banting and Best’s work was only one part of the discovery process.
The only other response to Roberts was H.H. Dale’s letter in the next issue of the British Medical Journal, claiming that it was out of place for Roberts to belittle “the simple, honest record” of Banting and Best’s experiments. Like Macleod, Dale did not address Roberts’ substantial points. Insulin had, after all, been discovered. “And, if it proves to have resulted from a stumble into the right road, where it crossed the course laid down by a faulty conception, surely the case is not unique in the history of science. The world could afford to exchange a whole library of criticism for one such productive blunder…” Dale also seemed to say that if only Roberts had realized how unqualified Banting and Best were to do good work, he would have been more charitable:
He did not know that the work he attacks was the first, unaided attempt at research by two young enthusiasts; that one spent half the war as a combatant, and the rest, after being seriously wounded, as a medical officer in England, while the other has not even yet completed his student course. He had no conception of the personal sacrifice and heroic labour in which their enterprise involved them. Working thus on their own initiative, without the invaluable help and co-operation given later by the head of the laboratory,…they may have wandered along a wrong trail for a time, though this has yet to be proved. It may be that they made an unnecessary detour, before finding themselves at the point where E.L. Scott had stopped. The important point is that Scott did stop, and that Dr. Roberts would not be writing about his work now if Banting and Best and the other Toronto workers had not gone much further…. It may be that the enthusiasm, which carried them further, was fired by an imperfect interpretation of their earlier results. If so, the mistake will be cleared up in time by others working more calmly and with more experience, and the truth will emerge.83
Dale’s letter was much too censorious. Perhaps it reflected a distaste for scientific controversy; perhaps Dale wanted to protect the people he had met and liked in Toronto; perhaps he wrote out of concern that intense criticism of the Toronto work could upset the still uncertain patent situation. Nonetheless, Roberts’ criticisms were fair comment on Banting and Best’s work. They were not pointlessly destructive, but centred on a factual point of some importance in physiology about whether Banting’s trypsin-antagonism hypothesis had been proven. The critical examination is also significant for those trying to assess Banting and Best’s contribution to the discovery, as opposed to Macleod’s and Collip’s. Roberts did not realize that at the time. Nor, having made his points, did the young scientist have any taste for a public dispute with the powerful H.H. Dale. He wrote nothing more on the subject. His critical article was referred to a few times in European surveys of the insulin literature, a few times more in anti-vivisectionist propaganda, and then forgotten.
For the next thirty years no one else studied Banting and Best’s experiments carefully and critically. Banting himself never seems to have read or known about Roberts’ criticisms, and he did not know enough physiology to correct his own errors; Best believed, probably correctly, that Banting went to his grave secure in the knowledge that his great Idea, the duct ligation to prevent trypsin action hypothesis, had been the breakthrough leading to the discovery. The pandora’s box Roberts had opened and Dale had slammed shut was only finally reopened in the late 1940s when Joseph H. Pratt of Boston undertook his detailed study of the insulin research, culminating in the paper he published in 1954.
In that paper, and in a much longer, more sharply phrased draft of it, Pratt raised all of Roberts’ points (actually he had arrived at the same conclusions independently before learning about Roberts’ article) and added some new criticisms of Banting and Best’s work. He was not sure, for example, that they had succeeded in ligating ducts properly, for what they said were degenerated pancreases seemed to produce a surprising amount of extract. Their surgical hypothesis, that ligation causes acini to degenerate while the islets remain intact, was also technically wrong; both groups of cells degenerate, though usually at different rates. Pointing out how difficult it is to do a complete pancreatectomy, Pratt also questioned whether Banting and Best’s animals, especially the dog Marjorie, were actually diabetic. Such data as the Canadians had provided on the most accurate index of diabetes in the animals, the D:N ratio, suggested that the dogs were not. Finally, Pratt argued, Banting and Best had not found as many toxic side-effects in their dogs as researchers like Zuelzer, Scott, and Kleiner had reported, because they had not looked for them. Fever was the most commonly reported side-effect; Banting and Best had not published any temperatures of their dogs (as we have seen, they only once checked for fever, found it, and did not check again). When Pratt made up an aqueous extract of pancreas, following Banting and Best’s original method, it brought on a mild fever in a normal dog.34
Unlike Roberts, Pratt was interested in the problem of apportioning credit for the discovery. (In passing, Pratt scored heavily against a generation of textbook authors who had discussed the duct ligation, trypsin elimination process as physiological gospel.) Taking account of the work of the predecessors, and noting Banting’s own admission in 1929 that his and Best’s results were “not as encouraging as those obtained by Zuelzer in 1908,”35 Pratt emphasized the multi-step nature of the research. He particularly stressed the contribution of Collip. Banting and Best had taken the work to the point Scott and Zuelzer had reached. Collip, by producing the first non-toxic extract, had gone beyond.36
VI
Roberts’ and Pratt’s criticisms of Banting and Best’s conception, execution, and interpretation of their experiments were, for the most part, well taken and unanswerable. (W.R. Feasby’s attempted answer to Pratt was a pathetic piece of work, a nearly incoherent combination of nit-picking, special pleading, unwarranted ex cathedra claims, and – particularly unfortunate from Banting and Best’s point of view – appeals to the authority of H.H. Dale.37) Had these critics been able to go beyond the published papers to the notebooks, and discovered the errors and other problems in the research as described in chapters three and four of this book, they might have been even more severe in their judgments. The evidence indicates that Fred Banting and Charley Best were, as H.H. Dale said, “two young enthusiasts,” engaged in their first attempt at research. They did wander along a wrong trail; their enthusiasm was fired by a misinterpretation of their early results; insulin did result from “a stumble into the right road, where it crossed th
e course laid down by a faulty conception.”
On their own, Banting and Best were not experienced and knowledgeable enough to have carried their work through to a successful conclusion. They badly needed Macleod’s advice. Indeed, Macleod’s real failure as a scientist in the 1921 research was not, as Banting thought, in his being so critical of their results, but in his apparent failure to notice the many flaws in what were not, in fact, very competent experiments. Some of this was understandable. Roberts notwithstanding, Macleod and many other physiologists saw merit in the hypothesis that digestive enzymes in the pancreas destroyed the internal secretion.38 They did not trouble to reconsider the hypothesis after the experiments, which seemed to have succeeded, had gone on to a far more exciting stage. The excitement at what the experiments resulted in – insulin, with all the opportunities and challenges it opened up – seems to explain why Macleod joined almost everyone else in being less than critical of Banting and Best’s work. As indicated earlier, he may also have been kind to the young enthusiasts, saying less in criticism of their work than he could have.
Why he did not offer such truly useful criticism as correcting their error about Paulesco, however, is more difficult to explain. Probably it was just an oversight; perhaps, as commonly happens with even the best-informed professors, Macleod had not yet read Paulesco. Most of Macleod’s attention in 1920 and most of 1921 was being given to his substantial university duties and to his own experiments on anoxemia.
Even so, without Macleod’s directions in the spring of 1921 Banting and Best might never have prepared an effective extract of any kind. There was a problem with enzyme action in pancreatic extracts, but Banting’s great idea did nothing to overcome it. It was the immediate chilling of all the pancreatic material, as suggested by Macleod, that stopped self-digestion of the fresh pancreases by the activated enzymes. Then, in October and November, Macleod appears to have stopped Banting and Best from becoming side-tracked in futile grafting experiments. Macleod had first suggested to the pair that they use Scott’s method of extracting with alcohol. At exactly the same time as Collip was making very rapid progress in December, Banting and Best were failing repeatedly to produce pancreatic extracts with any potency at all. Their clinical test on Leonard Thompson was a failure. While hypothetical statements are always unprovable, there is no good reason to assume that Banting and Best possessed the experience or the skill to purify their extract on their own. In any case, as Best wrote in 1922, they had had that chance before the task was given to Collip. Banting’s impatience to get something that would work clinically on diabetics was probably the greatest single factor pressuring Macleod to expand the team.
Banting and Best alone did not discover insulin. Their work was part of the discovery of insulin. It was not the whole discovery. Banting and Best began the process that led directly and without significant interruption to success at Toronto. But it was a multi-stage or multi-step process, to which Collip, Macleod, and perhaps others made vital contributions. It is particularly important to repeat that Banting’s great Idea, duct ligation, played no essential part in the discovery. Except in the sense that it got Banting and Best making pancreatic extracts in Macleod’s lab. So many of their extracts were potent, from whatever kind of pancreas they used, that everybody decided there had to be an internal secretion at work. In December 1921 and January 1922, the team isolated the internal secretion (in potent enough form to prove that there was an internal secretion; in a strict sense isolation did not occur until the production of pure crystalline insulin some years later).
Another way of arguing to the same conclusion is to ask at what point in the Toronto research it could be said that insulin had been discovered. If it had been discovered when Banting and Best’s first extracts lowered the blood sugar of their dogs, then priority for the discovery belongs to Zuelzer, Scott, Murlin, Kleiner, Paulesco, and others, who had all done as much, or more, earlier. If it had been discovered when an extract had anti-diabetic effects on a human, although also having toxic side-effects, Zuelzer again – as Banting indicated – had done this earlier. But both of these concepts of discovery are very thin, begging many questions about what could be claimed to have been discovered.
There are really only two tenable views of the “moment” of discovery. One is that insulin had been discovered when a non-toxic preparation of it reduced the cardinal symptoms of diabetes in a human being. That happened with Collip’s insulin in January 1922. And it was the distinction Toronto used in its patent hearing to distance itself from Zuelzer and the others with their unworkable extracts. According to both insulin patents and patients, the discoverers were Banting, Collip, and Best. To them we should probably add Macleod.
The other view, following Darwin’s maxim of credit going to the man who convinces the world, is that insulin had been discovered when convincing evidence of its existence had been presented. There is a possible argument that this criterion leads back to Minkowski and von Mering in 1889. But the much stronger argument is that it leads to the May 3, 1922, presentation to the Association of American Physicians. At that time, the Toronto team of Banting, Best, Collip, Campbell, Fletcher, Macleod, and E.C. Noble, presented evidence of the existence of insulin which their peers accepted. On the basis of authorship of the critical paper, every one of the seven was part of the discovery team.
A not uncommon layman’s view of the discovery holds that without the Toronto work the world might still be without insulin. This is impossibly unlikely. The internal secretion of the pancreas had been “discovered” theoretically back in 1889; its practical isolation and therapeutic use was only a matter of time, determination, ingenuity, technical skill, and resources. Many of Toronto’s predecessors, including Zuelzer, Scott, Murlin, Kleiner, and Paulesco, did have active pancreatic extracts – that is, extracts containing insulin. None of them, however, had been able to purify their extracts sufficiently to eliminate their toxic properties and convince the medical world that the internal secretion had been obtained. If the experiments leading to success had not been begun in Toronto, they would almost certainly have been soon tried somewhere else. Perhaps Paulesco would have purified his extract; this can never be known, though my judgment is that his limited resources, primitive techniques, and theoretical misconceptions would have held him back. Possibly Murlin at Rochester, or Scott at Columbia, both of whose interest was renewed by Paulesco’s publications, would have published the great paper. Perhaps someone else might have reread Kleiner’s 1919 paper carefully, and thought about where it led. Perhaps Frederick Allen’s search for a pancreatic extract, begun in the early months of 1922, would have been successful.* Without Toronto, insulin might have been discovered within five months, or within five years, certainly no more than that. These months, or years, of course, meant the difference between life and death for Leonard Thompson, Jim Havens, Elizabeth Hughes, and thousands of other diabetics.
Why was insulin discovered at the University of Toronto rather than somewhere else? To us, and sometimes to themselves, the discoverers were using incredibly primitive apparatus in dingy, smelly rooms, and with little help from a penny-pinching university. Actually, by the standards of the time, the surprising thing was that the University of Toronto had the resources (such as the dogs and their quarters) to sustain major animal research, and that it had the money and prestige necessary to assemble the team that discovered insulin. Most North American and European universities in the early 1920s were not as fortunate as Toronto. The recent technological advance in the micro-estimation of blood sugar was another vital factor. But, most important, Toronto was the one place where a total determination to find the internal secretion of the pancreas was coupled with the technical expertise to do it. Fred Banting, aided indispensably by Best, provided the determination. Macleod, like Carlson, Allen, and many other experts, had his doubts; Banting, the novice, believed. Whatever the results of the experiments, Banting considered they were good, and urged Macleod to go on to the next stage. Ba
nting possessed unshakeable, unscientific faith.39
To those who understand the university world of the early twentieth century, or readers who noticed how Zuelzer was treated at the University of Berlin in chapter one, the surprising aspect of J.J.R. Macleod’s handling of Banting is that Macleod gave him so much, endured so much, and finally saw clearly enough the importance of the work that he added his and Collip’s, and then Campbell’s, Fletcher’s, and Noble’s expertise to the team. The tragedy of the interaction was that the compound of powerful personalities necessary to produce the great scientific advance was so unstable. The team was impossibly volatile. Its members were literally fighting about the discovery of insulin on virtually the day it was made.
It was partly a problem in human relations, and there is a temptation to see Macleod as a classic example of a professor too busy, or too authoritarian – or, as some who knew him believe, too shy – to handle a difficult “student” with sensitivity and finesse. Professors usually have to bend a good deal in their relations with students, but even in these latter days of student power and teaching evaluations, there are limits. Some students are simply impossible to deal with. Macleod could have done better, perhaps, but only a superman could have led the untutored, insecure, bull-headed Banting through to insulin without major troubles. It would have been like going through a whole Canadian hockey season without allowing a single fist-fight.
CHAPTER NINE
Honouring the Prophets
Most people were not interested in or equipped to understand the fairly technical distinctions and subtle arguments involved in any accurate or fair apportionment of credit for the discovery of insulin. To all but the experts, the story seemed clear. Fred Banting’s idea led to the discovery of insulin. He had the idea, he should have the credit.
The Discovery of Insulin Page 29