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J. J. R. Macleod and the discovery of insulin

Lloyd G. Stevenson

When Professor J. B. Collip, as director of a celebrated laboratory at McGill and later at the University of Western Ontario, presided at a meeting of his co-workers to discuss research in progress or to plan a new project he always insisted that there should be a detailed record of all the ideas brought forward and all the proposals made. This way, said Professor Collip, there could be no subsequent dispute. In adopting this policy he was motivated by sorry experience in the Department of Physiology of the Univer- sity of Toronto during the course of the important investigations which led to the discovery of insulin.

In Toronto Collip had worked with Frederick G. Banting and Charles H. Best, all under the direction of the chairman of the department, Professor J. J. R. Macleod, and there he had witnessed a bitter dispute about priority. The vials of Banting’s wrath were even poured on Collip at one time, but the principal victim, then and later, was Macleod; whereas Banting and Collip became friends subsequently, Banting was still unreconciled to his old chief when Macleod died in 1935. The Nobel Prize ‘for the discovery of insulin’ was awarded to Banting and Macleod in 1923 and while Banting shared his half of the award with his young colleague, Best, Professor Macleod shared his with Collip.

In spite of his status as a Nobel laureate, Macleod, faced by Banting’s hostility, must have had an uncomfortable five years in Toronto before he accepted the chair at Aberdeen in 1928. Banting, who was killed in an airplane crash in Newfoundland in 1941, outlived Macleod by six years. Between 1928, when Macleod departed for Scotland, and 1941, the date of the Newfoundland tragedy, Banting, internationally famous and director of the Institute named for him in Toronto, did nothing to alter the picture of Macleod as having encroached on the glory that was properly his and Best’s; nor did Best retouch the picture in any

Lloyd G. Stevenson is William H. Welch Professor of History of Medicine and Director of the Institute of the History of Medicine at Johns Hopkins University, 1900 East Monument St, Baltimore, MD 21205, U.S.A.

effective way before his recent death. This appears to have settled the story. What is more, and more to be deplored, is that a ‘recent British film on the discovery of insulin has vividly confirmed it - the ambiguous image of the unfortunate Macleod memorably realized by Ralph Richardson. Although Collip never shared Banting’s opinion of Macleod, he never openly and firmly differed from it. And the one never heard from, the one who kept silence for a dozen years (was it sad resignation or cold hauteur?) was Macleod himself. Yet he remains on the record, clearly and unquestionably. The reason that neither book nor film has ventured to question the portrait of Macleod as limned by Banting is that for 56 years the University of Toronto has steadfastly declined to release to Banting’s biographers or others the statement of Macleod’s side of the story, which he submitted to the chairman of the university’s board of governors in 1922. Nor, as a matter of fact, has the statement been released even yet. In 1949, however, a copy was discovered among Macleod’s papers in Aberdeen and a transcript of this found its way across the Atlantic. At some point Collip arranged to have a copy sent to the Medical Research Council in Ottawa and another copy has been deposited in the Public Archives of Canada. Nearly 60 years after it was written, Macleod’s statement has found its way into print.

Macleod’s early career I have remarked that Banting was never

reconciled with his old chief. Possibly ‘old chief is not the proper term. Banting was aged 30, Macleod 45, when they first met, and their association, although moment- ous, was brief. Macleod, born in 1876 in Cluny, Perthshire, and educated chiefly in Aberdeen, carried his medical qualifica- tion to the Physiology Institute at Leipzig where he studied biochemistry under Siegfried and Burian. Later, he worked at the London Hospital Medical College under Leonard Hill, principally on prob- lems of respiration, and took his diploma in public health at Cambridge. In 1903, he was appointed professor of physiology at Western Reserve (now Case Western Reserve) University, Cleveland, remain-

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J. J. R. Macleod

ing as teacher and researcher for 15 years. In 1918 he became professor of physiol- ogy at the University of Toronto and not long afterward published, with col- laborators, a textbook of nearly 1000 pages, Physiology and Biochemistry in Modern Medicine. His most important work at Cleveland had been studies on the breakdown of liver glycogen. In 1913, nearly 10 years before the discovery of insulin, he had written a book on diabetes and its pathological physiology.

Macleod’s first years in Toronto were devoted chiefly YO studying the peculiarities of respiration in decerebrate animals and the effects of anoxemia and of excess oxygen. At the end of 1920, however, he was visited by Banting, a Toronto graduate in medicine who was attempting to set himself up as a surgeon in London, Ontario. Banting brought with him his idea that a duct-ligated pancreas would be free of its digestive enzyme, permitting the extraction from it of the putative internal secretion produced by the islets of Langerhans. It was this which turned Macleod’s attention once again to carbohydrate metabolism, a subject to which he had devoted many years and on which he was a recognized authority.

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Months later he was informed that among ‘the causes for the misunderstandings which have arisen from time to time’ was this: ‘My critical attitude during the early stages of the investigation. In explaining this attitude, I may state that after the investigation had been planned I encour- aged Banting and Best in each step of the work, but 1 urged them to keep to the main problem so that no doubt might exist when their results were published that they had really achieved much more than their predecessors. In view of my knowledge of the previous attempts that had been made to prove the presence of an anti-diabetic hormone and the extremely confusing nature of the results, I maintain that this was the correct attitude to adopt. At the same time, I constantly encouraged the investigators to continue and I placed all the available resources I could command at their disposal.’

Macleod leaves for Scotland

Certainly the most important arrange- ment made initially by Macleod was to see to it that a brilliant research fellow, Charles H. Best, would participate fully in the summer’s work with Banting. That he himself then went off to Scotland was enough to deprive him, in the eyes of Banting and Best, of any claim to have played an important part. Collip after- wards wrote to Macleod: ‘I was in your office early in May, 1921, when you gave Banting full directions for his summer’s campaign.’ In Macleod’s absence, how- ever, Banting and Best, as tyros in research, apparently felt the need of guidance and turned on occasion to Professor Velyien Henderson. It was to Henderson, as well, that Banting after- wards owed a part-time appointment as teaching assistant in the Department of Pharmacology to piece out his meagre income. The extent and importance of Macleod’s contributions before he went to Scotland are subject to dispute. It is obvious that he took time to counsel Banting in considerable detail. ‘I advised him to use the HCdon method for extirpation of the pancreas, gave him the necessary references, and assisted him in the first operation.’ But according to Best, ‘we eventually abandoned the HCdon procedure of removing the pancreas in two stages and adopted a technique, which Banting developed, for complete pancre- atectomy at one operation.’ Henderson seems to have suggested, later on, that the results obtained by the collaborators in their first successful experiments might be explained by blood dilution. They per-

formed experiments to eliminate this possibility.

It was in August, 1921, that Banting and Best reported encouraging results to Macleod and that he replied with further advice by mail. ‘I pointed out, in this letter or after my return to Toronto, the necessity of making sure that the reduc- tion in the percentage of blood sugar was not due to dilution of the blood, and suggested that haemoglobin and red corpuscles should be measured to control this. In that letter or on my return to Toronto I also said that the evidence was incomplete until the total utilization of sugar had been more carefully measured. I have no copy of this letter since it was written in ink.’ Whether or not this letter was ever received remains unclear. Various other steps were either prescribed by Macleod before his departure from Toronto or, according to the statement he submitted to Col. Gooderham, chairman of the university board of governors*, transmitted as’instructions by mail during the course of the summer. However this may have been, a number of the proposals made by him on his return were for steps already taken.

The summer of ‘21 -discovery completed?

It is obvious that what had been achieved in the summer of 1921 consti- tuted, for Banting and Best, the discovery of insulin, and that the part played in this achievement by Macleod had been, in their view, a minor one. It is difficult, and in all likelihood impossible, to arrive at a position of certainty about this, but it is possible also to take the view that, however important the summer’s work (in which Macleod claimed a very substantial role), it was by no means the whole story. It had required, in the opinion of Macleod, the collaborative effort of several workers: (1) to make an extract; (2) to make it safe for clinical use; (3) to find a practical method for testing the potency of the extract; and (4) ‘to demonstrate that the action of the active principle in the extracts on animals was more far-reaching than to lower the blood sugar and the urinary sugar in depancreated animals.’ Most of this was still unaccomplished when Macleod came back from Scotland.

* The full text of the long statement submitted by Macleod in September, 1922, to Col. Albert Gooderham, chairman of the board of governors of the University of Toronto, has been published as ‘History of the Researches Leading to the Discovery of Insulin’ (Macleod’s title) in the Bulletin of the History of Medicine, Fall, 1978.

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Who said what at the conferences which followed nobody can now be sure.

In the meantime, Macleod’s activity at scientific meetings and with the press had led Banting to make open, angry charges that the Professor was stealing his results. Macleod wrote:

‘I saw Prof. Clarence Starr that same evening and he promised to see Banting immediately. Next morning Banting after an interview with Dr Starr came to see me and apologized for what he had done. He told me that he misunder- stood my actions and assured me that he would do his utmost to undo the harm he had done me among his friends. How thoroughly he did this I cannot say, but I can easily see that my reputation for fair-dealing had been very seriously undermined in Toronto. At this confer- ence Dr Banting assured me that he would not misunderstand me in the future and would not conceal any doubts he might have as to whether I was treating him properly. I agreed to continue collaborating with him and I assured him that I had no intention of robbing him of any of the glory that was his due. I agreed further to have the names of those who participated in the researches, then underway in my department, in which the physiological action of Pancreatic extracts was being investigated, published with the names in alphabetical order. This placed his name first and Best’s second.

‘The researches referred to were as follows:

1.

2.

3.

4.

5.

6.

The preparation of the extract. (Banting, Best, Collip and Mac- leod.) The action of the extract on normal rabbits. (Banting, Best, Collip, Mac- leod and Noble.) Its action on rabbits with experimen- tal hyperglycaemia. (Banting, Best, Collip, Macleod and Noble.) The glycogen content of the liver and heart in depancreated dogs treated with Insulin. (Banting, Best, Collip and Macleod.) The acetone body decretion of depancreated dogs treated with Insulin. (Banting, Best, Collip and Macleod.) The Respiratory Quotient of depancreated dogs treated with Insulin. (Banting, Best, Collip and Macleod.)

‘I assigned E. C. Noble to No. 3 for his M.A. thesis and Best agreed to

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collaborate with Dr J. Hepburn for No. 5. Dr Collip had already made observations under Nos 2,4 and 5 (6). All of these researches with the exception of the first were planned in conference, and I directed the various steps in carrying them out.’

From this categorization at least one project has been omitted, one which Macleod dealt with elsewhere in his statement to Gooderham: ‘Banting inde- pendently of any suggestion from me prepared extracts from the foetal pancreas of the ox. . . .’ Even in this work, however, a number of technical directives were supplied by the chief.

Leaving aside, as we must, the detailed story of the claims and counter-claims about what took place at meetings in Toronto, New Haven and elsewhere, it is apparent that there were two different conceptsof what constituted discovery. It was Macleod’s contention that Banting’s paper read in New Haven at a meeting of

the American Physiological Society ‘had not succeeded in convincing all of his audience that the results obtained proved the presence of an internal secretion of the pancreas. . . any more definitely than had those of previous investigators.’ Con- vinced, of course, that the point had really been proved, he could not leave the occasion to Banting. Hence his interven- tion, which Banting fiercely resented. Continued research in Toronto was not, however, a consequence of this. It was merely the normal sequence of a thorough investigation. When, in September, 1922, Macleod wrote his statement for Col. Gooderham he was able to say that ‘the present status of our knowledge of Insulin depends practically entirely on work which has been done in this Department with the collaboration of the Medical Clinic and the Connaught Laboratories. Through concentrated effort, for the co-ordination of which I have been responsible, we have given to Science in

TIBS - July I979

little more than one year a practically completed piece of research work - we have proved the value of Insulin. . . .’

Back in November, 192 1, Macleod had asked Banting and Best to give their results at the Journal Club but had himself (at Banting’s request) introduced the subject. ‘I was told, in January [1922], that Banting considered that in doing this I did not sufficiently indicate the share he had in the work. Had I been told of this attitude of Banting at the time, it would have served to warn me of his peculiar temperament and of his entirely unwar- ranted suspicions that I was trying to receive the credit for the results he had obtained.’ That Banting’s suspicions were entirely unwarranted is true. It is also true, of course, that he possessed a ‘peculiar temperament’ of a not uncommon kind. Macleod was perhaps, in a social sense, somewhat imperceptive. He was also, however, a very distinguished scientist and a deserving Nobel laureate.

Letters to the Editor Thermodynamic concepts taken in vain?

A change in Gibbs function does represent a quantity of energy SIR: I am sure that there are many biochemists like myself who can scarce forbear to cheer when Banks and Vernon come down with the tablets of stone and expose some of the more flagrant ways in which thermodynamic concepts are taken in vain. It is good sport. Nevertheless, most of us would admit that we do not conceive of exploding packets of energy located in certain kinds of chemical bonds, and that we find calculations of so-called efficiency, derived from comparison of standard free energy changes, meaning- less. Like Dr Garratt (TZBS 4, March, N52), although I would not subscribe to everything he writes, I feel that Banks and Vernon, by concentrating on largely unspecified writers of biochemistry text- books, tend to cast doubt on them all. If they were to take exception to (or even to praise) some more modern textbooks, for example that of Metzler, this would be more instructive to those who believe that thermodynamics may have something to say about the functioning of living organisms.

Beyond this general comment, how- ever, another issue of interpretation arises. In their most recent articles (TZBS 3, July, N156, and 4, March, N53) we are told that changes in Gibbs function,

whether actual or standard, are given in energy units but are not in fact energy changes. Now it is understandable in the case of AGo that the logarithm of an equilibrium constant, when multiplied by RT, is still a disguised equilibrium constant and is best thought of in that way. However, the quantity RT, and hence AGO, contains the units of energy, and some explanation is required about its significance. To pursue the point a little further, it is the physical chemists who derive the relationships of classical thermodynamics, amongst which the following (sometimes also seen in its standard form) can be found in textbooks of physical chemistry:

AG=AH-TAS

If concepts cannot be discussed in words we shall make little progress. I take it, therefore, that this relationship, in general terms, means something like the follow- ing. ‘The extent to which the reactants and products of a reaction are displaced from equilibrium, and therefore possess the potential to perform work and to give rise to thermal energy, is equivalent to the differences between the enthalpies of the reactants and products, after making due allowance for the fact that compounds or states permitting an increased degree of randomness will be favoured.’ If this

interpretation is unacceptable to Banks and Vernon, allowing for the fact that it is given in less than 70 words, I hope they will attempt an alternative. The fact remains that since the terms on the right-hand side are represented in terms of quantities of energy, it is difficult to avoid the conclusion that the change in Gibbs function, having the same dimensions of work or energy, also represents a quantity of energy, albeit potential energy. Yet we are told it does not. Wherein lies the paradox? Or are we bogged down in semantics?

Finally, returning to living organisms, is there any thermodynamic significance in the fact that the following step of a metabolic pathway contains two enzymes rather than one, and that the two enzymes facilitate the reactions in the directions shown by the arrows rather than the reverse? Clearly there may be kinetic advantages, and clearly the reactions can only be properly appreciated in the context of what is happening elsewhere in the cell: but can thermodynamics tell us anything?

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