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Diabetes & Metabolism
Vol 31, N° 1  - février 2005
pp. 29-34
Doi : DM-02-2005-31-1-1262-3636-101019-200512004
John J.R. Macleod (1876-1935) 70th Anniversary of his death
 

Tirés à part : D Bataille [1]

[1] INSERM U 376 “Endocrinologie des peptides et régulation génique”, CHU Arnaud-de-Villeneuve, 34295 Montpellier Cedex 05, France. bataille@montp.inserm.fr

Biography

John, James, Richard Macleod was born on September 6 1876, in Cluny (Scotland) near Dunkeld in Perthshire. He is the son of Reverend Robert Macleod. When the family settles in Aberdeen, John registers at the Marischal University College where he studies medicine. In 1898, he obtains his degree with honours and receives the Anderson Travelling Fellowship which allows him to work for one year at the Physiological Institute in Leipzig. In 1899, he becomes demonstrator of physiology at the London Hospital Medical School, under the supervision of Pr Leonard Hill, then in 1902, lecturer in biochemistry at the same college. He obtains the McKinnon research grant that he keeps until 1903, when he leaves for USA for teaching physiology at the Western Reserve University, Cleveland, Ohio with the position of professor. He stays there until 1918. During WWI, he fulfils his military duties and occupies a position of professor in physiology at McGill University in Montreal during winter 1916.

During the second part of his career, between 1918 and 1928, he stays in Toronto where he is in charge of teaching physiology and is nominated vice-dean of the Faculty of Medicine. The work on insulin, run under his supervision by Banting, Best and Collip when he was in Toronto, will eventually leads to the 1923 Nobel Prize in Physiology that he shares with Banting.

In 1928, he leaves Toronto (his professorship is held by Charles Best) for his native land, Scotland, where he gets a position as a professor of physiology in Aberdeen, position that he will keep together with an activity of consultant in physiology at the Rowett Institute for animal nutrition, in spite of a very painful and disabling arthritis, until his premature death at the age of 59.

In addition to his activities in teaching and research, he was a member of many scientific societies, being elected in 1919 at the Royal Society of Canada, in 1923 at the London Royal Society, in 1930 at the London Royal College of Physicians, in 1932 at the Royal Society of Edimburg. He was the chairman of the American Physiological Society between 1921 and 1923 and of the Royal Canadian Institute between 1925 and 1926. He was Doctor honoris causa of the universities of Toronto, Cambridge, Aberdeen and of Pennsylvania, of the Western Reserve University and of the Jefferson Medical College, honorary member of the Academia Medica and of the Societá Medica Chirurgica of Rome, corresponding member of the Bologne's Medical and Surgical Society, Medical Society of the Halle's Deutsche Akademie der Naturforscher Leopoldina and associate foreign member of the College of Physicians of Philadelphia.

Regarding John Macleod's personality, everyone agreed about his human and professional qualities. He was highly appreciated by his pupils, thanks to his deep erudition and to the very attractive way he presented the teaching matters. In the way he organized and supervised the research, the two major words were “accuracy” and “humbleness”, two main features of his character. He was upset by approximations in the work and by scientific thoughts supported only by vague notions. This was implicated at a high level in the human relationship, sometimes a bit harsh, that he had with Banting.

He spent all his life in developing and improving medical teaching and in introducing new methods in clinical investigation and practice.

Outside the laboratory, he spent most of his free time in golfing and gardening, as well as enjoying and practising several arts, in particular painting. He was described by those who have met him as a sensible, honest and affectionate person, with a very attractive character and who has faced with serenity and courage the painful and paralyzing illness which rendered hard the latest time of his well occupied life.

John Macleod was married to Mary McWalter. He deceased from his illness on the 16th of March, 1935.

First works

Before the discovery of insulin, John Macleod was interested at the beginning of his career in carbohydrate metabolism and diabetes, with many publications on the subject, with a preference for experimentally induced glycosuria. His first work, performed at the London hospital, was devoted to the content of muscles in phosphorus. In 1908, following the works performed by Claude Bernard on diabetes, he has shown that the hepatic neoglucogenesis is controlled by the parasympathetic nervous system. Besides his studies on carbohydrate metabolism, he has also developed important works on respiratory physiology, including the troubles encountered by people breathing compressed air (diver's sickness), on electric shock, on purine bases, on bacillus tuberculosis and on carbamates. However, the majority of his researches was devoted to carbohydrate metabolism and to its dysregulation in diabetes. He has always worked as a physiologist, convinced that the sicknesses and illnesses are due to dysregulation of physiological events that must be discovered and studied in details. His scientific approaches were always made with a high level of methodical precision. In this respect, the twelve articles published in the American Journal of Physiology on experimental glycosuria are testimonies to these scientific qualities. It is clear that, as a complement of the Banting's ‘young-blood' qualities (passion, enthusiasm), the Macleod's thorough culture on diabetes has been a key-element in the success of the Toronto's group and that he has fully deserved to share the Nobel Prize with Banting.

Insulin

The discovery of insulin, crowned by the 1923 Nobel Prize to Frederik G. Banting and John J. R. Macleod of Toronto University, was a crucial step in the long quest for practitioners and scientists towards the understanding of the causes of diabetes mellitus, an illness the symptoms of which were described many centuries ago, in the hope of treating them. As for every great discovery, the way was paved by several predecessors, and it is useful to make a brief recall of the early times.

Distinction between diabetes mellitus and diabetes insipidus was made by Thomas Willis in 1673. Later, Claude Bernard, the father of experimental medicine, carried out studies on the symptoms of diabetes mellitus (in particular hyperglycemia) and discovered in 1855 the role of the liver in carbohydrate metabolism with the importance of glycogen. It is also necessary to remind the original anatomo-clinical studies by Lancereaux (Lancereaux, 1880) on distinction between “lean diabetes” or “insulin-dependent” diabetes (called today type 1 diabetes) accompanied by an atrophic pancreas and “fat diabetes” or non-insulino-dependent diabetes (now type 2 diabetes) with a anatomically normal pancreas.

The experimental demonstration of the pancreatic origin of diabetes mellitus arose from studies by Von Mering and Minkowski (Von Mering & Minkowski, 1890) who, after having performed a total pancreatectomy in order to study the importance of the organ in digestion of fat, have observed the symptoms of “lean diabetes” in the animal.

After those works by two German researchers working in Strasbourg (a German town at that time), the quest for the antidiabetic substance present in the pancreas led, during the following years, to a competition between several groups: Lépine (Lépine, 1889) believes in a “glycolytic ferment” (an enzyme that would degrade blood sugar), while Laguesse (Laguesse, 1893), suggests for the first time that this substance of unknown nature is produced by the pancreatic islets, anatomical structures dispersed in the pancreatic tissue which were discovered by the morphologist Paul Langerhans in 1869 (Langerhans, 1869). At that point, it is necessary to recall that the first bona fide demonstration of the existence of a hormone, a substance produced by a specialized organ which will reach its target(s) through the general circulation, appeared at the very beginning of the 20th century about secretin, a peptide stimulating pancreatic exocrine secretion (Bayliss and Starling, 1902), even though the idea of an ‘internal secretion' was suggested earlier by several authors.

Some attempts made to obtain an antidiabetic extract had some success, thanks to the works by Zuelzer (1908), Scott (1912) or Kleiner (1919). Zuelzer, in particular, appears to have obtained extracts that have proven to be active, including in coma diabetic patients, but considerable side effects led him to stop his works, in part under the pressure of Minkowski who considered them as dangerous and in part as a consequence of the beginning of WWI.

One of the major controversy about the discovery of insulin came from works that preceded those performed in Toronto by a romanian physiologist, Nicolas Paulesco, who came to Paris for studying medicine. His doctoral supervisor, Pr Dastre at the Sorbonne, has launched him on the tracks of the antidiabetic substance from pancreas. The work was carried out in Paris until he returned to Bucarest. Unfortunately, health troubles (renal insufficiency) rendered difficult the travels between Romania and France and invasion of Romania by German troops during WWI definitely cut the links between him and his parisian friends. This situation rendered impossible the publication of his works (probably dating 1916) before 1920 with Lancereaux (Lancereaux and Paulesco, 1920) and alone in 1921 (Paulesco, 1921). The published results obviously show that he succeeded to obtain pancreatic extracts clearly beneficial when injected to dogs rendered diabetic, in view of the measured parameters such as glycaemia, glycosuria, cetonuria and blood urea. His article, recognized by the international scientific community since it was published in a journal that every physiologist was supposed to read at that time, appeared in 1921, well before the paper (1922) from the Toronto group.

Accordingly, a part of the scientific community consider that he was the real ‘father of insulin' and that Nobel Prize rewarding only the Toronto group was not justified.

This is not the role of the present author to enter into this controversy but to describe the works run in Toronto under the supervision of John Macleod, inasmuch as a ‘polemic inside the polemic' exists (or at least has existed) concerning the exact role of each person in the famous discovery.

The success, crowned by the Nobel Prize, of the works by the Canadian group came from the complementarity between several persons, each with specific qualities.

Frederic G. Banting, Canadian surgeon born 1891, sometimes presented as “not really brilliant”, even “knowing nothing about carbohydrate metabolism”, sometimes as a “WWI hero” (he was wounded in Cambrai while on the front as a physician), but also “muddled minded in his researches” (clearly his character was the subject of passionate debates), had the idea of ligaturating the pancreatic ducts in order to induce exocrine pancreatic tissue degeneration while keeping intact the islets and to “try to isolate the internal secretion allowing to treat glycosuria”, thus integrating several old works. Indeed, as noted above, the majority of the pancreas is made of exocrine tissue which produces huge amounts of digestive, in particular proteolytic, enzymes and extracting insulin (a peptide) in the biologically active intact form inside a ‘sea' of proteolytic enzymes is a real challenge. The simple fact that he has thought at this ‘trick' (after having read an article) proves that his detractors are wrong when they say that he had no knowledge of the literature. This also proves that he had the ‘flash' that some researchers have at a certain stage of their career, sometimes corresponding to the beginning of a great scientific adventure. However, as explained below, the final success did not come from this idea but from another ‘trick', discovered by Collip, that is to use precipitation by concentrated ethanol from a pancreatic extract made in dilute ethanol, conditions which considerably reduces the action of proteases.

John J. R. Macleod, is, at that time, already a respected ‘great man', Professor in Physiology in Toronto, quite aware of the researches on carbohydrate metabolism. Banting, as suggested by Dr Starr who lives in the same city as Banting, introduces himself to Macleod, who is not immediately convinced by the way Banting presents his project. He his more attracted by the general interest of the work than inclined to think that Banting will succeed. However, he decides to provide him with a laboratory, which has to be reorganized, at the Toronto Faculty. He adds to the new research group Charles Best, a young student of Toronto University who is aware of sugar assay in blood and in urine. It appears that Macleod, not fully convinced by the apparent Banting's capabilities, hope, after this summer time when he is away from Toronto, to set up a more robust research team in autumn with the venue for a sabbatical year of James B. Collip, a famous biochemist and professor at University of Alberta.

The first experiments are run between may and September 1921 by Banting and Best while Macleod travels in several European countries including his native land, Scotland. They do not seem to be fully successful, apparently due to a great difficulty in mastering pancreatectomy with problems both in surgery and in the post-surgery care used to maintain the animal alive.

When he returns to Toronto, Macleod takes things in hand again and the results of the experiments improve in such a way that it is decided to present them on the 10th of November in front of a few colleagues. From the ensuing discussion, in spite of some disputes between Banting and Macleod, a situation which will become worth and worth with time, it is concluded that it is necessary to improve the surgical method as well as the post-surgery care and, concerning the extraction itself, to take advantage of the skills in biochemistry of Collip who starts his sabbatical year on the 12th of December. The collaboration between Banting and Collip turns out to be stormy, due to the considerable difference in their personalities, the first one being enthusiastic, ambitious and eager to quickly realize his ideas, the second being calm, serious and meticulous. Macleod pays much attention to the results and, as the head of the laboratory provides his advices generously. When the results with the dogs become exciting enough, it is decided to present them during a physiology meeting held at New Heaven on the 30th of December 1921. Macleod proposes that the results are presented by Banting who, apparently, does not succeed in presenting the results with the precision and exactness necessary in front of such a learned assembly. In order to save the situation, Macleod begins to speak, makes a new synthesis and answers the colleague's questions. This is the beginning of a real quarrel between the two men, Banting, considering himself as the discoverer, imagines that Macleod tries to ‘steal' the results of his work.

The following trials made with several animal models and using the Collip's extracts, that turn out to be excellent, are better and better.

Then, Banting suggests to Macleod that it is time to perform an experimentation in man. A 14-years old boy, Leonard Thompson, at the end-stage of the illness, is selected. Banting is so sure of the quality of his method of extraction, that he proposes to inject, on the 11th of January 1922, one of his preparation instead of one prepared by Collip, in spite of the fact that the latter turned out to be much better in the dog. It appears that Banting's error was due to the fact that his extract was indeed active on one of the dogs (the famous ‘Margerie') which turned out to be incompletely pancreatectomized. After a first intramuscular injection, in spite of a small decrease in glycaemia, the other parameters keep steady, showing the failure of the trial. Since Collip had prepared a new extract using his method (precipitation with concentrated ethanol of a pancreatic extract using dilute ethanol), that extract is injected to Leonard Thompson on the 23rd of January. Then the results are obvious, with the disappearance of glycosuria and a remarkable improvement in the clinical status. It is a ‘miracle'.

These spectacular results, first bona fide demonstration of the efficiency of a pancreatic extract in a human subject suffering from end-stage diabetes, without the deleterious effects of the extracts used by Zuelzer, are published in the Journal of Laboratory and Clinical Medicine on the 22nd of February, 1922. This article is signed exclusively by Banting and Best, a fact which explains why the discovery of insulin is attributed to those two researchers in most of the Handbooks of Endocrinology. It appears today that Macleod did not sign the article in an attempt to leave all the glory to his young “assistants” working “under his supervision”, all terms refuted by Banting who wanted to keep for himself the recognition for the discovery of insulin. It is noteworthy that Macleod decided that the authors would sign the articles according to the alphabetical order, giving the best share to Banting. He will accept to sign the following articles only later, in the same alphabetical order (Banting et al. 1922). On the other hand, it is strange that, as the head of the laboratory, he did not insist for having Collip (whose contribution is obvious in the success of the treatments as well as in the following studies) signing the famous article which, according to some observers, is full of errors and inaccuracies and which “today would not cross successfully the analysis by a refereeing committee” (Lestradet 1996). In addition to the errors in presenting the results, Banting and Best in this original article cite the works by Paulesco (Macleod was aware of his publications) but in an erroneous way, so that Paulesco appears to have written the reverse that he did in reality. Much later, Best, in a letter cited by Lestradet (Lestradet 1996) dated October 15, 1969 to Pr Pavel who was preparing the celebration of the 50th anniversary of insulin's discovery and who intended to rehabilitate Paulesco at this occasion, a letter full of apology, explained that this mistake was due to their lack of knowledge in the French language and recognizes the importance of Paulesco's work. This might be interpreted as a polite answer from Best, who was always considered as a courteous person, since no-one from the Canadian team has ever officially admitted the pre-eminence of Paulesco's work.

On May 3rd 1922, Macleod in Washington makes a highly successful synthetic presentation of the results accumulated in his laboratory. Banting, who leads Best to behave the same way, does not attend, again thinking that Macleod is trying to monopolize the glory.

The successful treatment of Leonard Thompson was followed by many other spectacular successes in diabetic patients, among them the best known were Elisabeth Hugues and Jim Havens. With the help of the companies Eli Lilly in the USA and Novo-Nordisk in Denmark, more and more pure insulin preparations were obtained and used by a large number of diabetic patients in the world, in particular thanks to an advertising campaign in newspapers (in which Ernest Hemingway was implicated), the beginning of the commercial phase which goes on today. During the whole large scale development of this work, Macleod is recognized as a major actor, both as a scientist and a coordinator.

The Nobel Committee has decided to award the 1923 Nobel Prize to Banting and Macleod for the discovery of insulin, a decision which triggered many reactions. The two antagonistic “clans” (Banting and Best on one hand, Macleod and Collip on the other hand) trying to outdo each other in generosity, Banting sharing the half of the prize with Best, Macleod sharing his half with Collip.

Since that time, the polemic is fading away together with the death of the protagonists, but it remains that most of the handbooks in Endocrinology has retained only the name of Banting and Best, while it is necessary that researchers, physicians and millions of diabetic people saved from an absolutely certain death keep, keep in mind the names of Macleod, Collip and Paulesco who must share with Banting and Best the reward for this great scientific success.

As a conclusion, if we try to have a clear and calm judgment on this saga which resulted in an essential landmark in the history of medical research applied to physiology and medicine, it is important to put every actor at its proper place, notwithstanding the fact that there might still be, after all those years, some shadows

  • Paulesco, whose quality and anteriority of the results are obvious. He suffered from several drawbacks: i) he published in French; ii) he endured an illness which rendered impossible a sustained collaboration with his French colleagues; iii) his researches developed in a quite difficult international context.
  • – Banting, a young and ambitious surgeon who had the excellent idea, inspired from previous works on the degeneration of the pancreas with the exception of the islets of Langerhans, to prepare insulin from this experimental model largely devoid of proteolytic activity (the peptidic nature of insulin, rendering it highly sensitive to degradation by proteases such as trypsin and chemotrypsin, was uncovered many years later). He has, most probably, exaggerated his own importance in the story, in the sense that, driven by his enthusiastic character, he has underestimated the importance of his colleagues and that, accordingly, he considered himself as the leader of the whole thing and, thus, as the “father of insulin”. His quick-tempered personal feature, his self-estimation and the high importance that he considered of the role that he played in the whole story does not make him, a priori, a very pleasant person. On the other hand, it is certainly way too excessive to reduce, as some did, to almost nothing his role in the discovery of insulin.
  • – Best, young student in Macleod's laboratory, who was implicated in this great adventure under the impulse of Macleod, the head of the laboratory. He has introduced, beside Banting, all his energy into the project and has certainly contributed to a great extent to its success.
  • – Collip, the meticulous researcher whose pancreatic preparations (without any doubt, the best possible in those days when very little was known about the nature of the molecule) have been essential pieces of the puzzle. Without his contribution, it is likely that the results in humans, of major importance for the huge media interest and the consecutive universal sympathy towards the Toronto laboratory which was, most probably, one element in the attribution of the Nobel Prize award, would not have been obtained in so short a time.
  • – Macleod, on whom the present paper is focused, was a central figure of this adventure. From the beginning, he was quite aware of the famous work published in 1889 by Von Mering and Minkowski and, although he was convinced that the pancreas was deeply implicated in diabetes, he did not succeed in determining its precise role. Although Laguesse had suggested in 1893 that the islets of Langerhans produce an ‘internal secretion' (in other words a hormone) which controls sugar metabolism and that Sharpey-Shafer had called it ‘insulin' in 1916, nobody had been able to prove its existence. After a time of hesitation because of a certain lack of confidence towards the Banting's capability, he has understood the huge importance of the subject proposed by the young surgeon. Then, he offered him a place to work and the help of three people whose capabilities were quite complementary to the Banting's ones. He has also renounced to most of his own researches, so as to put all the strength of the laboratory towards the quest for insulin. He has provided all the possible help to the staff, in particular from the intellectual point-of-view, thanks to his knowledge of the literature that he possessed to a much higher degree than his young colleague did, and the necessary follow-up of the experiments as the head of the laboratory.

It also appears that, even if some experiments carried out during the summer 1921 by Banting and Best, when alone in Toronto, led to expected results (this is not universally accepted), it is clear that the huge impact in the media, that eventually resulted in the Nobel prize, of the “miraculous” results obtained by the group on diabetic patients is, in large part, the results of Macleod's efforts in his organization capabilities and to Collip's competences who was the sole person able to prepare insulin preparations efficient via injection with little side-effects. It must also be recalled that Macleod, in about one-and-a-half year, has orchestrated a very efficient and large cooperation providing many medical structures all over the world, who were eager to obtain the “miraculous” treatment, with the necessary tool for rescuing their diabetic patients.

Thus, it is legitimate to consider, as almost universally thought today, Macleod as a key-character inside this wonderful scientific and medical adventure, who, instead of trying to ‘steal' the glory from his young collaborator, has always been on his side, providing helpful hints as well as the necessary financial support and qualified complementary persons, compensating the drawbacks of his colleague and, finally, has led to the success. Far from being a laboratory boss who has tried to get from the laboratory under his supervision the best for himself, John Macleod should be considered as a person with a pleasant character, whose human dimension has been universally recognized, since, as pinpointed (in essence) by Hudson (Hudson, 1979) “one may wonder how many established scientists playing the role of an autocratic German professor in that times would have provided precious laboratory resources to an unknown surgeon, after he had mistyped the name of the great man in the first three letters through which he was asking for his help?”

The works by Banting and Macleod, notwithstanding the importance of Best, Collip and, before them, of Paulesco, has demonstrated the importance of and, later, have provide the whole community with this so precious compound.

It must also be recalled that a patent for treating the diabetic patients with insulin preparations was obtained by the Toronto group, who, in a wonderful consensus, decided that all the financial repercussions of the patent should go to the “British Medical Research Council for the Encouragement of Research”, the inventors having, deliberately, decided that they should get no money for themselves. figure 1

Références

[1]
Banting FG. Diabetes and insulin. Nobel lecture, Stockholm, September 15th 1925.
[2]
Banting FG, Best CH. The internal secretion of the pancreas. J Lab Clin Med, 1922, 7, 251.
[3]
Banting FG, Best CH, Collip JB, et al. The effect produced on diabetes by extractions of pancreas. Transact Am Physicians 1922, 37, 337.
[4]
Bayliss W, Starling EH. Mechanisms of pancreatic secretion. J Physiol (London), 1902, 28, 325.
[5]
De Meyer J. Sur les relations entre la sécrétion interne du pancréas et la fonction glygogénique du foie. Arch Intern Physiol, 1910, 9, 1-100.
[6]
Hudson RP. New light on the insulin controversy (Frederick G. Banting and J. J. R. Macleod). Ann Intern Med, 1979, 91, 311.
[7]
Kleiner SS. The action of intraveinous injection of pancreatic emulsions in experimental diabetes. J Biol Chem, 1919, 40, 153.
[8]
Laguesse GE. Sur la formation des îlots de Langerhans dans le pancréas. C.R. Soc Biol Paris, 1893, 45, 819-20.
[9]
Lancereaux E. Le diabète maigre: les symptômes, son évolution, son pronostic, son traitement, ses rapports avec les altérations du pancréas. Etudes comparatives du diabète maigre et du diabète gras. Coup d'œil rétrospectif sur les diabètes. Union Médicale, 1880, 15, 161-167, 16, 205-11.
Lancereaux E, Paulesco N. Traité de Physiologie médicale. Vigot (ed.), Paris, 1920, 2, 295-327.
Langerhans P. Zur mikroskopischen anatomie der bauchspeicheldrüse. Thèse de médecine et chirurgie, Berlin, 18 février 1869.
Lestradet H. Note historique, le 75e anniversaire de la découverte de l'insuline. Diabetes Metabol, 1997, 23, 112-7.
Lestradet H. La découverte de l'insuline. Bull. Acad Natle Méd, 1996, 180, 437-48.
Lépine R. Nouvelle théorie du diabète. Lyon Med, 1889, 62, 619-21.
Macleod JJR. Insulin. Encyclopedia britannica. 14e édition, 12, 451.
Macleod JJR. The source of insulin: a study of the effect produced on blood sugar by extracts of the pancreas and principal islets of fishes. J Metabol Res Morristown, 1922, 2, S 149.
Paulesco NC. Action de l'extrait pancréatique injecté dans le sang chez un animal diabétique. Action de l'extrait pancréatique dans le sang d'un animal normal. Influence de la quantité de pancréas employée pour préparer l'extrait injecté dans le sang diabétique. Influence du laps de temps écoulé depuis l'injection intraveineuse de l'extrait pancréatique chez un animal diabétique. C. R. Soc. Biol. 85, 555-559. (La communication a été présentée à la branche de Bucarest de la Société de Biologie lors de sa séance du 23 juillet 1921).
Paulesco NC. Recherche sur le rôle du pancréas dans l'assimilation nutritive. Arch Int Physiol, 1921, 17, 85-103.
Scott EL. On the influence of intravenous administration of an extract of the pancreas on experimental pancreatic diabetes. Am J Physiol, 1912, 29, 306.
Von Mering J, Minkowski O. Diabetes mellitus nach pankreas extirpation. Arch Exp Pathol Pharmacol, 1890, 26, 371-87.
Zuelzer GL. Ueber Versuche einer specifschen Fermenttherapie des Diabetes. Z. Exp Pathol Therap, 1908, 5, 307-18.

Articles about J.J.R. Macleod

Steudel J. John J. Macleod, ein Wegbereiter der Diabetes Forschung. Der Diabetiker 1, 62-4, 1951.

Allan FN. J.J.R. Macleod. Diabetes 4, 491-2, 1955.

Allan FN. The discovery of insulin [letter]. N. Engl. J. Med., 297, 283-4, 1977.

Hudson RP. New light on the insulin controversy (Frederick G. Banting and J. J. R. Macleod). Ann. Intern. Med. 91, 311, 1979.

Steenrod WJ. Jr. The discovery of insulin [letter]. Ann. Intern. Med., 92, 443, 1980.

Bliss M. J. J. R. Macleod and the discovery of insulin. Q. J. Exp. Physiol. 74, 87-96, 1989.

Williams M.J. J. J. R. Macleod: the co-discoverer of insulin. Proc. R. Coll. Physicians Edinb. 23, 1-125, 1993.

Herrington G.M. The discovery of insulin. Ala. Med. 64, 6-12, 1995.

Bliss M. The discovery of insulin: the inside story. Publ. Am. Inst. Hist. Pharm. 16, 93-9, 1997.

Raju TN. The Nobel Chronicles. 1923: Frederick G. Banting (1891-1941), John J. R. Macleod (1876-1935). Lancet 352, 1482, 1998.

Obituary

Brit. Med. J. 1, 624, 1935.

Lancet 1, 716-7, 1935.

Siglo Med. 95, 350, 1935.

Nature London 135, 533-4, 1935.

Can. J. Med. & Surg. 77, 155-6, 1935.

Biochem. J. 29,1253-6, 1935.

Quart. J. Exper. Physiol. 25, 105-8, 1935.

Henderson VE. John James Rickard Macleod. Science 81, 355, 1935.

Orr JB, Chick H. John James Rickard Macleod, 1876-1935. Nutrition Abstr. & Rev. 4: x, 1935.

Carrasco Formiguera R. John James Rickard Macleod, 1876-1935. Rev. Méd. de Barcelona 23, 384, 1935.

Coelho J. John James Rickard Macleod, 1876-1935. Presse Méd 43, 731, 1935.


It was said that Joseph Zinck, the laboratory mate who took care of the dog, observed the symptoms and correctly interpreted them, before making a report to the head of the laboratory.
The exocrine pancreas, which represents the major part of the pancreas, produces many digestive enzymes such as trypsin and chymotrypsin which destroy peptides (including insulin) in crude pancreatic extracts.
The ‘pro-Banting' pretend that this is not true and that the Banting's method using a degenerate pancreas for extracting the substance while Macleod was away is quite successful and that Banting and Best are the real “insulin's fathers”.
It must be recalled that Claude Bernard considered pancreatectomy as ‘unrealistic', because the animals die rapidly from diabetic coma. However, some researchers (such as Paulesco) succeeded to carry out succesfully this difficult operation.
This is not Banting's version who, three years later, stated that “immediately after injection of the extract, glycaemia drops down and sugar disappears from urine” Lestradet states at this occasion “the lack of precision in the mind of Banting, who relies on his memory rather than on facts for his descriptions”.
According to another version, Banting, anxious not to be “overtaken” by Mcleod and Collip during the therapeutic trials, has secretly injected one of his extracts to one, and perhaps two patient(s), with no result. Collip's extract would have been injected straight away with great success to the young boy who had been selected by the staff headed by Macleod with the help of two famous clinicians, Campbell and Fletcher.
Best has explained in a letter that he had to use all his physical strength so as to avoid a physical aggression from Banting towards Collip who, facing the Banting's obstinacy to use, during the first clinical trials, his own extract rather than the Collip's one, which had shown a much better efficiency in animals, intended to keep his own ‘recipe' for himself.
Banting had written ‘MacLeod' instead of ‘Macleod'.





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