Acta Diabetologica (2023) 60:1241–1256 https://doi.org/10.1007/s00592-023-02098-9 ORIGINAL ARTICLE The Nobel Prize of Physiology or Medicine, 1923: controversies on the discovery of the antidiabetic hormone Alberto de Leiva‑Hidalgo1,2 · Alejandra de Leiva‑Pérez2 Received: 15 February 2023 / Accepted: 11 April 2023 / Published online: 2 June 2023 © The Author(s) 2023 Abstract Aims To analyze the main contributions to the discovery of the antidiabetic hormone in the period between 1889, the year in which Oskar Minkowski demonstrated that complete pancreatectomy in dogs caused diabetes, and the year 1923, the date in which the clinical use of insulin was consolidated. A main objective has been to review the controversies that followed the Nobel Prize and to outline the role of the priority rule in Science. Methods We have considered the priority rule defined by Robert Merton in 1957, which takes into account the date of acceptance of the report of a discovery in an accredited scientific journal and/or the granting of a patent, complemented by the criteria set out by Ronald Vale and Anthony Hyman (2016) regarding the transfer of information to the scientific com- munity and its validation by it. The awarding of the Nobel Prize in Physiology or Medicine in October 1923 has represented a frame of reference. The claims and disputes regarding the prioritization of the contributions of the main researchers in the organotherapy of diabetes have been analyzed through the study of their scientific production and the debate generated in academic institutions. Main results and conclusions (1) According to the criteria of Merton, Vale and Hyman, the priority of the discovery of the antidiabetic hormone corresponds to the investigations developed in Europe by E. Gley (1900), GL Zülzer (1908) and NC Paulescu (1920). (2) The active principle of the pancreatic extracts developed by Zülzer (acomatol), Paulescu (pancreina) and Banting and Best (insulin) was the same. (3) JB Collip succeeded in isolating the active ingredient from the pancreatic extract in January 1922, eliminating impurities to the point of enabling its use in the clinic. (4) In 1972, the Nobel Foundation modified the purpose of the 1923 Physiology or Medicine award to Banting and Macleod by introducing a new wording: "the credit for having produced the pancreatic hormone in a practical available form" (instead of “for the discovery of insulin”). Keywords Nobel Prize · Priority rule · Acomatol · Pancreina · Insulin Alfred Nobel's Testament (1895) children) a legacy of 100,000 crowns. The rest of his for- tune (about 33 million crowns) was allocated to the annual On November 27, 1895, a year before his death from a award of the Physics, Chemistry, Physiology or Medicine, cerebral hemorrhage, Alfred Nobel (1833–1896) dictated Literature and Peace Prizes (Figs. 1, 2) [1, 2]. his will at the Swedish-Norwegian club in Paris, by which he bequeathed to his relatives (he did not marry or have The award of the 1923 Nobel Prize in Physiology or Medicine Managed by Massimo Federici . Jan Lindstein and Nils Ringertz have described in depth Alberto de Leiva-Hidalgo and Alejandra de Leiva-Pérez have contributed equally to this work. the procedure followed in the election of the Nobel Prizes in Physiology or Medicine in the period between 1901 and * Alberto de Leiva‑Hidalgo 2000 [3]. aleiva@fdiabem.org The activity regarding the awarding of the Nobel Prize 1 Universitat Autònoma de Barcelona, Barcelona, Spain in Physiology or Medicine is carried out by the Nobel 2 Committee, elected by the Nobel Assembly from among Fundació DIABEM, Barcelona, Spain 13 Vol.:(0123456789) 1242 Acta Diabetologica (2023) 60:1241–1256 submitting proposals is January 31 of the year of the award. Between the months of March and May, the Nobel Commit- tee invites international experts to submit their reports. All candidates are evaluated by members of the Nobel Assembly and external reviewers; the evaluations are sent before the end of August. In September, the Nobel Committee sends its recommendations on potential candidates to the Nobel Assembly. In the month of October, the election takes place by majority vote. This decision is final, with no possibility of appeal. The laureates are immediately informed and the decision is announced at a press conference. The Nobel Prize award ceremony takes place on December 10 in Stockholm, during which the laureates receive a gold medal, a diploma and a monetary award. Influence of August Krogh in awarding the Nobel Prize to Banting and Macleod Schack August Stenberg Krogh (1874–1949) received the Nobel Prize in Physiology or Medicine in 1920 "for his discovery of the regulatory mechanisms of capillary circulation". His wife, Dr. Birte Marie Krogh, was diagnosed with dia- Fig. 1  Portrait of Alfred Nobel. Unknown date and author [1]. Public betes mellitus in 1921, under the medical care of Dr. Hans domain Christian Hagedorn (1868–1971). In 1922, Krogh received an invitation to give several lectures in the USA. In Novem- its members, all of whom are professors at the Karolinska ber, in Boston, Dr. Elliot P. Joslin briefed him on research Institute. The Nobel Assembly is independent, both from the from the University of Toronto into the therapeutic benefits legal point of view and from the economic-administrative. and purification process of insulin. On October 23, 1922, Funding for the prizes comes exclusively from the Nobel Krogh wrote to Macleod from Minneapolis, informing him Foundation. The Nobel Assembly has freedom to reward, of his interest in investigating the actions of the pancreatic indistinctly, areas in the broad field of biomedical research extract and producing insulin in Denmark. Macleod imme- and clinical medicine. The prize is awarded for an extraor- diately responded in favorable terms (Fig. 3). dinary discovery and not for a scientific career of a lifetime. Krogh decided to extend his trip, going to Toronto as a The concession must recognize a contribution or discovery guest of Prof. JJR Macleod. He returned to Copenhagen in of the highest level made during the previous year, a very December 1922. Marie successfully started her insulin treat- difficult standard to meet, since the discovery must be pub- ment in December 1922, and Krogh obtained the license lished, known and evaluated by a group of internationally from the University of Toronto to produce insulin in Scan- qualified researchers, a process that rarely lasts less than one dinavia (Suppl. Fig. 1). year. To solve this dilemma, the pragmatic solution was to The day after their arrival in Denmark, Krogh and Hage- interpret that what matters is that the benefit of the discovery dorn began an intensive investigative process. The first has become evident to the members of the Nobel Assembly experiments were carried out in Hagedorn's own house and during the year preceding the date of the award. in the laboratory of the Institute of Zoology, directed by In the month of September of the year prior to the award- Krogh. Very soon, on December 21, 1922, they successfully ing of the prize, invitations are sent to some 3,000 scientists obtained a small amount of insulin from bovine pancreas. from non-Scandinavian universities and academic institu- Immediately, August Krogh and Hans Christian Hagedorn tions chosen by a rotating system, to make proposals for founded the Nordisk Insulin Laboratory company, with the appointments. Proposals must be made according to a model financial contribution of August Kongsted (1870–1939), sent by the Nobel Committee. Scientists previously recipi- pharmacist and owner of the company Løvens Kemiske ents of the Nobel Prize in Physiology or Medicine and pro- Fabrik (Leo Pharmaceutical Products). Kongsted financed fessors at medical schools in the Nordic countries can exer- the research and production process. In compensation for cise their right to make proposals each year. The deadline for such an important contribution, the condition requested by 13 Acta Diabetologica (2023) 60:1241–1256 1243 Fig. 2  Testament of Alfred Nobel [2]. Public domain Kongsted was to name the first manufactured product "Insu- of Cleveland, Ohio, USA), on behalf of FG Banting; and lin Leo", which became available in the spring of 1923. The Georg N. Stewart (Professor of Experimental Medicine, first Danish patient treated with “Insulin Leo” received his Case Western Reserve University, Cleveland) on behalf of initial dose on March 13, 1923. JJR Macleod. Prof. August Krogh and Prof. Göran Liljestrand (Execu- August Krogh reasoned his joint proposal of Macleod and tive Secretary of the Nobel Committee since 1918) were Banting in the following terms: friends. Their relationship intensified after Liljestrand did an With the information which I personally have obtained academic stay in Copenhagen. On January 20, 1923, Krogh in Toronto, and which also, although less clearly so, wrote a letter to Göran Liljestrand, in the following terms emerges from the published works, one may conclude (Suppl. Fig. 2): that the credit for the idea behind the work which led As you understand from my discourse, it is my opinion to the discovery undoubtedly goes to Banting, who is that the discovery of insulin is of extraordinary both a young and apparently very talented man. However, theoretical and practical importance and it will hardly he would definitely not have been able to carry out surprise you that I intend to submit a nomination that the investigations, which from the start and during all the Nobel Prize be awarded to Dr. Banting and Profes- stages have been supervised by Professor Macleod. sor Macleod. Macleod's special contributions to experimental work The Nobel Committee for the award of Physiology or had only been partially published before the January 31, Medicine of the year 1923 consisted of 5 members, in addi- 1923, deadline. Macleod, working alone, had located insulin tion to its president and executive secretary (Prof. Göran in the pancreas of teleost fish, demonstrating its hormonal Liljestrand). The Archives of the Karolinska Institutet function; he had also conducted investigations of the insulin received within the stipulated period the joint proposal of actions on intermediary metabolism and respiratory quo- August Krogh in favor of FG Banting and JJR Macleod, tient. Written reports on the proposals were prepared by two and the individual proposals of Francis G Benedict (Prof. members of the Nobel Committee, John Sjöqvist, Professor of Physiology, Harvard University, Cambridge, Mass., of Chemistry and Pharmacy, and Hans Christian Jacobeus, USA) and Georg W Crile (Prof. of Surgery, University Professor of Internal Medicine. Sjöqvist focused primarily 13 1244 Acta Diabetologica (2023) 60:1241–1256 Fig. 3  August Krogh sent this letter to JJR Macleod on October 23, 1922, proposing a possible collaboration with HC Hagedorn to extend insu- lin production and therapeutic trials to the University of Copenhagen (Archives of the University of Toronto Library) on its physiological importance. He discussed the work of The Committee considered valid the argument that several predecessors, especially Georg Ludwig Zülzer. In although the discovery corresponded, initially, to Banting's his conclusion, he supported the joint request of A. Krogh, idea, Macleod's guidance was decisive for its successful accepting the suggestion of dividing the prize between Bant- fulfillment. Finally, the nineteen professors of the Karolin- ing and Macleod. Banting had the original idea and the first ska Institutet cast their secret ballot, ruling that “The Nobel initiative; Macleod was the leader of the scientific work. Award of Physiology and Medicine was jointly granted on Jacobeus’ decision was more difficult because “Macleod’s October 25, 1923, to Frederick Grant Banting and John contribution was not apparent from the consulted bibliog- James Rickard Macleod, for the discovery of insulin, one raphy” [2]. He then continued: “Banting came to Macleod year before” [7]. with his idea… it is very likely that the discovery would not It is logical to assume that Krogh's influence on Macle- have been made if Macleod had not supervised him, at least od's candidacy for the Nobel Prize was manifest, particularly not as rapidly as is now the case… I am most prone to give as Krogh was previously laureated in 1920 and was informed Banting and Macleod a joint Nobel Prize” [4]. by Macleod in Toronto on the scientific activities carried After the Nobel Assembly had discussed the matter, the out in situ, benefiting from the license of the University of recommendation was sent back to the Committee for recon- Toronto to produce insulin in Denmark [8]. sideration on October 11, 1923. The objection responded to Frederick G. Banting learned of the Nobel Prize award the need to verify the foundations of Krogh’s joint proposal, on the morning of October 26, 1923, from the front page of based on his visit to Toronto [5]. The Globe newspaper (Fig. 4). The Committee met again, reaffirmed his recommenda- Banting was furious about having to share the award with tion and made an extensive written statement to finally con- JJR Macleod, and his first intention was to reject the prize. clude that “… it is not possible to make a more thorough JG Fitzgerald, director of Connaught Laboratories, tried to investigation of this discovery and the relative contributions persuade him. Banting’s answer was: “I will not accept the by Banting and Macleod, nor is it necessary” [6]. prize: I am going to cable Stockholm that not only would I 13 Acta Diabetologica (2023) 60:1241–1256 1245 of the prize has reached 10 million SEK (1,103,148; USD; 964, 000 €) [10]. The University of Toronto celebrated the Nobel award with a special ceremony on November 26, 1923, in which both laureates, FG Banting and JJR Macleod, received the honorary degree of Doctor of Science. A banquet in the Great Hall of Start House that evening capped off the cel- ebration with more than 400 guests representing the North American government, scientific, and medical professionals (Suppl. Fig. 3). On December 10, 1923, Prof. J. Sjöquist, member of the Nobel Committee for Physiology or Medicine, delivered the Presentation Lecture for the Nobel Prize to Dr. Frederick Grant Banting and Professor John James Rickard Macleod “by the discovery of insulin”. In the absence of the laureates, the British Minister received the prizes from the hands of His Majesty the King, for future transfer to them [11]. Banting took all possible actions to make unpleasant Macleod’s life. The Scottish Professor felt he had to start legal actions against Banting, but he finally decided to leave the University and the city of Toronto in 1928. When the University held a farewell dinner for Macleod, Banting not only refused to attend, he requested that there be an empty Fig. 4  Front page of The Globe newspaper, October 23, 1923, report- place set for him at the table [5]. ing the award of the Nobel Prize in Medicine to Doctors Banting and Macleod Discovery of the pancreatic origin not accept but that they and the old foggy Krogh could go to of diabetes: Oskar Minkowski hell…I defied you to name one idea that had originated in Macleod’s brain – or to name one experiment he had done In April 1889, Oskar Minkowski, of the Department of with his own hands”. Medicine at the University of Strasbourg (directed by Pro- Fitzgerald was soon able to calm him and suggested he fessor Naunyn), met Joseph von Mering in the library of the should meet Albert E. Gooderham, chairman of the Insulin Hoppe-Seyler's Institute, University of Strasbourg. In 1886, Committee of the University of Toronto Board of Gover- von Mering had generated experimental diabetes with the nors. Gooderham managed to convince Banting, arguing that administration of phloridzin and was then investigating the other considerations deserved to be taken into account: “I enzymatic function of the pancreas in the digestion of fatty must think of my country. What would the people of Canada foods. think if the first Canadian to receive this honor were to turn Minkowski suggested that to achieve this goal it would it down? Banting did not say he will decide it immediately be highly desirable to investigate the effects of total pan- and better wait 24 h”. On October 26, Banting grabbed a createctomy and was able to overcome initial resistance notepad and wrote a telegram to Best (he was in Boston): from von Mering, who felt that such surgery was impos- “Nobel trustees have conferred prize on Macleod and me. sible to perform successfully. That same day they agreed You are with me in my share always” [9]. that Minkowski would perform, with Mering's help, a com- Banting decided to split 50% of the corresponding finan- plete pancreatectomy in the experimental laboratory of the cial contribution with Charles H. Best. Macleod first heard Department of Medicine on one of the dogs at Hoppe Sey- the Nobel news on a steamship returning from Scotland to ler's laboratory. After the first pancreatectomy, Mering did Canada. He decided also to split 50% of the corresponding not participate in further research on this matter, directing amount with James B. Collip. his excellent academic career elsewhere. Minkowski repro- The monetary value of the prize in 1923 was 114,935 duced the effects of complete pancreatectomy in three other Swedish Crowns (SEK) (24,000 USD). This amount would dogs. The first two died, but the third survived and in less be equivalent in 2021 to approximately 3,241,843 SEK than 48 h presented glycosuria, polydipsia and polyuria. (419,888 USD). In the years 2021–2022, the monetary value In the weeks following surgery, gradual weight loss was 13 1246 Acta Diabetologica (2023) 60:1241–1256 observed in spite of excessive energy intake, also showing Synoptic review of the main contributions persistent glycosuria, ketonuria and hyperglycemia. toward the discovery of the antidiabetic Minkowski presented the first paper at the International hormone antedating the announcement Congress of Physiology in Basel. The first publication was of the development of insulin a short communication in 1889 [12]. More extensive reports at the University of Toronto appeared in 1890, 1892 and 1893 [13–15]. Minkowski and Naunyn had previously shown that beta- hydroxybutyric acid is an agent responsible for diabetic aci- Oskar Minkowski (1858–1931) dosis and that the concentration of carbon dioxide in the blood markedly decreases in this acute metabolic emergency A. Minkowski demonstrated that complete pancreatectomy [16]. was determinant of the generation of diabetes mellitus Rolf Luft (1914–2007), Professor of Endocrinology, in the dog. Karolinska Hospital, Stockholm, in asking who discovered B. In addition, he developed liver and muscle analysis insulin declared that “Minkowski was the first to show that which demonstrated the disappearance of glycogen after diabetes is the consequence of the absence of the pancreatic experimental pancreatectomy (1889–1990) [13, 19]. substance carried by the bloodstream, which motivated all the subsequent activities aimed at extracting the antidiabetic Emmanuel Charles Edouard Hédon (1863–1933) hormone. It has been the most important original discovery in the history of diabetes” [17]. A. Hédon characterized the dual role (exocrine-endocrine) of the pancreatic gland and introduced the original method of pancreatectomy in two stages (1891–1892) [20–22]. Protests over the awarding of the Nobel Prize in Physiology or Medicine in 1923 Marcel Eugène Émile Gley (1857–1930) The decision of the 19 signatories from the Karolinska Insti- A. Gley reported the presence of the antidiabetic principle tutet was protested in subsequent weeks and months by at in the extract of "sclerosed pancreas" (1891) (Fig. 5) least four researchers, who claimed their priority in isolating [23] the antidiabetic hormone: Georg Ludwig Zülzer (Berlin), B. Gley was the first to reveal that the parenteral adminis- Ernest Lyman Scott (Chicago), John Raymond Murlin (New tration of extracts of "sclerosed pancreas" reduces gly- York) and Nicolae Constantin Paulescu (Bucharest). Many cosuria and symptoms of experimental diabetes (1900) years later, Charles Herbert Best would also claim the dis- [24]. covery (Figs. 5, 6) [18]. Fig. 5  Left: Portrait of Marcel Eugène Émile Gley. Unknown author and date. Public domain. Right: Portrait of Georg Ludwig Zülzer. Courtesy of Viktor Jörgens (Jörgens V (2022). Die Geschichte der Diabetes- forschung—vom Opium zum Insulin. Verlag Kirchheim Mainz) 13 Acta Diabetologica (2023) 60:1241–1256 1247 Fig. 6  From left to right: Photograph of Ernest L Scott in 1917 in Murlin Papers. Eskind Biomedical Library Special Collections, Van- military uniform. Charles Best Papers (University of Toronto). Pho- derbilt University Medical Center. Portrait of Nicolae C. Paulescu. tograph of Israel S. Kleiner in 1915. Author: Louis Schmidt. Source: Unknown date and author. Academia Romana Filiala Cluj-Napoca. Rockefeller Archive Center. Portrait of John R. Murlin. Source: John Public domain Georg Ludwig Zülzer (1870–1949) Ernest Lyman Scott (1877–1966) A. Georg Ludwig Zülzer demonstrated that the pancreatic Ernest L. Scott (Fig. 6) defended in 1911 his M.Sc. thesis extract prevented the diabetogenic effect of adrenalin in entitled “The effect of pancreas extract on depancreatized experimental animals (1907) and reduced the glycosuria dogs, carried out in the Department of Physiology at the of depancreatized dogs (Fig. 5) [25, 26]. University of Chicago, a manuscript in which he described B. Zülzer was the first to report the partial success achieved his original procedures for obtaining aqueous and alcoholic by the treatment with pancreatic extracts in a group of extracts of pancreas, which he administered intravenously eight patients with diabetes. The treatment was associ- to depancreatized dogs. The injection of the aqueous extract ated with adverse side effects (1906–1908) [27, 28]. determined the reduction in glycosuria, associated with a C. Zülzer obtained patents in Germany, Great Britain and decrease in the urinary D/N ratio in two out of the three USA for acomatol, his original formulation of pancre- investigated animals. For Scott, the active principle present atic extract (1908–1912) [29]. in the pancreatic extract was of a protein nature [18, 33, 34]. D. Zülzer and Camille Reuter managed to minimize the In the summer of 1911, Scott finished the thesis manu- toxicity of the pancreatic extract and increase its power script and delivered three copies to his supervisor Anton to such an extent that it generated severe hypoglycemia J. Carlson, head of the Physiology department. Scott left (years 1913–1914) in the dog [30]. The start of the First Chicago with his family in September to accept an academic World War and the decision of Hoffmann La Roche to position at the University of Kansas. Professor AJ Carlson cancel the financial support precluded the continuation submitted EL Scott's thesis manuscript to the American of the research project [28, 29]. In 1923, Zülzer claimed Journal of Physiology under Scott's signature as sole author, the priority of the discovery of insulin in a document without consulting him. Furthermore, Carlson substantially released by an international agency (Suppl. Fig. 4) modified the content of the manuscript. In Scott's original [31] and in an article published in Medizinische Klinik document, the first conclusion was: “There is an internal (Suppl. Fig. 5) [32]. secretion from the pancreas controlling the sugar metabo- lism”, and the text of the second conclusion: “By proper methods this secretion may be extracted and still retain its I feel entitled to claim priority in this discovery (…) activity”. However, in the final paragraphs of the article pub- because in the German scientific literature, partly due lished in Am J Physiol, Carlson disavows Scott, modifying to ignorance, the role I played in the discovery was not the essential result of the thesis: “It does not follow that always correctly perceived [26] these effects are due to the internal secretion of the pan- creas in the extract (…). The pancreas extract may decrease the output of sugar from the tissues by a toxic or depres- sor action, rather than by a specific regulatory action of the pancreas” [35]. 13 1248 Acta Diabetologica (2023) 60:1241–1256 Scott did not have access to the manuscript until its pub- the duodenum was extracted with Ringer’s solution made lication in 1912. On May 3, 1964, he signed a document alkaline with sodium carbonate. As identical findings were denying authorship of the article submitted by Carlson [36]. exhibited on the same dog, the authors concluded that the Scott claimed priority for the isolation of the antidia- reduced glucose excretion was due to a change in the perme- betic hormone in a letter to the editor of the Journal of the ability of the kidney and not to a hormonal effect. Additional American Medical Association, published in October 1923, calorimetric experiments showed no effect of the organic in which he defended the pioneering nature of his experi- extracts on the combustion of sugar [42]. mental work. In his opinion, the procedures for making and B—In 1917, John Murlin achieved the position of Pro- administering the adult bovine pancreatic extract described fessor of Physiology at the University of Rochester. His by Banting, Best and Collip in their application to the US research team demonstrated in 1922 the adverse influence Patent Office reproduced his own experience [37]. of elevated pH upon the metabolic effects of the administra- Dickinson W. Richards (Nobel Prize in Physiology or tion of pancreatic extracts to depancreatized animals, which Medicine, 1956), Professor of Medicine at Bellevue Hospi- provided an explanation of the conflicting results of its pre- tal, University of Columbia, New York, and former student vious publication in 1913 [43]. of Scott's, published the thesis in its original form in 1966 C—In the same year, the team headed by John Murlin [38]. After Scott’s death, his widow, Aleita H.Scott, accessed demonstrated that the biological actions of the pancreatic the archives of the University of Chicago to retrieve the orig- extract in pancreatectomized dogs were only manifested inal documents related to this conflict [39]. after parenteral administration, other routes of administra- tion being ineffective. In the majority of cases, they observed Israel Simon Kleiner (1885–1960) a biphasic blood glucose response consisting of an initial rise in blood glucose, followed by the expected lowering of Israel Kleiner (Fig. 6) received his PhD in Biochemistry at the sugar in blood and urine. The lowest level of blood sugar the University of Yale in 1909. Between 1910 and 1919, he was reached in 4 h from the time of injection, whether the worked at the Rockefeller Institute. extract was given into vein, peritoneum, muscle or under the skin [44]. Murlin attributed the initial rise in blood glucose A. In collaboration with SJ Seltzer, Kleiner published in to a substance of pancreatic origin he named glucagon [45]. 1915 that pancreatic extracts lowered blood glucose D—In cooperation with C. Sutter, Murlin reported the in normal and pancreatectomized dogs intravenously case of a diabetic patient with ketosis treated at the Roch- infused with glucose, which suggested that the internal ester General Hospital in July 1922 with pancreatic extract secretion of the pancreas contributed to the rapid disap- administered through a gastrointestinal catheter and by oral pearance of glucose from the general circulation [40]. and subcutaneous routes. Only in this latter case could gly- B. Kleiner published in 1919 that intravenous adminis- cosuria and ketonuria be decreased. On July 26, 1922, blood tration of a pancreatic emulsion achieved a significant glucose level went down from 513 to 241 mg/dL [29; pp. reduction in blood glucose in a series of depancreatized 168, 46]. dogs and toxic effects did not occur [41]. Nicolae Constantin Paulescu (1869–1931) John Raymond Murlin (1874–1960) A. Nicolae Constantin Paulescu (Fig. 6) published in 1920 A—John Murlin, PhD (Univ. Pennsylvania, 1901), Assis- an original procedure for the complete pancreas abla- tant professor at Cornell University Medical College tion, the protocol to elaborate a successful pancreatic (1909–1917) (Fig. 6), reported in 1913, in collaboration with extract [47], and the effect of pancreas ablation on gly- B. Kramer, that parenteral administration of the pancreatic cogen stores [48]. All experiments had been carried out extract did not change the respiratory quotient in healthy before 1916. dogs, generating uncertainty about previous observations. B. Between April and June of the year 1921, Paulescu They treated several dogs, depancreatized using Hédon’s published four short papers covering nine experiments, method, by injecting them intravenously with pancreatic showing the convincing results achieved by central extract. The urine collected in twenty-four hours periods and peripheral intravenous injections of the pancreatic showed an increase in the dextrose:nitrogen ratio on the fol- extract on carbohydrate, protein and fat metabolism in lowing days, and the marked fall in blood glucose levels depancreatized dogs [49]. lasted between four to ten hours. In parallel, they repeated C. Paulescu illustrated the time sequence of these metabolic the experiments with a double extract of dog’s pancreas and changes [50], the relation between the amount of the duodenal mucosa, observing much greater effects. Surpris- administered extract and the observed results [51], and ingly, they found similar results when either the pancreas or 13 Acta Diabetologica (2023) 60:1241–1256 1249 the provocation of hypoglycemia by the extract on the had already said, well-in advance, about the decrease normal dog [52]. in hyperglycemia and glycosuria, blood and urinary D. On August 31, 1921, he published a comprehensive urea, acetonemia and acetonuria, under the influence article, describing a summary of experiments con- of injections of intravenous pancreatic extract in dia- ducted over 20 years of research, showing the technique betic animals. to achieve a sterile extract, the methods to estimate In volume IV of the treatise on Medicine by E Lancereaux the metabolic effects, the clinical manifestations of and NC Paulescu, the Romanian scientist wrote: untreated and treated depancreatized dogs, the informed autopsies, the results of control experiments, and the Before, I believed that the scientist works safely side effects of the pancreatic preparation that he named because of the conviction that the date of publication pancreina [53]. protects him from any injustice. Unfortunately, today E. On April 12, 1922, Paulescu registered the patent of I am forced to admit that I was completely wrong [57]. pancreina in the Romanian Ministry of Industry [18, 54]. On October 30, 1969, SM Milcu (Vicepresident of the Romanian Academy) and Ion Pavel (President of the Sec- Nicolae C. Paulescu's protest was probably the most tion of Diabetes and Nutritional Diseases, Romanian Acad- acid and bitter. On February 5, 1923, he wrote to Frederick emy) wrote to Arne Tiselius, Director of the Nobel Institute, Banting, enclosing his 1921 publications on the treatment of asking for recognition of NC Paulescu as posthumous dis- experimental diabetes. Banting never replied. On November coverer of the anti-diabetic hormone [58]. They also men- 6, 1923, Paulescu sent a letter to the President of the Nobel tioned that in the first paper published by Banting and Best Commission; in the letter he claimed against the award of the in February 1922 [59], the Canadian researchers incorrectly Nobel Prize to Banting and Macleod. According to Paulescu, reported Paulescu’s earlier work [49]. We reproduce some the Toronto team had violated his intellectual property excerpts of the letter: rights and his discovery of the antidiabetic hormone had been stolen by the Canadian researchers. For this reason, he (…) Paulescu’s comprehensive paper, which is a model demanded from the Commission a conduct consistent with of scientific research (…) is dated August 31, 1923, the application of the principles of justice [18, 55]. which definitely proves that he is the discoverer of Shortly before dying, Paulescu declared (1931) [18]: insulin. Actually, Banting and Best added nothing in their article published 8 months later (…). We found Formerly I believed and maintained that a scientist can a basic error in Banting’s work which could certainly work in perfect safety, convinced as I was that the date have influenced the decision for the 1923 Nobel Prize. of his publications protected him against any injustice. On page 253 of his article of February 1922, the Unfortunately, I am obliged to admit now that I was author, who was acquainted with Paulescu’s work and utterly mistaken in this regard. I am not dominated by cited his work, misrepresented the sense of the results pride and I struggle against this odious vice. Indeed, concerning the effect of the aqueous pancreas extract on publishing my discovery I never for one moment obtained by the Romanian scientist. Here is their text. thought of publicity, which could have affected my “He (Paulescu) stated that injections into peripheral modesty that I consider one of the first qualities of a veins produced no effect and his experiments show that scientist. But I certainly cannot accept another, more second injections do not produce such marked effects odious defect, that of the theft of someone else’s sci- as the first.” Paulescu, however, wrote exactly the con- entific property. trary as may be seen from the conclusions on his paper The Romanian scientist and other researchers denounced comprising experiment IV (August 1921). the infringement of Paulescu’s intellectual property rights in Paulescu’s original text read [49]: “Les mêmes effets, several occasions: c’est-à-dire une diminution ou même une suppression pas- A.1. In a letter Paulescu sent to the president of the Nobel sagère de l’hyperglycémie et de la glycosurie, s’observent Institute on November 6, 1923 (Fig. Suppl. S6) [56]. aussi lorsqu’on injecte l’extrait pancréatique, non plus dans We transcribe some excerpts of the letter, translated from une veine périphérique, mais dans une branche de la veine French: porte, par exemple: dans une veinule mésaraïque ou dans une (...) I beg to be allowed to protest against the fact that veinule splénique”. Uncertainty persists as to whether Bant- this distinction [the Nobel] has been awarded to people ing and Best's misrepresentation of Paulescu’s results was who do not deserve it. Indeed, the discovery of these deliberate or an error due to the Canadian researchers' poor physiological and therapeutic effects belongs entirely knowledge of French. The historian Michael Bliss wrote the to me. (...) These articles do nothing but repeat what I following about this unfortunate incident: “Could it have 13 1250 Acta Diabetologica (2023) 60:1241–1256 been a deliberate denigration of a competitor, potentially and men, such treatment being effective in controlling the a scientific scandal? Well, in my hand was the index card symptoms of diabetes mellitus in diabetic dogs and human containing Charles Best’s 1921 precis of the key Paulescu patients (…). There can be little doubt that Paulescu, as well article, which had been published in French. There on the as Banting and Best, obtained a pancreatic extract which card was Best’obvious translation error, mistaking the words contained insulin, and that the pancrein and the insulin pre- non plus as meaning no good” [60: pp. 203–204]. sent in the crude extracts in which the hormone was first The Director of the Nobel Institute answered Milcu and obtained, are the same substance” [66]. Pavel’s letter on December, 29, 1969, stating that, accord- Eric Martin, Professor of Medicine at the University of ing to the statutes of the Nobel Foundation, the Nobel Prize Geneva, stated in 1971: “There is not the slightest doubt that can only be awarded to shortlisted candidates, but Paulescu Paulescu was the first to demonstrate, in an exemplary way, had not been nominated. Tiselius added that, in his opinion, the antidiabetogenic and antiketogenic effect of the pancre- Paulescu also deserved the prize [61]. atic extract. (…) We must insist on the cardinal importance A significant number of experts from different countries of Paulescu's discovery, a discovery that Canadian doc- publicly expressed their support for Paulescu's priority in tors were aware of, but that they interpreted incorrectly, the discovery of the antidiabetic hormone, agreeing that with which certain studies by the Romanian physiologist Paulescu's results published in August 1921 were practically remained hidden in the shadows” [67]. identical to those published by Banting and Best in February 1922. Some examples are mentioned below. Alfredo Sordelli, from Bernardo Houssay's research The purification of the antidiabetic group, was Professor of Biological Chemistry at the Bue- hormone could not be completed prior nos Aires School of Medicine, President of the Academy of to the development of insulin Physical and Natural Sciences of the Harvey Society, Acad- emy of Sciences (New York) and of the Société de Biologie The patented pancreatic extracts with antidiabetic effects de Paris. In collaboration with Juan T. Lewis, he declared that preceded insulin (acomatol, pancreina) did not spread in 1924 that Paulescu's results, published in August 1921, to general medical practice due to the potential risks of the were practically identical to Banting and Best’s February observed side effects (fever, sweating, vomiting, muscle 1922 publication [62]. hypertonia, stomatitis, local “aseptic abscess” and hypo- Ian Murray, Professor of Physiology at Anderson College glycemia), attributable to polluting substances, mainly of a of Medicine in Glasgow and co-founder of the IDF found protein nature [27, 28, 68]. compelling evidence that several researchers had obtained In the case of acomatol, the explosion of the First World pancreatic extracts able to improve experimental diabetes in War interrupted a very promising phase of the project, in depancreatized dogs, in anticipation of the experiences at the which, mainly thanks to the contribution of chemical engi- University of Toronto. According to the Scottish researcher, neer Camille Reuter, the extract obtained had greater bio- among all these pioneering contributions, the most signifi- logical potency and minimal toxicity. Furthermore, Zülzer’s cant was that of Nicolae Paulescu, who Murray thought to recruitment into the war, Hoffmann La Roche’s cancella- be the discoverer of the antidiabetic hormone (pancrein) [63, tion of the funding and, years later, Zülzer’s expulsion 64]. from the university and his professional disqualification by Murray stated that the work of Banting and Best was to the National Socialist authorities, dictated the end of his be described as confirming Paulescu's discoveries: “Pan- research activities. crein and insulin are identical (…). The recognition of the Zülzer’s expulsion from the University of Berlin and from work of Paulescu, a distinguished Romanian scientist, has Lankwitz hospital was the consequence of racial repres- been entirely insufficient. As the Toronto team began their sion by the National Socialist authorities, determined by research, Paulescu had already successfully produced the the “Enabling Act of 1933” (“Ermächtigungsgesetz vom antidiabetic pancreatic extract from the pancreas and dem- 24. März 1933”, officially titled “Gesetz zur Behebung der onstrated its efficacy in reducing hyperglycemia in diabetic Not von Volk und Reich”) and the “Law for the Restoration dogs” [65]. of the Civil Service” (“Gesetz zur Wiederherstellung des During the celebration in Buenos Aires of the seventh Berufsbeamtentums”), which excluded Jews and other politi- congress of the IDF, a work commission on the discovery cal opponents of Nazism from all civil service positions in of insulin was set up. We reproduce the following extract Germany. Zülzer had adopted the Protestant religion after his of the report issued by the commission: “Banting and Best father’s death, but the German Minister of Culture revoked did not isolate insulin. What they did was to produce for Zülzer’s teaching license on November 24. The vast majority the first time pancreatic extracts containing that substance of doctors at Lankwitz Hospital (almost all Jews) were fired. which were suitable for subcutaneous injection into animals The list of members of the Charité, Medical School of the 13 Acta Diabetologica (2023) 60:1241–1256 1251 University of Berlin, who were expelled between 1933 and • pancreatic islets of bony or teleost fish (islet tissue 1935 included more than 160 teachers and researchers and separated from the acinar in clearly recognizable more than 30 health workers; some were killed by the Nazis nodules), or committed suicide [69]. • pancreatic acinar tissue, free of islets, of teleost fish. In the case of pancreina, NC Paulescu, working alone • These experiments were the first showing direct with precarious means and failing health, could not make evidence that the production of the antidiabetic hor- any meaningful progress in the purification of the extract. mone is selective of the islet of Langerhans [77]. Paulescu’s radical antisemitism and extreme Orthodox Christianity facilitated his fall into oblivion with the rise to James Bertrand Collip power of the Communist Party. Paulescu, cofounder of right- wing political organizations, was erased from the history of James B. Collip (1892–1965) eliminated lipid impurities Romanian science for a long time [18, 70]. from the pancreatic extract by double extraction with sul- furic ether and protein impurities by precipitation with 80% ethyl alcohol, followed by centrifugation. Finally, Collip achieved the isolation of the active principle by selective Synoptic review of the main contributions precipitation with 95% ethanol (January 19, 1922). toward the development of insulin On September and October, 1923, respectively, American in the Departments of Physiology patents were granted to the semipurified pancreatic extract and Medicine at the University of Toronto of Collip, crediting as inventors FG Banting, CH Best and (1921–1923) JB Collip, and as owners the Governors of the University of Toronto [78, 79]. John James Rickard Macleod Effective Introduction of Antidiabetic Hormone John James Rickard Macleod (1876–1935), Professor and in the clinic (1922) Chair of the Department of Physiology at the University of Toronto, delivered a keynote address to the Association of The success achieved by the administration of Collip's pan- American Physicians in Washington DC on May 3, 1922. creatic extract to Leonard Thompson and six additional In this lecture, Macleod described the main experiments patients, admitted to Toronto General Hospital (TGH) in carried out under his coordination between May 1921 and February 1922, was published in March of the same year April 1922 and published by the following researchers who [80]. agreed to be listed in alphabetical order: FG Banting, CH Before the end of 1922, more than fifty diabetic patients Best, WR Campbell, JB Collip, AA Fletcher, JJR Macleod, had successfully received insulin treatment at the Diabe- and EC Noble. tes Clinic of the TGH by Walter R. Campbell, Andrew A. Fletcher and Frederick G. Banting, under the supervision of A1. Effects of insulin in hyperglycemic situations induced Prof. Duncan A. Graham [81, 82]. by various experimental procedures: Claude Bernard’s piqûre diabétique, subcutaneous injection of adrenaline, mechanical asphyxia and carbon dioxide poisoning [71– The priority in scientific discoveries: analysis 75]. and controversies A2. Glycogen and fat deposits in the liver and other organs of diabetic animals and effects of insulin administration For a researcher, communicating a discovery that contributes on those deposits [74]. to the advancement of scientific knowledge is a matter of the A3. Effect of insulin on the respiratory quotient in pancrea- utmost importance, and the recognition of the priority of tectomized dogs and in patients with diabetes [76]. the discovery by institutions and the academic community B. In the summer of 1922, JJR Macleod carried out a represents a main achievement. It is therefore not surprising total of 18 experiments in which he observed the serial that the determining principles of the attribution of priority changes in blood glucose at programmed intervals have been from time immemorial, and continue to be so (Shaffer-Hartmann method) induced in healthy rabbits today, a matter of controversy. by subcutaneous injection of: • pancreatic extracts from fish with a cartilaginous skeleton or elasmobranchs (diffuse distribution of the islets in a compact gland close to the duodenum), 13 1252 Acta Diabetologica (2023) 60:1241–1256 Fig. 7  From left to right: Portrait of RK Merton. Unknown date and traits of Ronald D. Vale, Emeritus Professor of Cellular and Molecu- author. Robert K. Merton described in the presidential address of lar Pharmacology at the University of California, San Francisco, and the American Sociological Society (1957) the characteristic values, Vicepresident and Executive Director of the Howard Hughes Medical norms and organization of the institution of science, as well as the Institute; and Anthony A. Hyman, director of the Max Planck Insti- basis for the sociological investigation of priority in science. Por- tute of Molecular Cell Biology and Genetics Robert King Merton (1910–2003): Organization disclosure of discovery (letters, books, articles in scientific of science and priority rule journals) (Fig. 7) [86]. According to R.D. Vale (UC San Francisco) and Anthony Robert K. Merton (original name, Meyer Robert Schkol- Hyman (Max Planck Institute) (Fig. 7), the recognition of nick), was born in Philadelphia, into a humble Jewish family, the primacy of a scientific discovery requires satisfactory who immigrated to the United States from Eastern Europe. fulfillment of the accreditation requirements of two decisive At Harvard, George Sarton, Professor of Sociology, directed factors: revelation of the discovery and validation by the his doctoral thesis, titled Science, Technology and Society in scientific community [87, 88]. Seventeenth Century England [83]. The recognition of priority of the scientific discovery Merton spent the rest of his academic life as a professor must avoid behavioral deviations regarding its originality at Columbia University (New York). His text Social Theory (fraud, plagiarism, fabrication of non-existing data and and Social Structure is a landmark publication in sociology, exclusion of unsatisfactory results) [89]. translated to over 20 languages. In 1998, the International Examples of behavioral deviation by FG Banting and CH Sociological Association listed this book as the third most Best are described below: important sociological book of the twentieth century [84]. A—On February 5, 1923, Paulescu wrote to FG Banting, Merton explained the origin of modern science, identi- asking for cooperation and enclosed with the letter his 1921 fied the set of values and norms (ethos) that should guide publications showing the positive results of pancreina on scientists and the reward mechanisms of science. He inves- experimental diabetes. Banting never answered. On Novem- tigated the originality of creation, plagiarism, tradition and ber 6, 1923, Paulescu bitterly protested against the conce- progress in the scientific world and the importance of the sion of the Nobel Award to Banting and Macleod and stated contributions of multiple researchers over time toward a that the Toronto team had infringed his intellectual property certain exceptional discovery, endorsing Newton's famous rights [29]. phrase “On the shoulders of giants” (“If I have come to see B—Banting and Best’s first article contained formal further, it was by standing on the shoulders of giants”) [85]. errors, meaningful mistakes and discrepancies between text In his presidential address at the annual meeting of the and figures. The main figures of the manuscript showed that American Sociological Society (1957) Merton defined the the administration of the “degenerated pancreas extract” priority rule as the credit granted to an individual or a only achieved a partial decrease in the levels of blood and group of individuals who made the discovery in the first urine glucose in only some of the depancreatized dogs. Nev- place, documenting it through an original publication. The ertheless, Banting and Best felt that these results justified priority date corresponds to the date on which the publi- stating that the extract contained the internal pancreatic cation was sent. Certified knowledge is legitimized by secretion. JJR Macleod decided not to sign the manuscript the institution of science through codification norms and as coauthor [29: pp. 175–176]. The transcription of the sat- isfactory results only and the exclusion of the unsatisfactory 13 Acta Diabetologica (2023) 60:1241–1256 1253 results is a manifestation of dishonesty and constitutes an authors previously, was an achievement attributable in error [90]. Besides, as mentioned a few pages above, Bant- 1922, almost exclusively, to James Bertrand Collip, ing and Best incorrectly reported Paulescu’s results. absent from the list of nominees. This clause strictly The physiologist Ffrangcon Roberts (University of Cam- excludes all alternative candidates, with the exception of bridge) published a letter to the editor in the British Medical C.H. Best. However, the reality is that the deliberation Journal criticizing Banting and Best’s experiments. He qual- of the commission and international experts takes time ified them as “badly designed, badly conducted and badly (an exceptional case was that of Peyton Rous, who dis- interpreted”. Michael Bliss corroborated and expanded on covered the tumor virus in chickens in 1916 and received that comment: “Banting and Best’s research was so badly the award 50 years later). For this reason, the current done that, without the help of Macleod and Collip, and a interpretation for the Nobel Foundation is that "the ben- much more subtle view of the constituents of the discovery efits of the discovery have been apparent to the members of insulin, the two young Canadians would be fated to disap- of the Karolinska Institute during the previous year" [4]. pear from medical history” [91]. 6. As for the "scientific value" of the discovery, the question is more complex. Insulin does not meet the The award of the Nobel Prize in Physiology required criteria ("discover something hidden, unknown or Medicine, 1923 or secret"), as it was the last of the organotherapeutic preparations with antihyperglycemic activity investi- The award of the Nobel Prize in Physiology or Medicine gated between 1889 and 1922. in 1923 to Banting and Macleod was peculiar in several 7. It is essential to differentiate the terms "discovery of respects. the antidiabetic hormone" and "discovery of insulin". The greatest contribution of the researchers from the 1. Banting was the first Canadian to receive the award. University of Toronto was the purification of the extract, 2. The awarding of the Nobel to a candidate in the first year making it suitable for clinical use. This was recognized in which it was proposed had only happened previously in 1971 by the Special Committee of the IDF, editor of to four laureates: in 1901, Nobel awarded to Emil A. von the report on the investigations related to the discovery Behring for his work on serum therapy, especially for its of the antidiabetic hormone [66]. In the third edition of application to diphtheria; in 1912 to Alexis Carrel for his the text Nobel, The Man and his Prizes (1972) revised by contributions to vascular suturing and to transplantation Carl Gustaf Bernhard, professor at the Karolinska Insti- of blood vessels and organs; and in 1922, Nobel awarded tute between 1948 and 1971 and permanent secretary of jointly to Archibald V. Hill for his discoveries in muscle the Royal Swedish Academy of Sciences between 1973 thermodynamics and to Otto F. Meyerhof for his discov- and 1981, the Nobel Prize of Physiology or Medicine, ery on the relationship between oxygen consumption and 1923, was given “to the credit for having produced the lactic acid metabolism in muscle [92]. pancreatic hormone in a practical available form” [93: 3. The limited information available to the members of the pp. 224–225]. Nobel Committee on the nominations received, consist- ing of a small number of documents. 4. The researchers who protested the decision of the Nobel Who discovered the antidiabetic Committee (G.L. Zülzer, E.L. Scott, J. Murlin, N.C. hormone? Proposals of the authors by way Paulescu, C.H.Best) were not on the list of nominees. of conclusions According to the statutes, that’s the reason why they were not eligible (although there have been cases where The discovery of the antidiabetic hormone (acomatol, pan- Nobel awards were granted in the absence of external crein, insulin) has been the result of a complex process, nominations, in which case, the candidates were pro- extended over time, through different stages and contribu- posed by members of the Nobel Committee themselves). tions from multiple actors. The answer to the priority dispute Interestingly, one of them was the 1920 Nobel, awarded may differ according to the following considerations [22, to August Krogh, who was nominated by the chairman 28, 29]: of the Nobel Committee and professor at the Karolinska Institute, Johan E. Johansson. A. If we consider that the most important achievement 5. The postulate of the "greatest benefit to humanity dur- was the first demonstration of the beneficial effect of ing the year prior to the date of the award", included in the administration of pancreatic extracts to an animal Alfred Nobel's will, was undoubtedly a factor of definite with experimental diabetes, credit must go to the pioneer importance. However, the purification process that made research of Eugène Gley (1900). the difference with regard to the extracts tested by other 13 1254 Acta Diabetologica (2023) 60:1241–1256 B. If we apply the criteria formally established by the Pri- Declarations ority Rule (RK Merton, R Vale and A. Hyman), the pri- macy should be assigned to GL Zülzer (first publication Conflict of interest The authors declare that they have no conflict of interest. in 1906 and first patents for acomatol in 1908, 1909 and 1912). Human and animal rights disclosure Statements on animal rights and C. If we estimate that primacy corresponds to the first dem- human consent are not required, due to the historiographic character onstration that the pancreatic extract exerts antidiabetic of this research. effects in humans (even with collateral toxicity), credit must go to GL Zülzer (1908). Informed consent disclosure This article is an original historiographic research. Therefore, the informed consent is not required. D. If we place greater importance on the scientific quality of the investigations regarding the physiological basis Open Access This article is licensed under a Creative Commons Attri- of the endocrine action of the pancreas, with the high- bution 4.0 International License, which permits use, sharing, adapta- est excellence in the descriptions of the experimental tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, method and the metabolic and beneficial effects exerted provide a link to the Creative Commons licence, and indicate if changes by the pancreatic extract on experimental diabetes, the were made. The images or other third party material in this article are priority of discovery should be shared by NC Paulescu included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in (1916) and JJR Macleod (1922). the article's Creative Commons licence and your intended use is not E. If the elected alternative is the greatest benefit for permitted by statutory regulation or exceeds the permitted use, you will humanity, the primacy would correspond to the success need to obtain permission directly from the copyright holder. To view a in the purification of the extract and its introduction in copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. the clinic by JB Collip, WR Campbell and AA Fletcher (1922). References Supplementary Information The online version contains supplemen- tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00592-0​ 23-0​ 2098-9. 1. Fernández T, Tamaro E (2004) Biografía de Alfred Nobel. Bio- grafías y Vidas. La enciclopedia biográfica en línea https://w ​ ww.​ Acknowledgements We would like to thank Reviewers for their valu- biogr​afias​yvidas.​com/​biogr​afia/n/​nobel.​htm. 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