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100858 AVANCES 26 5Indd avances en Diabetología Av Diabetol. 2010;26:373-82 Historical perspective From pancreatic extracts to artificial pancreas: history, science and controversies about the discovery of the pancreatic antidiabetic hormone V: The controversy. Who discovered insulin? A. de Leiva-Pérez1, E. Brugués-Brugués1,2, A. de Leiva-Hidalgo1,2,3,4 1Fundación DIABEM. 2Servicio de Endocrinología y Nutrición e Instituto de Investigación. Hospital de la Santa Creu i Sant Pau. Barcelona. 3Centro de Historia de la Ciencia. Universitat Autònoma de Barcelona. 4CIBER-BBN-ISCIII The Nobel Prize controversy were provided by two members of the objection was to making an award on “he- The 1923 Nobel Award Nobel Committee: John Sjöqvist, Profes- resy evidence” from unknown persons or of Physiology or Medicine sor of Chemistry and Pharmacy, and Hans on statements in the two appraisals, like In April 1923, a total of 57 nominations Christian Jacobaeus, Professor of Internal “it is beyond doubt”, or comments as with merits were reviewed by the Nobel Medicine. Sjökvist arrived to the same ”things that are thought as very possible”; Committee. The examiners concluded conclusion as A. Krogh: the prize should the Assembly should take only verifi able that the discovery of insulin was of funda- be divided between Banting and Macleod. facts. The Committee reconsidered and mental importance. The archives of the Professor Göran Liljstrand was the Secre- reconfirmed its previous recommenda- Karolinska Institute depict that Macleod tary of the Nobel Committee from 1918 to tion. August Krogh was identifi ed as the and Banting were nominated for the fi rst 1960. He was a great friend of August source of the “heresy evidence”; he time in 1923: Banting by G.W. Crile (Cle- Krogh. The archives of the Royal Swedish emphasized that he made the joint recom- veland) and August Krogh and Macleod Academy of Sciences keep an interesting mendation based on his visit to Toronto. by G.N. Stuart (Cleveland) and August correspondence between Krogh and Lil- On October 25, 1923, the nineteen Krogh. There was also a joint nomination jestrand. The Committee concluded that Professors of the Caroline Institute, vo- of Banting and Macleod from August although the discovery was initially ted by secret ballot. The Nobel Award of Krogh. Written evaluations of Banting Banting’s idea alone, Macleod’s guiding Physiology and Medicine was jointly and Macleod’s scientific contributions hand helped Banting’s idea to reach such granted to Frederick Grant Banting and a happy culmination. John James Richard Macleod, “for the Date received: 15th July 2010 The Faculty members of the Karolinska discovery of insulin”, one year before. th Date accepted: 7 September 2010 Institute (Royal Caroline Institute), the Banting decided to share his monetary Correspondence: Nobel Assembly, as its October 11 mee- fraction of the prize with Charles H. Prof. Alberto de Leiva-Hidalgo. Fundació DIABEM. ting, decided to send back the proposal to Best; Macleod did the same with James Cartagena, 245, 1-5. 08025 Barcelona. E-mail: [email protected] the Committee for reconsideration. The B. Collip (fi gure 1). 373 Av Diabetol. 2010;26:373-82 Figure 1. Nobel Prize Diploma to Banting and Macleod The protests In December 1922, Dr. F. Roberts, phy- Figure 2. A) Letter from Paulescu to Banting (February 5, 1923), who did not reply. B) Letter from siologist from Cambridge, had already re- Paulescu to the Nobel Commission (November 6, 1923) (Courtesy of Dan Angelescu). Available on: http://www.library.utoronto.ca ported in a letter to the British Medical Journal a serious criticism to Banting and Best’s work in their fi rst two publications Banting did not reply. On November 6, Archives Internationales de Physiologie, in the Journal of Laboratory and Clinical 1923, Paulescu claimed to the President Paulescu described the various attempts to Medicine.1 Roberts claimed that the pto- of the Nobel Commission (fi gure 2) that treat one male patient with “thin diabe- teolytic enzyme (trypsinogen) existing in his work had been stolen by the Canadian tes”, and a woman with “obese diabetes”. the pancreatic gland needs to be activated research group, and he asked for justice. In both cases the intravenous administra- by enterokinase secreted by the small in- Paulescu enclosed a copy of his article tion of pancréine induced favorable testine; therefore, there were no physiolo- “Recherche sur le rôle du pancréas dans outcomes regarding the symptoms, blood gical basis for the duct-ligation experi- l’assimilation nutritive” published in Ar- glucose levels and glycosuria. Neverthe- ment. chives Internationales de Physiologie de less, the development of a toxic syndrome Shortly after the announcement of the Liège on the 31st August 1921 (accepted with high fever obliged to the interruption Nobel Committee’s decision, various re- on the 22 June). Paulescu’s article had of clinical experiments afterwards. searchers claimed against such a provision. been published six months prior to Ban- On April 1922, the University of Toron- Georg Ludwig Zuelzer sent furious letters ting and Best’s article “The Internal Se- to submitted a formal application for an of protest from Berlin, pleading for some cretion of the Pancreas” (Journal of Labo- USA patent granted to Charles Best and recognition of his priority. Ernest Lyman ratory and Clinical Medicine, issue of James Bertrand Collip. The USA govern- Scott called the attention to his experi- February 5, 1922). ment rejected the application, in order to ments in the fi eld. In his opinion, the prio- protect the rights of the ACOMATOL pa- rity of isolation and in the development of “Je vous demande la permission de protester tent already granted to George L. Suelzer fundamental principles involved in extrac- contre le fait que cette distinction [Nobel] a été on May 28, 1912. The process fi nally en- tion clearly belonged to the work reported accordée à des personnes qui ne la méritaient ded with the provision of a patent registry from the laboratory of Chicago.2 The me- point. En effet, la découverte de ces effets in November 1922, shared by the Univer- thod of fi nal purifi cation was not necessary physiologiques et thérapeutiques m’appartient sity of Toronto (INSULIN) and Eli Lilly for obtaining the active principle. John Ra- toute entière (…). Dans ces articles, ils n’ont (ILETIN) (fi gure 3). ymond Murlin argued that he had perfor- fait que répéter ce que j’avais dit bien avant Accordingly to the Bylaws of the Nobel eux sur la diminution de l’hyperglycémie et de med, at earlier times than the researchers la glycosurie, de l’urée sanguine et urinaire, de Foundation: “To be considered eligible from Toronto, both experimental and clini- l’acétonémie et de l’acétonurie, sous for an award, it is necessary to be nomi- cal studies with the pancreatic extracts. Is- l’influence des injections intra-veineuses de nated in writing by a person competent to rael S. Kleiner made no claims. l’extrait pancréatique, chez un animale diabé- make such a nomination. A personal On February 5, 1923, Nicolae C. Pau- tique (…).” (N.C. Paulescu. November, 1923) application for an award shall not be con- lescu had written Banting, asking for mu- sidered. Each year the prize adjudication tual correspondence regarding their re- On April 10, 1922, the license application shall embrace such nominations as have search activities (fi gure 2); Paulescu sent 6254, PANCRÉINE, was registered. In been submitted during the preceding twel- to Toronto his main publications of 1921. the issue of March 5, 1923, of the journal ve months up to February 1”. 3 374 Historical perspective V: The controversy. Who discovered insulin? A. de Leiva-Pérez, et al. complete, and inadequately documented. He ended: “it seems to me that I have the PANCREINE (N.C. Paulescu) right and even the duty, to re-establish the License application # 6254, truth and to protest against a process ne- issued by the Romanian Ministry of Industry. April 1922 ver permitted in science, in re-establis- hing the facts with total accuracy”.4 In 1923, Paulescu had already published the results of attempts at purifi cation of pan- créine, in an effort to make it suitable for use in humans.5 He studied the effects of acidic and basic solutions, heat and alcohol, on the USA Patent. impurities in his extract, and found them all November, 1922 ISLETIN / INSULIN inadequate. In his textbook of medicine pu- blished in 1930,6 Paulescu showed his em- bitterment and disappointment: “Formerly, I used to believed taught that a scientist F.G. Banting C.H. Best J.B. Collip J.J.R. Macleod may work in safety, because I was convin- ced that the date of his publications shelte- Figure 3. red him from any iniquity. Unfortunately, today, I am forced to acknowledge that I was completely wrong”. August Krogh and Hans C. Hagedorn A decisive person in the concession of the Nobel Award to Banting and Macleod, as it was mentioned before, was August Krogh, a renowned Danish scientist, who had obtained in 1920 the Nobel Prize in Physiology and Medicine for his disco- very of the mechanism of regulation of capillary fl ow in the skeletal muscle. In 1922, August Krogh traveled to the USA with his wife Marie (also a scientist). Ma- rie Krogh had been found a year before to have maturity onset diabetes. The renow- ned American diabetologist Elliot P. Jos- August and Marie Krogh Hans Christian Hagedorn lin informed August and Marie Krogh that insulin had just been discovered and puri- Figure 4. August Krogh, the Nobel Prize of 1923, Hans C. Hagedorn, and his wife Mary fi ed in Toronto. They decided to extend their trip and spent some days in Toronto Paulescu was never nominated.
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