On the occasion of the centennial of insulin therapy (1922-2022), II-Organotherapy of diabetes mellitus (1906-1923): Acomatol. Pancreina. Insulin

Abstract

Aims: The general objective has been the historiographical investigation of the organotherapy of diabetes mellitus between 1906 and 1923 in its scientific, social and political dimensions, with special emphasis on the most relevant contributions of researchers and institutions and on the controversies generated on the priority of the "discovery" of antidiabetic hormone.

Methods: We have analyzed the experimental procedures and determination of biological parameters used by researchers during the investigated period (1906-1923): pancreatic ablation techniques, induction of acinar atrophy with preservation of pancreatic islets, preparation of pancreatic extracts (PE) with antidiabetic activity, clinical chemistry procedures (glycemia, glycosuria, ketonemia, ketonuria, etc.). The field investigation has included on-site and online visits to cities, towns, buildings, laboratories, universities, museums and research centers where the reported events took place, obtaining documents, photographic images, audiovisual recordings, as well as personal interviews complementary to the documentation consulted (primary sources, critical bibliography, reference works). The documentary archival sources have been classified according to theme, including those consulted in situ with those extracted online and digitized copies received mainly by email. Among the many archives contacted, those listed below have been most useful and have been consulted on site and on repeated visits: National Library of Medicine-Historical Archives (Bethesda, MD, USA); Archives, University of Toronto and Thomas Fisher Rare Books Library (Toronto, Ontario, Canada); Francis A. County Library of Medicine, Harvard University (Boston, Mass, USA); Zentralbibliothek der Humboldt-Universität (Berlin, DE), Geheimarchiv des Preuβischen Staates (Berlin, DE); Landesamt für Bürger-und Ordnungsangelegenheiten (LABO) (Berlin, DE); Arhivele Academiei Române şi Universitǎții Carol Davila (Bucharest, RO).

Main results and conclusions: A) The European researchers Zülzer (Z Exp Path Ther 23:307-318, 1908) and Paulescu (CR Seances Soc Biol Fil 85:558, 1921) meet the requirements of the priority rule in the discovery of the antidiabetic hormone. B) Factors of socioeconomic and political nature related with the First World War and the inter-war period delayed the process of purification of the antidiabetic hormone in Europe. C) The Canadian scientist J. Collip, University of Alberta, temporarily assimilated to the University of Toronto, and the American chemist and researcher G. Walden, with the expert collaboration of Eli Lilly & Co., were the main authors of the purification process of the antidiabetic hormone. D) The scientific evidence, reflected in the heuristics of this research, allows to assert that the basic investigation carried out by the Department of Physiology of the University of Toronto, directed by the Scottish J. Macleod, in conjunction with the clinical research undertaken by the Department of Medicine of the University of Toronto (W. Campbell, A. Fletcher, D. Graham) made it possible in record time the successful treatment of patients with what was until then a deadly disease.

Keywords: Acomatol; Insulin; Organotherapy; Pancreatic extracts; Pancreina; Patents.

Fig. 1

Photography of Georg L. Zülzer; unknown author and date. Historical Archive, Humboldt University, Berlin. Public domain. Case 3: A 6-year-old boy with severe diabetes, ketonuria, heavy glycosuria and malnutrition. Effect of the pancreatic extract [7]

Fig. 2

G.L. Zülzer. German (1908), British (1909) and USA (1912) patents for Acomatol. Public domain

Fig. 3

Portrait of Camille Reuter. Unknown date and author. (Courtesy of V. Jörgens)

Fig. 4

Left Nicolae Paulescu published four short articles covering nine experiments in CR Société de Biologie, showing the results of the administration of his pancreatic extract to dogs with experimental diabetes. Right The four graphs are from his long original article, published in August 1921. They illustrate: a the development of diabetes after complete pancreatic ablation; b the effect of parenteral administration of pancreina on the glycemic profile in the pancreatectomized dog; c serial study of the variations in glycemia and glucosuria over 24 h induced by the injection of pancreina; d evaluation of the intensity of the glycemic response in the animal with experimental diabetes depending on the amount of pancreatic extract administered [60]. (Courtesy of Constantin Ionescu-Tirgoviste)

Fig. 5

Main results and conclusions of the experiments carried out by NC Paulescu demonstrating the effects of pancreina on the metabolism of carbohydrates, proteins and ketone bodies and the absence of response observed in control experiments (other organs than the pancreas, saline and sodium nucleinate) [60]

Fig. 6

Nicolae Paulescu: Registration of the pancreina patent. Romanian Ministry of Industry (April 10, 1922)

Fig. 7

Left Letter from Nicolae Paulescu to Frederick Banting (February 5, 1923). University of Toronto Archive. Right Letter of protest from Nicolae Paulescu to the Chairman of the Nobel Commission for the award of the Nobel Prize in Physiology or Medicine to Frederick Banting and John Macleod (NC Paulescu personal papers; courtesy of Dan Angelescu)

Fig. 8

Left Photographs of the University of Toronto School of Medicine building and Laboratory of Physiology, University of Toronto; summer of 1921. Archives of the University of Toronto. https://nobelprize.orf/prizes/medicine/1923/banting/photo-gallery/. Right The first article of Frederick Banting and Charles Best (February, 1922) reported results of at least 75 doses of pancreatic extracts from “degenerated pancreas” [70]

Fig. 9

Portrait of Leonard Thompson (L.T.). Unknown date and author. University of Toronto Archives. Recorded effects of the administration of Collip's pancreatic extract to L.T., the first diabetic patient successfully treated in the Inpatient Ward of the Department of Medicine, Toronto General Hospital. Left Daily chart record between January 1 and February 20, 1922, of urinary glucose excretion. Right Rapid elimination of ketonuria. Reduction of blood glucose and glycosuria fractionated over 24 h. [79]

Fig. 10

Between May 1921 and May 1922, the Diabetes Research Project led by Prof. JJR Macleod, Chair of the Department of Physiology at the University of Toronto, demonstrated the metabolic actions exerted by the pancreatic extract on healthy animals and the therapeutic effects observed in animals with hyperglycemia experimentally induced by various procedures. The photographs of the main authors of this research (JJR Macleod, FG Banting, CH Best and JB Collip) come from the Archives of the University of Toronto. Public domain

Fig. 11

In the summer of 1922, JJR Macleod investigated alone at the Marine Biological Station in St. Andrew's, New Brunswick, the comparative effect of administration of islet-free acinar pancreas from elasmobranch fishes with administration of islets of Langerhans encapsulated in nodules and separated from the acinar tissue of bony fishes (teleostei). Macleod also performed control experiments with liver extracts [93]

Fig. 12

Insulin Patents. Patents 234,336 were issued to inventors FG Banting and CH Best and 234,337 to inventors PJ Moloney and D.M. Findlay (Canadian Intellectual Property Office) on September 18, 1923. Patent 1,469,994 (United States Patent Office) was granted on October 9, 1923. All of them were assigned ownership to the University of Toronto Board of Governors. In the absence of a fully purified substance and its clinical formulation, the patented product (extract obtainable from the pancreas of mammals or fish) was defined by a sufficient degree of purity that surpassed that of the preceding preparations, as well as its physiological effects and beneficial therapeutics for patients with diabetes [94]

Fig. 13

In the summer of 1923, a conflictive situation arose between Eli Lilly and the University of Toronto due to the intention of G. Clowes, Director of Research at Lilly, to apply for a new patent based on the development of a new exclusive extraction procedure, invented by G.B. Walden, showing that isoelectric precipitation markedly reduced the residual nitrogen in the preparation and increased the purity of the preparation between 10 and 100 times compared to the standard product. The pressure exerted by the Insulin Committee of the University of Toronto finally decided to assign the intellectual property shared with the University of Toronto: US Patent 1,520,673. Inventor George B. Walden. Owners: The Governors of the University of Toronto (December 23, 1924). Photographs of G.B. Walden and G. Clowes are from the Lilly Archives [99]

Fig. 14

Sir Frederick Banting, victim of plane crush (February 20, 1941). News report on the accident in the Alliston Herald. Public domain

Fig. 15

Charles Best backdated the discovery of insulin to the first weeks of the summer of 1921. The Banting and Best Center of the University of Toronto celebrated the centenary of the discovery of insulin—insulin100.com -, on April 15–17, 2021, advertised with only images of researchers Banting and Best