They Got Very Near the Goal: Zülzer, Scott, and Paulescu
Viktor Jörgens
Executive Director EASD/EFSD 1987–2015, Düsseldorf, Germany
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Abstract
Of the many investigators who went in search of the blood sugar-lowering hormone, three came very close to the goal. They owned patents for their extracts and, following the discoveries in Toronto, they attempted to claim their precedence. Georg Ludwig Zülzer in Berlin treated animals and patients with his acomatol – initially the results were inconsistent but in later years, together with Dr. Camille Reuter from Roche, a very effective insulin preparation was produced – sadly just at the time when the First World War began in 1914. The project ended with the war. In Chicago, Ernest Lyman Scott produced an effective extract when working on his thesis – but sadly the publication of his results was written so badly by his head of department that the manuscript passed unnoticed. Nicolai Paulescu produced insulin in Bucharest and observed positive effects in animals and patients. The results were published shortly before the work of Banting and Best, and for many years he and his Romanian colleagues fought for the recognition of his contribution to the discovery of insulin. His unforgivable extreme right-wing political activities only became known internationally after many years. The stories of the various reasons for the failures to produce a suitable extract for the treatment of diabetes is a lesson that teaches us how to avoid pitfalls in research.
© 2020 S. Karger AG, Basel
On account of the experiments Oskar Minkowski had conducted in Strasbourg, it was clear that the pancreas releases a substance of “internal secretion” that reduces glucosuria and glycemia. Minkowski had implanted a small piece of pancreas subcutaneously into pancreatectomized dogs, and the symptoms of diabetes had disappeared. Lanceraux had suggested that it might be the islets of Langerhans from where this endocrine active substance originated. Endocrinology was a booming discipline, it had taken off with Claude Bernard’s successor, Brown-Séquard, who had demonstrated, in his famous self-experiment with testosterone, what a first-class rejuvenating effect this hormone had on an old man. Consequently, several researchers tried to isolate an agent from the pancreas that could be used to treat diabetes mellitus. As to be expected, all experiments with orally administered pancreatic preparations were ineffective. For this reason, researchers tried to produce extracts and to inject them. However, this was far more difficult compared to hormones from other endocrine glands. Why? Because in most animals, the insulin-producing islets are embedded into the tissue of the pancreas, therefore most of the pancreas functions as an exocrine gland. Simply cutting the pancreas into pieces and injecting it leads to considerable inflammation and the extracts no longer contain insulin due to the enzymes of the exocrine pancreas.
Claude Bernard had already noticed that there is no exocrine function in the fetal pancreas. Hence, attempts were made to obtain insulin from fetal pancreatic tissue. Another attempted method was to try to induce a degeneration of the exocrine part of the pancreas by suppressing the pancreatic duct from the rest, making it easier to extract the desired hormone. Both methods were of course not suitable for extracting large amounts of the substance. The search was made more difficult by the fact that, for a long time, it was assumed that the substance was not a protein. Of the many investigators who went in search of the blood sugar-lowering hormone, three were very close to the goal and, following the discoveries in Toronto, they attempted to claim their precedence. The stories of the various reasons for their failure to produce a suitable extract for the treatment of diabetes is a lesson teaching us how to avoid pitfalls in research.
Georg Ludwig Zülzer, Camille Reuter, and Their Acomatol
Georg Ludwig Zülzer (Fig. 1) was the closest of all the “precursors” to the discovery of insulin and its successful application for the treatment of diabetes. His father, Prof. Wilhelm Zülzer (1834–1893), came from a wealthy Jewish family in Breslau (now Wroclaw), which probably had their roots in the Jewish city of Zülz in Silesia. He worked at the Charité in Berlin and became known for his publications in epidemiology and urology. His son, Georg Ludwig Zülzer, was born on April 10, 1870 in Berlin. After medical studies in Freiburg and Berlin he worked as an assistant in various clinics, among others with the metabolism researcher Prof. Raphael Lépine in Lyon. In Giessen he met his later friend, the endocrinologist Ferdinand Blum. In 1901, Blum described “adrenalin diabetes.” This inspired Zülzer to come up with an idea regarding the pathogenesis of diabetes, which he formulated in 1907. He suspected that diabetes was caused by an imbalance between the secretion of adrenaline and the blood sugar-lowering substance from the pancreatic islets [1]. Blum later founded a research institute for endocrinology in Frankfurt but was forced to immigrate to Switzerland in 1939.
Fig. 1. Georg Ludwig Zülzer. From Mellinghoff [1].
Zülzer opened a private practice in Berlin in 1900. Occasionally it is stated in the literature that he worked as a pediatrician. This however is a case of mistaken identity as it was his son who became a renowned researcher in pediatrics in the USA. Zülzer dealt with internal medicine, and he also wrote a two-volume textbook on this subject [2]. In 1908 he became chief physician at the Hasenheide Clinic in Berlin (Fig. 2). After the First World War he became the head of the Department for Internal Medicine in the Hospital Berlin Lankwitz [1].
Fig. 2. The hospital Hasenheide in Berlin, where Zülzer’s laboratory was located (postcard, collection Dr. V. Jörgens).
For 12 years – from 1902 to 1914 – Zülzer conducted research aiming at the production of a pancreatic extract for the treatment of diabetes. In the first years he used the laboratory of the institute of Prof. T.W. Engelmann in Berlin. Eight publications and three patent specifications bear witness to this tireless work. He first injected adrenal extract into rabbits and glucosuria occurred. When he injected his pancreatic extract at the same time, this increase of glucosuria did not occur. He did not describe all the details of the methods he used to produce the extract in these early studies [3]. However, he wrote: “In order to obtain a pancreatic preparation that is not too toxic, all proteins of the pancreas must be removed” [3]. At first, Zülzer tried to obtain pancreata from the slaughterhouse, but this proved to be very difficult. Then he came up with the idea of sacrificing large dogs and using theirs. In the hope that the pancreas would then contain more of the hormone, he fed the animals plenty of carbohydrates beforehand. He stated later in his US patent application: “The pancreas preparation may be made as follows: the pancreas gland of an animal in narcosis is laid bare, the animal being preferably in a state when the process of digestion is at its height, the principle efferent vein is ligatured... In a similar manner the remaining veins of the pancreas are tied and swell greatly after the first ligature. After one or two hours the pancreas is removed for further treatment. This treatment consists in cutting
