Читать книгу Unveiling Diabetes - Historical Milestones in Diabetology - Группа авторов - Страница 45

Oskar Minkowski was nominated six times for the Nobel Prize. He can be called the “grandfather of the discovery of insulin” since in 1889 he discovered that the removal of the pancreas in dogs induced diabetes mellitus. The presentation of this discovery together with his senior colleague Freiherr Josef von Mering was the highlight of the first world congress of physiology in 1889. Minkowski was born 1858 in the Lithuanian city of Kaunas. His family immigrated to Königsberg in Prussia, where he studied medicine. Prof. Bernhard Naunyn became supervisor of his thesis and Minkowski followed him to Strasbourg in 1988. Finally, in 1909, Minkowski was nominated in the prominent University of Breslau, the capital of Silesia, where he worked until his retirement in 1926. During his time in Breslau, Minkowski became one of the leaders of German Internal Medicine and chaired the first German insulin committee. When the German government decided to send a team of the best German physicians to Moscow to support the care of Lenin, Minkowski was one of those chosen. Prof. Oskar Minkowski died near Berlin on June 18, 1931.

© 2020 S. Karger AG, Basel

One hundred years after the discovery of pancreatic diabetes, Rolf Luft stated in Diabetologia: “Undoubtedly Oscar Minkowski contributed one of the most important discoveries to diabetes research. To my mind, Minkowski presented the first proof of the impact of the pancreas in diabetes, and that the disease was a consequence of the lack of a pancreatic substance transported by the blood stream. This work was the real impetus for all latter work to extract insulin. It was certainly an original discovery, and the most important one in the history of diabetes” [1].

The story begins in Kaunas, the second largest city in Lithuania. As you leave the old city center to cross the “quiet river” Nemunas (“Memel” in German) towards the suburb of Alexotas which, before World War II, was home to a mainly Jewish community, you will find Hermann and Oskar Minkowski Street, a street proudly named after two famous sons of the city.

Oskar Minkowski was born here on 13 January 1858. In 1872 anti-Semitic measures adopted by the tsarist government forced the Minkowski family to emigrate to the nearby Königsberg in Prussia. Max, Minkowski’s older brother, later took over the family business and became prosperous here as a middleman, trading in grain. Hermann, his younger brother, become a world-famous professor of mathematics and found a place in history – all students of mathematics know his name. His contributions to the geometry of numbers were essential and his book Space and Time was a precursor to the discoveries of Einstein, who attended his lectures. It is highly probable that Hermann would have shared the Noble Prize with Einstein had he not died on January 12, 1909 from appendicitis.

In Königsberg (now Kaliningrad) the family lived in the city center, in Knochenstrasse 31–32, near the river Pregel. This was a street lined with the buildings of merchants, akin to the streets of Lübeck as depicted in Thomas Mann’s literary masterpiece Buddenbrooks. His father’s business was flourishing and two of his sons went to the University of Königsberg, which dates back to 1544. This place of learning was the proud alma mater of such imminent names as Immanuel Kant and the physician and physicist Prof. Hermann von Helmholtz, who invented the ophthalmoscope in Königsberg in 1851 – a discovery which became vital for people with diabetes.

Oskar Minkowski studied medicine in Freiburg and Strasbourg and completed his medical studies in Königsberg. His medical thesis was accepted in 1881. The supervisor of his thesis was Prof. Bernhard Naunyn (1839–1925; Fig. 1), who was the head of the Medical University Clinic in Königsberg from 1872 to 1888. Before Königsberg, Naunyn had worked in Berlin, Dorpat, and Bern.

In his autobiography, Bernhard Naunyn describes his favorite pupil, Oscar Minkowski: “I found a first-class employee in Oskar Minkowski. He was of substantial benefit to me. Minkowski is a man of outstanding intelligence. His independent and clear way of thinking and his mental mobility based on very speedy and precise perceptions gave him a perfect basis for scientific research” [2].

Fig. 1. Prof. Bernhard Naunyn, from Naunyn [2].

Minkowski’s dissertation was a study of the relationship between electrical stimulation of the brain and blood circulation. His abilities won him an assistantship in Naunyn’s clinic. Ernst Stadelmann, Minkowski’s predecessor, had been analyzing diabetic urine and had isolated an unknown acid as one of its components. In 1884 Minkowski identified this substance as β-hydroxybutyrate [3]. Further research enabled Minkowski to confirm the importance of acidosis in diabetic coma. Naunyn was also investigating the role of the liver in metabolism. In 1885, Naunyn proposed observing the effects of hepatectomy on a dove and asked Minkowski to attempt this delicate operation. Minkowski, who was interested in animal experiments, had previously succeeded where others had failed. He had managed to hepatectomize birds, such as geese, years before any others. Naunyn and Minkowski were also interested in determining the origins of bile pigments. In 1886, the hepatectomies allowed Minkowski to demonstrate the liver’s role in hemolytic jaundice [4].

Fig. 2. Prof. Adolph Kussmaul (Deutsches Archiv für klinische Medizin 73, Leipzig 1902).

In 1888 Bernhard Naunyn was appointed to the chair of Internal Medicine at the Kaiser Wilhelm University of Strasbourg. This new university was, at the time, the highest funded place for medical research in the German Empire, perhaps in the world – the German Emperor wanted to influence local opinion in favor of Germany. The university attracted a myriad of scientists who went on to achieve fame. Names such as Adolf Kussmaul, Friedrich Daniel von Recklinghausen, Hans Chiary, Wilhelm Konrad Röntgen, and Emil Fischer, to name but a few, were associated with this prestigious educational institution.

Bernard Naunyn was the successor of Adolf Kussmaul, known for his description of the “deep” respiration in diabetic ketoacidosis (Fig. 2). When he was a student, Kussmaul introduced, through poetic compositions, a character named “Biedermeier” – this name would later baptize a trend and style associated with the beginning of the 19th century. Naunyn knew that Kussmaul had not at all supported his nomination (like Hoppe-Seyler, the biochemist in Strasbourg) and therefore he avoided meeting Kussmaul when he moved to Strasbourg. Kussmaul left the stunning professor’s villa in Elisabethstrasse 7, adjacent to the hospital, in the morning of April 8, 1888. Naunyn turned up in the afternoon, once his predecessor had left (Fig. 3).

In 1888, Oskar Minkowski followed Naunyn to Strasbourg. It was here that he made his major discovery of pancreatic diabetes. This revelation began in April 1889 with a discussion between two researchers from different fields: the 31-year-young Dr. Oscar Minkowski, working in Nau­nyn’s Clinical Department who had arrived just a year beforehand, and the 40-year-old Prof. Extraordinarius Freiherr Josef von Mering, who was working in biochemistry and physiology and internal medicine. Von Mering was well established in Strasburg having been situated there since 1878. He had published numerous papers, including one on his discovery of the glucosuric effect of phlorizin in 1885 [5]. Their discussion took place in the library of Prof. Hoppe-Seyler’s institute of biochemistry (the first of its kind worldwide) and von Mering had the “home field advantage.”

Decades later there was some discussion concerning the contribution of the two researchers to the discovery of pancreatic diabetes. A student of von Mering wrote a letter to Minkowski, stating that von Mering’s contribution was not reported correctly. Therefore, Minkowski wrote a letter in 1926 describing the events surrounding the discovery and deposited it in the archives in Breslau (known today as Wrocław) in case “at some future time a student of the history of diabetes may be interested in the true facts.” Two professors, dismissed following the Nazi takeover in 1933, rescued the letter from the archives before leaving Germany. In the letter Minkowski wrote:

Fig. 3. Elisabethstrasse 7 in Strasbourg, home of Kussmaul and Naunyn (photo Dr. Jörgens).

In April 1889, I went to the biochemical institute to read some chemical publications, which were not available in our clinic, and I met von Mering in the library. He had recently recommended Lipantin, an oil preparation with 6% of free fatty acids as a replacement of cod-liver oil because he thought that the free fatty acids may be the most important substance acting in cod-liver oil.

Von Mering asked me, “Do you use Lipantin frequently in your clinic?” “Oh no,” I replied. “We give only good butter to our patients and not rancid oil.”

“Don’t laugh,” he said. “Healthy people must metabolize lipids and if the pancreas doesn’t work correctly, we have to give metabolized lipids to them.”

“Did you prove this in an experiment?” I asked him. This conversation was followed by a discussion on how to do the experiment and finally, Minkowski mentioned that this question should be studied in a dog following pancreatectomy.

“This is not so easy,” continued von Mering, “since the enzymes of the pancreas will still go into the intestines when you perform a ligation of the ductus pancreaticus.”

“What I mean is, we should take out the whole pancreas!”

“This operation is impossible,” von Mering replied.

Since I did not know about Claude Bernard’s publication stating that no animal would survive total pancreatectomy, and due to my young age, overestimating my capacities as a laboratory surgeon, I exclaimed, “There are no impossible operations. Give me a dog and I will take out his pancreas today.” Von Mehring replied, “Okay, I have a dog and you can try it.” The same day, I performed pancreatectomy in a dog in Naunyn’s laboratory with the assistance of von Mehring. The animal survived and initially seemed to be doing well. The day after the operation, von Mehring had to travel to Colmar because his father-in-law was suffering from severe pneumonia. He had to stay for one week. In the meantime the dog, which had been clean before, started to urinate more and more frequently in the laboratory. I reprimanded the laboratory assistant for not walking the dog frequently enough, but he replied, “I do walk him frequently but this animal is funny. As soon as it returns, it urinates again even immediately after having done it outside.” This observation led me to examine the urine of the dog [6].

Without this controversial discussion on lipids – which had no relation to the final discovery – the experiments would not have been carried out. Von Mering provided the dog and they performed the surgery together in Naunyn’s laboratory that same afternoon. Minkowski was legendary for his manual dexterity, and, as mentioned, had performed the world’s first successful hepatectomy upon a goose (successful in that the creature did not expire immediately). Sauerbruch, a giant in German surgery, called Minkowski “the greatest experimental physiologist of his time.” However, von Mering was also very well trained in experimental physiology – he had worked in the institute of Prof. Ludwig in Leipzig, one of the founders of modern physiology and had published a superlative study on glucose metabolism [7]. In the same institute some years later a young Scottish physician was trained in physiology and published his first paper (in German language), it was J.J.R. Macleod – honored with the Noble Prize for the discovery of insulin.

Fig. 4. The scientific laboratory of Naunyn’s hospital (archives of the Strasbourg University, provided by Prof. Brogard^†, Strasbourg, unpubl.).

Minkowski and von Mering were a surgical “dream team” and succeeded, in contrast to Claude Bernard, in successfully performing a pancreatectomy. The operation was carried out in Naunyn’s laboratory which was located on Elisabethstrasse near Naunyn’s house.

Thanks to the historic research of Prof. Brogard in Strasbourg we know the floorplan of this laboratory (Fig. 4). Claude Bernard, in his first most productive years, would have dreamt of such a considerable laboratory on two floors with many rooms and personnel. The building does not exist anymore, having been replaced by a catholic chapel, but Elisabethstrasse looks much as it did back in 1889, when the laboratory assistant Josef Zinck would regularly walk the polyuric diabetic dogs.

By chance, von Mering was not present when Zinck reported to Minkowski that the dogs were urinating frequently. Both collaborated to write the papers. Minkowski had to perform pancreatectomy in more dogs, the first one had been treated with phlorizin beforehand by von Mering and Minkowski wanted to be sure that glucosuria was not simply a consequence of the administration of phlorizin. The results were published in June 1889 and with more details in 1890 [8, 9] (Fig. 5). It was a masterpiece of a succinct publication – the title provides the full message: Diabetes Mellitus following the Extirpation of the Pancreas. In September 1889 Minkowski and von Mering attended the first World Congress of Physiology in Basel accompanied by a pancreatectomized dog. It was the highlight of the conference and von Mering and Minkowski became famous worldwide.

Fig. 5. The famous publication on pancreatic diabetes, 1889 [8].

In April 1894, Elliott Proctor Joslin, already a renowned specialist in diabetes research, praised the discoveries of Minkowski and von Mering in the Boston Medical and Surgical Journal (in 1928 the name changed to New England Journal of Medicine). Joslin summarized: “The experimental work of Herr [sic!] von Mering and Herr Minkowski on the production of diabetes by pancreatic extirpation, forms one of the foremost chapters in all experimental pathology… The abdominal grafts of the pancreas are by far the most striking part of Minkowski’s and von Mering’s work. The art of the experimenter is here given full range. The pancreas is a fragile organ and quickly dies. Moreover, an animal which has been submitted to an operation on the gland is in great danger of peritonitis. Both obstacles were overcome in the following manner. The pancreas was carefully dissected from its attachments in the abdominal cavity, turned on its axis and stitched to the abdominal wall. The blood supply was disturbed as little as possible. The wound was allowed to heal, and gradually the pancreas became engrafted on its new surroundings. When this was firmly established the dog was submitted to another operation, in which the internal part of the gland was removed. On the recovery of the animal no diabetes resulted. After an interval of some time, the engrafted pancreas was removed; and when this was done, diabetes in all its forms appeared. What more striking proof could be asked for the action of the pancreas in producing diabetes?” [10]

However, there is one mistake in the Joslin’s report: von Mering was not present when the grafting experiments were carried out. After the first discovery the following research on pancreatic diabetes was performed exclusively by Minkowski. Three reasons which may explain why von Mering did not continue diabetes research are, firstly, that following some unsuccessful applications Josef von Mering was nominated in 1890 in the University of Halle an der Saale and therefore moved with his wife and his four children from Strasbourg to Halle in April 1891. The second reason is that in Halle he had signed up for an incredibly multitasking life – becoming director of the Medical Polyclinic (which included medical teaching), lecturing on otorhinolaryngology, medical chemistry, and legal medicine, as well as becoming head of department in a Catholic hospital in Halle. The third reason is that von Mering worked, with great success, in many different areas of research. He, together with the Noble prize winner Emil Fischer, discovered the first barbiturate. Indeed, von Mering also holds the accolade of having published the first clinical paper on paracetamol. Freiherr Josef von Mering, born in 1849 in Cologne, died in 1908 in Halle an der Saale. Despite his numerous discoveries there is neither a renowned academic prize, a street, nor a plaque on the places where he lived to commemorate this outstanding researcher. This may change in the future since his discovery of “phlorizin diabetes” was the beginning of the use of SGLT inhibition in diabetes care over 100 years later [11]. In contrast to von Mering, Minkowski continued diabetes research throughout his career. In the first years after the discovery of pancreatic diabetes he had to reply to numerous voices of criticism, particularly that of Eduard Pflüger [12].

Minkowski married Marie Johanna Siegel in 1894. Their two children, Rudolph and Laure, were born in Strasbourg (Fig. 6). As usual in the realm of an academic career, he had to look for a position as head of department. His applications to universities were unsuccessful, and some authors assume that German faculties were reluctant to call for Jewish candidates. Minkowski finally accepted to serve as head of department in the city-owned Augusta Hospital in Cologne. This immense hospital with over 600 beds was co-directed by the Professors Heinrich Hochhaus and Minkowski (Fig. 7). In her autobiography, the widow of Hochhaus provided the only very personal description of the Minkowskis: “Whenever a professional or scientific topic came up, his zeal and his stream of words couldn’t be stopped. He spoke precisely and always very logically and sharply, a pupil of his teacher Naunyn, pressed by an overabundance of ideas and suggestions. He forgot his counterpart completely in this world of ideas. Mrs. Minkowski was called ‘the beautiful Minka.’ She had radiant black eyes. No important cultural event and no ceremony in Cologne in which our two couples would not have taken part” [13].

Fig. 6. Birth certificate of Minkowski’s son Rudolph (online birth registry, Strasbourg).

Fig. 7. Augusta Hospital in Cologne, where Minkowski worked from July 15, 1900 to March 31, 1904 (postcard, collection Dr. Jörgens).

The Minkowski family must have enjoyed a pleasant time in Cologne. Their home was an impressive villa, walking distance from the Augusta hospital, located on Mozart Street 28. It is detestable to know that, this once-magnificent abode of a Jewish-born scientist, later became the regional headquarters, or “Gauleitung,” of the National Socialist German Workers Party (it became known in Cologne as the “brown house”) and also the headquarters for SA and SS.

Nevertheless, Cologne was just a medical academy and Minkowski was, for all intents and purposes, looking for a position in a recognized university. Eventually he was called for the chair of internal medicine in Greifswald – a small university on the Baltic Sea. Although Minkowski had some initial problems finding a suitable apartment for his family in Greifswald, he finally found an appropriate residence in Bahnhofstrasse 48/49.

Naunyn, his “scientific godfather” took a hand in Minkowski’s career. He wrote a letter to the imperial ministry of research in Berlin criticizing the fact that a renowned researcher, such as Minkowski, was working in such an irrelevant place like Greifswald. His grievances were heard and, in 1909, Minkowski was nominated in the prominent university of Breslau, the capital of Silesia, where he worked until his retirement in 1926 (Fig. 8).

Fig. 8. Prof. Oskar Minkowski in Breslau (photo collection Dr. Jörgens).

Fig. 9. Vossische Zeitung, Berlin June 21, 1931.

Minkowski and his team were very successful scientifically. Minkowski later regretted only one major mistake during his career as a researcher, namely that he had missed the discovery of insulin. The analysis of Zülzer’s extract should have attracted his attention – but he paid little attention to this work and later regretted it, very much. The full story about Zülzer’s extract is recounted in the chapter by V. Jörgens [this vol., pp. 58–63].

During his time in Breslau, Minkowski became one of the leaders of German Internal Medicine. When the German government decided to send a team of the best German physicians to Moscow to support the care of Lenin, Minkowski was one of those chosen.

Fig. 10. Cemetery Heerstrasse in Berlin Charlottenburg. Professors Hermann and Oskar Minkowski (photo Dr. Jörgens).

Oskar Minkowski was nominated six times for the Nobel Prize for physiology and medicine, but not in the year when the prize for the discovery of insulin was awarded. The first German insulin committee to monitor the quality of insulin preparations elected him as its chairman.

Fig. 11. Minkowski Street in Wrocław (the former Bres­lau), Prof. Leszek Czupryniak (photo Dr. Jörgens).

Fig. 12. Oskar Minkowski Prize of the European Association for the Study of Diabetes (photo EASD).

After his retirement in 1926, Oskar Minkowski moved, with his wife, to Wiesbaden for a time. However, the couple eventually decided to move to Berlin where their daughter lived with her family. It was here that Minkowski caught pneumonia and, in a hospital in Fürstenberg on the Havel headed by one of his former students, he died on June 18, 1931 (Fig. 9). Today, within walking distance of the Nazi concentration camp of Ravensbrück, stands a commemorative memorial monument to Minkowski. Oscar Minkowski’s tomb, together with that of his brother Hermann, is located in the cemetery Heerstrasse in Berlin (Fig. 10).

Paul Morawitz, chairman of the German Congress of Internal Medicine, honored Minkowski in his opening speech in 1932: “With Oskar Minkowski we have lost one of our greatest. As a young assistant in Königsberg, he found β-hydroxy butyrate in the urine of diabetics. In Strasbourg, the 30-year-old discovered pancreatic diabetes in collaboration with von Mering. The discovery of hemolytic icterus was his third great achievement. There have been few clinicians whose life’s work can be compared to that of Oskar Minkowski. He attended our Congress beginning with its first session in 1882, one of the most faithful members. How often he spoke here! When his awe-inspiring figure entered the lectern, there was attentive silence: ‘The discoverer of pancreatic diabetes speaks! A great historical moment!’ Until the end we could admire in him – those qualities which made his successes possible: the crystal-clear mind, without any mysticism, his sharp criticism and at the same time that touch of fantasy – that artistic touch one needs to become an outstanding researcher… His works will live when all those who knew him face to face are no longer there” [14].

In 1938, Minkowski’s daughter, Laure Minkowski, forced by the odious policies of the Nazi government, opted to emigrate from Germany together with her husband and two sons. They settled in Buenos Aires, where Laure struggled to organize the emigration of her mother. On the last day of 1940, with the help of the Banting Society and the support of the Noble Prize winner Prof. Bernardo Houssay, who lived in Buenos Aires, Oskar’s widow, Marie Siegel Minkowski, was able to leave Germany to join her daughter in Argentina. Laure passed away in Buenos Aires in 1983 [15].

Minkowski’s son, Rudolph, earned his PhD in physics, and went on to become an astrophysicist. He left Germany in 1935 to take up a position at the Mount Wilson Observatory in California. Rudolph went on to become a well-known radio-astronomer and even has a protoplanetary nebula named after him, the Minkowski’s Footprint (Minkowski 92), located in the constellation of Cygnus.

The entire Minkowski family played an outstanding role in European science. They stand for innovative ideas followed by well-designed experiments and precise observation of unexpected results and their interpretation [15].

A street in Wrocław commemorates the name of Oskar Minkowski (Fig. 11). The European Association for the Study of Diabetes has, since 1966, awarded the Minkowski Prize for outstanding contributions to the advancement of knowledge in the field of diabetes mellitus (Fig. 12).