Josef Freiherr von Mering (1849-1908)

Josef Freiherr von Mering was born in Cologne on the 28th February 1849, and claimed descent from a family of noble patricians, first mentioned in 1553, whose aristocratic title awarded by the free cities of the German Empire. After 1700 the family assumed the title “von” to express their noble origins [1]. Josef von Mering's father was Friedrich Everhard von Mering (born 1799), whose main interest was private historic research, and his numerous publications included an important local history of the region around Cologne, for which he was awarded the title of Dr. honoris causa by the university of Munich. Although relatively wealthy in early life, he died in poverty[2]. Josef von Mering himself is remembered for several notable discoveries including the use of phlorizin (the precursor of the SGLT2 inhibitors), the discovery of veronal and paracetamol, and for his partnership with Oskar Minkowski which uncovered the pancreatic origins of diabetes.

Background and Education

Prof. Freiherr von Mering
Prof. Freiherr von Mering
A young lady named Ursula Schmitz took care of Everhard von Mering’s household for many years, and he finally decided to marry her when he was 44 years old. He wrote in his autobiography that “I should have done this earlier, people miss the best because they usually ask themselves what the rest of the world might think about it” [3]. After two daughters the son Josef von Mering was born 28.2.1849 when his father was 50 years old. His father died in 1861, leaving his young wife and three children in a difficult financial situation.

Thanks to the support of his godfather Caspar von Bianco, Josef von Mering did however receive an excellent education. He went to the gymnasium in Cologne and studied medicine in Bonn, Greifswald and Strasburg. He participated as a volunteer in the Franco-Prussian war of 1870/71. His thesis as a medical doctor was accepted in Strasburg in 1874. Prof. Hoppe-Seyler, one of the founders of biochemistry, stimulated work which resulted in a thesis about the biochemistry of cartilage. He was then employed as physician in the department of psychiatry of the Medical university in Strasburg. This new German university – created by the German Emperor following the annexation of Alsace - was at the time the best funded place for medical research in Germany, possibly in the world, and attracted a galaxy of scientists who went on to achieve fame, including Adolf Kussmaul, Friedrich Daniel von Recklinghausen, Hans Chiary, Bernhard Naunyn, Wilhelm Konrad Röntgen, Oswald von Schmiedeberg and Emil Fischer.

In Strasburg (and throughout his academic carrier) von Mering refused to specialize. His initial interest in psychiatry led on to research into hypnotics, as a result of which he co-discovered Veronal, otherwise known as barbitone (Barbital in the USA), which was widely used as a sleeping tablet in the first half of the 20th century.

In 1875 von Mering moved to Berlin and joined the department of Prof. Frerichs, a renowned specialist in hepatic diseases and diabetes. He worked there on liver metabolism. The summers of 1877/78 were spent in providing medical services to patrons of a bathing resort in Bad Salzschlirf, a small spa in Hessen, probably because he needed the money, but in the winters he visited the university laboratories in Strasburg and Bonn, and in 1878 he was offered a position at Hoppe Seyler's institute of physiology in Strasburg. An additional task was to provide medical services for prison inmates, an experience that initiated his research on typhus [1].

In 1879 von Mering wrote his habilitation (thesis) about the effects of mercury in animals, and in 1886 he became Professor “Extraordinarius” - which included the requirement to lecture on legal medicine (1886-1891). In parallel he was asked to set up a clinic for otorhinolaryngology [1][4].

Following unsuccessful applications for permanent positions in Greifswald, Marburg and Vienna he was finally nominated 1891 by the university of Halle. But there was a problem, for von Mering was Catholic and the statutes of the University of Halle required protestant professors; a personal decision of Emperor Wilhelm II was needed to overrule these regulations. The appointment obliged him to take on a range of responsibilities, for he became director of the Medical Polyclinic (which included medical teaching), and in addition had to lecture on otorhinolaryngology, medical chemistry and legal medicine - as well as becoming head of department in a Catholic hospital in Halle. This degree of medical multitasking would be unthinkable today.

Whilst in Strasburg, Freiherr von Mering married Maria Fuxius from Trier on 17th April 1879, and they had four children by the time they moved to Halle. As his income increased substantially, he built an impressive villa near the Leopoldina - the German academy of natural sciences - in the university area and moved there with his family in 1895. The villa still exists but the address has changed from Friedrichstrasse to August Bebel Strasse No. 49.

Von Mering published a famous textbook on internal medicine in 1901 [5]. He recruited a young team of authors and the book became a great success. In the preface to the first edition he wrote: “Only the researcher is able to review the enormous number of details and to provide a succinct summary for busy clinicians and medical students" [5]. The book was continued by J. Krehl in Heidelberg, and its 16th edition reported on the discovery of insulin [6].

In 1903 von Mering was proposed for the title of “Geheimer Medizinalrat”, awarded by the Emperor, but this was rejected because the administration in Berlin which regulated the titles of the nobility did not accept the title “Freiherr” which von Mering used in all documents [1]. He was finally awarded the former title following another nomination by the university in 1905 which omitted the title of "Freiherr". The controversy continued after his death. In the obituary notice by the family he was called Geheimer Medizinalrat Prof. Freiherr von Mering, but the Freiherr was not mentioned in the notice by the university.

He died in 1908 at the age of 59. It was typical of him to make his funeral a special one, very much in the tradition of his “Cologne spirit” which was always critical of authorities, particularly Prussian ones. He had supported an association promoting cremation, but cremation was prohibited in Prussia. According to his last wish the body was accompanied by the family to the railway station and taken by train to Eisenach in Thuringia. In Eisenach – the city near the castle where Martin Luther translated the Bible – cremation was not prohibited. The files describe von Mering as protestant, which may either have been a mistake, or else perhaps stated by the family in order to ensure the presence of a clergyman, since Catholic priests were not allowed to assist at cremations [1].

All leading medical journals in Germany, nine in total, published obituaries [1][7][8]. These pointed out his widespread interest in medical research and highlight three major discoveries: pancreatic diabetes, the barbiturate Veronal and Paracetamol.

The Discovery of Pancreatic Diabetes

What was his role in these discoveries? Typically enough, all his discoveries were the result of collaboration. The discovery of pancreatic diabetes started with an academic discussion between two researchers from different fields: the 31 year-old Oskar Minkowski, an internist in Naunyn’s Department who had arrived a year ago with Naunyn from Königsberg - and the 40 year old Prof. Extraordinarius von Mering, working mainly in biochemistry and physiology. Von Mering was well established in Straßburg since 1878 and had published a lot including his discovery of the diabetic effect of phlorizin in 1885 [9]. Their discussion took place in Hoppe Seyler's department – thus giving the “home field advantage” to von Mering. Their meeting was described in a letter by Oskar Minkowski, whereas von Mering’s views remain unknown. Minkowski wrote:

“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 codliver 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 metabolise lipids and if the pancreas doesn’t work correctly, we have to give metabolised 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 may 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, over estimating 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 Mering 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 [10].

Figure 1: “Diabetes following pancreatectomy” – publication by von Mering and Minkowski 1889 (14)
Figure 1: “Diabetes following pancreatectomy” – publication by von Mering and Minkowski 1889 (14)
Did one of the two contribute more to the discovery? Without their controversial discussion on lipid absorption - which had no relation to the final discovery - the experiments would not have been carried out. Von Mering provided the dogs and they performed the surgery together in Naunyn’s laboratory. By chance von Mering was not present when the laboratory assistant reported to Minkowski that the dogs were suffering from polyuria. Both collaborated to write the papers. The data collected in April were – shame on our medical journals today - already published by June 1889 [11][12], (figure 1). The paper was brilliantly written, a masterpiece of a succinct publication – the title and the first sentence provide the full message. Both travelled together to the first World Congress of Physiology in Basel where 11.9.1889 Minkowski and von Mering presented one of the diabetic dogs – the highlight of the conference.

Neither of the two claimed to have more merit than the other in the discovery of pancreatic diabetes. They continued to collaborate, and von Mering invited Minkowski to write two chapters in his textbook [5]. Von Mering described the discovery of pancreatic diabetes in his chapter on Diabetes: “We both found that dogs become diabetic following pancreatectomy” (5, p. 985). They were very different characters – the quiet Minkowski with Jewish roots in Lithuania and an east Prussian education in Königsberg, the city of Immanuel Kant, and the extrovert tall nobleman from Cologne redoubtable for his brilliant skills as a swordsman [1].

Both derived academic benefit from the discovery, but it took more time for Minkowski to be nominated in a university – this occurred only in 1906 in the tiny University of Greifswald, before he worked as head of department in a Catholic hospital in Cologne. But von Mering died young and Minkowski continued to carry out research in diabetes. His most productive time came when he worked in Breslau (today's Wroclaw) where he moved in 1909. Minkowski was repeatedly nominated for the Nobel Price and chaired the first German Insulin committee.

Whereas Minkowski is commemorated by academic societies (the European Association for the Study of Diabetes awards the Minkowski Prize) the memory of Freiherr Josef von Mering has been relatively neglected, and he misses all the postmortem honours Minkowski received: no academic prize – no fellowship – no keynote lecture – no street - no monument – no postage stamp. Minkowski’s head of department Bernhard Naunyn somehow managed to downgrade von Mering's contribution to the discovery of pancreatic diabetes in his autobiography by pointing out that Minkowski performed the surgery - his first pancreatectomy in a dog - and von Mering only assisted. But Naunyn’s view may be biased, given that Minkowski was one of his preferred collaborators [13] and that Naunyn – a leading figure in diabetology in Germany at the time - claimed some of the success for himself. He mentions in the first edition of his textbook, “Der Diabetes melitus(sic)”, that “the work following this great discovery was mainly carried out by Minkowski, and several others involved will have to be commemorated”. Undoubtedly he was talking about himself ([14], page 87).

The second major discovery of von Mering was barbitone (Veronal or Barbital) in 1902 together with chemist Emil Fischer. Fischer was an old friend of his from their student days in Bonn. Fischer received the Nobel prize in 1902, mainly for his work on sugars. Together with Emil Fischer he published the discovery of Veronal (Barbital) in 1903 in a paper entitled “About a new class of hypnotics” [15]. This described the discovery of barbiturates, a new Figure 2: Veronal: discovered by Josef von Mering and Emil Fischer in 1902
Figure 2: Veronal: discovered by Josef von Mering and Emil Fischer in 1902
class of sedative drugs used for insomnia, epilepsy, anxiety, and for anaesthesia. They observed that barbital (diethyl-barbituric acid) had sedative properties in humans. The drug was named Veronal – probably because von Mering and Fischer were passing Verona by train when the name was discussed [1] (figure 2). It was the first commercially available barbiturate and had an overwhelming commercial success until 1950s. But it also became a common drug with which to commit suicide – the very long list of suicides with Veronal includes Stefan Zweig and his wife.

Figure 3: Rüger’s Power Cacao Chocolate, “following the advice of Prof. Freiherr von Mering”
Figure 3: Rüger’s Power Cacao Chocolate, “following the advice of Prof. Freiherr von Mering”
Several nutritional products were produced following the advice of von Mering, a chocolate for children (figure 3), special food for people with stomach disease and Lipantin – a product to replace cod liver oil. He was one of the first physicians to discover the scientific and (sometimes) financial advantages of collaboration with industry.

Another lesser known discovery of von Mering was his contribution to the clinical use of Paracetamol – he published the first clinical study with this drug, which is nowadays included in the WHO list of “essential drugs” [16].

Freiherr Josef von Mering was an outstanding “bench to bedside” scientist with a broad interest in many fields. His importance in medical history is truly underestimated. Since he could be called the “grandfather of SGLT inhibitors” for to his work on Phlorozin [9] his name may become better known in the future.

References

  1. ^ Lippold, Christa, born von Mering (2007) Ein Professor von Mering in Halle, in: EKKEHARD, Familien- und regionalgeschichtliche Forschungen, Hallische Familienforscher "EKKEHARD" e.V., Neue Folge 14, Heft 2

  2. ^ Von Mering F E (1833-1861) Geschichte der Burgen, Rittergüter, Abteien und Klöster in den Rheinlanden und den Provinzen Jülich, Cleve, Berg und Westfalen, 12 Volumes

  3. ^ Von Mering F E (1844) Autobiography: dedicated to my dear wife and all good friends, Cologne, cited from (1)

  4. ^ Gärtner R (1968) Das Leben und Wirken des Hallenser Klinikers Friedrich Julius Freiherr von Mering. Medical Thesis, University of Halle

  5. ^ Von Mering J (1901) Lehrbuch der Inneren Medizin. Jena, 1st edition, Verlag Gustav Fischer

  6. ^ Krehl L (1929) Von Merings Lehrbuch der Inneren Medizin. Jena Verlag Gustav Fischer 16th Edition

  7. ^ Schmidt A: Josef Freiherr von Mering (1908) Deutsche Medizinische Wochenschrift 34:206

  8. ^ Winternitz H, Zuntz N (1908) Josef Freiherr von Mering Münchner Medizinische Wochenschrift 55:400

  9. ^ Von Mering J (1886) Über künstlichen Diabetes; Centralblatt für die medizinische Wissenschaft 22:31

  10. ^ Excerpt from a letter written by Oskar Minkowski describing his discovery and O. Minkowski (1929) Münchner Medizinische Wochenschrift 79:311-315

  11. ^ Von Mering J, Minkowski O (1889) Diabetes nach Pankreasextirpation; Centralblatt für Klinische Medizin 23:394

  12. ^ Von Mering J, Minkowski O (1890) Diabetes mellitus nach Pankreasexstirpation. Arch. f. exp. Path. u. Pharm. 26:371–387

  13. ^ Naunyn B (1925) Erinnerungen, Gedanken und Meinungen; J.F. Bergmann Verlag München p. 475

  14. ^ Naunyn B (1889) Der Diabetes melitus (sic!); Alfred Hölder, Wien. P 87

  15. ^ E. Fischer J. von Mering (1903) Über eine neue Klasse von Schlafmitteln. In: Therapie der Gegenwart. 44:97–101

  16. ^ Von Mering J. (1893) Beiträge zur Kenntnis der Antipyretica. Therapeutische Monatsschrift 7:577–587

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