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The name Paul Langerhans will, forever, be associated with two discoveries that he made: the islets of Langerhans in the pancreas and the cells he discovered in the skin. Working in the laboratory of Prof. Rudolf Virchow, in Berlin, Langerhans characterized for the first time the islets of Langerhans in his 1869 medical thesis. Yet, what most diabetologists tend to ignore, is the fact that he was also the first to describe the “dendritic cells” in the suprabasal region of the epidermis. These cells were first identified and reported by Paul Langerhans in 1896. These Langerhans cells in the skin received much attention in allergy research from 1973 onwards. They play an important role in the pathophysiology of immune reactions, not only in the skin. Thus, Paul Langerhans, during his last year of undergraduate studies in the laboratory of Rudolf Virchow in Berlin, made his name immortal in medical history not once, but twice.

© 2020 S. Karger AG, Basel

Prof. Björn M. Hausen, who was a renowned expert in allergology and published an outstanding biography on Paul Langerhans, died in 2017. This article is based upon his work with the permission of his widow.

Paul Wilhelm Heinrich Langerhans was born in Berlin on July 25, 1847. His father, Dr. med. Paul August Herrmann Langerhans (1820–1909), had been practicing medicine in Berlin since 1842. His mother was Anna Louise Caroline Langerhans, born Keibel (1824–1853). Dr. H. Morrison, who researched Langerhans for an introductory essay [1], believed her to be a cousin of the Histologist Franz Keibel (1861–1929). Björn Hausen discovered that their great-grandfathers were brothers. The Langerhans family lived in Berlin at Köpenickerstrasse 111 in the eastern part of the city – the house was destroyed in World War II and was subsequently replaced by an East German prefabricated building.

On October 5, 1853, Anna Langerhans died of tuberculosis. She was 29 years old at the time of her passing and Paul was just 6 years old. In later years, despite the discoveries of Robert Koch proving otherwise, Paul continued to believe that tuberculosis was a hereditary condition because himself, his mother, and his brother each became victims of this bacterial disease.

Fig. 1. Watercolor by Paul Langerhans: The island of Usedom, where the Langerhans family spent the holidays, about 1863 [9].

His father remarried 2 years after Anna’s passing, and luckily the stepmother was loved by the children. Langerhans states, in his curriculum vitae, which was written for his final examination in 1865, that his stepmother virtually replaced his real mother and the family life was happy and cheerful. His father, Paul Langerhans senior, was the son of a wealthy architect and attended the Grey Monastery (Graues Kloster), one of the most prestigious gymnasiums (the equivalent of a grammar school) in Prussia. Otto von Bismarck, the first chancellor of united Germany, attended this school at the same time. He studied medicine and the title of his dissertation was De Amputationem Artuum. He graduated in both medicine and surgery as, in 1842, the two topics still required separate specific graduations. His private praxis in Berlin was running very well. Langerhans senior participated actively in the revolution of 1848 – he was fighting on the barricades in Berlin for democracy and against the troops of the Prussian king. Together with the famous Pathologist Rudolf Virchow, in 1861 he founded the liberal party (Deutsche Fortschrittspartei). Rudolf Virchow was his best personal friend. Over the years Langerhans senior became more and more involved in politics and abandoned his work as a medical doctor. He was an elected member of the city council of Berlin and of the parliament in Prussia, and he was elected to the Reichstag from 1891 to 1903. He became honorary citizen of Berlin in 1900 and died in 1909 at the age of 89 years. As a member of the liberal party he was like Rudolf Virchow, continuously fighting against the conservative political actions of Bismarck and his successors.

Paul Langerhans often spent his holidays in Heringsdorf on the island of Usedom, and his watercolor with a view of the beach proves his talent as a painter (Fig. 1). He went to the same renowned gymnasium as his father, and had already made his decision to study medicine when he was 14 years of age. Rudolf Virchow gave advice on how he should organize his medical studies. For the preclinical studies he proposed the University of Jena. This university was at the time the leading place for critical modern research. The “German Darwin” Ernst Haeckel, was teaching there – attacked unabashedly by conservatives and particularly the Catholic Church. With his direction already planned, 2 weeks after his excellent baccalaureate, Paul Langerhans registered at the University of Jena (Fig. 2). He was the first student to register for the recently established course on human histology, by Ernst Haeckel (Fig. 3).

Fig. 2. Paul Langerhans at the age of 19 years, 1869 [9].

Fig. 3. Langerhans was the first to register for Prof. Haeckel’s lecture at the University of Jena [9].

Langerhans stayed 3 semesters in Jena and witnessed Haeckel speaking on “Darwin’s theory about the development of species.” This lecture was later followed by a nationwide, very controversial, discussion. Another lecture Langerhans attended was on the “natural history of Coelenterata.” he would subsequently go on to study the latter topic in Madeira.

For his clinical studies Langerhans moved home to Berlin, one of his teachers was Rudolf Virchow. Finally, in the summer of 1867, Langerhans began with the work on his thesis about the histology of the pancreas – a proposal of Rudolf Virchow. However, after 3 months he stopped working on this project and set another priority. The reason for this was an award by the University for the best histological research on the nerves of the skin. He submitted his work entitled: “Fiant observations microscopicae de corpusculorum tactus alterationibus pathologicis, praesertim in morbis cutis et systematis nervosa.”

On May 14, 1867, the prize committee, consisting of three professors (one of them being Rudolf Virchow) awarded the prize to Paul Langerhans. The award, a golden coin, had a value of 25 Dukaten, which represented slightly more than 80 g of 999 gold – even today, this could still be considered as a convincing motivation for students to work on a project. We will brush aside what happened to this golden coin.

A year later, Langerhans published his corresponding work “On the Nerves of the Human Skin” in Virchow’s archive [2] (Fig. 4). He believed to have described in this paper a new type of epidermal nerve cells. Using the gold chloride technique, invented by Julius Cohnheim, he detailed dendritic non-pigmentary cells in the epidermis and regarded these cells as “intraepidermal receptors for extra cutaneous signals of the nervous system.”

These cells were an enigma for dermatology for over a century before researchers recognized their immunological function. Today we know that the Langerhans cells fulfil a receptor-like function, but in a very different way than Langerhans originally thought. It was Sigmund Merkel, in 1875, who was the first to name the dendritic cells in the skin after Langerhans. However, for decades there was not much interest in these cells until the work of Inga Silberberg in the group of R.L. Baer in New York, who discovered their importance in the mechanism of allergic reactions.

Fig. 4. From the publication “About the Nerves of the Skin,” 1868 [2, 9].

Since then, a slew of publications has tried to unveil the functions of these cells which migrate throughout the body. Generally, dendritic cells take care of the capture, uptake, and processing of antigens. They play an important role in the process of infection, for example, with HIV or HPV viruses. Langerhans cells also contain langerin – a protein of importance in immune mechanisms. Langerin, on mucosal Langerhans cells of the human genital epithelium, binds to HIV-1 and subsequently internalizes it into Birbeck granules to be degraded.

After this intermission, Paul returned to work on his thesis. He described nine types of cells in the pancreas. The ninth group of cells he labeled as being small, quite homogenous cells which are located together in small groups (Zellhäufchen). At the end of the short description of these cells he stated that he has no clue about their function (Fig. 5). Initially it had been his intention to continue his work with experiments on the function of the pancreas but he found that it was technically impossible for him to study the function of the pancreas without being able to keep rabbits he was using alive, even for a while. Only 20 years later, Minkowski and von Mering managed to perform a pancreatectomy in dogs while also being able to keep them alive. It is, by the way, astonishing that nobody before Langerhans had the idea to inject vermilion or any other color into the aorta before studying the histology of the pancreas.

After his doctorate, Langerhans had no further dealings with the pancreas and the cell clusters he described went unnoticed. That was, of course, until Prof. Édouard Laguesse, in Lille, became aware of the peculiar islands in the pancreas again. It is, in itself, curious that Laguesse even had knowledge of Langerhans’ doctoral thesis. Only 150 copies were ever printed and the vast majority of them were to be found in German Universities. Today, only very few copies have survived; Björn Hausen found only 8 original copies worldwide.

At a meeting of the biological society in Paris in 1893, Laguesse reported on the peculiar structures in the pancreas and called them ilôts de Langerhans [1, 3]. Laguesse had already previously expressed the hypothesis that there were two forms of diabetes and that one of these had something to do with the pancreas.

It is very surprising that the doctoral thesis does not contain a single drawing – in contrast to the publication on the Langerhans cells of the skin. Paul was by no means lacking a talent for drawing. He was a very capable draughtsman and painter, a talent he shared with another renowned discoverer in diabetology, Frederik Banting.

However, Paul’s “godfather” Rudolf Virchow must not have been entirely satisfied with the thesis. The grade given for this doctoral thesis was moderate, although the work is dedicated to him “in reverence and gratitude.” Also, in his rigorosum Paul receives the worst grade of the three evaluating professors from Prof. Virchow – sufficient.

On March 18 Paul Langerhans received his certificate of passing the medical examination. Initially he continued to work in Prof. Virchow’s laboratory together with his lifelong best friend Friedrich Albin Hoffmann. Hoffmann wrote in his autobiography about Langerhans: “His winning nature and his great diligence made him very pleasant to me. We had lunch together at Töpfer’s hotel (just in front of the Charité hospital in Karlsr. 7), discussed what we were working on and what interesting sections Virchow had. Soon he took me with him to his parents’ house, where his father, his stepmother and his sister were most kind to me. I soon felt very comfortable in this entourage.” We also know from Hoffmann that Paul did not belong to any student fraternity, which was extremely unusual in German academic circles in the 19th century where it was practically obligatory.

Fig. 5. The thesis of Paul Langerhans with the description of the islets, 1869 [10].

Research trips to far-flung places were very popular with academicians at the time. Flora, fauna, and all manner of ethnological pieces were brought to Europe, researched, and exhibited. Langerhans also partook in such travels, probably to follow in the footsteps of Haeckel and Virchow. Fortunately for him he had a wealthy sponsor, namely his beloved grandmother, and, on February 18, 1870, he too set off on a voyage of research, to the Near East. Beforehand, in preparation for his upcoming journey, Langerhans wrote to Prof. Ernst Haeckel in Jena:

Highly respected gentleman!

On February 18 I intend to accompany the geographer Professor Kiepert on a five-month journey to Lower Egypt, Palestine, Syria and Istanbul. I would be very pleased if this itinerary and my, despite your efforts in this subject, only rudimentary knowledge combined with good will quantum satis were sufficient to carry out any zoological or similar order from you and I therefore ask you to write to me, if you have such an order.

With warm greetings from my father,

Your grateful pupil,

Paul Langerhans.

Prof. Kiepert and Langerhans went by train to Trieste and from there, by ship, to Egypt. At a market in Cairo, Langerhans bought a selection of fish for Haeckel’s collection. They continued their journey by sea to Jaffa (Tel Aviv did not exist at that time) and onwards over land to Jerusalem.

From Kiepert’s report and sketchbook we learn in more details about this trip – they rode to Jericho, the Dead Sea, Amman, and Tiberias. Kiepert fell ill with typhoid in Jerusalem where Langerhans collected skeletal bones and became interested in leprosy. He wrote about his experiences to Virchow, who had the letter about leprosy printed in his archive [4]. The research about the different ethnic groups in Palestine was published in 1873 [5].

In June Kiepert and Langerhans continued their journey via Cyprus and Rhodes to Smyrna and then on to Constantinople. To his great regret, Langerhans’ clothes, revolver, and most of the skulls, which had been collected for Haeckel, together with other biological objects, were stolen there. But even worse was news which reached them whilst returning to Germany by ship on the Danube. As a result of the Ems Dispatch, a statement issued by Bismarck, France declared war on Prussia. The journey to Berlin now became hurried. Langerhans was called up to serve in the army of Prussia and for 3 months he worked in a military hospital in Berlin. In July, Langerhans was called to the front in France as a military physician. We know from the letters of his friend Hoffmann, how terrible the experiences of a military doctor in this war were. Although there was already the possibility of anesthesia, asepsis was not clinical practice and the infections which followed surgical procedures were catastrophic.

In May 1871, Langerhans returned to Berlin but failed to find employment. Coincidentally, at this time, an opportunity arose to accompany Prof. Karl von Kupffer, the first describer of Kupffer’s cells in the liver, on a research trip to Norway. Paul accompanied him and the two fished, for a whole month, at Arendal, located near to Oslo, to find Ascidians.

After this expedition came to an end, Paul made his way to the “Mecca” of physiology, to Prof. Carl Ludwig at the University of Leipzig. As a side-note, some years later, a young Scot named John James Rickard Macleod also trained there in physiological research. Macleod later received the Nobel Prize for the application of the hormone that is formed in the islands named after Langerhans.

Langerhans stayed in Leipzig for only a few weeks. In Freiburg, a position in pathology became available. However, this position required a habilitation. Langerhans hurriedly completed this but it contained a mere 16 pages. Virchow stepped in and wrote some letters to support the nomination. Langerhans reciprocally sent a letter of thanks to Rudolf Virchow:

Dear Uncle

You have become a prosector in Freiburg. That is, in fact I am, but it is as clear as day that I am as innocent of it as an encephalitic newborn, because without your letter Ludwig would never have written to Ecker and I would never have got this position. So allow me to assure you explicitly that I am perfectly clear about how great the disproportion between your goodness and my own merit is again here.

Your grateful pupil,

Paul Langerhans

Freiburg im Breisgau 23.10.1871

In Freiburg, Langerhans lectured on osteology and led the microscopic course. He was no longer interested in research on the pancreas – but his friend Albin Hofmann was still working on this topic in the laboratory of Prof. Frerichs (the teacher of Bernhard Naunyn) in Berlin. When Hofmann was appointed to a chair at Dorpat (Tartu in Estonian), his successor was a young Baron, born in Cologne, named Josef von Mering. Von Mering, together with Oskar Minkowski, later discovered pancreatic diabetes while at the University of Strasbourg.

At the end of 1873, Paul tried to become a professor. The dean of the faculty, Prof. Kussmaul (well-known because of his description of “Kussmaul breathing” in diabetic ketoacidosis) was in support of this appointment, but the ministry of the Kingdom of Baden refused due to him not having lectured for a sufficient time.

During his time in Freiburg, Langerhans also travelled regularly to Sweden and Norway and, in the summer of 1873, together with Albin Hoffmann, to Italy. Finally, a few days after his 27th birthday, Paul Langerhans was appointed Professor Extraordinarius in Freiburg. To celebrate this, he and his friend Albin Hoffmann, who had travelled from Dorpat, journeyed together to Switzerland – the two did not know that this would be their last happy trip together. On September 11, 1874, Prof. Nothnagel diagnosed Paul Langerhans with pulmonary tuberculosis. Nothnagel was a good friend of Langerhans in Freiburg. Later, when Nothnagel held the chair in Jena, Langerhans travelled to Jena to continue to consult him.

After having received the news about Paul’s diagnosis Hoffmann wrote to him from Estonia, dated September 20, 1872:

My dear friend,

You can imagine how I was touched by your letter. You must absolutely not stay north of the Alps until late October. It would be a pleasure for me to visit you in Cairo. We may give up hopes and plans, but we are young enough to start new ones, and the friendships will continue. I am convinced that everywhere in the world you can find interesting work, you should not consider two years of life in Germany as valid as 20 years in Egypt.

In the case of tuberculosis, the most important medical advice at the time was to escape the cold winter in the north. Langerhans took his friend’s suggestions seriously. He went to Naples, allegedly to work for one semester at the Zoological Institute there. However, he struggled to work and spent the winter in Capri with fever attacks. He had to extend his vacation several times and finally decided to move on to Madeira.

Madeira, the island of eternal spring, was considered, in the 19th century, to have an ideal climate for people with tuberculosis. Many wealthy German and English tuberculosis patients were sent there. It was once again his rich grandmother who financed Langerhans’ travel to and stay in Madeira. There have never been any controlled investigations as to whether Madeira really had a positive influence on the course of the disease. But at least the sick member of the family was far away and did not cough blood any more at home! Later the “Zauberberg hospitals” in the Alps came into fashion as an exile of people with tuberculosis. In October 1875, Langerhans arrived in Funchal, Madeira. He did not know anyone there and lived, bedridden, in a hotel where he continued to suffer from fever attacks. After a few months though he felt better and rented an apartment. He even began zoological research again. Through Rudolf Virchow he managed to receive a scholarship of 2,000 Reichsmarks from the Berlin Academy.

In 1878 Langerhans travelled to Berlin. For Prof. Ehlers he brought along a collection of annelids (also known as ringed worms) and prepared publications about them. He also visited Prof. Nothnagel in Jena to ask for his medical advice. Langerhans finally quit his employment in Freiburg and travelled from Berlin to Tenerife, but returned to Madeira in July 1879. He continued his research on annelids – some of them today are still named after Langerhans [6].

Fig. 6. Handbook on Madeira by Paul Langerhans, 1885 [7, 9].

In the meantime, his grandmother passed away and he had to earn his own living. As a result, Langerhans opened a private practice, specifically for German tuberculosis patients. One of his patients was the wealthy Alfred Ebarth, who hoped to improve his tuberculosis with his wife, Margarethe, and his daughter on Madeira.

The Ebarth family arrived in Funchal in October 1879. Langerhans treated the tuberculosis-stricken Alfred for many years. He also treated the Ebarth’s young son, who died of diphtheria on Madeira at the age of 1.5 years. Alfred Ebarth died in April 1883.

Paul must have been in love with the wife of his patient for some time, even prior to Alfred’s death. Margarethe promised to marry Paul provided he respected a waiting period of 2 years after the passing of her husband. In January 1885, she informed her 8-year-old daughter Frieda that she had promised the “uncle professor” to become his wife. Langerhans married a very wealthy lady. Her father, Gustav Jordan, was owner of a manor 50 km north of Berlin in Kuhhorst near Nauen. Her deceased husband owned a manor near Stettin and an important paper factory in Spechthausen, Brandenburg, which had been built at the suggestion of Frederick the Great. In 1799 the factory began producing banknotes and from 1874 to 1945 this paper mill produced the paper for almost all banknotes produced by the German Reich. The paper for the counterfeit pound bills dropped by the Nazis over London during the “Operation Bernhard” during World War II to destabilize the British currency also came from this factory. From 1882, all 100 Reichsmark notes were printed in the factory for the entire German Reich – the family of the wife of Paul Langerhans not only earned a lot of money, they literally printed it.

On June 13, 1885, the couple married in Berlin – a great wedding celebration for two distinguished families. It was probably the happiest time of his life. First the two undertook a honeymoon trip through Germany. Then, in Madeira they rented a spacious villa, employed a caretaker couple, a governess for the daughter, and other house staff. In the same year as his wedding, Langerhans also published a manual for Madeira (Fig. 6). It contained maps of the island and the capital Funchal. The history, flora, and fauna of the autonomous Portuguese region are described in detail. The manual also contained many hints for tuberculosis patients as well as a complete list of all 93 quintas which were offered for rent on the island at the time. Even the Merian booklet, published in 1969, mentions that there is no better book on Madeira as the one written by Langerhans [7].

Fig. 7. Paul and Margarethe Langerhans and Frieda Ebart in Funchal, 1886 [9].

Fig. 8. The Quinta Lambert in Funchal, the last home of the Langerhans family [9].

In 1886 Paul’s state of health deteriorated. Together, he and Margarethe decided to move from their house situated in the middle of the city to the seaside (Fig. 7). They chose the most beautiful villa in Funchal: the Quinta Lambert in the Rua da Imperatriz Amalia (Fig. 8). It was enthroned in a large park above the harbor. With an outlandish annual rent of 400 pounds it was the most expensive property on the whole island. Although initially only planned as a summer residence, it was so beautiful that the family decided to move there permanently from their city apartment, bringing with them their magnificent Bechstein piano. The Quinta Lambert (also Quinta das Angustias) was replaced in 1970 by a new building which became the official residence of the regional government of Madeira in 1984. The beautiful park is a tourist attraction.

Fig. 9. The English cemetery in Funchal with the tomb of Prof. Paul Langerhans (photo Dr. V. Jörgens).

Unfortunately, the family’s luck in the Villa Lambert was only temporary. Although Langerhans enjoyed the visit of his friend Prof. Albin Hoffmann, who had meanwhile accepted a call to the chair in Leipzig, his health soon declined and tuberculosis began to affect his larynx and the kidneys.

On his last trip to Germany, everyone was aware that it was a farewell. After his return to Madeira he suffered from unbearable pain, and at least every 12 h he injected morphine. He gave up his practice. On July 20, 1887, Prof. Paul Langerhans died in the Villa Lambert – 5 days before his 41st birthday. Langerhans had already chosen his grave site, the English cemetery in Funchal (Fig. 9). In his handbook about Madeira he wrote about this cemetery as being a true cemetery, “lost in the world and quiet, in which it must rest well.” Paul Langerhans chose the inscription for his marble gravestone himself: “He also did not want to live, nor see the light of the shining sun” (Fig. 10). It is a quote from the Lament of Menelaus in the fourth song of the Odyssey.

Fig. 10. The plate on the tomb of Prof. Paul Langerhans (photo Dr. V. Jörgens).

It was not until 1973 that the grave was rediscovered, and in 1975 the German diabetologist Dr. G. Wolff suggested that the German Diabetes Society place a commemorative plaque there. Frightened by two plane accidents, no German diabetologist dared to make the trip to Madeira. So, the plaque travelled by mail to Madeira and was installed by the German consul. In 1978, the German Diabetes Society decided to award a Paul Langerhans medal annually, with the first recipient being Prof. E.R. Froesch from Zurich.

In 1988, dermatologists also commemorated the eponym of the Langerhans cells. On March 18 that year, a commemorative plaque of the German Dermatological Society was placed on the grave. A Langerhans bronze bust, which is located in front of Virchow’s institute in the Charité in Berlin, was donated by EASD in 2012 (Fig. 11).

Fig. 11. Langerhans bronze bust in front of Prof. Virchow’s institute in the Charité in Berlin, donated by EASD 2012 (photo Dr. V. Jörgens).

The Portuguese Diabetes Society frequently commemorates Paul Langerhans, especially at conferences in Madeira, and recently decided to publish the biography by Prof. Björn M. Hausen in Portuguese [8]. The original edition is out of print [9].