Medical and Pediatric Oncology 22: 129-132 (1994)

Paul Langerhans Jr. (1847-1888): A Short Life, Yet Two Eponymic Legacies

R. Maarten Egeler, MD, Arty R. Zantinga, MA, and Max J. Coppes, MD, PhD

Before visiting the Portuguese island of Madeira in the Atlantic Ocean, north of the Spanish Canary islands, one might want to become familiar with some of the customs, wines, agriculture, history, botany, zoology, and meteo- rology of this island. The over 100-year-old “Handbuch fur Madeira” by Dr. Paul Langerhans [ 1 J seems particu- larly suitable for physicians, as this unknown work of yet another giant in medicine enables us to discover this beautiful island in the Atlantic Ocean. Dr. Langerhans’ guide is a translation of a handbook written by James Yate Johnson [2], but it contains several new chapters and more accurate maps 141. For example, the chapter on meteorology indicates the temperature every morning at nine o’clock between 1875 and 1883 recorded by Langer- ham himself 131. Langerhans’ decision to move to Ma- deira was caused by his contracting tuberculosis, which was diagnosed weeks following his appointment as full professor of pathology. Needless to say, the disease would change his life dramatically.

Paul Wilhelm Heinrich Langerhans was born in Berlin on July 25, 1847 as the first son of Dr. Paul August Herrmann Langerhans, a well-known physician active in Berlin’s political affairs, and Anna Luise Caroline Langerhans, nee Keibel [5,6]. Two girls, Elise and Ger- trud, were born of this marriage before Paul’s mother died of tuberculosis in 1853. After Paul Langerhans Sr. remarried, to Luke Clara Sophie Komitsch, two more sons were born (Fig. 1). The oldest, Richard Friedrich, practiced medicine in Berlin and advanced to the position of Public Health Officer, while the youngest son, Ernst Robert, became Virchow’s assistant for a long time and in 1896 became a professor of pathology at the University of Berlin [5].

At the age of 17, Paul Langerhans Jr. completed high school at the Gymnasium zum Grauen Kloster in Berlin, the most famous school in Germany which was destroyed in a bombing raid in 1945 and has not been rebuilt [5]. In 1865, only two weeks after his graduation, he left for Jena, Germany, to study medicine for three semesters under the famous German scientist and zoologist, Ernst Haeckel 171. He continued his medical studies at the University of Berlin and became a pupil of Cohnheim and Virchow. The latter was a close and personal friend of his father and one of the godparents of his half brother Rich- ard [7]. Langerhans made his first important contribution to medicine while still an undergraduate student. Using 0 1994 Wiley-Liss, Inc.

Cohnheim’s gold chloride staining technique he de- scribed a novel nonpigmentary dendritic cell in the epi- dermis. This work resulted in a paper entitled “Ueber die Nerven der menschlichen Haut” (On the Nerves of the Human Skin) [8]. He initially regarded these cells as intraepidermal receptors for extracutaneous signals of the nervous system, but corrected this interpretation in 1882. In a short communication, he acknowledged his errone- ous assumption: “However I am now convinced . . . that my cells are in no way essential for nerve endings” 191. Today we know that these cells are derived from promonocytes in the bone marrow. They represent the most peripheral outpost of our immune system, playing a role in delayed hypersensitivity 1101. These unique his- tiocytes are now eponymously referred to as Langerhans cells 1113 and the clonal proliferation of these cells is known as Langerhans cell histiocytosis (LCH) [ 12,131.

In 1867, just having started the experimental work for his thesis, Langerhans abandoned this project tempo- rarily to compete, successfully, for the University of Ber- lin Faculty of Medicine prize. He won the competition with a study of the tactile corpuscles in diseases of the skin and central nervous system [ 141. He then returned to his study on the fine structure of the pancreas under the supervision of Dr. Rudolf Virchow in the Institute of Pathology. His thesis, “Beitrage zur mikroskopischen Anatomie der Bauchspeicheldruse” (Contributions to the Microscopic Anatomy of the Pancreas), was defended successfully at the Friedrich Wilhelms University in Ber- lin. The histologic knowledge of this gland had been limited before then, especially compared to the excep- tional fruitful studies of the physiology of the pancreas in the two decades preceding Langerhans’ study [ 151. In his

From the Department of Pediatric Hematology-Oncology, University Hospital of Minnesota, Minneapolis, Minnesota (R.M.E.) and Depart- ment of Cancer Biology, The Cleveland Clinic Foundation, Cleveland, Ohio (A.R.Z., M. J.C.).

Received November 30, 1992; accepted November 30, 1992.

Address reprint requests to Dr. Max J. Coppes, Division of HematologylOncology, Alberta Children’s Hospital, 1820 Richmond Road SW, Calgary, AB, CanadaT2T 5C7.

Dr. R. Maarten Egeler is now at Section Hematology/Oncology, So- phia Children’s Hospital, Rotterdam, The Netherlands.

130 Egeler et al.

Fig. 1. The four Langerhans physicians photographed in Berlin, Sep- tember 10, 1884. Seated is Paul Langerhans Sr., standing left Richard, middle Paul Jr., and right Robert (courtesy Prof. Bjom M. Hausen, Hamburg, Germany).

thesis, Langerhans described nine different types of cells in the rabbit pancreas, two of which were really new: the spindle-shaped centroacinar glandular cells which secrete the pancreatic digestive enzymes, and scattered amongst them another cell type: “This cell is a small irregular polygonal structure. . . . Its cytoplasm is perfectly bril- liant and free of granules, its nucleus distinct, round, and of moderate size. . . . Its diameter is between 0.0096 0.012 mm in diameter. . . . These cells lie together gen- erally in considerable numbers” [16]. He suggested no name or possible function for these group of cells (Langerhans never used the term “islet”): “If the answer that I have given as to the nature of the centro-acinar cells was insufficient, the same is unfortunately true of these cells” [ 161. A quarter century later, the French histophys- iologist Edouard Laguesse found similar cells in the hu- man pancreas. After identifying these “groups of cells” with those described by Langerhans in 1869, Dr. Laguesse suggested the use of “ilots (islets) de Langer- hans” [17]. Dr. Laguesse was the first person to suggest that the islets of Langerhans were the site of internal

secretion, a hypothesis that would be confirmed by von Mehring and Minkowski [18,19] and Dr. Emmanuel He- don. The name insulin was introduced by Dr. De Meyer in 1909 [20].

Following his thesis defense on February 18, 1869, Langerhans remained another year in Virchow’s labora- tory studying the intravital distribution of cinnabar (red mercuric sulfide) injected intravenously in rabbits and guinea pigs. He performed this work in collaboration with Friedrich A. Hoffman, who later became his best friend. Hoffman and Langerhans demonstrated that cin- nabar was taken up by white blood corpuscles but never by the red [21]. Their study was one of the pioneering investigations that later led to Aschoff‘s concept of the reticuloendothelial system [22]. Subsequently, probably stemming from an interest to see more of the world and most likely affected by the strong anthropological interest of his friend and mentor Virchow, Langerhans joined an expedition of geographers to Syria, Palestine, and west- em Jordan in 1870 as a team physician [23]. His forced stay in Jerusalem when one of the members got typhoid fever enabled Langerhans to document the various mani- festations of leprosy in the local population [24], and to study the anatomy and anthropology of the inhabitants of this area [25-271.

In September 1870 after the outbreak of the Franco- Prussian War, Langerhans served his year of military duty as a physician in the army, partly in France [23]. In 187 1, at the end of the war, he worked for some time in Leipzig with the physiologist Carl Ludwig [7,23]. Pre- senting the data collected in Ludwig’s laboratory as his “Habilitationsschrift”’ he was made assistant professor in Pathology at the University of Freiburg in October of that same year (Fig. 2). Despite a heavy teaching load, Langerhans remained productive and subsequently pub- lished on myocardial morphology [28], and on the struc- ture of the spongiosa of the spine and adventitious glands of the sexual organs [29].

Langerhans went on frequent trips to Sweden and Nor- way, exhibiting an interest in the anatomy of marine animals. This was a research area with which he had become involved in August 1871, during a trip to Aren- dal, Norway. His companion was the well-known anato- mist Karl Kupffer (later Von Kupffer). This interest re- sulted in several papers [30-321 while his investigation on the lamprey resulted in the publication of a complete book [33].

Langerhans became Professor Extraordinarius (a full professorship) on August 4, 1874, a week after he had turned 27. Unfortunately a few weeks later, he was found to have renal tuberculosis [23] and forced to request a 6-

‘A second thesis required in Germany to become a lecturer/professor; comparable to Ph.D.

Paul Langerhans Jr. 131

edged by the senate of the University on July 22, 1878. Langerhans returned south in the fall of that same year and spent a short time on Tenerife, the largest of the Canary islands, just south of Madeira, where he wrote several papers on the worm fauna of Madeira [36-381. The last paper in this series was published in 1884 1391. His contributions were numerous and of excellent quality 1401, and resulted in several polychaete worms bearing the name of Langerhans 1411 (for example Verriliopsis lungerhansi a name introduced in 1909 by the distin- guished French zoologist Pierre Louis Andr6 Favel 131).

The final years of his life were full ones and mostly spent on Madeira, although he visited Europe on several occasions. The improvement of his own health enabled him to practice medicine on Madeira. He took care of a growing number of German and British patients who immigrated to this island for health reasons, usually suf- fering from tuberculosis [42]. Among the Germans sent to Madeira during the cold European winters were Alfred Ebart and his wife Luke Emilie Margarethe, nCe Jordan. Langerhans had specifically been instructed by his father to take care of the Ebarts [42], which he did. Two years after the death of Alfred Ebart in 1883, Paul Langerhans Jr. married Margarethe on June 13, 1885 in Berlin.

It is not surprising that Langerhans also became inter- ested in tuberculosis. He himself was affected, his mother had died of it when he had been six years of age, and finally, his half brother Robert also contracted the disease. Paul Langerhans Jr. published two manuscripts on tuberculosis, one dealing with the etiology of phthisis, and the second on the distribution of the tubercles in the human body [43,44]. The first paper was published in 1884 and discusses hereditary disposition as an important etiologic factor [43]. He recognized the limitation of his collected material, but nonetheless concluded that the bacillus alone was not sufficient to account for phthisis; hence a hereditary predisposition was invoked. Langer- hans was an outstanding and critical observer and re- searcher. Moreover, he had received an excellent scien- tific and medical training. Therefore it is not surprising that he had meticulously carried a model analysis of the occurrence of phthisis in Madeira using unassailable data. He compared these recordings with those of a pop- ulation in Germany, but unfortunately drew the wrong conclusion. He was convinced that phthisis and miliary tuberculosis were two separate disease entities of the same infective nature. What is perhaps surprising is not his notion that phthisis had a hereditary component (that view was shared by many others), but the fact that he did not discuss other possible explanations of his epidemio- logical findings [45]. There the matter rested, for he died soon thereafter on July 20, 1888, five days before his 41st birthday. The cause of death was uremia, due to progres- sive renal degeneration from chronic tuberculosis. He is buried in Funchal, the capital of Madeira.

Fig. 2. of Prof. Bjorn M. Hausen, Hamburg, Germany).

Paul Langerhans as lecturer in Freiburg, July 1872 (courtesy

month leave from the University of Freiburg. Dr. Langer- hans, constantly febrile, spent most of his time on Capri, occasionally visiting the Zoological station in Naples. Despite his illness, he did not stop working on the anat- omy of marine animals [34]. He was forced to apply for an extension of his leave of absence and then returned to Germany in 1875, but was immediately released from his duties at the University “until complete recovery” 1231. He traveled to Madeira in October of that year and he quickly developed a new area of research: the fauna of the Atlantic islands, especially Madeira. His work on marine worms (annelids) was highly successful and resulted in a grant of 2000 gold marks from the Berlin Academy. He even named one of the annelids after his mentor (Acicu- laria virchowii) [35]. He became free of fever for the first time a year after his arrival, but it would not be until the spring of 1878 that he would be able to return to Ger- many. Upon return to Jena, where his friend Hermann Nothnagel acted as his personal physician, he was forced to submit his resignation to the University of Freiburg, when his condition deteriorated so much that he began using morphine [23]. His decision was acknowl-

132 Egeler et al.

Langerhans did not live to rethink his view on the etiology of phthisis, but his correction with regard to the function of the Langerhans cells of the epidermis [9] suggests that he would have been sensitive to new evi- dence as it accumulated in the ensuing years. We may be ready to comfort ourselves with the thought that he, like lesser mortals, could sometimes be wrong, but are we also willing to follow him in admitting our own erroneous views when needed?

A C K N O W L E D G M E N T S

We would like to thank Prof. Dr. Bjorn M. Hausen, Department of Dermatology, University Hospital of Hamburg, Hamburg, Germany, for his helpful review and Adria Laboratories for their financial support.

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