In 1835, Theodor Schwann (bottom right), while working in the laboratory of Johannes Müller (top left), stumbled on a proteolytic enzyme whose properties he characterized and soon thereafter, in 1836, published (right). At the time, they were involved in measuring secretion from the gastric glands (top). Both articles were published sequentially in the same journal; Müller’s work was given precedence. It is of interest that the second reference in Müller’s work on the artificial digestion of proteins is to William Beaumont’s experiments and observations on the gastric juice and physiology of digestion (of 1830). In his studies, Schwann was able to extract a crude preparation of a digestive enzyme from gastric juice, which he demonstrated to have the ability to convert egg-white albumin to peptones in vitro. He named this water-soluble factor pepsin, after the Greek word for digestion. In the course of his studies, both Müller and Schwann noted that no gas evolved during pepsin digestion of food. These findings were thus able to dispel a notion that had been held for 3 centuries: that digestion was a fermentation-like process. The identification of the cell involved in pepsin secretion (top right) would require another half century, whereas the identification of the prolate ellipsoid structure of pepsinogen (the protein precursor of this enzyme), required an additional 100 years. Despite the identification of pepsin and its properties in 1836, neither the role of this factor in gastric pathology (peptic ulceration) nor its extragastric function has been entirely elucidated.

Rudolf Peter Heidenhain (1834-1897) (left) was the eldest of the 22 children of the physician Heinrich Jacob Heidenhain (1808-1868). Born January 29, 1834, in Marienwerder, East Prussia, he died October 13, 1897, in Breslau, Germany, having revolutionized many spheres of physiology. After completion of his secondary education in his native town at the age of 16 years, he began the study of nature on an estate near his home but soon turned to medicine at the University of Königsberg. He subsequently studied at a number of institutions before undertaking in 1867 a systematic investigation of the physiology of glands and of the secretory and absorption process, which remained his chief field of interest for the rest of his life. Heidenhain noted in the stomach two types of cells in the gastric glands and demonstrated that one produced pepsin and the other hydrochloric acid. By the late nineteenth century, investigators were able to differentiate between these chief cells (Hauptzellen, top) and granules from Belegzellen (parietal cells), which possessed canaliculi (bottom).

The obituary notice of John Newport Langley (1852-1925): “The main achievements of Langley’s research work are familiar to the readers of the Journal of Physiology and need little here in the way of description or comment. They stand permanently in their place, not merely as additions here and there to knowledge, but as indispensable stepping stones along which at this point, or that, the progress of knowledge has actually made its way. Each gain he made was a step placed securely and finally, and few indeed of them as the road has become more firmly and widely trodden by others following, have been found wrongly placed. All his chief works keep, and must always keep, their place in the significant history of Animal Physiology. The bare titles of his papers and books deployed there along the years give the plainest testimony to me to his unvarying, unhalting service to science. No single year in all that series, extending well nigh for half a century, from youth to age, appears without its contribution of effective work.” W. M. Fletcher. J Physiol 1926.

The study of pepsinogen and the mechanisms of its secretion was formalized by John Langley (bottom right) of Cambridge. Langley succeeded Sir Michael Foster (1836-1907) as the editor of the Journal of Physiology and trained J. S. Edkins (1863-1940) (top left). His introduction to the gland was by chance, because his initial assignment had been to elucidate the effects of the drug jaborandi (pilocarpine) on the heart. In 1874, this work led him toward the investigation of its effects on secretion. After an initial prelude in the submaxillary gland, he began to address the regulation of secretion in the stomach, a field of endeavor that would take him the better part of 20 years. Using the salamander as a model (bottom left), he undertook histologic studies of the gland structure in activity and rest and checked the interpretation of the appearance of killed and stained cells with that of direct observation of living gland cells. He correlated these findings with the effect of nervous influence on the glands and linked these observations to chemical estimations of the changes in the quality of pepsinogen secretion under different circumstances. In the background are esophageal glands of Rana temporana. This drawing by Langley (September 1879) shows the end tubes of the esophageal gland of a frog fed with a sponge for 35 hours before it was expelled by vomiting. The animal was killed 10 hours thereafter and the tissue placed in absolute alcohol for 24 hours and then dilute carmine for a further 24 hours. These cells show stained nongranular zones and unstained granular zones. This is consistent with contemporary biologic understanding of apical exocytosis of pepsinogen granules. Indeed, these drawings and sketches, although now more than 100 years old, attest to his clear understanding of the nature of zymogen secretion and the general mechanisms of its stimulation. In addition, Langley was so impressed with Heidenhain’s contribution that he was to borrow and translate the former’s terms for the cells in the stomach into English as border (Haupt) and chief (Beleg) cells, respectively, and also coined the term oxyntic to identify the role of the acid-secreting cells. In a series of publications between 1879 and 1882, Langley established the basic morphology and secretory characteristics of the pepsin-forming glands of the stomach and esophagus (center) and was, in addition, able to correct Heidenhain by demonstrating that, contrary to previous reports, gland cells became less granular as secretion took place. Langley demonstrated that granules were stored up during rest and discharged during secretion not only in the pancreas, but also in the stomach and salivary glands and that during this event, a chemical change in the zymogen occurred. To quote: “The fresh gastric glands contain no pepsin; they do however contain a large quantity of pepsinogen; consequently the granules of the chief cells consist wholly or in part of pepsinogen.” Langley’s pupil, Edkins, entered Cambridge University as a scholar of Caius College in 1881. Such was his ability that he was awarded two scholarships, one in mathematics and the other in natural sciences. After Cambridge, he worked with C. S. Sherrington (1857-1952) in Liverpool (who was later to attain a Nobel Prize in Neurophysiology). Edkins taught with great distinction at St. Bartholomew’s in London and subsequently became Chairman of Physiology at Bedford College for Women in 1914. In this capacity, he was responsible for training the majority of women physiologists in England between 1914 and 1930. Apart from his fundamental observations in regard to gastrin (he documented the existence of a novel antral stimulant of acid secretion-gastrin in 1905), he investigated the presence of spiral bacteria (Spirella regaudi) (Helicobacter felis) in the gastric mucosa of cats and their relevance to digestion (1923).