In this last century, Physiologists believed that signaling between organs occurred solely by conduction of electrical signal along the nerve, by analogy of the brain-muscle connection. The brain controls our muscular activity by metre long neurons that descend down the spinal cord and bring about contraction or relaxation of muscle fibres. An outstanding riddle for the early pioneers however was to explain how the pancreas could be stimulated to secrete bicarbonate and digestive enzymes into the upper intestine when the expected nerve connection could not found. The answer was provided exactly one hundred years ago, Ernest Henry Starling and William Maddock Bayliss found that it was not the nerve signal but a rather novel substance that stimulated secretion from the cells forming the intestinal mucosa, the substance named later as Secretin (1).

They decided that some substance must be produced by the action of the acid on the mucous membrane of the intestine, which then diffuses into the blood and, arriving at the pancreas excites it to action. The experiments of Bayliss and Starling, the work of a single afternoon and their dramatic conclusion constituted a hallmark in the history of physiological ideas. They opened a new era in gastrointestinal physiology and began the study of endocrinology. This discovery of theirs was to have fetched them the Nobel Prize but the world war prevented it and after war the prize was given to more recent works. The unequivocal proof of this mechanism of secretion was provided by the experiment of Ivy and associates who transplanted the uncinate process of pancreas and a segment of duodenum under the skin of a dog. When these transplants developed collateral circulation from the mammary vessels the original blood and nerve connections were severed leaving the transplant completely devoid of extrinsic nerves.  This small portion of denervated segment of pancreas secreted pancreatic juice in response to the presence of hydrochloric acid in the denervated segment of jejunum. There could be no intercommunication between these structures except by way of the blood stream and therefore the stimulating agent must be blood borne (5)!

In 1849 Berthold observed that removal of testes in a cock made it behave like a hen and that these effects could be avoided if the tests were grafted in the gut. This led to the view that the testes liberated some substances in the blood stream that was responsible for the masculine behaviour of the cock. Claude Bernard first coined the name “internal secretion” in 1855 for such secretions. In 1896 Schaefer extended the meaning of it and made it application to all the organs of the body and made “internal secretion” a recognized term in physiology and therefore in medicine. But Bayliss and Starling wanted a more suitable name. In Bayliss’ own words, “the mode by which pancreas is excited to activity, it became obvious that this chemical agent belonged to a group of substances previously known. The group…characterized by the property of serving as chemical messengers… They enable a chemical correlation of the functions of the organism brought about through blood side by side with that which is the function of the nervous system. This being so, it seemed desirable to posses a name to distinguish the group. That of the “internal secretion” already in use did not sufficiently emphasize their nature of chemical messengers”. Then finally the name, “hormone”, derived form the Greek word “harmao’, which means “I set in motion “ or “I rouse to activity” was originally proposed by W.B. Hardy for this chemicals messenger. Starling used it for the first time in the first of the Croonian lectures to the Royal College of Physicians. This doctrine of hormonal control made Schaefer to comment that physiology changes, in future, need to be explained in terms of chemical regulation as well as of nervous regulation.

William Bayliss Maddock, the only son of a wealthy manufacturer or ironware, Moses and Jane Maddock was born at Wolverhampton, England on 2 May 1960. In 1888 he obtained first class in School of Natural Science (physiology) in Wadham College and returned to University College, London, where he remained for the rest College and returned to University College. London, where he remained for the rest of his life. He actively participated in the activities of Physiology Society and held the posts of its Secretary and Treasurer. He also studied the electrical currents developed in salivary glands, activation of enzymes, blood vessel innervation, vascular reflexes, blood vessel autoregulation and intracranial pressure and cerebral circulation. In 1915 he published his magnum opus, Principles of General Physiology. He was awarded many honours; in 1903 he become a Fellow of the Royal Society, in 1904 he was Croonian Lecturer of Royal College of Physicians and in 1911 he received the Royal Medal. In 1922, he was knighted.

Ernest Henry Starling was born in London in 1866 and educated in King’s College School and Guy’s Hospital. He became Demonstrator of physiology and then the Head of the Physiology Department of that hospital. In 1899 at the age of 33 he was elected to the chair of physiology as Jodrell Professor at University College, a post which he held till 1922. He was elected a Fellow of Royal Society in 1899 and in 1913 was awarded the Society’s Royal medal. He also studied the secretion of lymph and other body fluids, glomerular functions of kidney and the laws that govern the activity of the heart. He wrote a number of books, one of the most outstanding being the Principles of Human Physiology in 1912, the classical textbook of its time.

The collaboration of Starling and Bayliss started at the university College (1860-1924). Bayliss was a kind, reticent and shy person, a dedicated, methodical, skilled, even-tempered experimenter, though a good teacher was only a moderate orator. In contrast Starling was a romantic personality in appearance, attitude and behaviour. He was generous, quick on the uptake, in his reactions, repartee, brilliant speaker, restless, energetic and driven by enthusiasm. The two complemented each other. Their partnership was described by Barcroft as an “alliance of two men of complementary genius”. Perhaps the most penetrating assessment of their characters came from Sherrington, when he wrote, “a resolute but placid enthusiasm of one met a high tension and impetuous enthusiasm of the other”. This fruitful association gave us the knowledge about the electrical activity of the mammalian heart, heart innervation, intravascular pressure changes at various sites, innervation and movements of the intestines and mechanism of pancreatic secretion. The story epitomized in a joint Croonian lecture delivered before the Royal Society in 1904 was the peak of their combined operation.

Secretin, a gastrointestinal hormone, has 27 amino acids, all of which are required for substantial activity. The only potent stimulus for its secretion by the S cells of the duodenum is H⁺ ions. Their major action is to stimulate pancreatic acinar cells to release bicarbonate ions and water to be transported to the duodenum and change the acidic pH to alkaline, thereby facilitating the action of pancreatic enzymes. The amount of hormone released is related to the length of the duodenum and jejunum exposed to the acid. It is released when the pH in the duodenum falls below 4.5 and also by fatty acids. Secretin is nicknamed as “nature’s antacid” as almost all of its actions like stimulating the pancreas to secrete bicarbonate ions, and liver to inhibit gastric secretion, emptying as well as released of gastrin, reduce the amount of acid in the duodenum. Secretin, along with cholecystokinin is also known to stimulate the growth of exocrine pancreas (6).

Since the discovery of secretin many attempts had been made to isolate it in pure state but in vain. In 1960, after 10 years of application of skillful perseverance, Jorpes and Mutt were successful in performing it from hog intestinal mucosa. The heroic scale of their efforts is illustrated by the fact that to obtain 1 mg of pure secretin it was necessary to use one thousand pieces of cooked hog duodenum, each one metre long. In 1971 Bodanszky synthesized secretin identical in potency with its natural product. Soon after the discovery of secretin, another gastsrointestinal hormone, gastrin was discovered by John Sidney Edkins in 1905. The first two hormones discovered were both gastrointestinal hormones. In the following decade endocrinology had blossomed by the discovery and isolation of steroid hormones form adrenals, ovaries and testes, large protein hormones of anterior pituitary, oxytocin and vasopressin of posterior pituitary and insulin from pancreatic islets. In the light of the immediate and often life saving actions of those breakthroughs, the interest for secretin faded to a degree that figuratively returned it to the darkness of the bowel, only to be rekindled by the accidental observation of Victroia Beck, mother of an autistic child who made connection between her son’s slow but certain recovery from an autistic state and an infusion with secretin performed during an investigative endoscopy for gastrointestinal problems. Different studies have shown contradictory results, with few autistic children showing good improvement, few moderate and few none at all (7, 8). Definitive proof that secretin therapy works will only come after more research. Preliminary tests are underway, but it could be a long while before secretin is approved as a treatment for this disorder.

All said and done, the discovery of secretin paved way to the start a new branch of medicine, Endocrinology, and also a new mechanism of action, without which many a functions of the body organs would not have been explained.

REFERENCES

1. Starting EH. Elements of human physiology. London, J and A Churchill Publications, 1907.
2. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiology 1902; 28: 325-353.
3. Gregory RA. The Bayliss-starling Lecture; 1973: The gastrointestinal hormones, a review of recent advances. J Physiology 1974; 241: 1-32.
4. Medvei VC. The History of Clinical Endocrinology. New York, Parthenon Publishing, 1993.
5. Mountcastle VB (ed). Medical physiology. Saint-Louis, Mosby Company, 1968.
6. Johnson LR (Ed). Gastrointestinal Physiology, Mosby Publications, 2001.
7. Coniglio SJ, Lewis JD, Lang C et al. A Randomized, double blind, placebo-controlled trail of single does intravenous Secretin as treatment for children with Autism. J Pediatr 2001; 138: 649-955.
8. Owley T, Steele E, Corsello C, Risi S et al, A double blind, placebo-controlled trial of Secretin for the treatment of Autistic disorder. Section of child and adolescent psychiatry Department of Psychiatry, University of Chicago, Chicago, IL, 1999.