J Physiol Pharmacol 2002;46 (4);
Hundred Years of Secretin, The First Hormone Discovered
PILLAI, Department of Physiology,
Seth G. S, Medical College,
Mumbai – 400 012
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).
discovery of Secretin followed the studies of Pavlov on the vagus
nerve and pancreatic secretion. Popielski 1901 showed acid in the
duodenum still stimulated pancreatic secretion after denervation of
vagi and splanchnics, destruction of medulla and spinal cord and extirpation
of celiac ganglia. Wertheimer and Le Page 1901 showed HCl instilled
into an isolated loop of jejunum produced pancreatic secretion. The
final discovery was by William Bayliss and Ernest Starling who worked
together. In 1902 Bayliss and Starling wrote: “They (Wert &Page)
did not perform the obvious control experiment of injecting acid into
an isolated loop of jejunum after extirpation of these ganglia…” (2).
In 1927, Sir Charles Martin, friend of Bayliss and Starling, described
the experiment they performed, “I happened to be present at their
discovery. In an anaesthetized dog they isolate a loop of duodenum,
and tied it at both ends. The nerves were dissected away so that it
was only connected to the body by blood vessels. On the introduction
of a few CCs of weak HCI into the denervated duodenum a marked secretion
of pancreatic juice was produced. I remember Starling out immediately
saying, “then it must be a chemical reflex”. Rapidly cutting out a
further piece of jejunum he rubbed its mucous membrance with sand
and weak HCI, filtered it and injected it into the jugular vein of
the dog. After a few moments the pancreas responded by a much greater
secretion than before. It was a great afternoon” (3, 4).
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)!
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.
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.
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.
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.
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).
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.
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.
EH. Elements of human physiology. London, J and A Churchill Publications,
WM, Starling EH. The mechanism of pancreatic secretion. J Physiology
1902; 28: 325-353.
RA. The Bayliss-starling Lecture; 1973: The gastrointestinal hormones,
a review of recent advances. J Physiology 1974; 241: 1-32.
VC. The History of Clinical Endocrinology. New York, Parthenon
VB (ed). Medical physiology. Saint-Louis, Mosby Company, 1968.
LR (Ed). Gastrointestinal Physiology, Mosby Publications, 2001.
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.
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.