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PHYSIOLOGY 19: 326–330, 2004; 10.1152/physiol.00034.2004
The First Nobel Prize for
Integrated Systems Physiology:
Ivan Petrovich Pavlov, 1904
the duties of his office with admirable
grace and skill” (1). Pavlov died in
February 1936.
Jackie D. Wood
Pavlov forever clung to the strong belief
that chronic studies in surgically prepared
conscious animals were most likely to
yield new insights into the integrated
physiology of organ systems in general
and the digestive system in particular.
Leading up to the Pavlovian period, acute
preparations in anesthetized animals
were the norm for experimental
physiology. Pavlov believed, and one
might say proved, that sequentially
repetitive studies in surgically prepared
conscious animals are most likely to
advance knowledge basic to humans.
That we must understand the normal
functioning of an organ in the alert
animal, as well as its anatomy, histology,
and cellular biology, to know disease has
been the standard since Pavlov. Pavlov’s
legacy in experimental surgery, which
could equally well be referred to as
“applied surgical physiology,” embraces
too many subsequent pioneers to
mention even a few. An early heir to the
legacy was F. C. Mann, followed by L. R.
Dragstedt, both of the Mayo Clinic in
Rochester, Minnesota, who with a
collection of colleagues and trainees in
their laboratories built on Pavlov’s
techniques and demonstrated, for
example, that withdrawal of duodenal
alkaline secretion and exposure to gastric
chyme for abnormally long periods
results in formation of an ulcer in a high
percentage of dogs (4, 5).
My own introduction to Pavlov’s legacy
for experimental surgery was at the
University of Illinois in 1967–1968 when I
was enrolled as a Ph.D. student in F. R.
Steggerda’s two-semester course in experimental dog surgery, which used the textbook of experimental surgery by
Markowitz, Archibald, and Downie (6).
The limited number of students admitted
to this hands-on course met for most of
the day twice each week to learn aseptic
methods, suturing techniques, and postsurgical care in the preparation of study
models, such as Pavlov and Heidenhain
gastric pouches, Thiry-Vella intestinal fistulas, and Biebl exteriorized intestinal
College of Medicine and Public Health, The Ohio
State University, Columbus, Ohio 43210
[email protected]
Abbreviated Biography
Pavlov was born the son of a priest in 1849
in Riazan, 200 miles southeast of Moscow,
and he studied for the priesthood before
matriculating into the Department of
Physical and Mathematical Sciences of
the University of St. Petersburg in
1873 and later into medical school at
the Medical-Surgical Academy of St.
Petersburg. He received his medical
degree with honors in 1879.
Pavlov was an apostle of Claude
Bernard and harbored deep admiration
for Bernard’s philosophy of modern life
science, which was in conflict with tsarist
metaphysical views. According to G. P.
Smith’s biographical account (12), Pavlov
A
was never interested in practicing medicine; rather, throughout his lifetime he
viewed research in systems physiology as
the basic science most likely to contribute
to the advancement of the practice of
medicine. Therefore, it seems that modern medicine’s prevailing mantra of
“bench to bedside” is rooted in Pavlov’s
personal philosophy.
Some years after his postdoctoral stints
in famous laboratories of experimental
physiology in Germany, Pavlov was
appointed chair of pharmacology at the
Military-Medical
Academy
in
St.
Petersburg in 1890 and to the chair of
physiology at the Imperial Medical
Academy in 1895. From that time forward,
he succeeded in the progressive development of an extensive research “empire”
that changed the world’s view of brain-gut
interactions and digestive physiology.
Nearing the end of his long and distinguished career, at eighty-six years of
age, Pavlov presided over the XVth
International Congress of Physiological
Sciences in St. Petersburg and Moscow in
August 1935. The distinguished American
physiologist, Walter B. Cannon, attended
the Congress and relates that much of
Pavlov’s characteristic alertness and nervous activity was obvious in his actions
during the formalities of the Congress.
Cannon states that, “in spite of the
demands imposed upon Pavlov by the
presidency of the Congress, he fulfilled
B
FIGURE 1. Academician Ivan P. Pavlov
A: photograph of I. P. Pavlov from the collection of photos at his country laboratory at Koltushi. B:
portrait of Pavlov located in his study at Koltushi.
326
1548-9213/04 5.00 ©2004 Int. Union Physiol. Sci./Am. Physiol. Soc.
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The centennial of the awarding of the
Nobel Prize in Physiology or Medicine to
Russian Academician Ivan P. Pavlov
(FIGURE 1) is an occasion for assessing
the paths opened to modern integrated
systems physiology and medicine by
discoveries at Pavlov’s city laboratory in
St. Petersburg and at his country
laboratory at Koltushi. Pavlov’s Nobel
Prize was the first ever awarded for
integrated systems physiology and the
first for a Russian.
Pavlov’s Legacies
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Gastric and pancreatic secretion
The traditional teaching of the “cephalic
phase” of gastric and pancreatic secretion
originated with Pavlov. Students learn that
stimulation of gastric secretion of acid
and pepsin and stimulation of pancreatic
secretion of digestive enzymes starts with
the anticipation of the ingestion of a
desirable meal and is mediated by input
to the stomach and pancreas from
efferent nerves of the vagus. Pavlov’s
cephalic phase was a brilliant demonstration of a brain-gut interaction. The
stimulation of secretion evoked by linking
environmental stimuli (e.g., lights and
sounds) with presentation of appetizing
food was discovered by Pavlov in his dogs
and was called by what is now a classic
term: a “conditioned reflex.” The
descriptions by the American army
surgeon, William Beaumont (1785–1853),
of how the appearance of the gastric
mucosa mirrored the emotional state of
his patient Alexis St. Martin preceded
Pavlov’s work on brain-gut interactions in
dogs. Beaumont’s studies laid the
groundwork for Pavlov’s work and are the
beginning of the arrow of time that points
to what modern physiologists now
understand about the digestive tract as an
integrated system.
Pavlov was a master experimental surgeon. His development of the “Pavlov
FIGURE 2. A Pavlov gastric pouch
pouch” enabled the discovery
The pouch is surgically prepared with a fistula formed
of the cephalic phase of secreby a segment of small intestine with stoma at the surface of the abdominal wall. Pavlov pouches had intact
tion and its role in the anticivagal innervations. A Heidenhain pouch was much the
patory preparation of the
same except vagally denervated. Adapted from Ref. 6
upper digestive tract for the
by permission of the Mayo
Foundation for Medical
ingestion of a meal. The Pavlov
Education and
gastric pouch is essentially the
Research. All rights
same as the pouch developed
reserved.
by Rudolph Heidenhain in
Germany,
with
the
exception that the
vagal innervation
remains intact
(FIGURE
2).
Pavlov’s discovery
that
severing
the
influvagal innervaenced
the
tion eliminated
discovery of histathe
cephalic
mine H2 receptor antagphase for both gastric and pancreatic
onists by Sir James W. Black
secretion underlies the discovery of
(Nobel Prize, 1988) of Kings College,
acetylcholine as the neurotransmitter and
London, and the more recent, dizzying
the muscarinic subtype as the involved
advances in the development of proton
receptor.
pump inhibitors in the 1980s and 1990s,
Needless to say, the invention of the
pioneered by George Sachs at the Center
now-obsolete selective vagotomy for
for Ulcer Research and Education (CURE)
treatment of peptic and duodenal ulcer
at the University of California, Los
disease in humans in the 1930s and the
Angeles; by the group of Lars Olbe,
successful pharmacological development
Christer Cederberg, and Tore Lind in the
of selective muscarinic receptor antagoDepartment of Surgery at the University
nists as therapy for gastric acid-related
of Götenborg; and by the research laboradisorders emanate from Pavlov’s discovtories of A. B. Hässle in Sweden. Without
ery and those of Latarjet in France (19).
these modern outcomes, scores of
Likewise, modern knowledge of the action
patients suffering from the acid-related
of histamine as a powerful gastric acid
disorders of heartburn, esophagitis, gassecretagogue evolved directly from
tric and duodenal ulcer disease, laryngitis,
Pavlov’s physiology factory. Nobel
certain forms of asthma, nighttime cough,
Laureate Adolf Windaus synthesized hisdecaying teeth, etc. and their physicians
tamine in 1906, and the extensive investiwould find themselves without effective
gation of its actions in the body were pubremedies.
lished by Sir Henry Dale and P. P. Laidlaw
Pavlov is responsible also for what we
in 1910–1911. Dale and Laidlaw did not
teach as the “gastric” and “intestinal”
report on the action of histamine on gasphases of mucosal secretion in the stomtric secretion, perhaps due to lack of expeach. The presence of food in the stomach
rience in surgical preparation of Pavlovstimulates the Pavlov or Heidenhain
type gastric fistulas in dogs. This was left
pouch to secrete, and this we teach as the
to L. Popielski, who was one of Pavlov’s
“gastric phase.” The significant difference
Polish trainees. Upon completion of his
between the cephalic and gastric phases
studies with Pavlov and upon his return to
of secretion is that the former is only
work in Poland, Popielski reported in 1916
effective in a vagally innervated Pavlov
that injection of histamine stimulated
pouch, whereas the gastric phase is also
copious secretion of gastric acid in dogs
seen in a Heidenhain pouch, which is
with surgically prepared gastric fistulas.
denervated. This showed that the gastric
Now, in the 21st century, we can specuphase must be due to a hormonal mechalate on the extent to which Pavlov’s legacy
nism, which we now know reflects the
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loops. J. H. Szurszewski’s experience as a
student in this course led to his development of methods for recording the electrical and mechanical activity of the intestine in awake dogs over extended periods
of weeks and to the data for his doctoral
dissertation (14, 15). Szurszewski continued the work as a fellow with C. F. Code at
the Mayo Clinic and made the seminal
observations on the now-classic interdigestive migrating motor complex (MMC)
that was named by Code as the “housekeeper” of the small intestine (13).
Hundreds of studies on the MMC now
appear in the literature! My own experience and insight gained from Steggerda’s
surgery course translated forward to the
year 2000 in a project in which my colleagues and I studied effects of stress on
inflammation in Thiry-Vella colonic loops
surgically prepared in a chronic primate
model for idiopathic ulcerative colitis
(20).
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evaluating the results for publication. His
factory approach to research was vastly
different from the norm in the 19th
century, when senior investigators ran a
small laboratory with only one or a few
colleagues and did hands-on research at
the bench. The factory approach might be
construed as a Pavlovian legacy, especially
in the United States, because it is not
uncommon in the 21st century for senior
investigators to embellish prestige by
supervising large laboratory groups
supported by funding from the National
Institutes of Health and not to spend time
at the bench themselves. Senior-in-Chief
status is identified by the appearance of
his or her name at the end of a string of
junior authors on published manuscripts.
Pavlov’s offering of research opportunities to young physicians was a forerunner
of modern-day fellowship programs in
clinical subspecialties. The young Russian
physicians in their first decade of practice
were accepted into a two-year research
fellowship, in which they became a cog in
Pavlov’s unified productive research
machine. Pavlov personally assigned specific research projects, saw to it that the
fellows received the necessary training
Pavlov’s physiology factory
and materials for pursuit of the project,
and supervised the preparation of the fel“Pavlov’s physiology factory” is a
low’s doctoral dissertation. Upon compledesignation used by D. P. Todes in his
tion of the dissertation and awarding
of the doctoral
“The factory approach might be
degree in medicine,
construed as a Pavlovian legacy....”
the research fellow
usually returned to
clinical practice. Pavlov’s opportunity for
scholarly biographical analysis of Pavlov’s
acquisition of a large workforce of clinical
scientific career (17, 18). Todes aptly used
fellows grew from an emerging philosothe analogy of an assembly line in a highly
phy in Western European countries and
organized factory to describe Pavlov’s
Russia that medicine was more than an
laboratory, because large numbers of
art and that physicians should be groundresearch fellows and assistants, working
ed in the scientific basis of medicine.
simultaneously at any one time in a large
laboratory space, efficiently produced
Pavlov’s gastric juice factory
large quantities of data and publications
that advanced science, gained doctoral
Among Pavlov’s many experimental
degrees for trainees, and advanced
surgical innovations was the esophaPavlov’s prestige. Neither the Russian
gostomy (FIGURE 3). The operation
Revolution nor World War I interrupted
involves dividing the esophagus and
Pavlov’s physiology factory. In the
bringing the superior and inferior ends
laboratory, Pavlov was the Professor-Inout as stomas sutured to the surface of the
Chief, moving about to oversee the
skin in the neck. It was designed for “sham
ongoing work of 15–20 personnel,
feeding” and appetite studies in which the
dictating the studies to be done, fineswallowed food is diverted to the outside
tuning each project as it progressed, and
via the superior stoma before reaching the
328
PHYSIOLOGY • Volume 19 • December 2004 • www.physiologyonline.org
stomach. The inferior stoma provides
access for introducing food and liquids
directly into the stomach and thereby
maintaining the health of the dog. A
fistula placed in the stomach drains the
gastric secretions for collection and
analysis. The dogs are placed on a stand
(i.e., a Pavlov stand) facing an elevated
platform with a bowl of food (FIGURE 3).
As they eat, the food falls into a container
on the outside and gastric juice drips
continuously from the gastric fistula.
Published accounts from Pavlov’s
laboratory describe how the dogs
immensely enjoyed participating in the
sham-feeding studies. They would
enthusiastically jump up onto the stand
and remain compliant for hours as they
continued to eat voraciously while their
stomachs secreted copious amounts of
gastric juice. These were early indications
of the importance of the palatability of
food in the interactions of appetite and
digestive functions.
The breakthrough provided by the
esophagotomized dog model was the
ability, for the first time, to collect copious
volumes of pure gastric juice uncontaminated by ingested food and saliva.
Approximately 150–300 ml of gastric juice
per day could be obtained from a single
dog without ill effects. One dog was
reported to produce 10,606 ml of gastric
juice in 45 sessions (18). The juice was
described as being an “entirely transparent, colorless liquid without any scent, or
sometimes with the same light scent of a
fresh solution of hydrochloric acid.”
Laboratory workers who tasted it
described the taste as acidic and not at all
unpleasant. For the biochemist, the pure
samples were ideal for the analysis of
uncontaminated pepsin, which at the
time was already identified as a proteolytic enzyme present in gastric juice.
It so happened in Europe in the late
19th century that concoctions of pepsin
and hydrochloric acid were widely touted
as therapy for dyspepsia. The symptoms
described as dyspepsia then were not so
different from what is described as dyspepsia in modern gastroenterology. In the
Rome II approach to symptom-based
diagnosis of functional gastrointestinal
disorders, the spectrum of symptoms in
dyspepsia includes 1) pain centered in the
upper abdomen, 2) discomfort centered
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food-stimulated release of the hormone
gastrin from enteroendocrine cells in the
gastric mucosa. The physiology of the
“intestinal phase” is similar to the gastric
phase, except that gastrin is released from
enteroendocrine cells in the small intestinal mucosa and the volume of gastric
juice secreted is relatively small.
The eventual understanding of the
physiology of acid secretion and the role
of gastrin in the functioning animal
turned out to be basic to insight into the
pathophysiology of the Zollinger-Ellison
syndrome in humans. This syndrome,
which was described by R. M. Zollinger
and E. H. Ellison of the Ohio State
University Department of Surgery in the
early 1950s, is characterized by hyperplasia of acid-secreting cells in the stomach,
hypersecretion of acid, and multiple persistent ulcers of the stomach and small
intestine together with the attendant
symptoms (21). Elucidation of the syndrome, which is due most often to a pancreatic islet cell tumor that hypersecretes
gastrin, might not have been possible in
the absence of the chain of advances
started by Pavlov.
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A
B
FIGURE 3. Pavlov’s esophagostomy and sham-feeding experiments
in the upper abdomen, 3) early satiety, 4)
unpleasant sensation of fullness, 5) bloating in the upper abdomen, 6) nausea, and
7) retching (16). Patients diagnosed with
dyspepsia are divided into those in which
a cause can be identified (e.g., peptic
ulcer, acid reflux disease, or biliary tract
disease) and those in which laboratory
tests and clinical examination find no
identifiable explanation for the symptoms. The latter satisfy symptom-based
criteria for functional dyspepsia (16). The
prevalence of dyspepsia in the year 2000
was estimated to be ~25% in populations
around the world (16). Obviously, dyspeptic symptoms have been present in
human populations for a long time. The
prevalence was probably similar in the
19th century Pavlovian era and explains
the strong interest of the pharmaceutical
industry in finding and marketing therapies then, as is the case today.
Before Pavlov developed his gastric
juice preparation, none of the multiple
pharmaceutical concoctions with pepsin
extracted from animal stomachs were
consumed enthusiastically by dyspeptic
patients, because they were putrid with a
foul odor and taste. Acceptance of Pavlov’s
product as an effective natural medicinal
product was slow because of Pavlov’s
reluctance to divert resources from basic
studies to produce commercial quantities
of the juice and because of patients’ aversion to using gastric juice from dogs as
medication. Nevertheless, daily consumption of multiple doses of the juice
proved to be efficacious in treating dyspeptic symptoms. Anecdotal praise from
the many clinical fellows in the laboratory
who tried it included statements such as
“when taken after a meal, I always
received a sensation of special lightness in
the stomach area, an absence of that sensation of unpleasant heaviness during
digestion that is characteristic of the
chronic, low degree of dyspepsia that I
have....[I]n just the same way, my comrade physicians in the laboratory and
those who visited the Institute drank the
juice, in part from curiosity, in part with
the medicinal goal of easing a sense of
heaviness during digestion, which was
quickly attained” (18). Daily doses of St.
Petersburg gastric juice were reported to
be efficacious (in some cases with placebo
controls) in treatment of poor appetite,
neurosis of the stomach, postprandial
epigastric pain, heartburn, gastritis, diarrhea, constipation in patients with typhus
infections, globus hystericus, and anemia.
Ultimately, the dispensing of gastric
juice by prescription through pharmacies,
a growing demand for the juice, and
financial exigencies in the Institute led to
expansion into a commercial enterprise
that generated significant monetary
income. Additional assistants were hired,
and five large dogs were carefully maintained for the specific purpose of the production of gastric juice. Thus was the
beginning of what Todes called “Pavlov’s
gastric juice factory” (17, 18).
Therapeutic action of Pavlov’s
gastric juice
The mechanism of therapeutic action of
Pavlov’s “pure” gastric juice remains open
to speculation. It is possible that
enhanced digestive action with the acidpepsin mix facilitates the trituration of
solids to reduced particle sizes and
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A: an original Pavlov stand as it appeared June 2004 in the Pavlov laboratory exhibit at Koltushi.
B: watercolor from the Pavlov exhibit at Koltushi showing a dog with esophagostomy and gastric
fistula for collection of “pure” gastric juice during sham feeding.
thereby facilitates gastric emptying. On
the one hand, additional acid might
suppress gastrin release and its
stimulatory action on gastric parietal cells
and enteric neurons. On the other hand,
the lowered pH of the gastric contents is
expected to slow gastric emptying
through duodenal feedback.
Reports that treatment with Pavlov’s
gastric juice stimulated production of red
blood cells in patients with anemia might
now be explained by what is now known
about the necessity of gastric secretion of
intrinsic factor for the absorption of
cobalamin (vitamin B12). Cobalamin was
not isolated until 12 years after Pavlov’s
death and was therefore unknown as a
possible explanation for the efficacy of
gastric juice in the treatment of pernicious anemia. Nevertheless, it was suggested by W. B. Castle shortly before
Pavlov died that a factor (i.e., intrinsic factor) necessary for the production of red
blood cells was secreted by the stomach in
association with acid secretion (2).
Castle’s hypothesis was based on his finding that 200 g of beef fed daily in combination with 150 ml of normal human gastric juice stimulated erythropoiesis and
maintained anemic patients in remission.
However, not until the mid-20th century
was it firmly established that binding of
cobalamin to intrinsic factor was necessary for absorption of vitamin B12 by the
terminal ileum (3).
Finally, on the subject of therapeutic
actions of gastric juice, I mention the
more
recent
reports
from
the
Pharmacology Institute in Zagreb, Croatia
that propose that a peptide isolated from
human gastric juice has broad protective
and healing powers. Immunoreactivity for
the 40,000-mol wt peptide is present in
stomach and brain, and therapeutic activity is reported to be achieved with a 15amino acid fragment that has no homology with known messenger peptides in the
gut (9, 11). The Croatian proponents
called the pentadecapeptide “body protection peptide 157” (BPC-157). Testing
with BPC-157 in animals reportedly found
protection of the gastric and duodenal
mucosa against lesion formation in several ulcer models, including restraint stress
and ethanol or cysteamine administration
and against pancreatitis in a bile duct-ligation model (10, 11). Moreover, BPC-157
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was reported to have anxiolytic actions (8)
and to promote burn-wound healing
when applied topically (7).
Pavlov and the antivivisection
movement
330
FIGURE 4. Bronze statue of Pavlov and
one of his dogs located on the grounds
of his laboratory at Koltushi
Photo taken by the author, June 2004.
the Nobel Prize and the influence of his
discoveries on modern medicine, both for
humans and animals, would be blank
pages had the antivivisectionists of his
time succeeded in their efforts to persuade their governments to forbid
research with animals. Availability of pancreatic enzyme formulations for the child
with cystic fibrosis and our choices of
treatments for our acid-related disorders
and discomfort might not be available
had the antivivisectionists in Pavlov’s
time, and through the years to the present, achieved their persistent objective of
stopping all animal research. References
1.
Cannon WB. The Way of an Investigator: A
Scientist’s Experiences in Medical Research. New
York: Norton, 1945.
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Castle WB. Observations on the etiologic relationship of achylia gastrica to pernicious anemia.
Am J Med Sci 178: 748–764, 1929.
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Heinle RW, Welch AD, Scharf V, Meacham GC,
and Prusoff WH. Studies of excretion (and
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Pavlov graduated from the university in
1875; restrictive legislation against the use
of animals for medical research was
passed in England in 1876. The
antivivisection movement, which reared
its head throughout Pavlov’s lifetime, has
progressed unabated into the 21st century
as a smothering damper on physiological
systems research. As Pavlov’s career
progressed, the significance of his
discoveries, the successful development
of a research-based therapy for dyspepsia,
and candidacy for a Nobel Prize elevated
him to star status on the world’s scientific
stage. As one of the most visible
experimenters on animals, he was not
deterred by the attention of the
antivivisectionists and served effectively
as the physiologists’ spokesperson against
their perverse and absurd accusations.
Explanations for Pavlov’s success
include his concern for his dogs and, in
particular, their comfortable recovery from
the surgical procedures. He understood
that valid results would come only from
studies in which the surgical technique
was impeccable and the postoperative care
of the animal the best possible. One particular event supports the impression that he
genuinely cared for his dogs. Early on,
Pavlov’s work progressed in the facilities
located in St. Petersburg. As time passed
and his respect from the Russian leadership grew, an expansive, modern facility
was constructed for his work outside the
city in a village called Koltushi. Legend has
it that a lady caretaker in his St. Petersburg
laboratory one day commented that she
felt the dogs would be happier if they were
free to exercise in the open air in the countryside. As the story goes, this was the
motivation for Pavlov to move his research
operation to Koltushi. Still standing on the
grounds outside his laboratory and apartment in Koltushi is a magnificent bronze
statue of Pavlov with one of his beloved
dogs happily at his side (FIGURE 4).
Luckily, Pavlov was a strong personality
not intimidated by the criticisms and
threats of zealous animal-rights activists.
The present chronicle of Pavlov’s path to
7.