by Acad. Yuri NATOCHIN
In October 1904 the Royal Caroline Institute of Stockholm awarded a Nobel Prize to Ivan Petrovich Pavlov "in token of recognition of his works on the physiology of digestion whereby he has revolutionized and expanded knowledge in this field". Pavlov was one of the first scientists to merit this prize instituted in 1901 in keeping with Alfred Nobel's will of November 1895.
Ivan Pavlov wrote his first major work on digestion in his college days as a student of H. M. St. Petersburg University. In the autumn of 1873 Prof. Ilya Cion, a physiologist, offered a theme to two students, Ivan Pavlov and Mikhail Afanasyev, on pancreatic innervation. They did the job fine, for which they merited a University Gold Medal in 1876.
On February 28, 1876, the two young men reported at a session of the Zoology Department of the St. Petersburg Society of Natural Scientists on their research findings. That day was a landmark date for Russia's physiologists: on Prof. Ivan Tarkhanov's initiative the Zoology Department of the St. Petersburg Society of Natural Scientists set up a Physiology Section. By 1917 it had upgraded its status to a Physiological Society in its own right, with Pavlov playing first fiddle in it.
Pavlov continued his research in Germany, at the laboratory of Rudolf Heidenhein, an eminent physiologist and histologist of the day. The visiting Russian researcher studied the reflex inhibition of glandular functions, including those of the pancreas. Pavlov worked on developing a proper method for obtaining pancreatic juice - that is he sought to initiate the secretion process under conditions optimized to natural ones. Besides, he looked into the role of glandular innervation. In 1888 Pavlov proved that the secretory nerves of the pancreas pass within the vagus nerve.
In the 1880s Pavlov concentrated on the nervous regulation of cardiac functions; he suggested a new method of researching into kidney functions by bringing part of the bladder mucous membrane and ostia uteretis (ureter openings) onto the surface of the abdomen. However, he never abandoned his work on the digestion physiology. In 1891 the young researcher was appointed head of the Physiology Department of the Institute of Experimental Medicine (on recommendation of Prince Alexander Oldenburg, honorary member of the St. Petersburg Academy of Sciences), where he continued his research.
Research into the digestion physiology dates back to the 18th century. The French savant and foreign member of the St. Petersburg Academy of Sciences Rene Antoine Reaumur (1683 - 1757), for instance, studied the process of digestion in the stomach. And William Beaumont, an American physician and physiol-
ogist, watched a Canadian huntsman having a spontaneous gastric fistula, the aftereffect of a gunshot injury. In the 19th century Vassily Basov, a Russian surgeon and physiologist, postulated the possibility of experimental techniques "at will". In 1842 he published his results on operations on dogs: "These experiments," he wrote, "indicate the possibility of making a similar artificial orifice in man, when the natural passage for food and drink in the stomach is closed or obstructed by excrescences, tumors and the like." His findings provided a basis for the gastrostomy techniques widely used in studying the physiology of gastric juice secretion and applied in clinical practice. In the 19th century W. Prout of Germany established the fact of hydrochloric acid secretion in the stomach (1824), and his compatriot, the histologist T. Schwann - the fact of pepsin secretion (1836). In 1851 the German physiologist Karl Ludwig made a description of the secretory nerves of salivary glands. But it was Pavlov who offered an overall picture of digestion in its integrity, from start to finish. His brilliant mind and virtuoso surgery (although a left-handed person, he could use his right hand just as deftly) combined with a talent of unorthodox approaches were behind his signal accomplishments, specifically, with regard to the role of the stomach and the pancreas in digestion.
Pavlov used two methods of surgery. First, he made artificial "openings", i.e. fistulae, and isolated glandular ducts for the purpose of studying juice secretion. Second, he dissected nerves guiding to a particular organ, resected or dissected it with the aim of interfering in the natural course of events. Here Pavlovian techniques can best be seen in the example of pancreatic fistulae, or the operation of contracting the stomach to what is known as "the Pavlov pouch", with the innervation kept intact. Pavlov also experimented with sham (fictitious) feeding by cutting off the esophagus. And finally, he succeeded in an operation of dissecting both vagus nerves in a dog named Vagus that lived on for more than a year and a half.
The Pavlov pouch operation proved to be quite laborious. The idea was to isolate a small part of the stomach but keep its innervation intact; no food should get into that miniature stomach which was to respond, like the other, larger part, to the action of regulation factors
and thus reflect events occurring in the overall process of gastric digestion. In this work the great Russian physiologist was assisted by a practicing surgeon, Pavel Khizhin, who came to him for consultations on a doctoral dissertation. All the previous surgeries had failed one after the other-as many as 30 dogs had been operated on with no results. Pavlov had sought the advice of Nikolai Uskov, the pathologist, but all in vain. At long last, the Pavlov pouch operation came off on a dog Druzhok by name, with Khizhin as surgeon; in 1894 he defended his doctoral thesis with much success.
Sham feeding experiments furnished answers to questions about the regulation of gastric gland functions and, furthermore, it became possible to obtain, for the first time ever, pure gastric juice without food impurities. The whole procedure amounted to the following: a dog's esophagus was severed, and its ends brought onto the neck. The food which the animal was eating fell into the bowl through the opening in the esophagus without reaching the stomach; and thus pure gastric juice could be obtained from the stomach fistula. The publication on this method of isolating the miniature stomach with its innervation intact opened up fresh opportunities for studying the nerve regulation of gastric functions.
Yet another noteworthy experiment. Food was introduced into a gastric fistula so that the dog could not notice it. In that case no juice was secreted and no digestion took place. But if some tidbit was shown to the dog, the juice started flowing freely and the food came to be digested. Pavlov gave an apt description of this phenomenon - "the primer juice". These experiments, rather simple in conception, explained the importance of a food-taking sequence-appetizer, soup, the main course, dessert... That is the mere sight of tasty food stimulates saliva and gastric juice secretion. The chewed up food is digested in the stomach where proteins are hydrolyzed in the process of proteolysis. Further digestion occurs in the small intestine where the proteolysis of organic compounds is terminated, and amino acids, monosaccharides, fatty acids and other substances are transported into blood through intestinal absorption.
Pavlov's research findings were published in journals at home and abroad. In 1897 his book - a course of lectures on the performance of the main digestive glands-came off the press. Hermann Munk, a German physiologist, wrote in his review that no other scientist could make so many discoveries in physiology as the Russian author did.
Pavlov owes such outstanding accomplishments to his genius and passionate involvement, to his ability to concentrate on a purposeful search. In 1935 the veteran scientist addressed his Letter to the Youth, in which he said in particular: "Science calls for much strain and great passion. May you be passionate in your work and in your searchings!" Fortune smiled on the great physiologist-to the end of his days he kept a fresh love of science and an unflagging passion for it.
In one of the chapters of the novel A Hero of Our Time (1840) by the Russian poet Mikhail Lermontov, the protagonist, Pechorin, mused in his diary on the nature of passion: "Passions are nothing else than ideas at their very inception; they are proper to the youth of the heart, and he is a fool who thinks to be possessed throughout his life; many languid rivers rise from roaring waterfalls, but none will ever scud in froth all along down to the sea..." But Pavlov, he epitomized "roaring waterfalls" - indeed, his violent passions and abandon brought him joy.
Professor Alexander Samoilov, a physiologist who worked for several years in Pavlov's laboratory in the 1890s, left his reminiscences about the Pavlovian style of work. Once he saw Pavlov looking through new journals in the library, obviously disgruntled. "I wish I had never seen all
that!" Pavlov referred to works on conduction, and on muscle and nerve cells. What rubbed our great physiologist the wrong way was that those works were a far remove from synthetic, composite physiology approaching a living organism comprehensively as an indivisible whole...
And now the main points of Pavlovian research in physiology for which he merited a Nobel Prize in 1904. First, he suggested novel methods of studying the functions of the stomach and the pancreas, something that allowed to obtain data on the role of individual digestive glands in the sequential proteolysis of food components, and clarify the dependence of the secretion of gastric glands on the nature of food. Discovered at his laboratory was the phenomenon of enzymic activation when inactive enzymes became active (as seen in the example of enterokinase).
In 1904 a group of foreign physiologists came to Ivan Pavlov to familiarize themselves with his works. Professor Robert Tigerstedt was in the group. His testimony: "... What Pavlov has already achieved certainly belongs to spectacular accomplishments in the physiology of vegetative functions."
In fact the idea of nervosism (nervosity) keynoted his research - Pavlov sought to understand the role of the nervous system as functional regulator. But experiment was always a supreme judge to him. Once Pavlov asked one of his pupils, Mironov, to look into the role of nervous links in the regulation of mammary gland secretion which went on even upon dissection of nerve fibers. So further studies were discontinued for good.
Pavlov and his coworkers revered fact. Making use of sophisticated surgery and elegant experiments, he sought to demonstrate the all-out role of the nervous system in the regulation of functions. Meanwhile experimental results both proved and disproved this approach. In the 1890s Leopold Popelsky, a junior scientific assistant working in his laboratory, discovered fibers within the vagus nerve which, when irritated, were inhibiting pancreatic juice secretion. This line of research was quite in keeping with the work which Pavlov had undertaken back in his college years. Popelsky wanted to demonstrate the total dependence of the pancreas on innervation. He severed all its nerve fibers, destroyed the nerve ganglia in the brain responsible for pancreatic functions, and even removed the solar plexus. But the obstinate pancreas still responded by enhanced secretion of juice upon injection of hydrochloric acid into the duodenum.
The purpose of those experiments was to explain the fact established by Ivan Dolinsky, a child doctor, in Pavlov's laboratory: as hydrochloric acid moves from the stomach into the duodenum, the pancreas responds by secretion. That seemed quite clear and logical, for pancreatic juice was needed for subsequent digestion in the small intestine. But Pavlov visualized the duodenal acid as a chemical signal for the nerve endings of the small intestine and the nervous system in general for triggering the next stage of digestion. However, Popelsky's experiments did not confirm the validity of that
explanation. Pavlov set forth these facts in his Lectures.
The puzzle was resolved quite unexpectedly-apart from the nervous system the organism has yet another regulatory system, the endocrine system. The very idea to this effect was in the air and not formulated. Two English physiologists, William Bayliss and Ernest Starling, got down to this problem in 1902. They made an extract from the duodenal mucous membrane, injected it to a dog and thus initiated secretion. They called this substance secretin and introduced the term "hormone". Pavlov asked one of his colleagues, V. Savich, to verify those experimental data on the secretin-mediated humoral regulation of pancreatic activity. The experiment, conducted in Pavlov's presence, corroborated the validity of the English data. Thereupon Pavlov silently retired into his study. He came out half an hour later. "They are right, of course. We are not the
only ones entitled to the discovery of new facts!"
This is how the logic of a quest begun at Pavlov's laboratory provided an incentive for a new trend in the physiology of digestion - the hormonal regulation of gastrointestinal glands, a process in which both the nervous and the endocrine systems are implicated.
Decades after that the veteran physiologist wrote in his Letter to the Youth: "It's often hard to see what is 'mine' and what is 'yours'." Back in his salad days, in 1897, Pavlov compared science to a construction site with so many hands at work in keeping with the division of labor. The edifice of the present-day physiology of digestion was erected in a similar way, like any other building. Pavlovian studies have long been canonized in textbooks and manuals on digestion. Today this body of knowledge has been expanded by information on the molecular mechanisms of multifarious regulatory influences responsible for the process of food digestion and intestinal absorption of products obtained through hydrolysis of organic substances-proteins, carbohydrates, lipids...
What is the secret of the unslackening interest in Pavlov, in his scientific legacy? Not all luminaries in the galaxy of Nobel prizewinners are now shining forth as brightly as before, when they merited this honor... Why? The point is that Pavlov has probed into the mechanisms of functions and their regulation in a living organism viewed as an entity, as an integral whole. He has achieved consummate perfection in his experiments on test animals making a complete recovery after the inevitable invasive techniques.
The international scientific community was quick to recognize Pavlov's talents. At a ceremony of conferring the title of Doctor Honoris Causa of Cambridge University college students presented a toy monkey to the great Charles Darwin. And a toy dog with so many fistulous tubes was presented to the great Pavlov. Archibald Hill (Nobel Prize 1923) attended that ceremony. Many years after the event he described the particulars in a letter to Khachatur Koshtoyants, corresponding member of the USSR Academy of Sciences. The ceremony was taking place in the Senate House. A group of students brought in a big dog, the very spit of a living one. Thereupon they adorned it with rubber and glass tubes, taps, cocks and all. And then they scurried off to the gallery. As the hero of the ceremony, having received a gift of honor, was walking down the aisle, the mischievous kids descended the dog on him by a rope. Pavlov, all abeam, hugged the doggy and took it away.
Ivan Pavlov was born 155 years ago; 100 years have passed since he was awarded a Nobel prize. And 68 years separate us from the sad day when his heart stopped beating. And yet the interest in his person has never flagged. Let us take the citation index of Pavlovian works. In eight years between 1995 and 2003 he was cited on 4,573 occasions; as many as 245 works of his were referred to; and his experiments on the physiology of digestion were cited 152 times.
Today we are witnessing staggering progress in natural sciences - in molecular biology, genetics and biochemistry. Crowned by Nobel prizes, these achievements have provided an insight into the chemical structure of numerous mediators of the nervous system, hormones and secondary messengers in the cell.
Now that we know about the existence of several molecular forms of receptors, about the diversity of G-proteins, and the presence of enzymic isozymes involved in the transmission of a signal, not to speak of many other processes in the cell, the picture of regulations turns out to be much more complicated. A large number of molecular proteins implicated in water channels (aquaporins) as well as ionic channels and ion pumps have been described. But all this novel information will take visual form as to the true role of the above factors in digestion, absorption, respiration, blood circulation and excretion only if we know how all that functions within an integral organism (and not within an individual cell only), and how its functions are regulated. Multiple regulatory factors act both upon the cell and upon the organism as a whole. Ivan Pavlov's spectacular achievements in physiology help unlock many riddles in this regard.
It would be apt to recall what Joseph Barcroft (1872 - 1947), a prominent British physiologist, said about Pavlov. It so happened that the life of this man, who has done much more than anyone else for experimental analysis of mental activity, concurred in time and in place with a culture that elevated human reason... Academician Pavlov's name is intimately associated with Science to which he dedicated his life, with Russia, his motherland-which he loved dearly and despising all good things of life, would not leave it despite its travails in the first three decades of the 12th century.
The author would like to express his cordial thanks to V. Samoilov, head of the Physiology Department of the Academy of Military Medicine, and Corresponding Member of the Russian Academy of Medicine as well as to workers of the I. P. Pavlov memorial museum, of the I. P. Pavlov Institute of Physiology (Russian Academy of Sciences), and of the Military-Medical Museum of the Defense Ministry of the Russian Federation for their kind help and assistance.
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