Originally, a gland meant something in the body which was seen to make something else, generally a juice or a liquid mixture of some sort. A classical example is the salivary glands elaborating saliva. The microscope has shown us that every gland is a chemical factory in which the cells are the workers. The product of the gland work is its secretion. Thus the sweat glands of the skin secrete the perspiration as their secretion, the lachrymal glands of the eyes the tears as theirs. The collectivism of management and control is the only essential difference between them and the modern soap factory or T.N.T. plant.
Man as a carnivor, and as a consequent anatomist, has been acquainted with these more superficially placed glands for some thousands of years. During all this time and during the epoch of the achievements of gross anatomy, it was believed that the secretions of all glands were poured out upon some surface of the body. Either an exterior surface like the skin, or some interior surface, the various mucous membranes. This was supported by the discovery of canal-like passage ways leading from the gland to the particular surface where its secretion was to act. These corridors, the secretory or excretory ducts, are present, for example, in the liver, conducting the bile to the small intestine. Devices of transportation fit happily into a comparison of a gland to a chemical factory, corresponding thus closely to the tramways and railroads of our industrial centers.
Little more than a hundred years ago, it was observed that certain organs, like the thyroid body in the neck, and the adrenal capsules in the abdomen, hitherto neglected because their function was hopelessly obscure, had a glandular structure. As in so much scientific advance, the discovery or improvement of a new instrument or method, a fresh tool of research, was responsible. The perfection of the microscope was the reason this time.
If one wishes to trace the idea of internal secretion by cells to an individual, it is convenient, if not pedantic, to give the credit to Theophile de Bordeu, a famous physician of Paris in the eighteenth century. Bordeu came to Paris as a brilliant provincial in his early twenties and by the charm of his manner and daring therapy fought his way to the most exclusive aristocratic practice of the court. Naturally a courtier, taking to the intrigues of the royal court like a duck to water, making enemies on every hand as well as friends, and with a fastidious and impatient clientele, he yet found time to dabble in the wonders of the newly perfected microscope and to speculate upon the meaning of the novelties revealed by it in the tissues. He coined the thought of a gland secretion into the blood.
It was in the year 1749 that he came to Paris from the Pyrenees, a young medical graduate, destined to become the most fashionable practitioner of his time. At the age of twenty-three he was holding the professorship of anatomy at his alma mater, Montpelier, where his father was a successful physician. At twenty-five he was elected corresponding member of the Royal Academy of Sciences. A handsome presence and a Tartarin de Tarascon disposition assured his success from the start. The medical world was then composed of the emulsion of charlatanry and science Molière ridiculed. Success stimulated envy and jealousy. One of the richest of the older medical men set himself the job of procuring his scalp. On a trumped-up charge of stealing jewels from a dead patient-a favorite accusation against the doctors of the eighteenth century-he had Bordeu's license taken away from him. The good graces of certain women to whom Bordeu had always appealed, and who indeed supplied the funds to get him started in Paris, rammed through two acts of Parliament to reinstate him. Nothing daunted, he returned to his quest for a court clientele, and was rewarded finally by having the moribund Louis XV as a patient.
This was the man with whom the modern history of the internal secretions begins. Not content with adventures among the courtiers and desperadoes of the most corrupt court in the most corrupt city of the world, he went in for research. The high power microscope that came into vogue when he was studying, revealed vague wonders which he described in a monograph, "Researches into the mucous tissues or cellular organs." But what makes him interesting is a slender volume on the "Medical Analysis of the Blood," published in the year of the American Declaration of Independence. The sexual side of men and women aroused Bordeu's most ardent enthusiasms. Starting with observations on the characters of eunuchs and capons, as well as spayed female animals, he formulated a conception of sexual secretions absorbed into the blood, settling the male or female tint of the organism and setting the seal upon the destiny of the individual. Thus he must be donated the credit of anticipating the most modern doctrine on the subject.
The generation after him witnessed the triumph of the cell as the recognized unit of structure of the tissues, the brick of the organs. It was soon found that the cells of the more familiar glands, like the sweat or tear glands, resembled the cells of the more mysterious structures named the thyroid in the neck, or adrenal in the abdomen, of which the function was unknown. What had hitherto prevented classification of the latter as glands was the fact that they possessed no visible pathways for the removal of their secretion. So now they were set apart as the ductless glands, the glands without ducts, as contrasted with the glands normally equipped with ducts. Since, too, they were observed to have an exceedingly rich supply of blood, the blood presented itself as the only conceivable mode of egress for the secretions packed within the cells. So they were also called the blood or vascular glands.
The names which became most popular were those which represented a contrast of the glands with the ducts, conveying their secretion to the exterior, as the glands of EXTERNAL SECRETION and the glands without the ducts, the secretions of which were kept within the body, absorbed by the blood and lymph to be used by the other cells, as the glands of INTERNAL SECRETION. How different these two classes of glands are may be realized by imagining the existence of great factories manufacturing food products, which would diffuse through their walls into the atmosphere, to be absorbed by our bodies.
There are certain terms for the glands of internal secretion which are used interchangeably. They are spoken of often as the endocrine glands and as the hormone producing glands. Endocrine is most convenient for it stands for both the gland and its secretion. Hormone is employed a good deal in the literature of the subject. But it applies specifically to the internal secretion, and not to the gland.
THE EXPERIMENTAL PIONEER
All this clarification of the concept of the glands of internal secretion occurred in the first quarter of the nineteenth century. However, no inkling of their real importance to the body, of which quantitatively they form so insignificant a part, was apparently revealed to anyone. Not even the most daring speculation or brilliant guess work in physiology engaged them as material. Thus Henle, the great anatomist, calmly affirmed that these glands "have no influence on animal life: they may be extirpated or they degenerate without sensation or motion suffering in the least." Johann Müller, the most celebrated physiologist of his day and contemporary of Henle, wrote in 1844 and coolly stated, "The ductless glands are alike in one particular-they either produce a different change in the blood which circulates through them or the lymph which they elaborate plays a special r?le in the formation of blood or of chyle." In other words, they were dismissed as curious nonentities, of no real significance to the running of the body. Laennec, the French founder of the Art of Diagnosis in Medicine, once said that nothing about a science is more interesting than the progress of that science itself. He might have added that nothing either was more interesting than the contradictions in that progress. For while these grand moguls of their sciences were enunciating their dogmas, pioneers here and there were already setting the mines that were to explode them.
The experimental method, to the value of which biologists were just beginning to awaken, was destined to be the vehicle of Time's revenges. An application of it to the mysteries of sex was the immediate occasion. Sex and sex differences have always more or less obsessed the imagination of mankind. The volumes of theories about them would constitute a respectable museum. Certain gross facts, however, were known. The effects of loss of the sex glands upon the configuration of the body and the predominating constitution in animals and eunuchs have always attracted attention. The proverbs and stories of all nations are full of references to them. But up to the nineteenth century no controlled experimental work was ever carried out regarding them. It was in 1849, that A.A. Berthold of G?ttingen, a quiet, sedate lecturer, carried out the pioneer experiment of removing the testes of four roosters and transplanting them under the skin. It was Berthold's idea to test whether a gland with a definite external secretion, and a duct through which that secretion was expelled, but which yet had powers over the body as a whole that were to be attributed only to an internal secretion, could not be shown, by a clean-cut experiment, to possess such an internal secretion. He succeeded perfectly. For he found that, though, in thus separating the gland from its duct and so cutting off its external secretion, the action of the cells manufacturing that secretion was destroyed, the general effects upon the body were not those of castration. The animals retained their male characteristics as regards voice, reproductive instinct, fighting spirit and growth of comb and wattles. Whereas if the glands were entirely removed, these male traits, peculiar to the rooster, were completely lost. The inference was the existence of an internal secretion.
To Berthold belongs the honor of being the first experimental demonstrator who proved the reality of a gland with a true internal secretion and the power it exercised through the blood upon the entire organism. Besides, he showed that a typical gland of external secretion could also have an internal secretion, a possibility never before considered. That two kinds of cells could live within the same gland: one set usually recognized as producing the external secretion, the other evolving the internal secretion, was an astounding original conception.
ENTER CLAUDE BERNARD
Science is supposed to be immune to the personal prejudices and emotional habits of the vulgar. It is the tradition that a new contribution to knowledge emerging from no matter how obscure the source, should be hailed as a gift from the gods. But the sad truth of the matter is that a new finding in science requires as much backing as a new project in high finance or social climbing. Berthold, like Mendel, the founder of genetics, was a great pioneer. But there was no personage, no person of consequence, with no patronage by anyone of consequence, no wife or kin, to push him, and no audience to stimulate him. His poor four little pages of a report, published ten years before Darwin's "Origin of Species," attracted not the slightest notice. Buried in the print of a journal with a subscription list of possibly two or three hundred, of whom perhaps two dozen may have been interested enough to read it, but without any recorded reaction on the part of any of them, it was a flash in the pan. Though it was good, original, conclusive stuff, it was cut dead, absolutely, by the scientific world. As a result, forty years elapsed before the implications of his studies were rediscovered by the Columbus of the modern approach to the internal secretions, the American Frenchman, Brown-Séquard.
It took a first class man of genius in his field, in Paris, with a respected position in the whirl of its medical planetary system and a university appointment, to boom and advertise the doctrine of the internal secretions, so that people began to sit up and listen and take sides-on the wrong grounds. This Frenchman was Claude Bernard. At a series of lectures on experimental physiology delivered at the College of France, in 1855, he coined the terms internal secretion and external secretion and emphasized the opposition between them, on the basis of an incorrect example, the function of the liver in the supply of sugar to the blood.
Just as Columbus reached America, carried on a series of logical syllogisms, built upon unreal pictures of a straight path to the East, Claude Bernard opened up the continent of the internal secretions to the experimental enthusiasts of his time by a discovery which today is not grouped among the phenomena of internal secretion at all. In attempting to throw light upon the disease diabetes, in which there is a loss of the normal ability of the cells to burn up sugar, he examined the sugar content of the blood in different regions of the body. He found that the blood of the veins, in general, contained less sugar than the blood of the arteries, which meant that sugar was taken from the blood in passing through the tissues. But the venous blood of the right side of the heart contained as much sugar as the arterial blood. Evidently, somewhere, sugar was added to the blood in the veins before it got to the heart. The blood of the vein which goes from the liver to the right side of the heart was then found to contain a higher percentage of sugar than is present in the arteries. The vein which transmits the blood from the intestines to the liver had the usual lower percentage of sugar corresponding to the analysis established for the other veins. The liver, therefore, must add sugar to the blood on its way to the heart. Extraction of the liver then revealed the presence in it of a form of starch, an animal starch, which Bernard called glycogen, the sugar-maker. The origin of the sugar added to the blood on its way from the liver to the heart was thus settled. Bernard went on to hail glycogen and the sugar derivable as the internal secretions of the liver, and to erect, and then drive home, a theory of internal secretions and their importance in the body economy.
The case he had hit upon was exquisitely fortunate, as the liver had hitherto been regarded purely a gland of external secretion, the bile. Nowadays, glycogen and the blood sugar are not considered internal secretions, because they are classified as elementary reserve food, while the concept of the internal secretions has become narrowed down to substances acting as starters or inhibitors of different processes. Moreover, the process of liberation of sugar from glycogen itself in the liver, upon demand, is today set down to the action of an internal secretion, adrenalin. Claude Bernard's conception, like a novelist's characters, has turned upon its creator, taken on a life of its own, and evolved into something he never intended. He looked upon an internal secretion as simply maintaining the normal composition of the blood, which bathed alike and treated alike the democracy of cells. Today, the blood is believed merely the transporting medium for the internal secretion, destined for a particular group of cells.
ADDISON'S AS THE FIRST ENGLISH CONTRIBUTION
The years 1855-56 are red-letter years in the history of the glands of internal secretion. They witnessed, not only the publication of Claude Bernard's "Lectures on Experimental Physiology," but also the appearance of a monograph by Thomas Addison, an English physician, entitled "On the constitutional and local effects of disease of the suprarenal bodies." In this, he described a fatal disease during which the individual affected became languid and weak, and developed a dingy or smoky discoloration of the whole surface of the body, a browning or bronzing of the skin, caused generally by destructive tuberculous disease of the suprarenal or adrenal bodies. Addison promptly put down these constitutional effects of loss of the adrenal bodies to loss of something produced by them of constitutional importance. He was particularly struck by the change in the pigmentation of the skin, so much so that his own designation for the affection was "bronzed skin." Since then, however, the condition has been universally styled Addison's Disease.
There is something spectacularly mysterious and picturesque about most of the malign, insidious effects of the disease which appealed at once to a number of investigators. The most adventurous, the most daring, the most imbued with enthusiasm for the experimental method, was the American Frenchman, Brown-Séquard, who is acknowledged the father of modern knowledge of the glands of internal secretion, though to Claude Bernard belong the honors of the grandfather.
BROWN-SéQUARD THE GREAT
Brown-Séquard, as the outstanding figure in the history of the glands of internal secretion, deserves some notice as a personality. In the words of the note-makers for novels and plays, he was a card. He was born in 1817 at Port-Louis, on the island of Mauritius, off Africa, then French property. His father was a Mr. Brown, an American sea captain; his mother a Mme. Séquard, a Frenchwoman. Early in childhood, the father sailed away on one of his voyages and never came back. The mother thereafter supported herself and her son sewing embroideries. At fifteen, Brown-Séquard, with the physical appearance of an Indian Creole, was clerking in a colonial store by day, and composing poetry, romances and plays by night. The call of Paris was in his blood, which was indeed a supersaturated solution of wanderlust.
Soon he was landed there to make his fortune in literature, only too speedily to be disillusioned. Exhibition of manuscripts to a leading literary light merely evoked curt advice to learn a trade or go into business. He would have none of either and studied medicine instead, earning his way by teaching as he learned. In the laboratories, he made the acquaintance of people who more than once were to be his salvation in the ups and downs of his career. In 1848 he was one of the secretaries of the Society of Biology, newly founded by Claude Bernard.
Some trouble, perhaps some effect upon his health of cholera which then swept Paris, caused him to return to his native Mauritius, to encounter an epidemic of cholera. There he slaved manfully, for which a gold medal was afterward struck for him. That over with, he embarked in 1852 for New York, without a word of American, learning English on board. This was the first of a series of voyages. As he often boasted, he crossed the ocean sixty times, not a bad record for the days when the Mauretania was still in the womb of time. He made a hopeless failure out of practice in New York, became so poor as to practice obstetrics at five dollars a case, and married a niece of Daniel Webster. Then he went back to Paris. Back to America next as Professor of Physiology at the University of Richmond, Virginia, a job occupied for a few months only because of his opinions on slavery, ostensibly anyhow.
To Paris then the rolling stone meandered again. So that soon after he was offered and accepted the charge of a great newly opened hospital for epileptics in London. That proved merely an interlude and in 1863 we find him back in his fatherland (if we may hold France his motherland) as Professor of Neuropathology at Harvard. In New York fame preceded him now with a thousand trumpets, so that on the day of his arrival, he was kept busy seeing patients until night, when he had to desist because of exhaustion. But still he did not prosper. An unfortunate second marriage almost broke his heart, and an attempt to found in New York a new medical periodical, the Archives of Scientific and Practical Medicine and Surgery, got him into hot water. Not until the death of Claude Bernard in 1878 left vacant the chair of physiology in the College of France, did he find peace and rest. He hastened to Paris, was appointed, and lived, in spite of the most erratic of existences, to the ripe old age of 78, working up to the last minute.
Addison's monograph stimulated Brown-Séquard, in the year after its printing, to reproduce the fatal disease experimentally by excising the suprarenal capsules in animals. Addison was very modest in his monograph. He stated that the first case of the malady had been reported by his great predecessor at Guy's Hospital, London, Richard Bright, the describer of Bright's Disease. Then he talks about the "curious facts" he had "stumbled upon" and refers to an "ill-defined impression" that these suprarenal bodies, in common with the spleen and other organs, "in some way or other minister to the elaboration of the blood." In the preface to his work he had spoken more confidently of the fact that Nature, as an experimenter and a vivisector, can beat the physiologist to a frazzle. Indeed, he begins like this: "If Pathology be to disease what Physiology is to health, it appears reasonable to conclude that, in any given structure or organ, the laws of the former will be as fixed and significant as those of the latter: and that the peculiar characters of any structure or organ may be as certainly recognized in the phenomena of disease as in the phenomena of health. Although pathology, therefore, as a branch of medical science, is necessarily founded on physiology, questions may nevertheless arise regarding the true character of a structure or organ, to which occasionally the pathologist may be able to return a more satisfactory and decisive reply than the physiologist-these two branches of medical knowledge being thus found mutually to advance and illustrate each other. Indeed, as regards the functions of individual organs, the mutual aids of these two branches of knowledge are probably much more nearly balanced than many may be disposed to admit: for in estimating them we are very apt to forget how large an amount of our present physiological knowledge respecting the functions of these organs has been the immediate result of casual observations made on the effects of disease." William James expressed the same thought some decades later, when he emphasized that the abnormal was but the normal exaggerated and magnified, played upon by the limelight, and therefore the best teacher and indicator of the exact definition and limitations of the normal.
Addison, speaking before the South London Medical Society in 1849, declared that in all of three afflicted individuals there was found a diseased condition of the suprarenal capsules, and that in spite of the consciousness "of the bias and prejudice inseparable from the hope or vanity of an original discovery ... he could not help entertaining a very strong impression that these hitherto mysterious organs-the suprarenal capsules-may be either directly or indirectly concerned in sanguification (the making of the blood): and that a diseased condition of them, functional or structural, may interfere with the proper elaboration of the body generally, or of the red particles more especially...." A modern, acquainted with after developments, would say that Addison was very hot upon the trail indeed. But withal, though he must have been well aware of John Hunter's advice to Jenner on vaccination, "Don't think, make some observations," his training in the indirect reasoning and deductions of the clinician prevented him from going right on to a direct experimental test of his theories.
This Brown-Séquard proceeded to do. Removing the adrenal glands in several species of animals, he found, meant a terrible weakness in twenty-four to forty-eight hours, and death shortly after. If only one were removed, there was no change apparent in the normal animal, but death occurred rapidly upon removal of the other, even after a long interval. Furthermore, transfusion of blood from a normal into one deprived of its suprarenals prevented death for a long time, indicating that the suprarenals normally secreted something into the blood necessary to life.
The years 1855-1856 beheld two other important glands of internal secretion, the thyroid, the gland in the neck astride the windpipe, and the thymus, in the chest above the heart, make their debut.
The thymus was introduced by the great classic monograph of Friedleben on the "Physiology of the Thymus," in which he mentioned the usual forgotten pioneers: Felix Plater, a Swiss physician, who in 1614 had found an enlarged thymus in an infant dying suddenly, and Restelli, an Italian, who interested himself in the effects of removal of the thymus more than ten years before. Friedleben believed that in the young without a thymus, there occurred a softening of the bones, and general physical and mental deterioration. He started the ball rolling for a number of researches.
Moritz Schiff, of Frankfort-on-the-Main, showed that excision of the thyroid gland in dogs is invariably fatal. A number of physicians in the first half of the century had reported certain remarkable symptoms associated with enlargement of the thyroid gland, as goitre. In 1825 the collected posthumous writings of Caleb Perry, an eminent physician of Bath, England, recorded eight cases, in which, together with enlargement of the gland, there developed enlargement and palpitation of the heart, a distinct protrusion of the eyes from their sockets and an appearance of agitation and distress. Schiff's paper was the first to throw any light on the subject. But for some reason, probably the same as in Berthold's forlorn experiments with the sex glands, the work of a person of no importance was ignored, or perhaps the more charitable view is that it was forgotten. Yet the tide of observation kept sweeping in relevant data.
In 1850, Curling, an English pathologist, studying the cretinous idiots of Salzburg, written about centuries before by Paracelsus, discovered that with their defective brain and mentality there was associated an absence of the thyroid body, and accompanying symmetrical swellings of fat tissue at the sides of the neck. Then Sir William Gull in 1873 painted the singular details of a cretinous condition developing in adult women, a condition to which another Englishman, William Ord, of London, five years later donated the title of myxedema, because of a characteristic thickening and infiltration of the skin that is one of its features.
Surgery then enters upon the scene. The great Swiss surgeon. Theodore Kocher, performed the first excision of the thyroid gland in human beings for goitre, in the same year. In 1882, J.L. Reverdin, another surgeon of Geneva, noticed that in man complete removal of the thyroid was followed by symptoms identical with those collected under the name of myxedema, and used the phrase "operative myxedema" to emphasize his conviction of the connection between them. Then Schiff, in 1884, neglected twenty-five years, came back, with an array of demonstrations, proving that the various symptoms, tremors, spasms and convulsions, following removal of the thyroid, could be prevented by a previous graft of a piece of the gland under the skin, or by the injection of thyroid juice into a vein or under the skin, or by the ingestion of thyroid juice or the raw thyroid by mouth.
A crystallization of ideas about the true function of the thyroid was now inevitable. In 1884, Sir Victor Horsley produced an experimental myxedema by removal of the thyroid in monkeys, resembling closely in its symptom-picture the disease as it occurs in human beings. M?bius, a German neurologist, came out boldly for the conception that a number of ailments could be due to qualitative and quantitative changes in the secretion of the thyroid, and that just as myxedema and cretinism were due to an insufficiency of the secretion, Parry's disease was to be ascribed to an excessive outpouring of it. The next steps were easy. In 1888, Sir Felix Semon, as an outcome of a collective investigation, established for all time that cretinism, myxedema and post-operative myxedema were one and the same.
It was bound to occur to someone that if human myxedema and animal experimental myxedema were one and the same, Schiff's procedure of prevention and cure by feeding thyroid gland by mouth in the latter could be applied to the former. The idea occurred to two men, Murray and Howitz, in 1891. Murray's patient, a Mrs. H., was shown before the Northcumberland and Durham Medical Society, an English country medical organization, in February, 1891. She was forty-two years old and had borne nine children. The illness attacking her had begun insidiously, with a gradual enlargement and thickening of her face and hands. She had become very slow in speech and gait, sensitive to cold, and languid and depressed in spirit to the point of inability to go about alone. Murray, employing the glycerin extract of the thyroid gland of a freshly killed sheep, injected twenty-four drops hypodermically, twice a week. There was an immediate and marvelous improvement, which continued steadily, Murray finding that it could be maintained by feeding the gland by mouth. The features and skin returned to the normal, speech quickened and she became able to walk about and live her life without hesitation or assistance. She lived to the age of seventy-four, dying in 1919. In the twenty-eight years, during which it was always necessary to administer the thyroid, she consumed over nine pints of thyroid, comprising the glands of 870 sheep.
Giants and dwarfs and fat people have always interested people as freaks, departures from the usual and the normal, and have formed the stock of popular museum, circus and country fair. Every mythology has concerned itself with them. The Titans among the Greeks, Og, Gog and Magog among the Hebrews, are examples of the fascination of the superlarge. John Hunter, the founder of experimental surgery, spent a fortune in chasing after the skeleton of a famous Irish Giant in 1783. Dwarfs have also fascinated-witness the short-limbed satyrs of the Greeks and the dwarf gods (Ptah and Bes) of Egypt, as well as the vogue of the court dwarf-buffoons, of whom Velasquez has left us some portraits. Fat people, obesity as a manifestation of personality, have aroused wonder and amusement the world over. The Fat Boy has always furnished good sport to the Sam Wellers.
All these characters, tall or short, fat or lean, are related to the activity of a gland of internal secretion in the head, the pituitary, which became a centre of interest in the late eighties. Because of its situation, the opinion of the ancients was that it was the source of the mucus of the nose, an opinion reinforced by the greatest anatomist of the Dark Ages, Galen, and held up to the seventeenth century. In other words, it was considered simply a gland of external secretion. Experimental removal of the pituitary was essayed by Horsley in 1886, the same man who two years before had reproduced myxedema successfully in monkeys. Others succeeded his attempt. But the conclusions drawn were uncertain or contradictory, resulting from the difficulties of the operative technique of getting at a gland placed at the base of the brain. Not until 1908 was the problem solved by Paulesco of Bucharest, who devised a way of reaching it by trepanning the skull. He was thus able to prove beyond a doubt that the pituitary gland was essential to life, and that without it no animal could continue to live for any length of time. Soon after, Harvey Gushing and his associates at Johns Hopkins Hospital discovered that removal of part of the gland was followed by a pronounced obesity and sluggishness. A basis for the understanding of obesity and growth was then established.
In the eighties, there came to the clinic of Pierre Marie in Paris, a pupil of the great Charcot, various women complaining of headache. They also told him about an enlargement of their hands and feet, and an alarming change in the bones of the face. He differentiated the affection from its imitators, and created its present designation of "acromegaly" (enlargement of the extremities). Also he correlated their relationship to the giants who have been mentioned. Acromegalics have been also likened to the Neanderthal Man, who had probably, as the gorillas may have, an excess of the pituitary in their systems. For four years he studied the morbid phenomena in the tissues of these sufferers at last consigned to their end. First one, and then another, and then a third and a fourth exhibited a striking hypertrophy of the pituitary body and a consequent widening of the portion of the base of the skull which cradles the gland. He proceeded to say so in the graduating thesis of his pupil, Souza Leite. The inference was inevitable that the entire process was to be put down to an overactivity of the pituitary. Ever since, too, the growth of the skeleton has been accepted as controlled by that gland.
About this time another set of old observations came to life again, related to those of Docent Berthold on the auto-grafting of the testes of a cock, with complete retention of its sexual characters, which he said, must be due "to the productive action of the testes, i.e., to its effect upon the blood, and thence to the corresponding effect of such blood upon the entire organism." Of course, stock raisers and poultry fanciers have noted the interesting outcome of castration for about as long as their professions have existed. And for ages the diminution of sexual activity as a predecessor to the decadence of senility has been harped upon. Rejuvenation, especially in connection with sexual activity, as well as with tissue and spiritual elasticity, has been one of the haunting phantoms of the imagination for as long as we have records of articulate humanity. Together with El Dorado, the Elixir of Youth has shared the honors with the Philosopher's Stone. The idea of employing the chemical materials of the sex glands, the testes or the ovaries, to bring back youth, to restore juvenility, had not, as far as we know, occurred to anyone who at any rate put himself on record, by word or deed, until 1889. The hero of the new departure was the hero of so many daring adventures among speculative experiments, Brown-Séquard.
At this time the wanderer was an aged sage, seventy-two years old, fit, as custom goes, only for retirement and resignation to the fate of all flesh. The old passion of experimenting upon himself as well as upon the guinea-pigs, dogs, cats and monkeys, by which he was always surrounded, was as alive and kicking as ever. I suppose he had been thinking for years concerning some method for the resumption of youth, for we find him exclaiming, when the opportunity loomed of a great laboratory on Agassiz Island, Long Island, on one of his recurrent flights to New York: "Would that I were thirty!" And other passages in his personal communications refer again and again to his consciousness of growing old. The miracles that were being performed by injecting thyroid and feeding thyroid in animals probably acted as the spark to an inflammable mass of ideas long smouldering in the subcellars of his mind. The effects were reported to the Society of Biology in Paris, one memorable evening, June 1, 1889, in two notes on the results of the hypodermic injection in man of the testis juice of monkeys and dogs, and certain generalizations deduced therefrom. Such juices, he stated, had a definite energy-mobilizing or, as he put it, dynamogenic action upon the subject himself, stimulating amazingly his general health, muscular power and mental activity.
These experiments, their nature, the manner in which they were conducted, the character and age of the experimenter, and the results claimed, were exquisitely good stuff for ridicule. Cartoonists and reporters leaped upon the theme with the avidity of the true-blue interviewer. Paris, where to be ridiculed is to be killed in public with the most ignominious of deaths, reacted as only the French temperament can react. The wits of the salons crackled, the bourgeoisie chortled, the proletariat roared. The Elixir of Life had been discovered and it was excellent sport.
But Brown-Séquard remained unshaken. He had all the roués of Paris running to him, and consequent charges of quackery and charlatanism. How much of these unsavory epithets really applied to him will not be determined until we have a better acquaintance with his more intimate life. A biography and collection of his letters is needed. But it is certain that the general principles he arrived at, aided as much by the wings of intuition as by the clues of incomplete and incompletely controlled experiments, survive as the foundations of whatever we know about the internal secretions, and all our present viewpoints. He summed these up in 1891 as follows:
"All the tissues, in our view, are modifiers of the blood by means of an internal secretion taken from them by the venous blood. From this we are forced to the conclusion that, if subcutaneous injections of the liquids drawn from these parts are ineffectual, then we should inject some of the venous blood supplying these parts.... We admit that each tissue, and, more generally, each cell of the organism, secretes on its own account, certain products or special ferments, which, through this medium (the blood), influence all other cells of the body, a definite solidarity being thus established among all the cells through a mechanism other than the nervous system.... All the tissues (glands and other organs) have thus a special internal secretion, and so give to the blood something more than the waste products of metabolism. The internal secretions, whether by direct favorable influence, or whether through the obstacles they oppose to deleterious processes, seem to be of great utility in maintaining the organism in its normal state."
The only part of this statement not conceded today is that relating to the formation of internal secretions by tissues other than those of which the cells are definitely glandular, that is secretory: as can be determined under the microscope. Brown-Séquard added to the concept of internal secretions, fathered by Claude Bernard, the idea of a correlation, a mutual influencing of them and of the different organs of the body through them. The nervous system had hitherto been regarded as the sole means of communication between cells, by its telegraphic arrangements of nerve filaments reaching out everywhere, interweaving with each other and the cells. The Brown-Séquard conception inferred the existence of a postal system between cells, the blood supplying the highway for travel and transmission of the post, the post consisting of the chemical substances secreted by the glands. To be sure, the doctrine was only an inference, though well-founded, of which the direct experimental proof was not to be obtained until the researches of Bayliss and Starling. Yet to Brown-Séquard belongs the immortal credit, if not of the originator, at any rate of the resurrector of the idea of using gland extracts to influence the body. The unwarranted hopes aroused by his enthusiastic reports of rejuvenating miracles have long since been dissipated. Moreover, they smeared the whole subject with a disrepute which clings to certain narrow and unreasonable minds to this day. But as every physiologist since has acknowledged, he was and remains the great path-breaker in the conquest of the internal secretions.
THE HORMONES
The problem of the internal secretions was now attacked from another angle. A great Russian physiologist, Pawlow, called attention to the fact that the introduction of a dilute mineral acid, such as the hydrochloric acid, normally a constituent of the stomach digestive fluid, into the upper part of the intestine, provoked a secretion of the pancreas, which is so important for intestinal digestion. He explained the phenomenon as a reflex, a matter of the nerves going from the intestine to the pancreas.
His pupil, Popielski, threw doubt upon so easy an explanation, by proving that the same reaction could be elicited even after all the nerve connections between the gut and the spinal cord were severed. If the relation was a reflex, it would have to be classed now as one of those local nerve circuits, which are pretty common among the viscera, a local call and reply as it were, without mediation of the great long distance trunk lines in the spinal cord and the medulla oblongata.
The work of Bayliss and Starling, two English physiologists, was commenced then to test the hypothesis. They soon found that the experiment could be so devised as to exclude any influence whatever on the part of the nervous tissues, and yet result positively. Thus, if a loop of intestine was so prepared as to be attached to the rest of the body only by means of its blood vessels, all the nerves being cut, putting some acid into it was still followed by a flow of pancreatic juice, no less marked than when none of the parts about the piece of gut had been disturbed. It was evident that the stimulus to the pancreas was carried by way of the blood stream. That the stimulating substance was not the acid itself, was shown by the failure of the reaction to occur when the acid was injected directly into the blood stream. Since there was this difference in the effects between acid in the intestine and acid in the blood, it was manifest that the active substance must be some material elaborated in the intestinal mucous membrane under the influence of the acid. So they scraped some of the lining of the bowel, rubbed it up with acid, and injected the filtered mixture into the blood. They were rewarded by a flow of pancreatic juice greater in amount than any obtained in their other experiments. From the filtered mixture they isolated in an impure form, a solid substance which, when introduced into the circulation, has a similar action. To this, of which the exact chemical make-up is as yet an unknown, they gave the name secretin.
Secretin and its properties they used to generalize as a perfectly direct and amply demonstrable example of an internal secretion. Metaphors are no less valuable in physiology than in poetry. They declared that the internal secretions appeared to them to be chemical messengers, telegraph boys sent from one organ to another through the public highways, the blood (really more like a moving platform). So they christened them all hormones, deriving the word from the Greek verb meaning to rouse or set in motion. As a science is a well-made language, a new word is an event. It sums up details, economizes brain-work and so is cherished by the intellect. The study of the internal secretions has advanced by leaps and bounds since it became convenient to speak of them as hormones. Withal, the brilliant work of Bayliss and Starling stands as the third great foundation stone, the first Claude Bernard's and the second Brown-Séquard's, in the architecture of the modern concepts of the internal secretions.
APP STORE
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