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Just what are the glands of internal secretion? And how have we become possessed of whatever information about them we have? A brief review of how the idea of a gland of internal secretion came into the human mind and of the contributions that have converged into a single body of knowledge is worth while.

A gland is a collection of cells (those viscous globules which are the units of all tissues and organs). It manufactures substances intended for a particular effect upon the body economy. The effect may be either local or upon the body as a whole.

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.