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, ent.i.tled "On the const.i.tutional 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 const.i.tutional effects of loss of the adrenal bodies to loss of something produced by them of const.i.tutional 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-Sequard, 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-SeQUARD THE GREAT

Brown-Sequard, 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. Sequard, 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-Sequard, 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 wanderl.u.s.t.

Soon he was landed there to make his fortune in literature, only too speedily to be disillusioned. Exhibition of ma.n.u.scripts 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-Sequard, 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 ill.u.s.trate 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-Sequard 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 cla.s.sic 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 a.s.sociated 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 s.e.x 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 a.s.sociated 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 t.i.tle 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. Mobius, a German neurologist, came out boldly for the conception that a number of ailments could be due to qualitative and quant.i.tative 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 Northc.u.mberland 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 a.s.sistance. 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 t.i.tans 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 G.o.ds (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 amus.e.m.e.nt 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 a.s.sociates at Johns Hopkins Hospital discovered that removal of part of the gland was followed by a p.r.o.nounced 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 c.o.c.k, with complete retention of its s.e.xual 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 s.e.xual activity as a predecessor to the decadence of senility has been harped upon. Rejuvenation, especially in connection with s.e.xual 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 s.e.x 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-Sequard.

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 pa.s.sion 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 Aga.s.siz Island, Long Island, on one of his recurrent flights to New York: "Would that I were thirty!" And other pa.s.sages 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 ma.s.s 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-Sequard remained unshaken. He had all the roues 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-Sequard 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-Sequard 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-Sequard 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 const.i.tuent 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 cla.s.sed 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 sc.r.a.ped 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-Sequard's, in the architecture of the modern concepts of the internal secretions.

CHAPTER II

THE GLANDS: THYROID AND PITUITARY

The glands of internal secretion, the history of which, as tools of thought, I reviewed in the previous chapter, have each an interesting evolutionary story. Without some acquaintance with that story, the rough outline of their physical architecture, and the particular work they are called upon to perform in the body, no adequate understanding of their influence upon types of human nature and personality is possible.

THE THYROID GLAND

This gland consists of two maroon colored ma.s.ses astride the neck, above the windpipe, close to the larynx. These are bridged by a narrow isthmus of the same tissue. They remind one of the flaps of a purse opened up. The gland has always attracted much attention because its enlargement const.i.tutes the prominent deformity known as goitre.

To begin with, the thyroid was once a s.e.x gland, pure and simple. In the lowest vertebrates and in the h.o.m.ologous tissues of the higher invertebrates, the fractions of the thyroid are intimately connected with the ducts of the s.e.xual organs. They are indeed accessory s.e.xual organs, uterine glands, satellites of the s.e.x process. From Petromyzon upward that relationship is lost, the thyroid migrates more and more to the head region, to become the great link between s.e.x and brain.

How alive that function still is, is grossly shown by the swelling of the gland with s.e.xual excitement, menstruation and pregnancy.

Relative to the body weight it is largest in the mammalia, and smallest in the fishes. It therefore grows larger as the vertebrate ascends in the scale. It has, in fact, developed in direct proportion to and side by side with the fundamental, differentiating vertebrate characteristics. Of these, the possession of a dry hairy skin instead of a moist or mucus bearing, chitinous skin, the ownership of an internal bony skeleton and a large skull, and a complicated development of brain, are the diagnostic signs. Thyroid internal secretion has a very definite controlling relation to all of them: to skin, its hairiness, moisture and amount of mucus, to the growth and size of the bones, especially the bones of the extremities and the skull, and to intelligence and the complexity of the convolutions of the brain. Injury to the thyroid, especially in growing animals, is followed by profound retrogression or arrest of development in skin, skeleton and brain.

In the fishes and the cyclostomes the thyroid is represented only by some small scrubby patches, little larger than the heads of pins, scattered along the aorta, the great blood vessels from the heart, and out a little way along each gill. It becomes larger and more compact among the amphibians and reptiles, but still remains quite small.

Large and prominent among the birds and mammalia, it is largest and most prominent among the primates and man. It is hence permissible to think of the thyroid as a dictator of evolution, to crown it as the vertebrate gland par excellence, and to call the typical vertebrate brand marks secondary _thyroid_ characteristics in precisely the sense of Darwin cla.s.sing the horns of cattle as secondary _s.e.xual_ characteristics.

In such enthusiasm for the thyroid as a determinant of evolution, its pillar of cloud by day and column of fire by night, one should not forget the other glands of internal secretion. In them all, we may suppose, Life, tired of inventing merely prehensile, destructive and reproductive organs, hit upon the happy thought of contrivances which are in essence chemical factories to speed up the rate of variation and so of a higher evolution.