CHEMISTRY IN RELATION TO BIOLOGY AND MEDICINE WITH ESPECIAL REFERENCE TO INSULIN

AND OTHER HORMONES1

YOUR speaker to-day is one who is primarily a worker in the field of experimental medicine; a chemist, if at all, only in so far as an imperfect mastery of your science became necessary for the solution of physiological and pharmacological problems that could not be undertaken or even formulated if their chemical aspects were to be ignored. Under the circumstances I can but feel a sense of deep unworthiness in venturing to address an audience in which are gathered so many distinguished representatives of your noble science. I am highly appreciative of the signal honor conferred upon me by the board of award of the Chicago Section of the American Chemical Society in the bestowal of the Willard Gibbs Medal and I beg the members of the board to believe that I am duly grateful to them.

There exists in our day an essential unity of outlook and interest among the majority of professional chemists, biologists and medical men in respect to the physical and chemical aspects of life. This unity of interest and unanimity of opinion in respect to the applicability of the laws of physics and chemistry to the elucidation of vital processes have their origin far in the past and date from a time long before chemistry had attained to its present dignity as an independent science. It is not my purpose to attempt to record even briefly the history of chemistry or that of medicine, subjects that have been so well treated by many learned men of both professions, but I would ask your forbearance toward an imperfect sketch of the points of contact between your professional ancestors and mine. I leave out of consideration here any reference to such contacts in the ancient or later alchemical periods, or to Arabian science in Western Europe, further than to remark that alchemy, which at its best combined far-reaching metaphysical speculations with a crude experimental chemistry, had, as one of its several aims, not alone the transmutation of the baser metals into gold, thus abolishing that "great disease, poverty," but also

1 The Willard Gibbs lecture delivered before the Seventh Midwest Intersectional Meeting on the occasion of the award of the Willard Gibbs Gold Medal by the Chicago Section of the American Chemical Society, May 27, 1927.

the cure of fleshly ills and the gift of "perfect health and length of days." Certainly the search throughout the long alchemical period for the "elixir of immortal health" supports the claim for this medical aspect of alchemy, even without proofs on the literary side.

To-day the modern alchemists among you have, in a most remarkable manner and in a most concrete way, actually realized the age-long dream of your predecessors. Paneth well describes the chemical and the medical actions of the modern philosophers' stone, radium, in the following words:

Thus we see that in a certain sense radium possesses the first and principal property ascribed to the philosophers' stone: it has the power of transmuting elements, although not of producing gold. And, oddly enough, even in respect to the second property which was ascribed to the philosophers' stone radium seems to have gotten something from its fabulous predecessor: it is a very valuable aid in the treatment of some severe diseases, although not a perfect remedy for every illness. So that to a certain degree the radium rays really produce the two very different effects of the philosophers' stone, transmutation and healing.

Even in the later alchemical period the older professions of medicine and pharmacy furnished opportunity, though often grudgingly given, for the development of chemistry, and they may justly be said to have been the parents of modern chemistry. Throughout this period, as in ancient times, there existed a large number of industries, such as the metallurgical industries, enamel- and glass-making, painting, brewing and wine-making, to give only a few examples. But the practice of these ancient arts could not lead to the development of a chemical science as long as the true character of organic principles of the elements and their compounds remained unknown. Especially close was the connection between chemistry and medicine in the days of the iatro- or physician-chemists of the sixteenth and seventeenth centuries. In the first half of the sixteenth century, at a time when the crude chemistry of that day was still entangled with the traditions and even downright impostures of alchemy, there appeared an extraordinary man, Paracelsus (1493-1541), "the very incarnation of the spirit of revolt" (Osler), who must indeed be regarded as one of our ancestors in both branches of learning. Remember that in his day medicine was already a long established and powerful profession and this bold innovator in chemical physiology, pathology and pharmacology, who heaped scorn on Galen and Avicenna, very naturally aroused the hostility of many of the leading physicians of the day.

He is the most notable figure among the earlier physician-chemists and, in the words of the historian E. v. Meyer, to him belongs incontestably the credit of fusing chemistry and medicine in the first half of the sixteenth century, of forcing both into new paths and of freeing chemistry from the shackles of alchemy. Up to our time some of his writings have appeared in no less than five hundred editions. He declared it the true purpose of chemistry not to be the making of gold but the preparation of medicines. "Alchemy is neither to make gold nor silver: its use is to make the supreme sciences and to direct them against disease." This too narrow a conception of the science was soon to be broadened out by the iatro-chemists of the century and more, following his death. He stated clearly that the processes of the animal organism are chemical in their nature and that health is a function of, or dependent on, the composition of the juices and tissues of the body. Even in regard to the rôle played by air in respiration, I find Robert Boyle, more than a century later, citing him in support of his own views, as saying "that as the stomach concicts meat and makes part of it useful to the body, rejecting the other part, so the lungs consume part of the air and proscribe the rest." Medical historians have occupied themselves more with an analysis of the medical achievements of Paracelsus, the Luther of medicine (Osler), than with his chemical discoveries, and his significance is perhaps greater for medicine than for chemistry. He is certainly of great importance in the history of chemical therapeutics and pharmacology. Sudhoff says of his work in these fields:

In

He was the first one to show how to separate the active principles from drugs and to use them in tinctures and extracts. He made important discoveries in chemistry: zinc, the various compounds of mercury, calomel, flowers of sulphur, among others, and he was a strong advocate of the use of preparations of iron and antimony. practical pharmacy he has perhaps had a greater reputation for the introduction of the tincture of opium"labdanum" or laudunum-with which he effected marvelous cures and the use of which he had probably learned in the East (Osler).

Naturally, I can not pause to give more than a very incomplete sketch of this innovator whom I here mention because of his constant insistence that physiological processes are chemical processes and that drugs by their chemical properties can bring about favorable chemical alterations in a diseased body.

It has for many years been a custom with me to characterize the vital importance of certain defensive substances and the products of internal secretion present in our bodies in the aphorism: We are walk

Also in human beings there is a natural apothecary in which are found all things as in the world (the macrocosm), good and bad, simples and composites, however they be named. As the outer world, the macrocosm, contains visible pharmacies and visible physicians, so in the microcosm, that is to say, in the human being, there is present an invisible pharmacy and an invisible physician who produces, prescribes, dispenses and administers suitable remedies as occasion demands. 1. Let it be known to all men then that had not God created and placed in the bodies of men natural remedies and a natural physician, then, notwithstanding all the efforts of our physicians, not a single creature of earth would remain alive.

In this quite modern fashion Paracelsus here restates the enduring canon of Hippocrates-Novowv φύσιες ιατροί-better known to us in its later paraphrased form as vis medicatrix naturae. Professor Max Neuburger, the learned professor of the history of medicine at Vienna, truly remarks that the problem of nature's healing power is probably the most weighty of all that have engaged the thoughts of physicians during thousands of years.

The iatro-chemists were the physiological chemists of their day. They possessed the highest scientific and humanistic culture of the time and historians of science agree in the opinion that chemistry profited greatly by passing into their hands. The study of their attempts to elucidate the phenomena of life and the chemical alterations associated with disease is a fascinating one. The physiologists, biochemists and pharmacologists of our day have at their disposal a great wealth of discovery in the more exact sciences— the gifts of the intervening centuries, but even with all this assistance modern iatro-chemists still find themselves trying, though confidently, to hack their way out of the jungle so boldly and gaily entered by their predecessors nearly three hundred years ago.

Naturally you will call to mind also, as every one must, the iatro-physicists of this period. It is thought that the physiological speculations of Descartes, as given in his treatise De Homine, had a great influence in turning men's minds to the possibility of basing physiology on physics and chemistry, but there is little doubt that the teachings and discoveries of Harvey had the greater influence on the development of iatro-physics. This phase of science, however, lies outside our present discussion.

I must content myself with recalling to your minds a few of the names of the iatro-chemists of this period -van Helmont and Sylvius, of whom Michael Foster, with a first-hand knowledge of their writings and those of their pupils, has given such an enlightened and sympathetic account in his Lane Lectures on the History of Physiology in the sixteenth and seventeenth centuries Tachenius, Willis, Mayow, Lémery, Hooke, Peyer, Brunner and many others of this time might be named who forwarded both chemistry and medicine in the latter half of the sixteenth and well on into the seventeenth century.

One great man, Robert Boyle, nobleman of wealth, stands out prominently in the seventeenth century, one whose name is revered alike by physicists, chemists and medical investigators. This greatest chemist of his day, though not trained as a medical man, nevertheless, says one of his biographers, Thomas Birch, "went very accurately through all the parts of Physic." A study of his writings furnishes ample evidence of his acquaintance with medicine and the medical theories of his day. This great man even occupied himself with therapeutical questions and published "collections of choice and safe remedies, for the most part simple and easily prepared, very useful in families and fitted for the service of country people." The historian Neuburger in his scholarly treatise entitled "Die Lehre von der Heilkraft der Natur im Wandel der Zeiten" devotes several pages to Boyle's views in regard to the respective rôles of "nature" and the physician "in restoring the distempered body to its pristine state of health," and states that Boyle's opinions on these matters were not without value and precipitated many controversies.

Boyle was particularly fascinated by that fundamental problem-the nature of the respiratory process -of which he says that "it is a subject of that difficulty to be explained and yet of that importance to human life that I shall not regret the trouble my experiments have caused me if they are found in any degree serviceable to the purpose for which they were designed." I have been surprised to learn, in my study of his writings, with what ardor Boyle pursued the effects of diminished air pressure, with his improved Guericke "pneumatic machine," on a great variety of animals. Bees, flies, butterflies, caterpillars, humming birds, sparrows, larks, mice, fishes, eels, unborn puppies, all served as objects of experiment in the study of this great problem which was to occupy the attention of his successors down to our day. At a time when, in spite of some earlier approaches to the truth, it was still generally held that the sole purpose of breathing is to cool the blood,

Boyle's experiments forced upon him the conviction expressed as follows:

Without denying that the inspired and expired air may be sometimes very useful by condensing and cooling the blood that passes through the lungs, I hold that the depuration of the blood in that passage is not only one of the ordinary, but one of the principal uses of that passage. But I am also apt to suspect that the air doth something else in respiration which hath not yet been sufficiently explained.

The last sentence suggests that Boyle may have had a prevision, years before the discovery of oxygen, that this "something else" is the respiration of the tissues themselves.

After citing the opinion of Paracelsus, an opinion not based on experimental evidence, that "the lungs consume part of the inspired air and proscribe the rest," Boyle, on the basis of his own extensive experimentation, makes the prophetic statement:

It seems we may suppose that there is in the air a little vital quintessence, if I may so call it, which serves to the refreshment and restauration of our vital spirits, for which use the grosser and incomparably greater part of the air being unserviceable, it need not seem strange that an animal stands in need of almost incessantly drawing in air.

of respiration. He mistakenly held that combustion occurs only in the lungs. Thus, in the well-known joint memoir with the great mathematician Laplace, published in 1780, the conclusion is arrived at:

Respiration is therefore a combustion, slow, it is true, but otherwise perfectly similar to the combustion of charcoal. It takes place in the interior of the lungs without giving rise to sensible light because the matter of the fire (the caloric), as soon as it is set free, is forthwith absorbed by the humidity of these organs. The heat developed by this combustion is communicated to the blood which is traversing the lungs, and from the lungs is distributed over the whole animal system (Foster's translation).

In spite, however, that the place where oxidation occurs is erroneously inferred to be in the lungs only rather than in the hidden recesses of the tissues of the body, Lavoisier is nevertheless the first chemist or physiologist to prove that the respiration exchange is the result of a combustion and he was the first to make quantitative measurements during respiration of the intake of the "respirable part" of the atmosphere (the oxygen of Scheele and Priestley, later so named by Lavoisier) and of the output of the "aeriform calcic acid" (the carbon dioxide or "fixed air" of Black). It is quite comprehensible that the creator of gravimetric analysis and the discoverer of the

All of his experiments lead him to support

the theory of Moebius that the genuine use of respiration is the ventilation not of heart but of the blood in its passage through the lungs, in which it is disburthened of those excrementitious steams proceeding for the most part from the superfluous serosities of the blood.

Truly, Boyle could touch no subject without leaving his mark on it. For example, the respiration of fishes, "being animals without lungs," also excited his curiosity, and he "thinks it not altogether absurd to say that their gills seem somewhat analogous (as to their use) to lungs." His experiments with the air pump had taught him that there is "wont to lurk in water many little parcels of interspersed air, whereof it is not impossible that fishes may make some use, either by separating it when they strain the water through their gills or in some other way."

Time and occasion permit only of a glance at a few other great peaks in the panorama that we are so hastily surveying. Let us pass at once from Boyle to Lavoisier, another immortal, one of the greatest among the founders of your science, often, indeed, called the creator of modern chemistry, but also one who made fundamental contributions to the theory

operations should have made this quantitative experiment in animal physiology.

There is not time while we are on this subject of the respiration to consider the work of Joseph Black, Robert Hooke, Richard Lower and others of that time. The physician-chemist John Mayow (164379), however, can not be passed over without a word. Like Boyle, Mayow saw clearly that respiration is supported, not by the air as a whole "but by the more active and subtle part of it, the spiritus nitroaerius," or spiritus igneo-aerius, and both by experiment and inference demonstrated the analogy between respiration and combustion. The increase of weight attending the calcination of metals he declares also as due to the absorption of the spiritus of the air. Mayow had sound notions in regard to the relation between increased muscular work and increased respiration a full century before Lavoisier and Priestley, but unfortunately, in conformity with the conceptions of his day, he states that his nitroaerial spirit is separated from the blood in the ventricles of the brain and passes thence in supposed nerve tubules to the muscles where it combines with "sulphur," in consequence of which union muscular contraction results. The numerous and ingenious experiments of Priestley (1733-1804), one of the last