Popular Science Monthly/Volume 66/December 1904/The Present Problems of Physiological Chemistry

by Russell Henry Chittenden

Layout 4

THE PRESENT PROBLEMS OF PHYSIOLOGICAL CHEMISTRY.^[1]

BY RUSSELL H. CHITTENDEN,

DIRECTOR OF THE SHEFFIELD SCIENTIFIC SCHOOL OF YALE UNIVERSITY.

IN considering a proper presentation of the subject assigned me, I am impressed with the influence which a man's own field of work and his own line of thought will naturally exercise upon his point of view. It may be questioned whether his judgment can be wholly trusted, whether he will not, in fact, unconsciously it may be, give a dwarfed or one-sided presentation of the subject from a natural habit of looking at things in their bearing upon the line of work and thought in which he himself is personally most interested. While this may not be wholly undesirable, still of greater advantage will be a brief but judicious presentation of all the more important problems that confront the physiological chemist of the present day, but whether this can be done satisfactorily in the time allotted is very questionable. However, the effort will be made to emphasize, so far as the time will allow, what to the writer seem the more significant and far-reaching problems in physiological chemistry that call for speedy solution.

Of fundamental importance is the question, what is the exact chemical constitution of proteid matter? The basis of all cell life, the most complex molecule that enters into the structure of the living organism, proteid or albuminous material holds a peculiar position. A labile molecule, it is easily prone to change, and its many decomposition products confront us on all sides in our study of life's processes. Yet to-day, in spite of all that has been accomplished, even with the brilliant work of Kossel and Emil Fischer, we still lack adequate knowledge of all the groups and radicles that are combined in this atomic complex.

In the study of metabolism and nutrition, both in health and in disease, in our conception of the anabolic processes of life, in our theories regarding the chemical relationships of the varied katabolites floating about through the organism and in many other connections, we need for our guidance a full knowledge of the chemical nature of this most important class of substances. Thanks to the work of many brilliant investigators, our knowledge is progressing and broadening, but we still lack that comprehensive understanding of the inner structure of the molecule that would serve to illuminate our field of vision and give us a clear conception of the chemical constitution of this group of physiologically important ground substances in living protoplasm.

As is well known, the proteid bodies constitute a group of widely divergent substances. Of these, the basic protamines are undoubtedly the simplest and lowest in the scale, and it is quite probable, as suggested by Kossel, that these substances constitute the nuclei of all proteids. The protamines differ somewhat among themselves, but as a group they are characterized by their high content of diamino-acids, especially arginin. Thus, salmin yields on decomposition 84 per cent, of arginin, clupein 82 per cent., cyclopterin 62 per cent., and sturin 58 per cent.^[2] Sturin also contains 13 per cent, of histidin and 12 per cent, of lysin, while the other protamines appear to contain no diaminoacids aside from arginin. Further, the protamines contain cliamidovalerianic acid, monoamido-valerianic acid, tyrosin or p-oxyphenylamidopropionic acid, skatolaminoacetic acid, a-pyrrolidincarbonic acid and serin.^[3] Salmin^[4] has also been shown to contain alanin, leucin, probably also phenylalanin and aspartic acid.

If we pass from the simplest of the proteid bodies to the most complex, as the nucleins, we find present in the latter not only arginin, lysin and histidin, but, in addition, such bodies as thymin, the purin bases, leucin, aspartic and glutamic acids, two sulphur-containing groups, furfurol-forming groups, pyrrolidincarbonic acid, a skatolforming group, phosphoric acid, amidovalerianic acid, a levulinic acidforming group, glycosamine, pentose, uracil and probably phenylamidopropionic acid.^[5] In the histon from the nucleohiston of the thymus, we find in addition to the hexone bases and the monoamido-acids characteristic of the ordinary albuminous bodies such substances as glycocoll, cystin and alanin.

These statements, brief and incomplete though they are, will serve to illustrate the complexity of the proteid molecule, and at the same time they indicate the close genetic relationship which unquestionably exists between the varied members of this large group of substances. There is no doubt that Kossel and his co-workers in their efforts to unravel the constitution of the protamines are pursuing a wise course in paving the way for a comprehension of the exact nature of the more complicated proteids. There is no doubt that the protamines of one type or another are integral parts of every proteid molecule, and when their chemical constitution is made quite clear, much will have been accomplished toward a fuller understanding of the more complicated forms.

It needs no imagination to foresee what a full knowledge of the chemical constitution of all types of proteid matter will mean for the physiologist and physiological chemist. Much that is now cloudy and uncertain in our understanding of cell and tissue metabolism, in our comprehension of nutritive changes in general, of digestive proteolysis and of intracellular autolysis, will become clear as crystal. The problem, however, is not a simple one, but is exceedingly complex, for it is to be remembered that just as the individual proteids differ from each other in superficial reactions and characteristics, so do they undoubtedly differ in their inner structure. Hence, we must expect to find variations in the make-up of the individual molecules, and it is one of the most important problems of to-day to ascertain the nature of these chemical variations, to recognize the individual groups that give character to the molecules and to learn how these groups are bound together to make the typical proteid of this and that tissue or organ. The solution of this problem promises much for the advancement of physiological chemistry, but it holds out the promise of even more for the good of physiology in general, since there is bound up in the chemical structure of the proteid molecules a full and complete explanation of tissue changes, and of many metabolic phenomena which to-day are as sealed volumes.

The development of our knowledge regarding the cell as a physiological unit has led to a fuller recognition of the importance of discriminating between the primary and secondary cell constituents. As a result, the physiological chemist has come to realize the necessity of more exact knowledge as to the nature and distribution of the primary components of cells, because of the bearing this knowledge may have upon the general question of how far the lines of chemical decomposition characteristic of each group of cells are dependent upon the character of the anabolic processes by which that particular cell protoplasm is formed, and how far the peculiar katabolic or retrogressive changes of that group of cells are due to outside influences, exerted by specific nerve fibers, or by the character of the blood and lymph stream. The physiological chemist would know whether the secret of glandular secretion, of tissue changes, of metabolic activity, is to be found in the particular forms of protoplasm that enter into the structure of the component cells, whether it is associated in any way with some inherent quality of the primary cell constituents.

There is something marvelous in the unerring certainty with which a given group of cells performs its work, never deviating a hair's breadth from the beaten course, and turning out year after year a definite line of products for the specific purpose in view. Why is it that the epithelial cells of the salivary glands always manufacture mucinogen and ptyalin; the gastric gland cells pepsinogen, renninogen and hydrochloric acid; the cells of the pancreas trypsinogen and steapsin; the hepatic cells bilirubin, biliverdin and the specific bile acids; the cells of the thyroid iodothyrin, and the cells of the adrenals epinephrin? Essentially the same blood and lymph bathe all these cells with a like nutritive pabulum, and yet each group of cells performs its own line of work, never going astray, in health, and never even temporarily producing a product which rightfully belongs to the other class of cells. Are we to suppose that all these varied products are manufactured from the same cell protoplasm, from a common stock, that each one owes its origin to some particular force controlled by extra-cellular influences, each group of cells' being made to manufacture a given product out of the same mother substance? Or, on the other hand, are we to assume that each group of cells, as it is developed, has as a birthright the quality of producing from its particular protoplasm a certain line of products, simply because of the peculiar chemical nature or constitution of that protoplasm?

In other words, do all the intricacies of cellular activity depend primarily upon the character of the anabolic processes by which that protoplasm is built up out of the food materials by which the cells are nourished? It may be just as difficult to explain why and how the cells are able to manufacture a specific protoplasm out of a common pabulum, but the main problem which confronts us is surely capable of being solved. We need to know how far the primary cell constituents of different groups of cells, of the different organs and tissues are similar or unlike each other. If it is shown that the primary cell constituents differ for each glandular organ and tissue, that each group of individualized cells has a protoplasm characterized by some specific feature, then we shall have reason to believe that the anabolic processes are as much, if not more, responsible for individuality of function than the katabolic processes. We may conceive of all protoplasm being built, so to speak, on a certain general plan of structure, but with side chains of varying nature, and that these side chains determine in a measure the character of the katabolic or alteration products that result from the natural activity of the cell protoplasm. In other words, if this conception be true, it is the chemical constitution of the cell protoplasm that is primarily responsible for the character of the changes that take place in all active tissues and organs. The extent of oxygenation as influenced by the circulating blood, the direct and indirect influence of various nerve fibers, etc., may all act as modifying agents, but only to the degree of accelerating or inhibiting the rhythmical process which travels along a certain definite channel because of the peculiar chemical nature of the cell protoplasm. Once started, the process of katabolism takes a definite course, with formation invariably of the same products, because that particular cell protoplasm, owing to its peculiar make-up, tends to break down along certain definite lines of cleavage, as it were, and so the products split off are always the same.

We already have considerable knowledge which tends to indicate that the cells of individual organs and tissues have a certain individuality as regards their primary components, notably in the nucleoproteids present, but our knowledge is by no means complete enough to permit of broad generalization. The problem is an interesting one, and permits of a definite answer by the application of thorough and persistent investigation.

As an allied question, more or less in harmony with what has just been said, reference may be made to the part which ferments and enzymes possibly play in initiating and carrying forward tissue changes, as well as the metabolic changes that occur in glandular organs. Ferments have come into such prominence of late years as responsible agents for so many transformations, that we may well query whether their influence does not extend far beyond the limits originally assigned to their field of activity. The discovery of oxidases and the part which these agents may play in tissue changes, the undoubted existence of ferments in such glands as the thymus, suprarenal, spleen, etc., by which the recently studied autolytic changes in these glands are produced, raise the question whether ferments or enzymes are not far more largely responsible for the many transformations that take place in active tissues than has been hitherto supposed. Consider for a moment the peculiar products which result from the self-digestion (autolysis) of many of the glands so far studied. Note how the nucleoproteid of the thymus, for example, breaks down, yielding xanthin and a little hypoxanthin, together with uracil, but no guanin, adenin or thymin.^[6] How the adrenal nucleoproteid likewise yields by autolysis considerable xanthin, but only traces at the most of the other alloxuric bases (Jones). By the self-digestion of the spleen, guanin as well as hypoxanthin is conspicuous, but it is a noticeable fact that in the autolysis of the thymus, for example, there is no appreciable amount of leucin to be detected, thus indicating that the above autolytic changes are not due to any ordinary proteolytic enzyme, but to some peculiar enzyme which acts directly and solely upon the nucleoproteids, splitting off certain of the contained alloxuric groups. In harmony with this view, Jones has just announced the presence in the pancreas, thymus and adrenals, of an enzyme to which he gives the name of guanase, which has the power of transforming guanin into xanthin. The same investigator also claims the presence in the spleen of a related enzyme, called adenase, which transforms adenin into hypoxanthin. The inference is that in many glands and tissues there are specific enzymes, as yet undiscovered, which may be responsible for at least some of the transformations known to occur there.

That autolysis may be a possible explanation of the process of animal metabolism has been suggested by Levene^[7] and also by Wells,^[8] It has been clearly indicated by such able workers as Salkowski, Jacoby and others, that practically all animal cells contain within themselves ferments or enzymes that are capable, under suitable conditions, of digesting or breaking down the cell contents by a process similar to ordinary proteolysis, and it may perhaps be assumed that all active cells carry forward their ordinary metabolic processes by the agency of these intra-cellular ferments. Moreover, it is not inconceivable that ferments or enzymes of several kinds may exist side by side in a given group of cells, just as they are known to exist in the pancreas, by which we might infer the possibility of a series of transformations taking place at essentially the same time, through the harmonious action of a row of enzymes physiologically quite distinct.

Further, the recently discovered reversible action of enzymes, on which we have at command so much valuable work, suggests the possibility of a maintenance of cell equilibrium through this peculiarity of action, thus affording a tangible explanation of the means by which intra-cellular nitrogenous or proteid equilibrium is maintained, the various cells of the body building up or breaking down the proteid matter of their own tissues as circumstances require. If these ideas are true, then our conception of ferment action must be considerably broadened, and we have before us the possibility of explaining many of the phenomena of tissue metabolism by the action and interaction of intra-cellular enzymes. This is a problem well worthy of broader study, with a view to the elucidation of the general laws that govern tissue changes in general. In this connection we also have suggested the possibility of interaction of another kind, viz., that interdependence of one tissue or gland upon another for the full development of its functional activity, as illustrated by the part played by the enterokinase of the intestinal glands in the development of an active trypsin from the zymogen of the pancreatic cells, and by the action of the internal secretion of the pancreas upon the inert constituents of the muscle to develop in the latter an active glycolytic enzyme. How far this general principle extends in the metabolic phenomena of the body is entirely problematical, but merits careful study. Here, then, we have an added field of inquiry, worthy of careful consideration, if we are to possess a clear understanding of nature's processes.

Between the animal and the vegetable cell certain sharp lines of distinction are frequently drawn. Physiologists are wont to believe that the processes characteristic of the cells of animal tissues and organs are essentially destructive, i. e., that they are principally katabolic, while in vegetable tissues, on the other hand, constructive processes are very conspicuous. In no way is this better illustrated than in the prevalent opinions regarding the parts played by the two classes of cells in the metabolism of proteid matter. We are accustomed to think that all proteid matter has its primary origin in the synthetical power of the vegetable cell, aided by its contained chlorophyll and the beneficent action of the sun's rays. The animal cell, on the other hand, can merely transform and reconstruct the various proteids furnished by the vegetable world, being without power to manufacture proteid matter de novo out of the simple groups and radicles which the vegetable cell utilizes so rapidly. In ordinary proteid katabolism, the various nitrogenous decomposition products are presumably all converted into urea and allied substances adapted for excretion. If, however, there is reversible ferment or enzyme action in the animal body, why may there not also be power to utilize, in some measure at least, the crystalline nitrogenous bases and amido-acids so abundantly formed in trypsin proteolysis, for the construction of fresh proteid matter? One may well query, considering the vigor of the proteolytic action of the enzymes poured into the alimentary tract, whether all these nitrogenous waste products represent just so much lost energy in their production and a further loss of energy in their immediate excretion from the body. In harmony with the 'luxus consumption' theory we may assume wisdom and ultimate gain in this speedy decomposition of excessive proteid foods in the alimentary tract, but the argument is not very convincing. Why may not animal cells, or the animal body as a whole, build up proteid matter out of simple nitrogenous compounds analogous to the action of plant cells? Loewi^[9] has indeed experimented in this direction and states that the biuret-free end-products resulting from the proteolysis of ordinary food albumin can be utilized by the animal body for the maintenance of nitrogenous equilibrium, etc., equally well with the common proteid food-stuffs. His conclusions, however, have been called in question by other investigators, notably by Lesser^[10] whose experimental data failed to confirm the above conclusion.

The problem, however, is an exceedingly important one. If the animal body has no power of utilizing the varied nitrogenous compounds of simple constitution formed in the gastro-intestinal tract by the digestive enzymes; if there is a complete lack of ability to construct new proteid matter out of these simple decomposition products, then surely we must inquire what is the real purpose of their formation? It is true that, with the limitations of our present knowledge, it is difficult to see why if digestive proteolysis has for its sole object the conversion of the proteid foods into forms suitable for absorption there should be any considerable breaking down of proteid beyond the proteose or peptone stage, since the latter bodies would seem to be most easily adaptable for transformation into the proteids of blood, lymph and tissue. On the other hand, it is well known that the proteid of the food is possessed of a physiological and chemical nature quite different from that of the proteid in the blood and tissues of the feeding animal, and it is quite conceivable that a synthetical process might be essential—in some degree—for the manufacture of the specific proteids called for by the blood and tissues of that particular species or individual. The question is one that demands careful consideration and thorough investigation, for it touches upon a chapter in nutrition on which we have at present very little satisfactory or convincing knowledge.

In this connection we may call attention to another problem, somewhat far reaching, but suggested by one of the preceding paragraphs, viz., the possible physiological action of the many katabolites, or decomposition products resulting from tissue changes throughout the animal body. In vegetable tissues, many of the nitrogenous products common to these structures are endowed with marked physiological power, as witness the vegetable alkaloids and the non-nitrogenous bodies like salicin, digitalin, picrotoxin, etc. Years ago, physiologists recognized that some of these nitrogenous bodies present in animal tissues did have a distinctly toxic action when introduced directly into the circulation, and hence they were frequently called animal alkaloids, but our knowledge upon these points is exceedingly obscure and indefinite. When we take into consideration the large number of nitrogenous products formed and present in the various tissues and organs of the body, products of proteolysis and of tissue changes; when we consider how these products circulate through the organism, in blood and lymph; how they come in more or less immediate contact with the different cells of the body prior to their decomposition or elimination, we can not avoid being impressed with the part they may play in stimulating and modifying tissue or other changes.

The significance of this suggestion is made all the more potent by the knowledge recently acquired concerning several of the internal secretions of the body and the powerful physiological influence exerted by their components. Where can be found a more active physiological agent than the blood-pressure raising constituent of the adrenals, the epinephrin? Where is there a more active agent in modifying the nutritional processes of the body than the iodine-containing constituent 01 the thyroid, the iodothyrin. These may truly be counted as representing a type of substances manufactured or secreted primarily for the physiological effect they are capable of exerting; but what about the host of other substances present in the body, many of them simple products of katabolism? May they not have some marked physiological property that if known would serve a sufficient excuse for their formation? Or, may they not possess some hidden or obscure property which if once understood would make clear a secondary or subsidiary function of no small import for the maintenance of physiological equilibrium, or for the welfare of the body? Many suggestions and some facts present themselves, illustrating how direct and indirect influences may be exerted, all pointing toward the harmonious action and interdependence in function of many of the substances formed in the body. Some, however, undoubtedly have more or less of a toxic action, especially when formed in excessive or undue amounts. Thus, the alloxuric bases seemingly cause fever when injected into the circulation or taken per os,^[11] and according to the recent observations of Mandel^[12] there is a very striking relationship between the quantity of alloxuric bases eliminated in the urine and the temperature of the body in cases of aseptic fevers, indicating that these substances, with possibly other incomplete products of tissue metabolism, are important factors in the production of febrile temperature. We may confidently expect that a thorough study of the physiological action of all the varied katabolic products formed in the body will result in a decided expansion of our knowledge regarding the part these substances may play in normal and abnormal metabolism, and in nutrition in general.

Just here, reference may be made to the many problems in the broad field of nutrition that confront the physiological chemist of the present day. The maintenance of life on a sound physiological basis is one of the practical problems in physiological chemistry, and its solution is not yet attained. We need fuller knowledge regarding the part played by the different nitrogenous food-stuffs, the relative physiological value of animal and vegetable proteid, the relative value of fats and carbohydrates as nutrients aside from their different calorific power, and by no means least a fuller and more accurate knowledge of the true physiological needs of the body for proteid foods. Our present dietetic standards are absolutely false and valueless. Our present conception of the physiological needs of the body is altogether faulty and distorted. Our ideas of the rate and extent of proteid metabolism necessary for the maintenance of health and strength are crude and inexact. We place the nitrogen requirement of the healthy man at an absurdly high level, apparently because observation has shown that man is disposed to consume an equivalent in proteid food per day. We need to ascertain by scientific experiment how far such standards are justified; to determine by definite analysis the amounts of nitrogen actually required to maintain nitrogen equilibrium and keep up bodily and mental vigor. Upon the physiological chemist of the present day rests the responsibility for the establishment of nutritive standards that will endure the test of scientific criticism, that will harmonize with daily experience, and that will prove to be physiologically correct.

Further, we need to know more concerning the relative decomposition within the body of the truly organized proteid matter of the tissues, and of the albuminous food-stuffs which, having been digested and absorbed, are in a sense a part of the tissues, but not thoroughly or completely incorporated as an integral part of the living cells. Does the urea of the daily excretion come primarily from the breaking down of the organized proteid, or does it come preferably from the disintegration of the circulating proteid? We recall the famous experiments of Schöndorff, in which blood was made to circulate through the muscles and liver of well-nourished and fasting dogs, with the result that the urea of the blood was increased only when the blood circulated through the tissues of a well-nourished animal. It made no difference with the result whether the blood employed was from a well-fed or a fasting animal; the essential factor was the condition of the muscle tissue through which the blood was made to flow. Schöndorff drew the natural conclusion that the extent of proteid metabolism was dependent upon the nutritive condition of the cells of the tissue, upon the mass of the living cell material, i. e., upon the amount of morphotic proteid present, and that the proteid content of the intermediary fluids, as blood or lymph, was of no moment in determining the rate of urea formation.

We may well doubt, however, if all the urea formed daily under ordinary conditions of life comes solely from the breaking down of the truly organized or morphotic proteid. It is more than probable that the urea has at least a two-fold origin, and, if so, it is an important matter to be able to discriminate between that which comes from the breaking down of the unorganized albumin, and that which is derived from the organized tissues. Unquestionably, the decomposition of organized proteid, the morphotic part of the living protoplasm, is quite different from that of the unorganized pabulum of the cell and surrounding media. Quite possibly, the influences controlling the two lines of metabolism are different; perhaps, there are even different kinds of nerve control.

Equally important is it for the physiologist to know more fully regarding the sources of the carbonic acid resulting from oxidation in the body. What proportion of the ever varying output of this gaseous product of metabolism comes from the oxidation of organized tissue material, and what from the oxidation of circulating carbohydrate and fat and unorganized material in general? We have learned, for example, that the excretion of carbonic acid runs more or less closely parallel with the degree of muscular activity, and we should possess the means of discriminating between the output from true tissue oxidation and that which is derived from extra-cellular sources. A study of the excretion of carbonic acid by fasting individuals, under different conditions of life and activity, would be helpful in throwing light upon this question, and also in giving us a clearer idea of the minimal requirements of the body for non-nitrogenous foods to make good the loss of energy in heat liberation, muscular work, etc. By such a study we might hope for added light upon that much discussed problem, the source of the energy of muscular contraction. While most physiologists are certainly agreed that this energy comes preferably from the oxidation of non-nitrogenous matter, there remain many obscure points upon which we need enlightenment.

We likewise need fuller and more exact knowledge of the ways in which uric acid originates in the body, especially regarding its relationship to intracellular decomposition. Our present understanding of the two-fold origin of this substance—endogenous and exogenous—is most helpful in making clear many formerly obscure points connected with the formation of this substance from the different classes of foodstuffs. To-day, however, we understand quite clearly the genetic relationship between the free and combined purin bases and uric acid, but we are still uncertain whether this substance is formed to some extent synthetically and whether when once formed it is all eliminated unchanged or undergoes oxidation, in part, into less harmful substances. In other words, we do not yet know how far the uric acid which is contained in the daily urine is a measure of the production of uric acid for the twenty-four hours. Uric acid and the alloxuric bases are such important substances, in their influence upon health and the general nutritive condition of the body, that it is extremely important for us to know more concerning their origin and their ultimate fate in the body. We may likewise inquire where uric acid is formed. Does it originate entirely in the liver, or are there other depots where it is produced and collected?

Turning our attention now in another direction, we may revert to the relationship between stereochemical configuration and physiological action as a fruitful subject for investigation. Many interesting facts have already been gleaned, and certain general rules or laws have been formulated, connecting given lines of physiological action with a definite chemical structure. Thus, it is well understood to-day, for example, that all substances which contain a nitro or nitroso group united with, or bound to, oxygen have the effect of dilating blood vessels, while, on the other hand, substances which contain the same nitro or nitroso group joined to carbon have a quite different physiological action, being mostly blood poisons. Further, nitrils, R. CN, tend to produce coma, while isonitriles, R. ${\ce {N = C}}$, are much more toxic and tend to produce paralysis of the respiratory center.^[13] In other words, it is clearly manifest that certain definite groupings within the molecule are the cause of the physiological action of the molecule. At the same time, it is also known that in order to have the physiological action of a substance manifest not only must it contain the necessary group or groupings, but there must likewise be present a second group which has the power of combining with and holding fast to the tissue upon which the physiological action manifests itself. Slight chemical alteration of a substance may, therefore, interfere with or nullify its ordinary physiological action without necessarily altering the physiologically active groups; but by simply changing these other groups through which the molecule ordinarily attaches itself, so that the latter can no longer adhere to the cell substance or tissue protoplasm, there occurs a consequent loss of physiological action.

Another fact clearly understood is that two substances having the same nucleus and like side chains, with an entirely similar grouping, may still be physiologically unlike, owing to a different arrangement in space. This is well illustrated by the dextro- and lævo-rotary tartaric acids, one of which is readily utilized by Penicillium glaucum as nutriment, while the other can not be so consumed. Many other illustrations might be cited, especially with various types of organic poisons, all tending to show that physiological action is dependent upon the arrangement of the atoms or radicles in space, as well as upon the nature of the atoms or radicles. With these facts before us, we see many lines of inquiry presenting themselves, many problems demanding solution, with reference both to pharmacology and physiology.

Confining our attention more especially to physiological matters, we are certainly justified in considering the application of these principles to many of the substances conspicuous in the processes of the body. The work and suggestions of Pasteur and Emil Fischer have indicated certain possibilities regarding the nature and action of enzymes, not to be overlooked. Stereochemical configuration may be just as much responsible for enzyme action, for proteolysis, amylolysis, etc., as any other feature of the active molecule, and how far other lines of physio logical action may be due to chemical structure and the configuration of the molecule, who can say? One's thoughts naturally turn to the living muscle plasma and the chemical changes that follow or accompany the advent of rigor mortis; to the circulating blood and lymph, and the transformations that occur when these fluids are withdrawn from the protecting influence of the endothelial lining of the living vessels; to the axis cylinder of the nerve fibers and the changes that occur when the fibers are severed from their connection with the ganglionic cells. These, and many other suggestions arise, all calling for a further study of the chemical constitution and stereochemical configuration of the molecules involved, since in the knowledge thus gained may be found the solution of many physiological processes now shrouded in mystery.

The reference just made to nerve fibers and ganglionic cells suggests another problem in physiological chemistry, solution of which has been long deferred, viz., the exact chemical nature of nerve tissue, and the character of the changes involved in the passage of a stimulus or nervous impulse through a nerve to its ending in the muscle or secreting cell. Further, what is the real purpose of the complex myelin surrounding the axis cylinder of medullated nerves, and the corresponding substance imbedded in the gray matter of the brain and cord? These are problems that have long waited solution, and yet they are vital to any clear understanding of the nutritive or other changes that take place in nerve tissue, either in rest or in activity. Nerve tissue is strikingly peculiar in its large content of phosphorized bodies of the lecithin type, cerebrosides and cholesterins. These substances, complex in nature and of large molecular structure, are all alike in having the physical properties of fats. Further, lecithin and the cerebrosides all contain fatty acid radicles in large amount, and in addition lecithin contains the radicle of glycero-phosphoric acid. Moreover, the cerebrosides contain a carbohydrate group yielding galactose on decomposition, so it is plain to see that the bodies which give character to the myelin material are highly nutritive substances with high calorific power. These facts might readily be taken as indicating that the function of the myelin is to nourish the more important axis cylinder, to furnish the necessary pabulum for growth and repair, as well as to meet the daily demand for energy-yielding material.

While we may speculate, however, as to the part these peculiar substances play in the life of nerve tissue, we really possess very little positive knowledge of their true purpose. Indeed, we do not know how these bodies actually exist in the living tissue, as is well evidenced by the utter lack of agreement among physiological chemists as to the entity of the so-called protagon. Whether this phosphorized substance, studied by so many investigators, exists as such in the living tissue, or whether it is simply an intimate mixture of lecithin, cerebrin and one or more other substances, is not yet settled to the satisfaction of all concerned. Further, it is not at all impossible that the cerebrosides, as well as lecithin and possibly cholesterin, may exist in the living tissue combined with some one or more of the proteids present there. Our lack of knowledge is deplorable, and yet, in the words of Sir Michael Foster, this is one of the 'master tissues' of the body. Surely, considering the preeminent position and controlling influence of this tissue, we may look for a speedy clearing away of the darkness that enshrouds our understanding of the exact chemical composition of nerve tissue, and especially of the way these peculiar substances of the myelin material exist in the living tissue.

Again, we may ask ourselves what is the nature of the chemical changes that take place in nerve tissue; in the ganglionic cells of the gray matter and in the axis cylinder of the nerve fibers? When a muscle contracts there is a measurable chemical decomposition. The energy of muscular contraction comes from the breaking down of non-nitrogenous components of the muscle, and perhaps in some measure from the decomposition of nitrogenous constituents. Further, there is a liberation of heat, a development of lactic acid, etc. When a stimulus is applied to a nerve, on the other hand, no such manifestations of chemical action are apparent. The muscle to which the nerve is attached contracts, the secreting cell pours forth the product of its activity, etc., but there is no noticeable change in the nerve itself, no recognizable liberation of heat, no change of reaction, no output of carbonic acid, that can be detected. Are we to conclude then that the axis cylinder of the nerve fiber acts simply as a conducting agent without itself undergoing any change? Is it to be compared to an electric wire, with the surrounding myelin material, the substance of Schwan, serving as a convenient insulating or protective medium? If we are to accept this view, what are we to say regarding the non-medullated fibers? Do not they need an insulating material likewise? We can argue that the myelin substance is especially adapted for the nourishment of the nerve, that its high potential value renders it peculiarly suitable as a concentrated nutriment, and that its intimate contact with the neuraxis and with the ganglionic cells of the gray matter proclaims its probable use in this direction. Moreover, if we follow this line of argument still further, we may be led to believe that the stimulation of a nerve, its power of conductivity, etc., are associated with chemical decompositions along its axis as marked in their way as those that occur in a contracting muscle fiber. Truly, we have here a multitude of questions, for which at present no satisfactory answers are to be found. The problems are on the surface awaiting solution.

Finally, emphasis must be laid upon a series of problems in {{hws|physio|physiological} {{hwe|logical|physiological} chemistry, true solution of which will do much to explain natural and artificial immunity, the action of toxins and antitoxins, the bactericidal action of blood sera, the effect of oxidizing enzymes of animal and vegetable origin upon toxins of various kinds, etc. Ehrlich's theories regarding the protection furnished by antitoxic and bactericidal serums, so elaborately devised, constitute a working hypothesis of great value, but we need much additional knowledge concerning the nature and action of the so-called complements and anticomplements, of amboceptors, of haptophor groups, of agglutinins, of precipitins and of hemolysis. The physiological chemist studies with care the important and suggestive work being carried forward by the many brilliant investigators in pathology and bacteriology, with the feeling, however, that the true explanations for most of the phenomena in question are chemical, and that the actions and interactions involved are chemical ones, to be eventually made clear by a fuller chemical knowledge of the toxic and antitoxic substances themselves, and of their alteration and combination under different physiological conditions.

The well-known natural immunity possessed by some animals toward certain diseases, together with the difficulty experienced by most micro-organisms in developing in the healthy body; a difficulty which at once disappears when from any cause the tissues of the body lose their original vitality and vigor, all point to the presence in the healthy body of certain general or specific substances which are directly deleterious to the micro-organisms. Such substances are obviously bactericidal, and it is equally plain that in the bodies of many species of animals there are specific antisubstances present which are lacking in other species, thereby explaining the natural immunity of the former towards certain diseases. As is well known, blood serum possesses, as a rule, a bactericidal power upon most micro-organisms, and we have every reason to believe in the existence of specific substances in the serum which exert some influence upon the growth and development of micro-organisms, and also upon the toxic products they tend to elaborate. These protective substances—the alexins of Buchner—appear to be proteid in nature, resembling globulins, since they are precipitated from serum by the action of certain strong solutions of alkali salts, as sodium sulphate. We know, however, very little regarding their chemical nature aside from the fact that they are obviously very complex, although perhaps even this point is not quite certain. These protective substances are presumably elaborated by the leucocytes of the blood and lymph, cells rich in nuclein and nucleoproteid material. Doubtless, also, some of the gland cells in the body have a corresponding action; statements which, if true, tend to emphasize the possible proteid nature of the protective substances.

While in a general way we may say that the natural immunity to certain bacteria possessed by some animals is due in large measure to an inhibition of the growth of the micro-organism, it must also be remembered that there is in many species a distinct immunity to the action of the poison which the specific micro-organism produces. This immunity depends either upon a destruction of the poison as by oxidation, upon a combination between the poison and some constituents of the active protoplasmic cells of the body, thereby rendering the poison inactive, or, lastly, to some action of the specific protoplasmic cells of the body usually affected by the poison, by which the latter is unable to combine with the cells upon which it ordinarily acts. All these suggestions, however, imply chemical reactions of some kind, and obviously should be understood for a betterment of our knowledge upon this important matter.

Again, the specific immunity which shows itself after exposure to a given disease, so that a second infection becomes practically impossible, can be explained satisfactorily only on chemical grounds, viz., by the presence in the blood and lymph of certain protective or immunizing substances which presumably originate through chemical changes in the blood-serum, under the influence of the bacteria causing the disease. These are chemical substances, formed through chemical decompositions or alterations of normal constituents of the blood, and obviously we need to know more of their exact nature.

Following Ehrlich's views, specific antitoxins, bactericidal sera, etc., result from the overproduction of molecules in cells which are sensitive to the action of toxins and other bacterial products. Antitoxins so formed unite with toxins, and the so-called complementary bodies and the bactericidal antibodies combine with the bacterial cells, thus affording protection. These processes of alteration and combination, however, are presumably all chemical, involving either alteration of chemical structure, or direct combination of bodies chemically the opposite of each other. Further, the so-called haptophor groups of the toxin molecule are probably represented in fact by chemical groups or radicles, which owe their power of combination with corresponding groups of other cells to chemical affinity. Again, the complementary body, normally present in all healthy blood sera and which is needed along with the specific antibody for the destruction of bacterial cells, must owe its activity to the power of chemical combination. Hence, we have presented to us at every turn the question of the chemical nature of these various substances, toxin and antitoxin, complement, receptor, haptophor, etc., which are of such vital importance in the production and maintenance of immunity and protection. Surely this is one of the most important problems of the present day in the domain of physiological chemistry, and calls for both patience and skill of the highest order in its solution.

1. Read before the Section of Physiological Chemistry in the International Congress of Arts and Science held at St. Louis, September 22, 1904.
2. Kossel and his students. See Kossel and Dakin, 'Ueber Salmin und Clupein,' Zeitschrift für physiologische Chemie, Band 41, p. 407.
3. Kossel und Dakin, 'Beiträge zum System der einfachsten Eiweisskörper,' Zeitschrift fur physiologische Chemie, Band 40, p. 565.
4. Abderhalden, 'Die Monoaminosäuren des Salmins' Zeitschrift füur physiologische Chemie, Band 41, p. 55.
5. See Kossel, 'Ueber den gegenwärtigen Stand der Eiweiss Chemie,' Berichte der Deutschen Chem. Gesellschcift, Jahrgang 34, p. 3214.
6. Jones, 'Ueber die Selbstverdauung von Nucleoproteiden,' Zeitschrift für physiologische Chemie, Band 42, p. 35.
7. 'Die Endprodukte der Selbstverdauung tierischer Organe,' Zeitschrift für physiologische Chemie, Band 41, p. 393.
8. 'On the Relation of Autolysis to Proteid Metabolism,' Amer. Journal of Physiology, Vol. 11, p. 351.
9. 'Ueber Eiweissynthese im Thierkörper, 5 Archiv für exper. Pharmakol. u. Pathol, Band 48, p. 303.
10. 'Ueber Stoffwechselversuche mit den Endprodukten peptischer und tryptischer Eiweissverdauung,' Zeitschr. für Biologie, Band 45, p. 497.
11. See Burian and Schur, Archiv für die gesammte Physiologie, Band 87, p. 239.
12. 'The Alloxuric bases in aseptic fevers' Am. Journal of Physiology, Vol. 10, p. 452.
13. See Fränkel, 'Ergebnisse der Physiologie,' Dritter Jahrgang. Biochemie, p. 291.