Popular Science Monthly/Volume 62/November 1902/The Present Position of Chemical Physiology
| THE PRESENT POSITION OF CHEMICAL PHYSIOLOGY.[1] |
By Professor W. D. HALLIBURTON, M.D., F.R.S.
KING'S COLLEGE, LONDON.
AN engineer who desires to thoroughly understand how a machine works must necessarily know its construction. If the machine becomes erratic in its action, and he wishes to put it into proper working order, a preliminary acquaintance with its normal structure and function is an obvious necessity.
If we apply this to the more delicate machinery of the animal body we at once see how a knowledge of function (physiology and pathology) is impossible without a preliminary acquaintance with structure or anatomy.
It is therefore not surprising, it is indeed in the nature of things, that physiology originated with the great anatomists of the past. It was not until Vesalius and Harvey by tedious dissections laid bare the broad facts of structure that any theorizing concerning the uses of the constituent organs of the body had any firm foundation.
Important and essential as the knowledge is that can be revealed by the scalpel, the introduction and use of the microscope furnished physiologists with a still more valuable instrument. By it much that was before unseen came into view, and microscopic anatomy and physiology grew in stature and knowledge simultaneously.
The weapons in the armory of the modern physiologist are multitudinous in number and complex in construction, and enable him in the experimental investigation of his subject to accurately measure and record the workings of the different parts of the machinery he has to study. But preeminent among these instruments stands the test tube and the chemical operations typified by that simple piece of glass.
Herein one sees at once a striking distinction between the mechanism of a living animal and that of a machine like a steam engine or a watch. It is quite possible to be an excellent watchmaker or to drive a steam engine intelligently without any chemical knowledge of the various metals that enter into its composition. In order to set the mechanism right if it goes wrong all the preliminary knowledge which is necessary is of an anatomical nature. The parts of which an engine is composed are stable; the oil that lubricates it and the fuel that feeds it never become integral parts of the machinery. But with the living engine all this is different. The parts of which it is made take up the nutriment or fuel and assimilate it, thus building up new living substance to replace that which is destroyed in the wear and tear associated with activity. This condition of unstable chemical equilibrium is usually designated metabolism, and metabolism is the great and essential attribute of a living as compared with a non-living thing.
It seems childish at the present day, and before such an audience as this, to point out how essential it is to know the chemical structure as well as the anatomical structure of the component parts of the body. But the early anatomists to whom I have alluded had no conception of the connection of the two sciences. Speaking of Vesalius, Sir Michael Foster says: "The great anatomist would no doubt have made use of his bitterest sarcasms had some one assured him that the fantastic school which was busy with occult secrets and had hopes of turning dross into gold would one day join hands in the investigation of the problems of life with the exact and clear anatomy so dear to him." Nor did Harvey, any more than Vesalius, pay heed to chemical learning. The scientific men of his time ignored and despised the beginning of that chemical knowledge which in later years was to become one of the foundations of physiology and the mainstay of the art of medicine.
The earliest to recognize this important connection was one whose name is usually associated more with charlatanry than with truth, namely, Paracelsus; and fifty years after the death of that remarkable and curious personality his doctrines were extended and developed by van Helmont. In spite, however, of van Helmont's remarkable insight into the processes of digestion and fermentation, his work was marred by the mysticism of the day which called in the aid of supernatural agencies to explain what could not otherwise be fully comprehended
In the two hundred and fifty years that have intervened between the death of van Helmont and the present day alchemy became a more and more exact science, and changed its name to chemistry, and a few striking names stand out of men who were able to take the new facts of chemistry and apply them to physiological uses. Of these one may mention Mayow, Lower, Boerhaave, Réaumur, Borelli, Spallanzani, and Lavoisier. Mulder and Holland and Liebig in Germany bring us almost to the present time, and I think they may be said to share the honor of being regarded as the father of modern chemical physiology. This branch of science was first placed on a firm basis by Wöhler when he showed that organic compounds can be built out of their elements in the laboratory, and his first successful experiments in connection with the comparatively simple substance urea have been followed by numberless others, which have made organic chemistry the vast subject it is to-day.
Sir Michael Foster's book on the History of Physiology, from which I have already quoted, treats of the older workers who laid the foundations of our science, and whose names I have not done much more than barely mention. Those interested in the giants of the past should consult it. But what I propose to take up this morning is the work of those who have during more recent days been engaged in the later stages of the building. The edifice is far from completion even now. It is one of the charms of physiological endeavor that as the older areas yield their secrets to the explorers new ones are opened out which require equally careful investigation.
If even a superficial survey of modern physiological literature is taken, one is at once struck with the great preponderance of papers and books which have a chemical bearing. In this the physiological journals of to-day contrast very markedly with those of thirty, twenty or even ten years ago. The sister science of chemical pathology is making similar rapid strides. In some universities the importance of biological chemistry is recognized by the foundation of chairs which deal with that subject alone; and though in the United Kingdom, owing mainly to lack of funds, this aspect of the advance of science is not very evident, there are signs that the date cannot be far distant when every well-equipped university or university college will follow the example set us at many seats of learning on the continent and at Liverpool.
With these introductory remarks let me now proceed to describe what appear to me to be the main features of chemical physiology at the present time.
The first point to which I shall direct your attention is the rapid way in which chemical physiology is becoming an exact science. Though it is less than twenty years since I began to teach physiology, I can remember perfectly well a time when those who devoted their work to the chemical side of the science might almost be counted on the fingers of one hand, and when chemists looked with scarcely veiled contempt on what was at that time called physiological chemistry: they stated that physiologists dealt with messes or impure materials, and therefore anything in the nature of correct knowledge was not possible. There was a good deal of truth in these statements, and if physiologists to-day cannot quite say that they have changed all that, they can at any rate assert with truth that they are changing it. This is due to a growing rapprochement between chemists and physiologists. Many of our younger physiologists now go through a thorough preliminary chemical training; and, on the other hand, there is a growing number of chemists—of whom Emil Fischer may be taken as a type—who are beginning to recognize the importance of a systematic study of substances of physiological interest. A very striking instance of this is seen in the progress of our knowledge of the carbohydrates, which has culminated in the actual synthesis of several members of the sugar group. Another instance is seen in the accurate information we now possess of the constitution of uric acid. When Miescher began his work on the chemical composition of the nuclei of cells, and separated from them the material he called nuclein, he little foresaw the wide practical application of his work. We now know that it is in the metabolism of cell-nuclei that we have to look for the oxidative formation of uric acid and other substances of the purine family. Already the chemical relationships of uric acid and nuclein have taught practical physicians some of the secrets that underlie the occurrence of gout and allied disorders.
With the time at my disposal, it would be impossible to discuss all the chemico-vital problems which the physiologists of the present day are attempting to solve, but there is one subject at which many of them are laboring which seems to me to be of supreme importance—I mean the chemical constitution of proteid or albuminous substances. Proteids are produced only in the living laboratory of plants and animals; proteid metabolism is the main chemical attribute of a living thing; proteid matter is the all-important material present in protoplasm. But in spite of the overwhelming importance of the subject chemists and physiologists alike have far too long fought shy of attempting to unravel the constitution of the proteid molecule. This molecule is the most complex that is known: it always contains five, and often six, or even seven elements. The task of thoroughly understanding its composition is necessarily vast, and advance slow. But little by little the puzzle is being solved, and this final conquest of organic chemistry, when it does arrive, will furnish physiologists with new light on many of the dark places of physiological science.
The revival of the vitalistic conception in physiological work appears to me a retrograde step. To explain anything we are not fully able to understand in the light of physics and chemistry by labeling it as vital or something we can never hope to understand is a confession of ignorance, and, what is still more harmful, a bar to progress. It may be that there is a special force in living things that distinguishes them from the inorganic world. If this is so, the laws that regulate this force must be discovered and measured, and I have no doubt that those laws when discovered will be found to be as immutable and regular as the force of gravitation. I am, however, hopeful that the scientific workers of the future will discover that this so-called vital force is due to certain physical or chemical properties of living matter which have not yet been brought into line with the known chemical and physical laws that operate in the inorganic world, but which as our knowledge of chemistry and physics increases will ultimately be found to be subservient to such laws.
Let me take as an example the subject of osmosis. The laws which regulate this phenomenon through dead membranes are fairly well known and can be experimentally verified; but in the living body there is some other manifestation of force which operates in such a way as to neutralize the known force of osmosis. Is it necessary to suppose that this force is a new one? May it not rather be that our much vaunted knowledge of osmosis is not yet complete? It is quite easy to understand why a dead and a living membrane should behave differently in relation to substances that are passing through them. The molecules of the dead membrane are, comparatively speaking, passive and stable; the molecules in a membrane made of living cells are in a constant state of chemical integration and disintegration; they are the most unstable molecules we know. It is to be expected that such molecules would allow water, or substances dissolved in water, to pass between them and remain entirely inactive? The probability appears to me to be all the other way; the substances passing, or attempting to pass, between the molecules will be called upon to participate in the chemical activities of the molecules themselves, and in the building up and breaking down of the compounds so formed there will be a transformation of chemical energy and a liberation of what looks like a new force. Before a physicist decides that his knowledge of osmosis is final, let him attempt to make a membrane of some material which is in a state of unstable chemical equilibrium, a state in some way comparable to what is called metabolism in living protoplasm. I cannot conceive that such a task is insuperable, and when accomplished, and the behavior of such a membrane in an osmometer or dialyser is studied, I am convinced that we shall find that the laws of osmosis as formulated for such dead substances as we have hitherto used will be found to require revision.
Such an attitude in reference to vital problems appears to be infinitely preferable to that which too many adopt of passive content, saying the phenomenon is vital and there is an end of it.
When a scientific man says this or that vital phenomenon cannot be explained by the laws of chemistry and physics, and therefore must be regulated by laws of some other nature, he most unjustifiably assumes that the laws of chemistry and physics have all been discovered. He forgets, for instance, that such an important detail as the constitution of the proteid molecule has still to be made out.
The recent history of science gives an emphatic denial to such a supposition. All my listeners have within the last few years seen the discovery of the Röntgen rays and the modern development of wireless telegraphy. On the chemical side we have witnessed the discovery of new elements in the atmosphere and the introduction of an entirely new branch of chemistry called physical chemistry. With such examples ready to our hands, who can say what further discoveries will not shortly be made, even in such well-worked fields as chemistry and physics?
The mention of physical chemistry brings me to what I may term the second head of my discourse, the second striking characteristic of modern chemical physiology: this is the increasing importance which physiologists recognize in a study of inorganic chemistry. The materials of which our bodies are composed are mainly organic compounds, among which the proteids stand out as preeminently important; but every one knows there are many substances of the mineral or inorganic kingdom present in addition. I need hardly mention the importance of water, of the oxygen of the air, and of salts like sodium chloride and calcium phosphate.
The new branch of inorganic chemistry called physical chemistry has given us entirely new ideas of the nature of solutions, and the fact that electrolytes in solution are broken up into their constituent ions is one of fundamental importance. One of the many physiological aspects of this subject is seen in a study of the action of mineral salts in solution on living organisms and parts of organisms. Many years ago Dr. Ringer showed that contractile tissues (heart, cilia, etc.) continue to manifest their activity in certain saline solutions. Howell goes so far as to say, and probably correctly say, that the cause of the rhythmical action of the heart is the presence of these inorganic substances in the blood or lymph which usually bathes it. The subject has more recently been taken up by Loeb and his colleagues at Chicago: they confirm Ringer's original statements, but interpret them now as ionic action. Contractile tissues will not contract in pure solutions of non-electrolytes like sugar or albumin. But different contractile tissues differ in the nature of the ions which are their most favorable stimuli. An optimum salt solution is one in which stimulating ions, like those of sodium, are mixed with a certain small amount of those which like calcium restrain activity. Loeb considers that the ions act because they affect either the physical condition of the colloidal substances (proteid, etc.) in protoplasm or the rapidity of chemical processes.
Amœboid movement, ciliary movement, the contraction of muscle, cell division and karyokinesis all fall into the same category as being mainly dependent on the stimulating action of ions.
Loeb has even gone so far as to consider that the process of fertilization is mainly ionic action; he denies that the nuclein of the male cell is essential, but asserts that all it does is to act as the stimulus in the due adjustment of the proportions of the surrounding ions, and supports this view by numerous experiments on ova in which without the presence of spermatozoa he has produced larvae by merely altering the saline constituents and so the osmotic pressure of the fluid that surrounds them. Whether such a sweeping and almost revolutionary notion will stand the test of further verification must be left to the future; so also must the equally important idea that nervous impulses are to be mainly explained on an electrolytic basis. But whether or not all the details of such work will stand the test of time, the experiments I have briefly alluded to are sufficient to show the importance of physical chemistry to the physiologist, and they also form a useful commentary on what I was saying just now about vitalism. Such eminently' vital phenomena as movement and fertilization are to be explained in whole or in part as due to the physical action of inorganic substances. Are not such suggestions indications of the undesirability of postulating the existence of any special mystic vital force?
I have spoken up to this point of physical chemistry as a branch of inorganic chemistry; there are already indications of its importance also in relation to organic chemistry. Many eminent chemists consider that the future advance of organic chemistry will be on the new physical lines. It is impossible to forecast where this will lead us; suffice it to say that not only physiology, but also pathology, pharmacology, and even therapeutics, will receive new accessions to knowledge the importance of which will be enormous.
I have now briefly sketched what appear to me to be the two main features of the chemical physiology of to-day, and the two lines, organic and inorganic, along which I believe it will progress in the future.
Let me now press upon you the importance in physiology, as in all experimental sciences, of the necessity first of bold experimentation, and secondly of bold theorizing from experimental data. Without experiment all theorizing is futile; the discovery of gravitation would never have seen the light if laborious years of work had not convinced Newton that it could be deduced from his observations. The Darwinian theory was similarly based upon data and experiments which occupied the greater part of its author's lifetime to collect and perform. Pasteur in France and Virchow in Germany supply other instances of the same devotion to work which was followed by the promulgation of wide-sweeping generalizations.
And after all it is the general law which is the main object of research; isolated facts may be interesting and are often of value, but it is not until facts are correlated and the discoveries ascertain their interrelationships that anything of epoch-making importance is given to the world.
It is, however, frequently the case that a thinker with keen insight can see the general law even before the facts upon which it rests are fully worked out. Often such bold theorizers are right, but even if they ultimately turn out to be wrong, or only partly right, they have given to their fellows some general idea on which to work; if the general idea is incorrect, it is important to prove it to be so in order to discover what is right later on. No one has ever seen an atom or a molecule, yet who can doubt that the atomic theory is the sheet anchor of chemistry? Mendeleeff formulated his periodic law before many of the elements were discovered; yet the accuracy of this great generalization has been such that it has actually led to the discovery of some of the missing elements.
I propose to illustrate these general remarks by a brief allusion to two typical sets of researches carried out during recent years in the region of chemical physiology. I do not pretend that either of them has the same overwhelming importance as the great discoveries I have alluded to, but I am inclined to think that one of them comes very near to that standard. The investigations in question are those of Ehrlich and of Pawlow. The work of Ehrlich mainly illustrates the useful part played by bold theorizing, the work of Pawlow that played by the introduction of new and bold methods of experiment.
I will take Pawlow first. This energetic and original Russian physiologist has by his new methods succeeded in throwing an entirely new light on the processes of digestion. Ingeniously devised surgical operations have enabled him to obtain the various digestive juices in a state of absolute purity and in large quantity. Their composition and their actions on the various foodstuffs have thus been ascertained in a manner never before accomplished; an apparently unfailing resourcefulness in devising and adapting experimental methods has enabled him and his fellow workers to discover the paths of the various nerve impulses by which secretion in the alimentary canal is regulated and controlled. The importance of the physical element in the process of digestion has been experimentally verified. If I were asked to point out what I considered to be the most important outcome of all this painstaking work, I should begin my answer by a number of negatives, and would say, not the discovery of the secretory nerves of the stomach or pancreas; not the correct analysis of the gastric juice, nor the fact that the intestinal juice has most useful digestive functions; all of these are discoveries of which any one might have been rightly proud; but after all they are more or less isolated facts. The main thing that Pawlow has shown is that digestion is not a succession of isolated acts, but each one is related to its predecessor and to that which follows it; the process of digestion is thus a continuous whole; for example, the acidity of the gastric juice provides for a delivery of pancreatic juice in proper quantity into the intestine; the intestinal juice acts upon the pancreatic, and so enables the latter to perform its powerful actions. I am afraid this example, as I have tersely stated it, presents the subject rather inadequately, but it will serve to show what I mean. Further, the composition of the various juices is admirably adjusted to the needs of the organism; when there is much proteid to be digested, the proteolytic activity of the juices secreted is correspondingly high, and the same is true for the other constituents of the food. It is such general conclusions as these, the correlation of isolated facts leading to the formulation of the law that the digestive process is continuous in the sense I have indicated and adapted to the needs of the work to be done, that constitute the great value of the work from the Russian laboratory. Work of this sort is sure to stimulate others to fill in the gaps and complete the picture, and already has borne fruit in this direction. It has, for instance, in Starling's hands led to the discovery of a chemical stimulus to pancreatic secretion. This is formed in the intestine as the result of the action of the gastric acid, and taken by the blood-stream to the pancreas. Whether this secretin as it is called may be one of a group of similar chemical stimuli which operate in other parts of the body has still to be found out.
The other series of researches to which I referred are those of Ehrlich and his colleagues and followers on the subject of immunity. This subject is one of such importance to every one of us that I am inclined to place the discovery on a level with those great discoveries of natural laws to which I alluded at the outset of this portion of my address. I hesitate to do so yet because many of the details of the theory still await verification. But up to the present all is working in that direction, and Ehrlich 's ideas illustrate the value of bold theorizing in the hands of clear-sighted and far-seeing individuals.
But when I say that the doctrine is bold, I do not mean to infer that the experimental facts are scanty; they are just the reverse. But in the same way that a chemist has never seen an atom, and yet he believes atoms exist, so no one has yet ever seen a toxin or antitoxin in a state of purity, and yet we know they exist, and this knowledge promises to be of incalculable benefit to suffering humanity.
It may not be uninteresting to state briefly, for the benefit of those to whom the subject is new, the main facts and an outline of the theory which is based upon them.
We are all aware that one attack of many infective maladies protects us against another attack of the same disease. The person is said to be immune either partially or completely against that disease. Vaccination produces in a patient an attack of cowpox or vaccinia. This disease is related to smallpox, and some still hold that it is smallpox modified and rendered less malignant by passing through the body of a calf. At any rate an attack of vaccinia renders a person immune to smallpox, or variola, for a certain number of years. Vaccination is an instance of what is called protective inoculation, which is now practised with more or less success in reference to other diseases like plague and typhoid fever. The study of immunity has also rendered possible what may be called curative inoculation, or the injection of antitoxic material as a cure for diphtheria, tetanus, snake poisoning, etc.
The power the blood possesses of slaying bacteria was first discovered when the effort was made to grow various kinds of bacteria in it; it was looked upon as probable that blood would prove a suitable soil or medium for this purpose. It was found in some instances to have exactly the opposite effect. The chemical characters of the substances which kill the bacteria are not fully known; indeed, the same is true for most of the substances we have to speak of in this connection. Absence of knowledge on this particular point has not, however, prevented important discoveries from being made.
So far as is known at present, the substances in question are proteid in nature. The bactericidal powers of blood are destroyed by heating it for an hour to 56° C. Whether the substances are enzymes is a disputed point. So also is the question whether they are derived from the leucocytes; the balance of evidence appears to me to be in favor of this view in many cases at any rate, and phagocytosis becomes more intelligible if this view is accepted. The substances, whatever be their source or their chemical nature, are sometimes called alexins, but the more usual name now applied to them is that of bacterio-lysins.
Closely allied to the bactericidal power of blood, or blood-serum, is its globulicidal power. By this one means that the blood-serum of one animal has the power of dissolving the red blood-corpuscles of another species. If the serum of one animal is injected into the blood-stream of an animal of another species, the result is a destruction of its red corpuscles, which may be so excessive as to lead to the passing of the liberated hæmoglobin into the urine (hæmoglobinuria). The substance or substances in the serum that possess this property are called hæmolysins, and though there is some doubt whether bacteriolysins and hæmo-lysins are absolutely identical, there is no doubt that they are closely related substances.
Another interesting chemical point in this connection is the fact that the bactericidal power of the blood is closely related to its alkalinity. Increase of alkalinity means increase of bactericidal power. Venous blood contains more diffusible alkali than arterial blood and is more bactericidal; dropsical effusions are more alkaline than normal lymph and kill bacteria more easily. In a condition like diabetes, when the blood is less alkaline than it should be, the susceptibility to infectious diseases is increased. Alkalinity is probably beneficial because it favors those oxidative processes in the cells of the body which are so essential for the maintenance of healthy life.
Normal blood possesses a certain amount of substances which are inimical to the life of our bacterial foes. But suppose a person gets run clown; every one knows he is then liable to 'catch anything.' This coincides with a diminution in the bactericidal power of his blood. But even a perfectly healthy person has not an unlimited supply of bacterio-lysin, and if the bacteria are sufficiently numerous he will fall a victim to the disease they produce. Here, however, comes in the remarkable part of the defence. In this struggle he will produce more and more bacterio-lysin, and if he gets well it means that the bacteria are finally vanquished, and his blood remains rich in the particular bacterio-lysin he has produced, and so will render him immune to further attacks from that particular species of bacterium. Every bacterium seems to cause the development of a specific bacterio-lysin.
Immunity can more conveniently be produced gradually in animals, and this applies, not only to the bacteria, but also to the toxins they form. If, for instance, the bacilli which produce diphtheria are grown in a suitable medium, they produce the diphtheria poison, or toxin, much in the same way that yeast-cells will produce alcohol when grown in a solution of sugar. Diphtheria toxin is associated with a proteose, as is also the case with the poison of snake venom. If a certain small dose called a 'lethal dose' is injected into a guinea-pig the result is death. But if the guinea-pig receive a smaller dose it will recover; a few days after it will stand a rather larger dose; and this may be continued until after many successive gradually increasing doses it will finally stand an amount equal to many lethal doses without any ill effects. The gradual introduction of the toxin has called forth the production of an antitoxin. If this is done in the horse instead of the guinea-pig the production of antitoxin is still more marked, and the serum obtained from the blood of an immunized horse may be used for injecting into human beings suffering from diphtheria, and rapidly cures the disease. The two actions of the blood, antitoxic and antibacterial, are frequently associated, but may be entirely distinct.
The antitoxin is also a proteid probably of the nature of a globulin; at any rate it is a proteid of larger molecular weight than a proteose. This suggests a practical point. In the case of snake-bite the poison gets into the blood rapidly owing to the comparative ease with which it diffuses, and so it is quickly carried all over the body. In treatment with the antitoxin or antivenin, speed is everything if life is to be saved; injection of this material under the skin is not much good, for the diffusion into the blood is too slow. It should be injected straight away into a blood-vessel.
There is no doubt that in these cases the antitoxin neutralizes the toxin much in the same way that an acid neutralizes an alkali. If the toxin and antitoxin are mixed in a test-tube, and time allowed for the interaction to occur, the result is an innocuous mixture. The toxin, however, is merely neutralized, not destroyed; for if the mixture in the test-tube is heated to 68° C. the antitoxin is coagulated and destroyed and the toxin remains as poisonous as ever.
Immunity is distinguished into active and passive. Active immunity is produced by the development of protective substances in the body; passive immunity by the injection of a protective serum. Of the two the former is the more permanent.
Ricin, the poisonous proteid of castor-oil seeds, and abrin, that of the Jequirity bean, also produce when gradually given to animals an immunity, due to the production of antiricin and antibrin respectively.
Ehrlich's hypothesis to explain such facts is usually spoken of as the side-chain theory of immunity. He considers that the toxins are capable of uniting with the protoplasm of living cells by possessing groups of atoms like those by which nutritive proteids are united to cells during normal assimilation. He terms these haptophor groups, and the groups to which these are attached in the cells he terms receptor groups. The introduction of a toxin stimulates an excessive production of receptors, which are finally thrown out into the circulation, and the free circulating receptors constitute the antitoxin. The comparison of the process to assimilation is justified by the fact that non-toxic substances like milk introduced gradually by successive doses into the blood-stream cause the formation of anti-substances capable of coagulating them.
Up to this point I have spoken only of the blood, but month by month workers are bringing forward evidence to show that other cells of the body may by similar measures be rendered capable of producing a corresponding protective mechanism.
One further development of the theory I must mention. At least two different substances are necessary to render a serum bactericidal or globulicidal. The bacterio-lysin or hæmolysin consists of these two substances. One of these is called the immune body, the other the complement. We may illustrate the use of these terms by an example. The repeated injection of the blood of an animal (e. g., the goat) into the blood of another animal (e. g., a sheep) after a time renders the latter animal immune to further injections, and at the same time causes the production of a serum which dissolves readily the red blood-corpuscles of the first animal. The sheep's serum is thus hæmolytic towards goat's blood-corpuscles. This power is destroyed by heating to 56° C. for half an hour, but returns when fresh goat's serum is added. The specific immunizing substance formed in the sheep is called the immune body; the ferment-like substance destroyed by heat is the complement. The latter is not specific, since it is furnished by the blood of non-immunized animals, but it is nevertheless essential for hæmolysis. Ehrlich believes that the immune body has two side groups one which connects with the receptor of the red corpuscles and one which unites with the haptophor group of the complement, and thus renders possible the ferment-like action of the complement on the red corpuscles. Various antibacterial serums which have not been the success in treating disease they were expected to be are probably too poor in complement, though they may contain plenty of the immune body.
Quite distinct from the bactericidal, globulicidal, and antitoxic properties of blood is its agglutinating action. This is another result of infection with many kinds of bacteria or their toxins. The blood acquires the property of rendering immobile and clumping together the specific bacteria used in the infection. The test applied to the blood in cases of typhoid fever, and generally called Widal's reaction, depends on this fact.
The substances that produce this effect are called agglutinins. They also are probably proteid-like in nature, but are more resistant to heat than the lysins. Prolonged heating to over 60° C. is necessary to destroy their activity.
Lastly, we come to a question which more directly appeals to the physiologist than the preceding, because experiments in relation to immunity have furnished us with what has hitherto been lacking, a means of distinguishing human blood from the blood of other animals.
The discovery was made by Tchistovitch (1899), and his original experiment was as follows: Rabbits, dogs, goats, and guinea-pigs were inoculated with eel-serum, which is toxic: he thereby obtained from these animals an antitoxic serum. But the serum was not only antitoxic, but produced a precipitate when added to eel-serum, but not when added to the serum of any other animal. In other words, not only has a specific antitoxin been produced, but also a specific precipitin. Numerous observers have since found that this is a general rule throughout the animal kingdom, including man. If, for instance, a rabbit is treated with human blood, the serum ultimately obtained from the rabbit contains a specific precipitin for human blood; that is to say, a precipitate is formed on adding such a rabbit's serum to human blood, but not when added to the blood of any other animal.[2] The great value of the test is its delicacy: it will detect the specific blood when it is greatly diluted, after it has been dried for weeks, or even when it is mixed with the blood of other animals.
I have entered into this subject at some length because it so admirably illustrates the kind of research which is now in progress; it is also of interest to others than mere physiologists. I have not by any means exhausted the subject, but for fear I may exhaust my audience let me hasten to a conclusion. I began by eulogizing the progress of the branch of science on which I have elected to speak to you. Let me conclude with a word of warning on the danger of over-specialization. The ultra-specialist is apt to become narrow, to confine himself so closely to his own groove that he forgets to notice what is occurring in the parallel and intercrossing grooves of others. But those who devote themselves to the chemical side of physiology run but little danger of this evil. The subject cannot be studied apart from other branches of physiology, so closely are both branches and roots intertwined. As an illustration of this may I be permitted to speak of some of my own work? During the past few years the energies of my laboratory have been devoted to investigations on the chemical side of nervous activity, and I have had the advantage of cooperating to this end with a number of investigators, of whom I may particularly mention Dr. Mott and Dr. T. G. Brodie. But we soon found that any narrow investigation of the chemical properties of nervous matter and the changes this undergoes during life and after death was impossible. Our work extended in a pathological direction so as to investigate the matter in the brains of those suffering from nervous disease; it extended in a histological direction so as to determine the chemical meaning of various staining reactions presented by normal and abnormal structures in the brain and spinal cord; it extended in an experimental direction in the elucidation of the phenomena of fatigue, and to ascertain whether there was any difference in medullated and non-medullated nerve fibers in this respect; it extended into what one may call a pharmacological direction in the investigation of the action of the poisonous products of the breakdown of nervous tissues. I think I have said enough to show you how intimate are the connections of the chemical with the other aspects of physiology, and although I have given you but one instance, that which is freshest to my mind, the same could be said for almost any other well-planned piece of research work of a bio-chemical nature.