# Popular Science Monthly/Volume 75/July 1909/Natural Resistance to Infectious Disease and its Reinforcement

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THE
POPULAR SCIENCE
MONTHLY
JULY, 1909
* NATURAL RESISTANCE TO INFECTIOUS DISEASE AND ITS REINFORCEMENT.
By Dr. SIMON FLEXNER
ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH
COMMON observations early indicated that individuals of all animal species, and of the human species especially, were very unequally subject to disease. This elementary fact is impressed every day upon the thoughtful and has been, from the earliest times, the object of much ingenious speculation. Even to-day, and in spite of the acquisition of a wealth of new facts in physiology and pathology, we are not able to define fully the conditions that make for or against disease. However, the new knowledge which has been acquired enables us to see much more deeply and clearly into the complex mechanisms of disease than could be seen half a century ago; but unfortunately our insight has not been strengthened as regards all diseases, but almost exclusively in relation to the infectious diseases. In respect to the other class, or noninfectious or chronic diseases, among which are Bright's disease, vascular disease, malignant tumors, the gains in fundamental knowledge are far less great.
It may be axiomatic to state that all actual progress in unraveling the complicated conditions of disease depends upon precise knowledge of its underlying causes; and yet in an age in which comparative ignorance still requires that a certain amount of practise shall be empirical, it is well to bear in mind this notion, so that what is undertaken through knowledge may be kept distinct from what is adventured through ignorance. It has been to the lasting credit of the medical profession of an early period, when actual knowledge of the underlying causes of disease had not, and in the then state of development ​of the physical sciences could not, have yielded a single concrete fact, that one method—vaccination—and the most perfect one yet discovered of preventing a disease, and two drugs—quinine and mercury—specific for two other infectious diseases, should have been found and so successfully applied. But in contrast to this slow, painful and halting advance in practical means for the relief of suffering, is to be placed the body of robust facts, acquired in a quarter of a century, during the present or bacteriological era in medicine, which enables us to view in some measure the mechanisms of disease and defense against it, and which has pointed the way to efficient modes of prevention, and, in a few brilliant instances, to the production of biologically perfect means of combating certain infectious maladies. To produce a means, as has been done through the perfection of curative sera, that shall strike down myriads of living parasitic organisms, within the interior of the body, amid millions of sensitive and even sentient cells of the organs, without inflicting on them the smallest injury, is indeed a great accomplishment. And if I am successful to-day in placing before you the main facts, now revealed, of the body's manner of defense to parasitic invasion, you will, I think, come to see that it has been by imitating nature's methods and by augmentation of the natural forces of defense, that good has been achieved.
The facts laboriously acquired, on which this presentation will rest, have been drawn from the study of spontaneous disease—so-called natural disease—among man and animals, and from experimental diseases produced in animals. I need scarcely point out that there is really no unnatural form of disease any more than there is a really natural one; in all instances we are dealing with natural laws of health and disease, the difference merely being that in one case we are often ignorant of the time and manner of entrance of the infecting germs into the body, and in the other they are purposely introduced, in a predetermined efficient manner, in a pure state into the animal body. Since we are so often ignorant of the precise manner of ingress of the germs in the non-experimental forms of disease, we conclude from the identity of the conditions present in the experimental and non-experimental forms of the disease, that in effect they are identical. This power exactly to reproduce at will, by pure bacterial cultures, infectious disease in animals has been of inestimable benefit in investigating disease.
To escape disease is not merely to remain without the zone of influence of the germs of disease. To do this in all cases is impossible, because with certain germ diseases—tuberculosis, for example—the germs are ubiquitous; and with several other diseases the germs are constant if not naturalized inhabitants of the body. Thus we carry on our skin surfaces constantly the germs of suppuration; on the mucous membranes of the nose and throat the germs of pneumonia, and sometimes those of diphtheria, tuberculosis and meningitis. The intestinal ​mucous membrane supports a rich and varied bacterial flora among which are several potentially harmful species and sometimes, even under conditions of health, the bacilli of typhoid fever, of dysentery, and in regions in which cholera is endemic, or during its epidemics, of cholera bacilli.
It is obvious, therefore, that it is practically impossible to escape the dangers of bacterial infection, and withdrawal absolutely from other human beings and from all human habitations would be powerless to accomplish this result. It is equally obvious that with such constant and universal exposure to bacterial infection the body must, for the greater part, easily defend itself against this class of its enemies. It is now known that this defense is not merely by exclusion of the bacteria from the interior of the body, although in itself this is an important means of protection for which special mechanisms are provided, but that constant small escapes of bacteria into the blood are taking place from the mucous membranes chiefly, and that there rarely ensues disease from this cause.
On the other hand, there is another class of disease germs that do not regularly inhabit the body and whose influence is occasional only. Some of these germs are exquisitely infectious, as, for example, those causing small-pox, measles and scarlet fever; and others require an intermediate agency to inoculate them as in malaria, yellow fever, and possibly bubonic plague. And yet, excluding small-pox, which in ante-vaccination days overlooked few if any persons in infected regions, a great diversity of susceptibility to infection has been noted again and again among exposed persons and animals. This variability of infectivity affects difference in species, race and individuals and constitutes one of the fundamental problems of disease. Certain diseases are naturally limited to certain species and can not at all, or can only with great difficulty, be transferred to another, although related, species; other diseases appear among several species widely separated from each other; still other diseases choose by preference or are quite restricted to certain breeds of a species; and finally, individuals of a homogeneous species exhibit wide differences of susceptibility to infection. A worked-out theory of infection to and immunity from disease would include and explain, all these, and many more, diversities which have been observed. I need not offer an apology for this at present unattained ideal.
It was early apparent that bacteria must sometimes escape into the blood and yet that infection did not follow. It was observed that frequently at death the interior of the body was free of bacteria and might remain so for many hours and until signs of putrefaction began to be apparent. The deduction from this observation was to the effect that the blood and organs must protect themselves during life and for a period after death from bacterial development. The remarkable anti-bacterial power of the blood was demonstrated directly by injecting ​putrescent fluids into the veins of rabbits and noting that not only might they survive the infections and remain quite normal, but that the blood drawn soon after the injection was made need not, when carefully collected, undergo putrefaction. This fundamental experiment, performed before pure cultures of bacteria were available, left no doubts that the body possesses internal means of ridding itself of large numbers of bacteria.
It is apparent that the body possesses two possible distinct ways of freeing itself of these bacteria: it might remove them through the excretory organs—the kidneys or liver; it might rid itself of them by destroying them inside the body. It was with the rise of modern bacteriology that proof was brought that the blood and certain other body fluids—peritoneal, pleural, pericardial transudates—possess a remarkable power of destroying bacteria. This power resides in shed blood, in the other fluids withdrawn from the body, and even in the fluids deprived of all their natural cellular constituents. Here was then a concrete fact: the fluids of the interior of the body are capable of killing large numbers of bacteria. It could now be shown that the bacteria introduced in large numbers into the blood of a living animal are not excreted but are destroyed within the body. This power of the blood is, however, not indefinite and is not exercised equally against all kinds of bacteria. Even with bacteria that readily succumb a very large number may exceed the blood's capacity to destroy, so that survival and multiplication would result; and certain bacterial species proved highly resistant to this blood destruction. Moreover, it was observed that the blood of all animals tested did not produce the same effects on given kinds of bacteria, that this power to destroy bacteria was lost spontaneously in a few days by the fluids removed from the body and was destroyed immediately by a temperature of 60° C. It is, therefore, a highly labile quality.
Apparently the way was opened up for the detection of the conditions which underlie infection and immunity and the various peculiarities determined by species, race and individual. Unfortunately, there proved to be no sharp relation between the bactericidal powers of shed blood and immunity from or susceptibility to infection. And important as these blood-phenomena proved to be, in accomplishing protection from infection, they do not in themselves account for all observed conditions.
The factors upon which the bactericidal properties of the blood depend have now been clearly ascertained. The chief substance has been called alexin or defensive substance, but in reality the alexin is a compound and consists of a sensitive body—complement—and a more stable substance—intermediary body. Bacteria are killed and disintegrated when the intermediate body can attach itself to them and bring them under the influence of the complement—a digestive enzymotic element, to which the intermediary body also attaches itself.
​Moreover, it is now quite certain that of the two principles the intermediary body alone is a fixed, native element of the blood plasma, and the complement is subject to considerable fluctuations in quantity. The origin of the intermediary body has not been determined, while it is quite established that the complement is yielded by the white corpuscles, or leucocytes, of the blood. This matter of the origin of the complement is very important because the protective value of the blood fluid is determined by the quantity of complement available at any one time and not so much by the more constant intermediary body which is usually in excess of the complement. The complement would appear to arise from the leucocytes partly as a secretion; but the quantity derived in this way would not appear to be considerable. It also arises from leucocytes which are brought by any cause to degeneration and disintegration, and this would seem to be a richer source than the other. Leucocytes are constantly being worn out by physiological use and as constantly yielding up their complement to the blood as they go to pieces. It would appear, then, that the very essential complement which exists in the circulating blood and passes from the blood into the lymph and serous cavities, will be more or less determined in quantity by the number of blood leucocytes and the conditions to which they are exposed, and as they are brought to slower or faster degeneration; and it is extremely probable that the secretion of complement is influenced also by the nature of the stimuli to which even the living leucocytes are exposed. It has been shown beyond peradventure that the blood plasma contains less complement than blood serum, as would now be expected since the origin of complement from degenerating leucocytes has been abundantly shown, and because in the clotting of the blood the leucocytes are so greatly disintegrated. But I do not think that even the most ardent adversaries of the view that the fluids of the interior of the body do not exert direct bactericidal effects, have been able to show that the plasma contains no complement. The complement is such a labile body that doubtless it is constantly used up physiologically and must therefore as constantly be renewed, and it is highly probable that the balance between production and destruction may not always be maintained, whence a considerable fluctuation may occur even in health. Whether the fluctuations ever synchronize with intending infections in such a manner as to promote them is not really known, but is not impossible.
It is, however, patent that the naturally operative defensive mechanisms against bacterial invasion must contain other factors than these humoral ones. We are all now prepared to admit that in the phagocytes, or the devouring white corpuscles of the blood, the body possesses another defensive system of high efficiency. The motile nature of these cells and their presence in the circulating blood accord them a high degree of mobility, so that they can be quickly dispatched to any part of the body threatened by invaders, and are hardly behind the fluids of ​the blood in this ability to be massed or delivered where needed. The phagocytic mechanism of defense operates through all the orders of the metazoa; and while it can hardly have been developed originally as a protective system against parasites, and doubtless represents a mechanism for disposing of effete and useless particulate matter in the body by a process of intracellular digestion, yet it has reached through evolutionary selection a high state of perfection and must have exercised no small influence in protecting from extinction certain living species.
There is good reason to believe that in the final disposal of bacteria intruded into the body the phagocytes play the terminal rôle: i. e., under favorable conditions they are attracted through chemical stimuli furnished by the bacteria to which they respond to englobe them, after which the bacteria are often disintegrated. But there is equally good reason to believe that, with few exceptions, this engulfing can not take place until the bacteria have been acted on by certain plasmatic constituents that prepare the bacteria to be taken into the body of the phagocytes. The further the phenomena of bacterial destruction in the body are probed the more certain does it become that there is no single and uniform process of their disposal. The humoral doctrine of bacterial destruction contains much of fact, the phagocytic doctrine much of fact, and it is quite certain that the practical defensive activities of the body constantly imply the use of both mechanisms.
And when we push the analysis of the manner in which bacteria injure the body and enumerate the various bactericidal substances which have now been determined as existing in the plasma and in the cells, we find that this interaction must be supposed to take place. Plasmatic bactericidal action and phagocytic inclusion are cooperative functions; plasmatic antitoxic action and phagocytic detoxication are cooperative functions; plasmatic opsonization and phagocytic ingestion are complemental functions; plasmatic agglutination and phagocytic engulfing are also complemental, although less essential functions. And although in intending infections the toxic action of the bacteria to be dealt with is less a matter of great consequence, yet in principle the disposal of a few bacteria is not different from the disposal of many; and in dealing with the poison or toxic elements of bacteria, the plasma possesses distinct power of direct neutralization as the phagocytes possess distinct ability to transform poisonous into non-poisonous molecules.
I desire now to refer again to the subject of racial and species immunity for which the humoral factors of bacterial destruction afforded an imperfect explanation, in order that I may point out that the introduction of bacteria, incapable of causing infection, into immune species is followed by immediate phagocytic ingestion and destruction of the microorganisms. The rapidity and perfection of the phagocytic reaction in insusceptible animals are very impressive and might readily lead to the decision that they suffice to explain the resistance or ​immunity. However, the matter does not permit of such summary disposal, since there appear to be other factors that enter into the phenomena. The frog that does not become tetanic when inoculated with tetanus bacilli or poison, develops tetanic spasms when the temperature is raised somewhat; the hen that does not respond to an anthrax inoculation develops the infection when the temperature is lowered somewhat. Even for the final ingestion of bacteria by the phagocytes of alien and insusceptible species the plasma principles are required.
Undoubtedly the phenomena of racial and species immunity are affected by phagocytosis. But our present knowledge does not justify us in disregarding other possible and contributing agencies. We are still so little informed of even the grosser features of the body's metabolism that it would be premature to deny to it influence on susceptibility to infection. Between the metabolism of birds and mammals there is such wide disparity that an influence could easily be conceived; but the metabolic disparity is less between the herbivora and carnivora, and still less between some closely related species which yet show marked differences in susceptibility to bacterial infection; and as between individuals of the same species it could only be the finer intramolecular variations that conceivably could come into play.
Although the properties of the defensive mechanisms of the blood have not been exhausted, yet they have been defined in such detail as to suffice for the moment and to permit us to turn attention, for a brief space, to some of the properties of the intending invading bacteria. It is matter of common experience, which each of us has suffered, that the elaborate mechanisms provided for our protection from bacterial infection do not always suffice, and now it becomes necessary to explain why they do not. In the first place, there are very great differences between the bacteria which seek to enter the body. Some species are never very harmful and are readily combated, excluded or destroyed; other species often possess only a moderate degree of virulence or potential power of doing injury and can also, as a rule, be overcome; while these second species sometimes acquire such highly virulent or invasive powers that the defenses prove quite inadequate to exclude or combat them. During the prevalence of great bacterial epidemics it is probable that this factor, virulence, plays a considerable rôle. Of course in epidemics the bacterial causes are by the exigencies of the situation more widely diffused than at other times, so that more individuals come under their influence; but with even such a common bacterium as the diplococcus which causes pneumonia and the bacillus which produces influenza, there arise conditions in which severe and often very extensive outbreaks, or localized epidemics, occur which are probably to be attributed to an accession in virulence of these germs, although the precise causes leading to the increase may not be discovered.
Now this quality of virulence, which is often evolved so quickly ​and apparently so mysteriously is expressed biologically in various ways besides in that of greater infective power: virulent bacteria may prove incapable of being charged with opsonin so that they can not be ingested by phagocytes; they may show unusual power to resist plasma or serum destruction; they may drive away or repel or act negatively in respect to chemical attraction on the phagocytes; and being thus unopposable they tend to multiply quickly and with little restraint and thus still further to break down and render ineffective the normal defensive mechanisms, and ultimately to damage seriously the sensitive cells of the organs. This constitutes disease.
Another power resides in the body that should be regarded, namely, the power to neutralize or destroy poisons as distinct from parasites; for the body is exposed to the deleterious action of poisons generated by living parasites that do not themselves penetrate within the body. Some of these poisons are generated away from the body, as is the case with certain food poisons; some by bacteria in the intestinal canal that do not seek to invade the blood; some by bacteria, like the diphtheria bacillus, that first kill tissue, usually of the mucous membranes, and then develop in the dead tissue and send the poison into the body. And besides this every bacterial disease resolves itself ultimately into a process of poisoning—of intoxication. In typhoid fever, in pneumonia, in meningitis and in the multitude of other bacterial invasive diseases of man and the lower animals, the severe symptoms are caused by the poisons liberated through disintegration of the invading bacteria which, however, continue by multiplication to recruit their numbers.
The condition of susceptibility to poisons varies with different races and species, very much as bacterial susceptibility does. The cold-blooded animals are indifferent to poisons that are very injurious to warm-blooded animals, but not all cold-blooded animals behave alike. Tetanus toxin is alike innocuous for the frog and the alligator; but by raising the temperature artificially the frog develops tetanus, but the alligator does not. Sometimes the effects depend merely upon the mode of entrance of the poison into the body. Tetanus toxin, diphtheria toxin and snake venom have no effect on mammals when swallowed unless the intestinal epithelium has been injured. These poisons can not pass through the epithelium to reach the blood, where alone they can exert their action. The toxin of the dysentery bacillus passes readily in the rabbit from the blood into the intestine, which it injures, but can not pass from the intestine into the blood. Tetanus toxin can be injected into the circulation of the hen but does no harm. Injected into the brain it produces tetanus. Introduced into the blood it remains there for many weeks, hence the failure to act can not be due to destruction, but probably is due to inability to pass through the blood vessels in order to reach the cells of the central nervous system in a sufficient state of concentration. The physiological state of the animal also exerts an influence: certain hibernating species are ​susceptible to tetanus poison in the summer but not during the winter sleep. There exist, therefore, different mechanisms for excluding poisons from the sensitive and reacting cells and among them are certain quantities of neutralizing, or antitoxic substances, normally contained in the blood. We know at least one such definite antitoxin, namely, the diphtheria antitoxin, which exists in minimal quantities in the blood of man and the horse.
The absence of numerical relation between the mechanism which destroys bacteria and neutralizes poisons sometimes works sad havoc for the body. The two capacities may differ naturally or are enhanced in different degrees by artificial means. The matter is one of great importance because almost without exception all bacterial diseases are examples of poisoning. The mechanical obstructions produced by the bacterial bodies are relatively unimportant. The body is more readily defended from the invasion of bacteria, with very few exceptions, than from the effects of their poisons. The capacity to dispose of typhoid and cholera bacilli is more easily produced than the power to neutralize or otherwise render innocuous the poisons liberated by the dissolved bacilli. It is precisely because we have not yet learned how to overcome this class of bacterial poisons within the body that we have not mastered the bacterial diseases as a whole. There are, however, certain bacterial poisons for which adequate antidotes are readily produced, thus, for example, for the diphtheria, tetanus, botulism and possibly the dysentery poisons. Here the poisons can be more easily neutralized than the bacilli can be got rid of, but by neutralizing the poisons we succeed in arresting the multiplication of the bacteria and often in curing the disease.
The normal body possesses a mean resistance to bacterial invasion and to bacterial poisoning which, while somewhat fluctuant, is of high value except under certain exceptional conditions in which infection readily develops. We know that certain general states of and influences exerted on the body are associated with a rise or a fall of this mean value. But we are not equally informed of the physical basis of this rise and fall. This particular topic is peculiarly difficult because of the large numbers of factors which enter into it. We know from observation that proper clothing, wholesome food, good hygienic surroundings, avoidance of over fatigue and of depressing psychic impressions, and that physical care of the body, all contribute toward maintaining health as the reverse conditions predispose to establishing disease. In seeking the physical basis of this difference we must avoid confusing cause with effect. Good hygienic surroundings may act chiefly by excluding the sources of infection rather than by enhancing resistance. Yet there is experimental as well as observational foundation for the belief in these general influences to affect the disposition to acquire or escape infectious disease. Animals which are made to fast, to over-exercise, are made anæmic, are given excessive quantities of ​alcohol and other poisons, or are exposed to abnormal cold by shaving of the skin, are more subject to certain infections than animals not so treated. If, now, it were found that the blood factors governing resistance fluctuated with these influences, became smaller and less conspicuous when the influences were bad and larger and more efficient when the influences were good, we should then have established an important concrete fact.
But the alexinic activity of the blood varies normally within such wide limits that only maximal changes could be regarded as significant, and it appears that it is only as the fatal termination of certain severe infections are reached—such as experimental anthrax and pneumococcus infections, for example—that the alexinic power falls greatly or disappears altogether. The determination of phagocytic activity outside the body has not thus far been carried out in such a manner as to indicate a functional depression which either precedes immediately or develops in the course of severe infections; although certain infections which take a severe course are characterized by a persistent reduction in the number of leucocytes in the circulating blood. This latter phenomenon must, however, probably be regarded as an effect and not as the cause of the infection. There is, however, known at least one example where paralysis of the phagocytes leads to a fatal infection under conditions in which the normal phagocytes are entirely competent to prevent infection. If to a guinea-pig a small dose of opium be administered and this is followed by the injection of a non-lethal quantity of a culture of the cholera bacillus, death will ensue because the sensitiveness of the phagocytes to the chemical stimulus exerted by the cholera poison has been diminished by the narcotic influence of the opium.
The mean phagocytic value of the blood can, however, be definitely raised by certain agencies, that are at the same time and through the rise in the number of phagocytes produced, useful in warding off and sometimes even in overcoming infection. The means employed to bring about an increase of leucocytes, or to establish a hyperleucocytosis, suffice to maintain the high value for short period relatively only, unless the stimulus is frequently repeated. A cold bath, a sun bath, the injection into the circulation of a number of simple chemical substances—peptone, albumose, nucleinic acid, spermin, pilocarpine—are all followed under physiological conditions by hyperleucocytosis and by a temporary state of increased resistance to bacterial invasion. Moreover, in certain experimental infections, at least, there can thus be aroused a heightened power to overcome established infections—those caused, for example, by the cholera, meningitis and pneumococcus germs. Perhaps the most striking example of the protective influence of hyperleucocytosis is afforded by the experimental infection described under the name of cholera peritonitis of the guinea-pig. If a fatal quantity of cholera germs be injected into the peritoneal cavity of a ​guinea-pig, symptoms of poisoning quickly set in and death results in a few hours. A study of the conditions present in the peritoneal cavity shows that the bacteria have developed freely, that some have been broken up and disintegrated, and that very few preserved phagocytes can be found. Examination of the blood reveals that the number of leucocytes in the general circulation has been reduced; and all the evidences point to the conclusion that not only has phagocytosis not taken place, but that there has been a general destruction of leucocytes produced by the cholera poison. If, however, there be introduced into the peritoneal cavity of a guinea-pig twelve to twenty-four hours prior to the inoculation of the cholera bacilli, a small amount of sterile salt solution, or bouillon, or one of the other chemicals mentioned, which procedure will bring into the peritoneum a considerable number of leucocytes at the same time that it causes a rise of leucocytes in the circulating blood, then the cholera germs are quickly taken up by the phagocytes, multiplication is prevented, and the animal escapes severe illness.
The value of hyperleucocytosis as a defensive measure against infection must, probably, always remain greater than its value as a cure for established infection. There are several reasons that make this conclusion probable: the capacity of the blood is increased in the direction of destroying bacteria without being augmented at the same time in the direction of neutralizing bacterial poisons; the organism that is already severely poisoned by infection reacts less certainly to the chemical agents that provoke hyperleucocytosis than the uninfected organism. And yet we may see the operation of the benign influence of hyperleucocytosis, associated with an increased passage of alexin-containing lymph through the vessels, upon certain local infections at least, in the results of measures that determine an augmented supply of blood to a diseased part; in the mechanical hyperemias produced through posture or superheated air; the influence (in part) of tuberculin injections; and the effects of poultices and embrocations, of counter-irritants, and of certain of the phenomena of local inflammation.
The facts at our command point to the great potential power of the normal organism to resist infection and indicate that the normal body possesses the capacity, on demand, to increase this power beyond the mean value, chiefly by opposing intending infection by hyperleucocytosis and also, probably, by the strengthening of its plasmatic defensive action through the additional soluble alexin substances thrown off by the augmented leucocytes. This defensive mechanism acts in the same manner on all bacterial invaders and is not specially adapted for any one or group of bacteria. The form of activity is strictly non-specific.
Let us now ask ourselves if in overcoming infectious disease, which luckily the organism is frequently able to accomplish, the mechanism put into operation is similar and only more intense than the one we have considered for warding off infection? The answer to this question ​is that recovery from infection consists in the bringing into being of a new set of phenomena that gradually reinforce the resistance; that recovery from infection is accomplished through a process of immunization. The evidences of this condition of immunization are found in the appearance in the blood some time between the fourth or fifth to the tenth day of the disease, and somewhat later than they have appeared in the spleen and bone marrow, of chemical substances which are directed in a specific manner to the neutralization of the poisons having been and still being produced by the bacterial causes of the disease, to the destruction of the bacteria themselves either outright by the plasmatic fluid which has now been enriched by a new quantity of intermediary substance of high potency that may bring the bacteria more readily under the dissolving influence of the complement, or by the phagocytes to which they are exposed in greater measure through the production of opsonins of higher strength and stability. As recovery progresses these immunity substances continue to increase until at the termination of the disease they are present in quantities that suffice often, by a passive transfer to another individual, to protect other animals more certainly from an infection, or to terminate abruptly an infection already established in them.
When the infectious disease is the expression not of the combined effects of poison and bacteria but of the poison chiefly which enters the blood, the bacteria remaining without as in diphtheria, then the blood changes characterizing the immune state are simpler and consist in the accumulation there of antitoxins that constitute the most perfect antidote to poisons that are known. The condition of immunity produces no demonstrable change in the properties of the phagocytes through which they are better enabled to overcome the poisonous bacteria. They do become, in course of the immunization, more sensitive to positive chemotactic stimuli; but it is still an unsettled question whether they are altered qualitatively by the immunization, or whether the plasmatic changes do not really react upon them and thus increase their efficiency.
It must now be patent that between what may be termed the process of physiological resistance and what is termed the condition of immunization, a wide distinction exists. The one is non-specific in its action, the other highly specific in its effects; the one is subject to a limited augmentation, the other may be carried to a high degree of potency and perfection; the one often fails to protect the organism in which it is developed, the other suffices to protect both itself and another organism. If therefore we were to be asked in what manner can the animal organism best be reinforced against infection, we should be compelled to answer by passing safely through the infection itself. This conclusion, which has been reached by purely experimental biological methods is supported on every side by common observation and experience with ​the acute infectious diseases of which one attack protects from a subsequent attack of the same disease.
It may conduce to clearness if we should enumerate the factors that have been described and assigned on the one hand to natural resistance, and on the other hand to acquired resistance or immunity. We can tabulate the factors in the following manner:
This tabulation exhibits the distinction between the physical basis of physiological resistance and of the state of immunity. There is another difference between them; any increase that can be called out beyond the mean of physiological resistance is accomplished in a few hours; and having been called out to meet a particular condition of need of the body and the effect having been exerted, it passes off very soon. It is rare that the effect of a hyperleucocytosis can be detected for more than three or four days after it has appeared. The development of the state of immunity, on the other hand, is a slow process relatively and depends upon the setting into motion of certain cell functions, through which new substances are produced, which, being first retained within the cells producing them, eventually are passed into the blood. Hence it is that these new substances can be detected at an earlier period of the infection in the spleen than in the blood. But once they have been produced, the substances endure either for an indefinite period, or the capacity to produce new ones of the same sort is retained by the organism often for years. The blood may grow weak in the typhoid immunity principle in the course of years following an attack of typhoid fever, or a rabbit immunized with typhoid bacilli may show after a time a great diminution of the blood agglutinins for typhoid bacilli; but the typhoid immunity persists in the one, as in the other-minimal quantities of typhoid bacilli will bring out, and without the original delay, a new production of agglutinin that will restore the lost amount.
​The facts on immunity which I have presented to you constitute the physical basis, also, of all artificial methods which are being pursued so successfully in preventing certain infections through vaccination, and in curing them through the use of immune serum products. The facts also account in an eminently satisfactory manner for the suppression of small-pox by cow-pox vaccination. The "vaccines" so-called for bacterial diseases, which are, I might say, at present being employed chiefly in protecting animals from epidemic infectious diseases to which they are much exposed, consist for the most part of bacteria either killed outright by heat or chemicals or of bacteria whose virulence has been diminished by special methods of cultivation or treatment. In human beings this method of vaccination has been employed only when large numbers of persons have been exposed to infections from the zone or focus of which they could not be removed, or from which, owing to the peculiar circumstances surrounding the infections, they could not readily or at all be protected by the suppression of the diseased germs at their sources. Thus it has been found advantageous in a few instances to employ vaccination against cholera and bubonic plague, on those especially exposed to these epidemic diseases, and against typhoid fever on troops going in time of war into heavily infected endemic zones of that disease.
In a few instances this method of vaccination has been successfully carried out in animals with infectious diseases in which the germs causing them have not been discovered. Thus it is possible to vaccinate cattle against the destructive rinderpest of Africa, the Philippines and other tropical countries, by employing the bile of animals which have succumbed to the infection, which contains the parasite of the disease somewhat modified by certain immunity principles contained within it along with parasites. In fact, this method of conjoint vaccination with the parasite of the disease and the blood containing immunity principles is one that offers a considerable field of practical application. On the one hand, there is accomplished a passive immunization of the body that becomes operative immediately and, on the other hand, a vaccination that after the usual interval leads to the production of a state of active immunity that rises to a higher level and is far more enduring than the passive state.
Incidentally we have discovered from this process of mixed or conjoint vaccination that immune sera prepared for bacteria or other parasites which are not toxin producers in the manner of the diphtheria bacillus, but which contain endotoxin, act not especially by neutralizing toxins, or by destroying outright the bacteria, but by exercising an efficient protective control over the injury which these parasites or their poisons tend to inflict on certain sensitive body cells. For example, if cattle are inoculated on one side of the body with virulent blood from animals dying of rinderpest, and on the other side with blood serum taken from animals that have recovered from the ​disease and subsequently have had their immunity intensified by injections of highly virulent blood, the cattle so vaccinated will develop rinderpest in a mild form and will subsequently on recovery be also immune; and yet during the process of immunization their blood contains highly virulent parasites so that if a little of it be introduced into non-protected and healthy cattle, they will be given rinderpest and will die of it.
The reaction of the body to the bacterial vaccines injected is out of proportion to the quantity of culture introduced. Thus two milligrams of dead cholera bacilli injected under the skin of human beings will yield enough of the specific immunity substance for these bacilli to bring about the destruction of 60,000 or more milligrams of the culture. There can be, therefore, no direct transformation of the cholera bacilli into immunity bodies, but they must exert a stimulus on certain cell functions through which the immunity. principles are produced; and the quantity of their formation depends not on the weight of crude bacilli introduced, but on the strength of the stimulus impressed upon the sensitive cells to which they react in a specific and remarkable manner.
Is it possible in the course of an established infection to reinforce the resistance of the body? I have already stated that it is not practicable to bring out at the height of an infection an efficient heightened reaction of physiological resistance; but from this it does not follow that under these conditions a special form of immunity reaction may not be elicited. The tuberculin reaction, or that part of it which is specific, may be cited as an example of this kind of reinforcement; and whatever there is of value in the treatment of infectious diseases by means of dead cultures of their specific bacteria—"vaccines" so-called—must be of the nature of an intensified immunity reaction. What is sought to be accomplished in the latter case is the formation in certain uninfected localities—in the subcutaneous tissues, for example—of immunity principles that afterwards by escaping into the blood shall assist in the termination of an infectious process situated elsewhere in the body. Such local foci of immunity as it is designed to create in the subcutaneous tissue are not unknown. The pleura can be given a local immunity to the typhoid bacilli; the subcutaneous tissue to tetanus toxin, and it is highly probable that the normal resistances exhibited by our mucous membranes to the pathogenic bacteria they harbor are examples of such local immunities.
I fear that I have carried you far afield and into somewhat devious paths of immunity to disease. You will, I know, not complain and hold it to the detriment of medical science, that these paths have not been already converted into fine open roads. But you will prefer to recall how brief is the time since where the paths now are there were only wood and tangle.