Simon Flexner

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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 ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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 ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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 ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”

“ 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. ”