IMMUNITY AND CURATIVE INOCULATIONS

During the last twenty years the whole attitude of the study and investigation of disease-causing microbes has advanced from the preliminary step of merely identifying certain microbes as the causes of certain diseases to a further step, viz. that of attempting to defend the animal and the human body against their attacks in the manner already so finely started by Pasteur. For many years disease after disease was examined and found to be caused by special bacteria or other microbes. Even non-infectious diseases or diseases only communicable under very special conditions were found to be due to microbes, so that it is probable that all disease that is not due to congenital malformation or to mechanical injury, or to poison fabricated in the weapons of larger animals and plants, or by man himself, is due to microbes. "Life," says Lord Justice Moulton, "is one ceaseless war against these enemies, and the periods of our too-transient successes are known as health." One of the last diseases traced to microbes is that sad condition known as "infantile paralysis," by which so many of the brightest and best members of the community have been crippled, from childhood onwards, through life.

Of late we have been making rapid strides in arriving at a knowledge as to how Nature herself protects higher creatures from the excesses and exuberance of destructive microbes, and we are now able to see that it is in adopting her methods that our best hope of increasing that protection lies. Nature is satisfied if the efficacy of her defence is sufficient to save enough individuals to carry on the race. Man desires in the case of his own fellows to out-do Nature and to save all.

A century and a half ago, before the true character of infective disease was understood, it was observed that an individual who was attacked by the smallpox and recovered became incapable of receiving the infection again. He was "protected" or "immune." The practice of "inoculation" was introduced from the East by Lady Montague. The infectious matter was introduced from a smallpox patient into the person to be protected by rubbing it into a scarified part of the skin. A much less severe attack of smallpox was thus produced than that which usually followed the natural infection, which (though we do not know precisely its mode of entrance) is more widely spread through the blood. At the same time the condition of "immunity" after the attack was brought about with equal efficacy. When Jenner introduced inoculation with "cowpox" for the purpose of establishing "immunity" in the vaccinated person, inoculation with smallpox itself was a very usual practice. It was open to the objection that sometimes an unexpectedly violent attack of the disease was produced, resulting in death, and that the active infection was kept alive and ever present in the community. The notion with regard to the mode in which "immunity" was produced by either the Montacutian or Jennerian inoculation was, even after the general knowledge of microbes as the living contagion of disease had been arrived at, that the mild attack due to inoculation "used up" something in the blood—in fact, exhausted the soil, so that the infective matter or microbe could no longer flourish in the blood. And this view was accepted as the explanation of the "immunity" to the anthrax disease conferred on cattle and sheep by Pasteur's inoculations of weakened, but still actively growing, cultures of the anthrax bacillus. Another theory was that they produced something in the blood by their own life-processes which checked their further growth, just as yeast will not grow in wort in which it has produced 8 per cent. of alcohol, and as a fire may be choked by its own smoke or ashes.

We now know that both these explanations of "immunity" are incorrect. Nature provides at least three varieties of defence within the blood of higher animals against disease-producing microbes which have broken through the outer line of fortification, the skin. These three methods are effective in different cases (one in this disease, the other in that), and, on the whole, are sufficient to preserve the races of animals (including man) from complete destruction. These are (1) the production in the blood of an antidote to the toxin or poison elaborated by the invading microbe—an antitoxin, which chemically neutralises the toxin; (2) the production in the blood of the attacked animal of a "germicidal" poison which repels and kills the attacking microbes themselves (not merely neutralising their poisonous products); (3) the extermination of the intrusive, disease-producing microbes by a kind of police, which scour the blood channels and tissues and "eat up"—actually engulf and digest—the hostile intruders. These latter agents, actual particles of the living animal in which they exist, are the "eater-cells," or "phagocytes"—minute, viscid, actively moving cells, resembling the animalcules called "amoeba." They are only the one two-thousandth of an inch in diameter, and are known as the white or colourless corpuscles of the blood. They are far less numerous than the red blood-corpuscles, which are the agents for carrying oxygen, but there are eight thousand million of them in a large spoonful of blood. They are the really important agents in protecting us from microbes, since they not only engulf and digest and so destroy those intruders, but it is probable (not certain) that they also are the manufacturers of the antitoxins and of the germicidal poisons.

If these three defensive processes given us by Nature are in working order, that is to say, if we are "healthy," they should secure to us a sufficient "immunity"—at at any rate, "recovery"—from any attack of disease-producing microbes. But they are not in "unselected," widely ranging mankind always equal (in their unaided natural state) to their task.

The attempts to produce immunity by vaccination with weakened or localised disease germs is really an attempt to train and develop to a high point the activities of the phagocytes or eater-cells of the blood.

The introduction of antitoxins by injection of them into the blood (as in the treatment of diphtheria, lock-jaw, and snake-bite) is an attempt to bring to the rescue of a patient who would sooner or later produce his own antitoxins (but perhaps too late or in insufficient quantity) the similar antitoxin obtained from the blood of another animal which has been artificially made to produce in its blood an excessive quantity of that substance.

Mithridates, King of Pontus, was, according to ancient legend, in consequence of his studies and experiments, soaked with all kinds of poisons to which he had become habituated by gradually increasing doses, and he had at last reached a condition in which no poison could harm him, so that when he was captured by the Romans and wished to kill himself (which was the correct thing in those days for a fallen king to do), he wept because he was unable to get any poisons which would act upon him. He was "immune" to all poisons. This real or supposed immunity resulting from the introduction into the living body at intervals of a series of doses of a poison gradually increasing strength has been called "Mithridatism," and animals and men so treated have been said to be "mithradatized." The toleration of poisonous drugs—such as tobacco and alcohol, and even of mineral poisons, such as arsenic—was, until lately, regarded as merely a special exhibition of that habituation of "adaptation by use" which living things often show in regard to some of the conditions of their life. Unusual cold, unusual heat, unusual moisture, salinity or the reverse, unusual deprivation of food, unusual muscular effort may be tolerated by animals without injury provided that they have been "gradually accustomed" to the unusual thing, or, in other words, that the unusual has been gradually made the usual; so that there is a saying that eels after a time even get used to being skinned. There was no attempt to explain the details of this process of habituation; it was assumed to be a part of the general "educability" of living matter.

The study of the education of living matter, in regard to various conditions which can act upon it, has yet to be further carried out, but the way in which the poisons made by disease germs and the like, and the disease germs themselves, are dealt with in the blood and tissues has, on account of its urgent importance, from a medical point of view, been already profoundly studied by experimental and microscopic methods of late years. The old notion as to "mithridatism" was that an animal or a man would have to be separately prepared and "immunised" by habituation for every distinct kind of poison. We now know that this is not the usual way in which Nature confers immunity to poisons. Most astonishing, and at first sight magical or mysterious, powers exist in the living protoplasmic cells in and around the blood of man and higher animals, which enable their possessors to resist and combat the poison-producing microbes, and also the poison itself, of all kinds, by which the race is liable to be attacked.

Few of us realise what a wonderful and exceptional fluid the blood of a higher animal is. The Australian natives attach so little importance to it that they actually cut themselves and use their blood as a sort of paste for sticking decorative feathers on to a pole! The Papuans are more advanced, since they regard the flow of blood from a cut or graze as an evil portent. And some respect to the greatness and wonder of blood is shown by those persons among civilised peoples (more frequently men than women) who faint when they see blood, or even at the mention of its name! This stream of red fluid within us (of which an average man has about fifteen pints in his vessels) courses at a tremendous rate from the heart through all the endless branches and networks of arteries, capillaries and veins, and back to the heart. It feeds, cleanses, warms and takes "vital air" (the old name for oxygen gas) dissolved in it to every particle of our bodies, fresh and fresh at every pulse-beat as it rushes on. It not only absorbs crude digested food through the walls of the gut, but conveys it to where it is worked up and distributes the worked-up product. It removes the quickly used-up substances from every part, and the choke-damp or carbonic acid which would stop the whole machine, and kill us, were it not got rid of through the lungs as the blood hurries through the walls of these air-sacs, whilst other used-up materials are carried by it to the kidneys and passed out of the body through them. Every part of the body is brought into common life with every other part by this impetuous blood-stream—which is here, there, and everywhere, right round, and back again, in twenty-five seconds! It is obviously a very serious thing if a poison-producing microbe gets into this blood-stream and multiplies within it, or if poison-producing microbes lodge somewhere beneath the skin in a wound, and keep on discharging virulent poison into the blood! The mischief is spread all over the body at once.

It is not surprising, then, that the long course of natural selection and survival of the fittest has resulted in the fixing in the blood and the living cells immediately connected with it of extraordinary protective powers. The floating scavenger cells (eater-cells or phagocytes, first recognised as such and so named by Metchnikoff) are already found in the blood of quite simple animals in worms, shell-fish and insects. I have watched them with the microscope at work in transparent minute living water-fleas eating up, and digesting microbes which had got into the water-flea's blood. In higher animals what we call "inflammation" is a condition—the result of a new and advantageous mechanism—which consists in a local retarding of the blood-current, effected by the action of the nerves on the muscular walls of the blood-vessels, and the consequent escape of the eater-cells into the injured or infected tissue, there to eat up and destroy the injurious microbes or other particles. Special and remarkable properties—chemical activities of an extraordinary character—have been gradually developed in the floating phagocytes and in similar non-floating fixed cells over which the blood flows.

These special chemical activities are of several distinct kinds. The first is the power to convert the poison of a microbe into a destroyer of that poison—toxin into antitoxin. The atoms of these poisons are elaborately composed combinations of the organic elements. By a "shake" or a "twist" (so to speak) administered by the living cells of the blood the combination is altered, and the toxin becomes an antitoxin, destroying by chemically combining with it the very toxin from which it was formed. This is a far more efficacious method than the supposed mithridatic "habituation" or "toleration" of a poison, with small doses of which you have to be gradually prepared. The healthy blood converts any one of a large series of microbe poisons into antitoxins. It is true that apparent "opposites" are often closely allied in Nature. Evil smells and tastes are closely allied to sweet perfumes and flavours, and what is healthy and agreeable to some men acts as virulent poison to others (e.g. shell-fish, egg, quinine, opium). The smallest change in the substance administered or the smallest difference in the living substance of an individual (what is called "idiosyncrasy") makes all the difference between "poison" and "meati."

If the phagocytes and similar cells in the blood of a man or animal exposed to the poison produced by localised microbes (such as those of tetanus, diphtheria and septic growths) cannot produce enough antitoxin so as to quickly destroy the poison, we can, and do, nowadays, save his life, by injecting into his blood the required antitoxin, obtained from another animal which we have caused (by injection of the toxin) to produce the antitoxin in excess. That is one sort of "immunity" or "resistance" which we can confer, and is largely in use at the present day—the "antitoxin" treatment.

The second poison-repelling chemical activity of the blood, produced by the living cells in and about it, consists in the blood becoming directly poisonous to injurious microbes. It becomes "bactericidal," produces a bactericidal poison (called an alexin) which is usually present in normal blood, but is greatly increased when large numbers of certain poisonous microbes (e.g. those of typhoid fever) get into the blood. Again, by other chemical substances produced in it, the blood may, without actually killing the invading bacteria, only paralyse them, and cause them to "agglutinate" (that is, to adhere to one another as an inactive "clot" or "lump"). As the "agglutinating" poison is peculiar (or nearly so) for each kind of microbe, we can tell whether a patient has typhoid by drawing a drop of his blood into a tube, and adding some fresh living typhoid bacilli to it. If the patient had typhoid he will have begun to form the "typhoid-agglutinating" or "typhoid-paralysing" poison in his blood, and the experiment will result in the "agglutination" (sticking together in a lump) of the typhoid bacilli. And so we prove, in a doubtful case, that the patient has typhoid.

The third chemical activity of the blood in dealing with poisonous microbes is also one which is conferred upon it by its living cells when excited by the presence of those microbes. It is the production of a "relish" (for so it must be called) which attaches itself to the microbes and renders them attractive to the eater-cells (the phagocytes), so that those swarming amoeba-like floating particles at once proceed to engulf the microbes with avidity. In the absence of the relish (the Greek word for it used by Sir Almroth Wright, its discoverer, is "opsonin"), the eater-cells are sluggish—too sluggish—in their work. They resemble a child who will not eat dry toast, or, at best, only slowly, but will devour rapidly many pieces when the toast is buttered. It is of the utmost importance to us that our white corpuscles, or eater-cells, should not be sluggish but greedy.

There are some microbes which will produce deadly poison if grown in the clear fluid (serum) of the blood of an animal (as, for instance, the cholera-microbe when grown in the serum of the frog's blood), yet when inoculated living into the blood of that animal never cause the slightest illness! Why? Because they are at once eaten by the vigilant phagocytes of the blood before they can produce any appreciable amount of poison. That is easily demonstrated by experiment. Our main means of defence against microbial disease, says Metchnikoff—though cleanliness and precaution against access of microbes are all very well in their way—is the activity of our phagocytes. Now it appears that just as in the other cases I have been considering, so in the production of "relish," the power to produce it resides in the blood (and perhaps the cells of its vessels), but is not set at work until the enemy is in the blood. Suppose there is an infection, an invasion of the blood and tissues by one or other disease-causing microbe. Gradually if the body is healthy the "relish" is produced and becomes attached to the invading microbes. The phagocytes swallow them greedily and make an end of the invasion.

It is proved that this aroused avidity of the phagocytes is due to no change in the phagocytes themselves; since if they are transferred to the serum of a normal man they show no such predilection for the special invading microbe. The "opsonin," or "relish," is something exuded into or produced in the blood fluid when the attacking microbe arrives. It attaches itself to them: that is the essential fact. In many of us the phagocytes are not at a given moment so "avid" of this or that disease-microbe as they should be in order to protect us from its multiplication and poison production. But it is found that by injecting boiled and cooled (therefore dead) microbes of a particular kind into the blood of a man, you can start the production of the "relish" appropriate to that kind. The dead microbes answer this purpose; they excite the production of the opsonin appropriate to them and yet are not themselves dangerous, since they are dead. When subsequently (or possibly concurrently in small quantity) living microbes of the same disease enter the blood, the opsonin is ready for them. They are, to put it picturesquely, like oysters at the oyster-bar, peppered and vinegared "in no time," and then swallowed by the phagocytes by the dozen. This seems almost too comic a view of the deadly struggle of man and higher animals for health and freedom from the swarming pests which everywhere invade him. Yet it is correct, and involves a simple and fundamental truth. Our properties and appetites are but the sum of those of the protoplasmic organisms—the cells—of which we are built up. Our need for a relish with oysters is the same thing as the need of the phagocyte for a relish with its microbes, not something "poetically" compared to it. The story of "the oysters and the carpenter" might be replaced by that of "the microbes and the phagocyte." The saying, "Fine words butter no parsnips," finds a parallel in the remark that "The drinking of drugs does not opsonise microbes."

Half-way between us and the amoeba-like unicellular organisms we find the earth-worm preparing his piece of lettuce (as Darwin showed) with a juice exuded from his mouth, a "relish" reminding one of the Kava drink of the South Sea Islanders. To "opsonise" or render attractive by the application of chemical "relish" is a proceeding which we find in operation in the feeding of the minute colourless corpuscles which engorge the still more minute bacteria—and also in the preparation of their food by various lower animals, and finally in the elaborate flavouring and cooking of his food by civilised man!