More Science from an Easy Chair

by Sir E. Ray Lankester

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 amœba-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."