As protection against disease is one of the most important amongst those questions which are engrossing the attention of humanity, it is natural that very great attention should have been devoted to it from the most remote times. We see primitive races, the ordinary layman, medical men, legislators and even the most subtle thinkers devoting their energies to the solution of the problem of immunity against poisoning and against infections. Historical science will never reveal to us the earliest sources of our knowledge on this question, so remote are their origins. The wide distribution of several methods for protecting man and cattle against certain diseases clearly proves that the origin of this practice dates from a very early period.

The frequency of venomous snakes in many countries has inspired a dread of these reptiles, and this must have led to the search for some method of fighting against the poisoning after the patient had been bitten. Thus, we find that many primitive races make use of various methods of immunising the body against the action of venom. The Portuguese colonel, Serpa Pinto^[839], in a letter addressed to d’Abbadie, describes the method by which he was vaccinated by the Vatuas, natives of the east coast of Africa. These savages extract the poison of snakes and prepare from it, by the addition of vegetable substances, a very brown glutinous paste which they introduce into incisions made in the skin. This operation is very painful and is followed by a swelling which lasts for a whole week. The Vatuas assert that this method confers a sure immunity against the venom. Serpa Pinto was never bitten by a snake, but, a short time after he had been vaccinated, he was stung, in the Seychelles Islands, by a scorpion without experiencing any ill effects. This experience confirms the assertion of the Vatuas, because it has been shown that the vaccine against snake venom is also efficacious against the bite of scorpions. The fact that after being stung by another scorpion ten years later Serpa Pinto was so ill that for eight days he believed that he was going to die or at least to lose an arm, shows that he did not enjoy natural immunity, and the innocuousness of the previous bite must therefore be attributed to a vaccination the effect of which had disappeared at the end of ten years.

Another vaccinal method used by primitive races is that against the pleuropneumonia of the Bovidae. De Rochebrune^[840] points out that the Moors and the Pouls of Senegambia have “a custom whose origin is lost in the obscurity of antiquity” which consists in the inoculation into their herds of cattle of the virus of the epizootic pleuropneumonia. “The point of a knife of primitive form, or of a dagger, is plunged into the lung of an animal that has died from the disease and an incision, sufficient to allow the virus to penetrate below the skin of the healthy animal, is made into the supranasal region. Experience has demonstrated the success of this protective operation.”

In Europe, the vaccinations of cattle with the virus of pleuropneumonia have certainly been known for more than a century, for, in a pamphlet published at Berne in 1773^[841], mention is made of the “inoculation” of Bovidae as a means of preventing the disease in England and in Holland, a disease against which it has been recognised that remedies are powerless.

The inoculation of the variolous virus into the healthy human subject, which comes into the same category as the inoculation of the pleuropneumonic virus into healthy bovine animals, is also a widely extended and very ancient method. The Chinese^[842] assert that they have known from the commencement of the 11th century the method of immunising against small-pox. Amongst them, as amongst the Siamese, the matter from the variolous scab is introduced into the nostrils. In Persia variolisation is practised by surgeons and by the staffs of bathing establishments, who introduce the powdered scabs into scratches in the skin. The Ashantis inoculate the variolous virus into seven places on the arms and legs. According to the account of Timoni, a Greek physician practising in Constantinople in the first half of the 18th century, the Circassians and Georgians, intent upon preserving the beauty of their daughters, make punctures at various points in the skin, with needles charged with variolous virus. Everybody is acquainted with the fact that it was from Constantinople that Lady Mary Wortley Montague at the same period (1721), imported into Europe “the Greek method,” which consisted in the inoculation of the contents of small-pox pustules with the object of producing a benign small-pox and of protecting the vaccinated person from severe and dangerous small-pox. This practice was widespread in Europe during the second half of the 18th century, but as it was not unattended by serious drawbacks an attempt was made to avoid them by the employment of all kinds of medicaments. As these, however, were found to be entirely ineffective, the need was felt of replacing variolisation by some more benign method.

It is asserted^[843] that in Baluchistan the custom of having cows suffering from cow-pox milked by children who had wounds on their hands has been widespread from time immemorial. This practice conferred upon these children an immunity against small-pox. It cannot be denied that the idea of being able to vaccinate with cow-pox was common knowledge amongst breeders and dairymen in several countries in Europe, especially in England, France, and Germany. It is stated that Edward Jenner learnt from the country people of his native county of Gloucestershire that contact with cow-pox protected against small-pox. Being a man of great understanding and culture, he set himself to verify this opinion experimentally. Having demonstrated by a great number of experiments that the inoculation of variolous virus into persons vaccinated by cow-pox had no ill result, he became the great propagandist of the new method. He worked at this subject for 20 years but only decided to publish his results (in 1798) after he had completely satisfied himself of the great utility of vaccination with the virus of cow-pox. At first Jenner’s discovery met with great opposition, but his method was soon verified in France and several other countries and it was not long before it was generally practised.

When Pasteur set himself to study the infective diseases in their relation to micro-organisms the idea of profiting by the discovery of these pathogenic organisms and of drawing from them a weapon against infections soon arose in his mind. He studied Jenner’s work in order to extract from it any indications capable of putting him into the right path. He induced his collaborators to carry out several series of experiments with the object of immunising the animal organism against infective micro-organisms. During this laborious and original work chance^[844] helped in the accomplishment of his task. When, at the conclusion of the holidays in the autumn of 1879, Pasteur and his collaborators Chamberland and Roux wished to resume their experiments on fowl cholera, they found to their great surprise that the micro-organisms of this disease, usually so fatal, had become innocuous. Fowls, that received doses of cultures much more than sufficient to cause death, did not experience any ill effect. Prepared by his previous knowledge and by the continual direction of his thoughts to the prevention of contagious diseases, Pasteur divined at once the great bearing of this check in his inoculations with old cultures, and immediately began to make precise experiments as to the vaccinating power of these micro-organisms which had become innocuous. These researches led him to the discovery of two great principles: that of the attenuation of viruses, and that of the vaccinating property of attenuated micro-organisms. Various memoirs by Pasteur^[845] established these laws in a very exact manner; moreover he gave all the information necessary to allow of the principal results being controlled and verified. In France, this great discovery was at once accepted by various investigators, though others found occasion to manifest their scepticism. Abroad this discovery met with very lively opposition and this from the highest authorities, who would not recognise the possibility either of attenuating the virus or of conferring immunity upon animals. The anthrax bacillus can be grown for a very long time on culture media, the potato, for example, without losing its pathogenic power in the slightest degree. Therefore, it was said, this attenuation of virus can have no actual existence. White rats that have resisted one or more inoculations of the anthrax bacillus may die from a later inoculation of the same micro-organism. Therefore there is no acquired immunity, etc. The principles laid down by Pasteur are from every point of view of such prime importance, that very numerous experiments were carried out at once for the purpose of verifying their exactness and the contest was not a long one. In the course of a few years it was universally recognised that the attenuation of viruses, and also the vaccination by attenuated micro-organisms, were realities which henceforth cannot be denied and which must pass into the domain of truths definitely acquired. An attempt was then made to extend these fresh victories to the other infective diseases. Pasteur, Chamberland, and Roux applied themselves to devising a method of vaccinating animals against anthrax and against rabic virus; Pasteur and Thuillier extended their researches on this subject to swine erysipelas. From several other quarters the search for vaccines was instituted. Toussaint made various attempts, at times crowned with success, to immunise animals against anthrax by means of heated anthrax blood. Arloing, Cornevin, and Thomas succeeded in vaccinating the Bovidae against symptomatic anthrax. Loeffler was the first in Germany to demonstrate that rabbits which had recovered from the disease set up by the bacillus of mouse septicaemia acquired an immunity against the attacks of this organism. It is not necessary to cite further examples, so numerous have they become and so unanimously confirmatory.

After the first steps had been taken along this new path Pasteur and his collaborators began to apply the knowledge they had gained to the preparation of vaccines capable of giving practical results. The two anti-anthrax vaccines and the two vaccines against swine erysipelas were the fruit of these attempts. Here, again, numerous objections were raised against these discoveries. Sheep which had received enormous quantities of the bacillus may die from anthrax in spite of the two Pasteurian vaccines and from that it was wished to conclude that these vaccines should not be employed in practice to protect sheep against the anthrax fever. The results of experiments made on a large scale in various parts of the globe have demonstrated the inadequacy of these objections and these questions are now regarded as definitely settled.

So large a number of investigations, in response to the most urgent and immediate needs, was not favourable to minute researches on the mechanism of this immunity which had been revealed in so marvellous a fashion. In spite of this, Pasteur applied himself to the solution of this problem so far as this was possible under the conditions in which he carried on his investigations. He thought that acquired immunity was the result of the impossibility of the growth of a pathogenic micro-organism in a medium in which it had previously been cultivated. When the micro-organism of fowl cholera sets up in certain individuals a disease which though grave is not fatal, or when the attenuated micro-organism produces a simple, transient discomfort, it lives in both cases in the fluids and tissues of the animal. This existence is possible in consequence of the absorption of certain nutrient substances. Once these substances are consumed they are not easily renewed, and in consequence the vaccinated organism becomes incapable of nourishing the special micro-organism a second or a third time. To support this brilliant hypothesis by precise facts Pasteur made experiments on the conditions met with in the development of the micro-organism of fowl cholera in vitro. He filtered a broth culture of this micro-organism after it had grown luxuriantly for several days, and into the fluid, which had now become clear and transparent, he sowed afresh the same micro-organism. No growth took place and the fluid remained quite clear. This absence of development might be explained either by the presence in the fluid of some excremental substance thrown off during the first culture or by the absence of some substance indispensable for the nutrition of the micro-organism. Pasteur excluded the first hypothesis by an experiment which demonstrated that it is sufficient to add to the filtered fluid a small quantity of fresh nutritive substances to enable the micro-organism again to develop abundantly. It is therefore to the absence of some element essential to the existence of the micro-organism that we must attribute the immunity enjoyed by animals which have been vaccinated or which have undergone spontaneous cure. This is how Pasteur^[846] expressed himself on this point: “the muscle which has been much affected has, even after healing and repair, become in some way incapable of supporting the growth of the micro-organism, as if the latter, by a previous culture, had eliminated from the muscle some principle that life does not bring back and whose absence prevents the development of the small organism. There is no doubt that this explanation, to which the plainest facts at the moment lead us, will become general and applicable to all the virulent diseases.”

This explanation appeared to be a reasonable one to several observers, amongst whom I may cite Chauveau^[847], the distinguished author of important works on viruses. “In all probability this seductive theory,” says Chauveau, “based on one of the most interesting of those clear and decisive experiments for which Pasteur is famous, applies to the majority of cases of immunity acquired by protective inoculation.” But Chauveau thinks that it does not explain natural immunity, especially that of the Algerian sheep, against anthrax, an example that he had studied on several occasions. When he inoculated into these animals large quantities of anthrax bacilli, not going beyond certain limits, the sheep resisted perfectly; but injections of enormous doses were nearly always capable of overcoming this natural immunity of the Algerian sheep and of inducing in them a fatal anthrax. Chauveau thinks that this fact is best explained by the presence of an inhibitory substance in the blood plasma, whose action becomes exhausted when distributed over a very large number of bacilli. This opinion was not, however, shared by Pasteur^[848], who raises the objection that natural immunity can really be produced and maintained without the presence of this inhibitory substance from the fact that fowls, which exhibit such marked resistance against anthrax, readily contract the disease when the temperature of their bodies is lowered. Under these conditions it is unimaginable that an inhibitory substance has disappeared under the influence of cold.

The controversy existent from the birth of theories on immunity shows us that from the very commencement the problem was found to be a very complex one, and that to attack it in a satisfactory way we must as far as possible multiply and deepen our study of the phenomena which accompany the resistance of the animal against pathogenic micro-organisms. Thus, Chauveau^[849] was not long before he undertook experiments having for their object the determination of the fate of anthrax bacilli when injected into the blood vessels of Algerian sheep. He found that these organisms disappeared from the blood at the end of a few hours, but they were then to be found accumulated in the lung, spleen, and certain other viscera. In these positions the bacilli become incapable of reproducing themselves and in refractory individuals soon disappear, being opposed by the inhibitory substances of the blood plasma.

The two theories just sketched have this point in common, that they both attribute the natural or acquired immunity to humoral and purely passive properties. According to one theory it is the impoverishment of the fluids of the animals which prevents the development of the pathogenic organism, whilst according to the other it is the presence of some bacterial poison which brings about the same result. To give experimental support to his theory Pasteur brought forward his attempts at sowing micro-organisms in culture media exhausted by a previous development of the same organism, eliminating, so to say, the active influence of the animal organism. It is true that, in order to explain natural immunity, it was necessary to ascribe a rôle to the “constitution” and to the “vital resistance,” interpreting this, as Naegeli had already done, in the sense of a competition for the oxygen and the nutritive substances between the parasites and the cells of the body.

Adopting this point of view, Hans Buchner^[850], a pupil of Naegeli, attempted to gain a more precise idea of the conditions under which acquired immunity against infective diseases is set up. He developed his theory in various publications; this theory consists, briefly, in the property of the animal organism to reinforce the local resistance of the organs by means of an inflammatory reaction. The starting-point of this local theory is the thesis that each pathogenic micro-organism can only manifest its pathogenic action when it enters the particular organ in which it is capable of living and maintaining itself. Thus, the pneumonococcus can live in the lungs only, the cholera vibrio in the intestines only, and so on. Every time that a pathogenic micro-organism becomes localised in its special organ, an inflammatory action is set up which results in the reinforcement of the living elements of the organ in question. Inflammation, therefore, is regarded by Buchner as a salutary reaction, which acts, not directly on the exciting morbific cause, but through the mediation of the specific cells of the organs. This theory of immunity led Buchner to propose arsenical treatment as a remedy against microbial disease, because arsenic is, of all drugs, the one capable of setting up the greatest inflammatory reaction.

Another German observer, Grawitz^[851], proposes a theory of acquired immunity, according to which a first attack of an infective disease sets up “the adaptation of the cells to the power of energetic assimilation of the fungi.” This reinforced adaptation is transmitted to the descendants of the cells which have acquired it, and for that reason the immunity may persist for months, and even years. Grawitz attempted to base his views on experiments on the acquired immunity against the fungus of the lily of the valley, but Loeffler^[852] soon demonstrated that this thesis could not be maintained, and that the immunity assumed by Grawitz did not, in reality, exist.

It will be seen that all the theories summarised above are marked by their vague character and want of precision; this is not at all astonishing when we take into consideration the very imperfect knowledge of the phenomena of immunity. It is evident that if we wish to gain a satisfactory idea of the mechanism of the resistance of the animal body against pathogenic micro-organisms, we must inform ourselves as to the modifications which take place in the organs and tissues at the time of the acquisition of the immunity, and also find out what becomes of the micro-organisms in a refractory animal.

We have seen that Chauveau demonstrated that anthrax bacilli when injected into the vessels of Algerian sheep disappear, but he was unable to say anything as to the way in which this disappearance was brought about in nature. Buchner accepted the reinforced resistance of inflamed organs without being able to describe the phenomena which manifest themselves during the inflammation of tissues invaded by the pathogenic micro-organisms.

Independently of these theoretical and rather speculative views on immunity, there has been an addition to our scientific assets of fairly exact data on the relation of certain pathogenic organisms to the organs and tissues of susceptible or refractory animals. When, as a result of the labours of Davaine and Obermeyer, the attention of pathologists, especially of those working at pathological histology, was drawn to the part played by micro-organisms in infective diseases, a diligent search was instituted for these organisms in sections of the organs of persons who had died from various diseases. Masses of cocci especially were found in the organs of individuals who had died from diphtheria, puerperal fever, and various forms of pyaemia. In the course of these investigations attention was drawn fairly frequently to the presence of micro-organisms inside the white corpuscles of pus and of other morbid products. Amongst the first to make this observation I may cite Hayem^[853] in France, and Birch-Hirschfeld^[854], Klebs, Rindfleisch, von Recklinghausen, and Waldeyer in Germany. Klebs^[855] speaks of the presence of micro-organisms in infected wounds, in the interior of contractile white corpuscles, and attributes to these cells the principal rôle in the transport of these parasites in the lymphatic tissue. Waldeyer^[856] cites a case of puerperal fever in which the corpuscles of the peritoneal pus were filled with bacteria. Similar observations were by no means rare; and they led to a general conclusion that micro-organisms meet with such favourable conditions inside the leucocytes that they would contribute to their dissemination through the body. This opinion had become so general that when Koch^[857], in frogs inoculated with anthrax bacilli, made the discovery of round cells containing large numbers of these micro-organisms he did not hesitate to conclude that the bacilli found a favourable medium in the substance of these elements. Now the frog, under ordinary conditions, is refractory to anthrax.

As early as 1874, however, Panum^[858] had given expression to the view, in a vague fashion it is true, that leucocytes might assist in the destruction of micro-organisms. In his memoir on putrefactive poisons we find a note wherein occurs the following reflection: “For the solution of the question as to how and in what situations the ordinary bacteria of putrefaction disappear, an interesting communication made by Birch-Hirschfeld seems to me to furnish an indication. According to this observer the micrococci, introduced into the circulation, are deposited in the lymphatic glands and in the spleen, after having, for the most part, entered into the blood corpuscles. That the ordinary bacilli of putrefaction really die in the body is proved, not only by the circumstance that they remain inactive after the acute paroxysm of putrid intoxication has been happily surmounted, but also by the important observations made by Eberth on the innocuousness of the inoculation of ordinary bacteria into the cornea.” These lines contain the indication that the corpuscles of the blood (in this case undoubtedly leucocytes) ingest the bacteria introduced in the blood current and destroy them.

Some years later, in 1877, Grawitz^[859], in connection with his researches on the parasite of the lily of the valley, made the remark that the fungi, when introduced into the blood of mammals, are seized by the white corpuscles and thus “withdrawn from contact with the assimilable fluid.” Gaule^[860] who, as we know, sought to demonstrate that the Drepanidium of the frog’s blood is nothing but the fragments of cell nuclei transformed into ‘Würmchen,’ has described the structure of these organisms in the amoeboid cells of the spleen. “I happened on one occasion,” he writes, “to observe an amoebocyte of the spleen of the frog which in a short time ingested three ‘Würmchen,’ and then went away briskly without leaving any trace of where it had been. Following its movements I was able at the first to make out within the contents of the amoebocyte the refractile body of the ‘Würmchen.’ But this body became paler, and half-an-hour later it had been completely assimilated.” Undoubtedly these “Würmchen” were nothing but parasites (Drepanidium), and have no connection with the cell nuclei of frogs. Their ingestion, followed by destruction, was, therefore, a defensive act on the part of the body manifested by the amoeboid cells of the splenic pulp.

In the same year, 1881, in which this observation by Gaule was published, Roser^[861], assistant in surgery at Marburg, published a small pamphlet on the lower animals. In this pamphlet the possibility of growing certain unicellular organisms in urine and milk and the adaptation of these organisms to saline solutions received special mention. At the end of one of his paragraphs Roser expresses his views on immunity, although this subject was not discussed at all in his pamphlet. He expresses himself thus: “The immunity of animals and plants in complete health depends in my opinion: (1) on the relative quantity of salt contained in their fluids, and (2) on the property of their contractile cells of ingesting the enemy which enters the animal body” (p. 18). As these statements have been put forth without receiving any further development, in the midst of all kinds of other speculations, it is not astonishing that the words I have just quoted, as well as Roser’s pamphlet itself, should not have attracted the attention of either zoologists or medical men. In the reviews for these two sciences (Schmidt’s Jahrbücher and the Zoologischer Jahresbericht of the Zoological Station at Naples) it is not even mentioned. It appears that not only did other biologists and medical men attach no importance to Roser’s speculations, but that the author himself did not claim any great value for them. I draw this conclusion from the fact that five years after his first pamphlet he published a second on inflammation and healing^[862] in which he does not apply his theory of immunity to explain these two phenomena. This new work is of an even more speculative character than was the first, and instead of attempting to show any relation between the anti-infective part played by the leucocytes and their migration during inflammation, Roser insists on the fundamental independence of this phenomenon of healing. For him the inflammation, accompanied by diapedesis, must not be looked upon as a healthy reaction of the body, but as a manifestation of disease. The heat which is observed under these conditions must be attributed in part at least to the production of heat by infective micro-organisms. I must confess that Roser’s two pamphlets were unknown to me for many years, and it was Hueppe who drew my attention to them by his mention of them in the fourth edition of his work on bacteriological methods^[863] which appeared in 1889. I had then, independently of the Marburg surgeon and by a totally different path, arrived at my conclusions as to the part played by the amoeboid cells. At the commencement of my researches on healing and immunity the passages cited above from the publications of Panum, Gaule, and Grawitz were also unknown to me. Having long studied the problem of the germinal layers in the animal series, I sought to gain some idea of their origin and significance. The part played by the ectoderm and the entoderm appeared quite clear, and the former might quite reasonably be regarded as the cutaneous investment of primitive multicellular animals, whilst the latter might be regarded as their organ of digestion. The discovery of intracellular digestion in many of the lower animals led me to regard this phenomenon as characteristic of those ancestral animals from which might be derived all the known types of the animal kingdom (excepting, of course, the Protozoa). The origin and the part played by the mesoderm appeared the most obscure. Thus, certain embryologists supposed that this layer corresponded to the reproductive organs of primitive animals: others regarded it as the prototype of the organs of locomotion. My embryological and physiological studies on sponges led me to the conclusion that the mesoderm must function in the hypothetically primitive animals as a mass of digestive cells, in all points similar to those of the entoderm. This hypothesis necessarily attracted my attention to the power of seizing foreign corpuscles possessed by the mesodermic cells. This fact has long been recognised. It was known that the white corpuscles of the Vertebrata often contained various kinds of cells, especially red and white blood corpuscles. It was known, also, that the amoeboid cells were capable of ingesting granules of coloured substances. When making an injection of indigo into the vessels of Thetys, Haeckel^[864] in 1858 was surprised to find the blue granules inside the amoeboid blood corpuscles of this beautiful gasteropod mollusk. This fact has since been confirmed by many observers, and the capacity of the amoeboid cells to take up foreign bodies became recognised as a general phenomenon. Nevertheless this phenomenon was not regarded as being analogous to digestion. Thus Haeckel^[865] himself, in his researches on the calcareous sponges, advocated the view that the foreign bodies penetrated into the interior of the viscous protoplasm in a purely passive fashion.

Observations that I made on sponges and on certain pelagic animals, transparent and of simple organisation, convinced me that the presence of foreign corpuscles in the amoeboid cells of the mesoderm must be attributed to an active ingestion by these cells which, in every respect, might be compared to the phenomena of intracellular digestion in the epithelial cells of the digestive canal of many of the lower animals. In order to demonstrate this fact clearly it was necessary to bring forward exact experimental proof. I set myself, therefore, during my stay at Messina in 1882 and 1883, to study the rôle of the amoeboid cells of the mesoderm from the point of view of intracellular digestion. I found it an easy matter to demonstrate that these elements seized foreign bodies of very varied nature by means of their living processes, and that certain of these bodies underwent a true digestion within the amoeboid cells. My principal thesis, that is to say the idea of the intimate relations between the entoderm and the mesoderm, was thus fully confirmed.

Pondering over these results, which were quite new at the time, the idea suggested itself to me that the digestive function, so profoundly rooted in the mesodermic elements, must play a part in many of the vital phenomena of animals. Starting from this standpoint, I succeeded in demonstrating that, during the very complicated metamorphoses of Echinoderms, such as the Synaptae, the amoeboid cells of the mesoderm fulfil a function in the atrophy of numerous larval organs. I have never prosecuted any medical studies; but some time before my departure for Messina I listened to the reading of Cohnheim’s treatise on General Pathology, and I was struck by his description of the facts and of his theory of inflammation. The former, especially his description of the diapedesis of the white corpuscles through the vessel wall, seemed to be of momentous interest. His theory, on the other hand, appeared to be extremely vague and nebulous. It occurred to me that a comparative study of inflammation in lower animals of simple organisation would certainly throw light on the very complex pathological phenomena in the Vertebrata, even in the frog which had served as the starting-point for Cohnheim’s remarkable experiments.

Since, in the atrophy of the larval organs of the Synaptae, the essential rôle is accomplished by the amoeboid cells of the mesoderm which accumulate and unite into masses, the richness of inflammatory exudations in white corpuscles may perhaps signify that these corpuscles have a very important function to fulfil. This reflection led me to make the following experiment: to wound and introduce spines beneath the skin of very transparent marine animals; if my hypothesis should be well founded this should bring about an accumulation of amoeboid cells at the injured spot. I selected for this purpose the large Bipinnaria larvae of starfish, so abundant at Messina, and inserted prickles of the rose into their bodies. Very shortly these prickles were found to be surrounded by a mass of amoeboid cells such as we see in human exudation as the result of the introduction of a spine or other foreign body. The whole process took place under my eyes in a transparent animal possessing neither blood nor other vessels, nor a nervous system. The first point was settled. The inflammatory exudation must be considered as a reaction against all kinds of lesions, the exudation being a more primitive and more ancient phenomenon in inflammation than are the functions of the nervous system or of the vessels.

I know quite well that, at the period when I made my researches (1882), pathologists regarded inflammation as the consequence, if not always, at least in the majority of cases, of the penetration of micro-organisms. From this followed the conclusion that the diapedesis and accumulation of white corpuscles in inflammatory diseases must be regarded as modes of defence of the organism against micro-organisms, the leucocytes in this struggle devouring and destroying the parasites. According to this hypothesis the significance of inflammation at once became simple and clear. With the object of verifying my hypothesis I began to make experiments on the lower animals, so abundant in the Straits of Messina, and to make myself acquainted with the results that had been obtained in general pathology and in pathological histology. A perusal of Ziegler’s treatise on Pathological Anatomy made it clear to me that in these branches of medical science there had long been accumulated a great number of observations fitted to facilitate the acceptation of the new hypothesis on inflammation and healing. Numerous and well-established facts on the absorption of extravasated blood, on the fate of the coloured corpuscles in the body, on the presence of micro-organisms inside leucocytes, etc., confirmed me in my view.

When I had got together certain information and a number of facts in support of my hypothesis I communicated the results to my lamented friend, Kleinenberg, at that time Professor in the University of Messina. Both medical man and zoologist, he was well qualified to offer a judgment upon the matter; this judgment was favourable. Sometime later I had the great pleasure of meeting the celebrated Professor Virchow at Messina. I imparted to him my ideas and he was kind enough to come with me to examine my preparations of Bipinnaria larvae and other lower animals in which I had set up the phenomena of inflammation without the assistance of nervous or vascular systems. This eminent observer greatly encouraged me to continue my investigations. When I explained to him my view that the inflammatory reaction on the part of the amoeboid cells could only be understood by accepting the hypothesis that the white corpuscles gave chase to the micro-organisms and destroyed them, Virchow replied that in pathology just the opposite was invariably taught. The general opinion was that micro-organisms were certainly found inside the leucocytes and that they made use of these cells as a means of transport and of dissemination through the body.

During my stay at Messina my researches were limited to the lower animals, but later I began to study inflammation and the phenomena of infection in the Vertebrata. It was not until eight months after I had commenced my researches in this direction that I decided to publish my results. I first set them forth in an address given at Odessa before the Congress of Naturalists and Medical Men in 1883. Later, they were published in a special article inserted in Claus’s Arbeiten at Vienna^[866], and in a small work which appeared in the Biologisches Centralblatt^[867]. I sought especially to develop the idea that the intracellular digestion of unicellular organisms and of many Invertebrata had been hereditarily transmitted to the higher animals and retained in them by the amoeboid cells of mesodermic origin. These cells, being capable of ingesting and digesting all kinds of histological elements, may apply the same power to the destruction of micro-organisms. In order to support this conclusion I introduced various kinds of bacteria into the bodies of some of the lower animals and I demonstrated that they were ingested and destroyed by the amoeboid cells. It was evident, however, that this proof was not sufficient. I then set myself to study the diseases of small Invertebrata sufficiently transparent to be observed directly under the microscope. The Daphniae, those small crustacea so numerous and so frequent in fresh-water, furnished me with a favourable medium in which to study a real struggle which takes place between their leucocytes and the spores of a vegetable parasite belonging to the group of the Blastomycetes. In many cases the amoeboid cells guarantee the integrity of the animal by devouring a large number of these spores and transforming them into an inert detritus. In other cases, on the contrary, the fungi get the upper hand in the struggle; they succeed in germinating and in overcoming the resistance of the leucocytes by reproducing themselves rapidly and by killing these cells with their poisons. The history of this disease and of this struggle was published in Virchow’s Archiv^[868].

Some time afterwards I published in the same journal my work on the anthrax bacillus^[869], in which I attempted to demonstrate that in the Vertebrata also the invasion of pathogenic micro-organisms sets up a desperate struggle between them and the amoeboid cells.

In these four works I made use of the term “phagocytes” to designate the amoeboid cells capable of seizing and digesting the micro-organisms and other formed elements. To the theory based on this property of the defensive cells I gave the name of “theory of phagocytes.”

I thought, as already mentioned above, that the observations on absorption and leucocytes, which had been accumulating for years in pathological histology, had sufficiently paved the way for a favourable reception to the idea that the amoeboid cells are defensive elements of the body capable of guaranteeing to it immunity and cure. In this I was mistaken. It was precisely the specialists in this branch of science who from the first manifested the most lively opposition to this theory.

However, in the Presidential Address delivered before the 66th meeting of the British Association held at Liverpool in 1896, Lord Lister said^[870]: “If ever there was a romantic chapter in pathology, it has surely been that of the story of phagocytosis.” These words encourage me to put before the reader the essential features of this story.

My first two memoirs published in 1883 did not in any way attract the attention of the medical public. These investigations had a character that was too zoological to be noticed by pathologists. But the two following publications, in which I treated of the Daphnia disease and especially of bacterial anthrax, immediately roused severe criticism. Baumgarten^[871], the well-known pathologist, opened the battle by the publication of a review of my researches on phagocytosis. He attempted to sap the basis of my theory, and not contented with à priori arguments, he set his pupils to make a series of researches on the fate of micro-organisms in the refractory animal. These researches resulted in several theses for the doctor’s degree which sought to demolish every point of the theory of phagocytosis.

Later, Baumgarten^[872] published a long and above all admirably written analytical article entitled: “Zur Kritik der Metschnikoff’schen Phagocytentheorie,” in which, with much talent and wit, he attempted to demolish the bases and conclusions of the phagocytic theory.

Baumgarten regards the precise observations which I had been accumulating for some years as incorrect and refuted by the observations and experiments of his pupils. The arguments that I give to justify my theory are, according to the same critic, contrary to logic and to truth. If the phagocytes are really elements destined to guarantee the integrity of the animal organism how is it, asks Baumgarten, that just at the moment of greatest danger, when the blood and the tissues are invaded by the micro-organisms, the leucocytes are conspicuous by their absence? The answer that there is no predestination in the phagocytosis, and that the danger is the greater the more feeble the phagocytic reaction—a fact which is in perfect harmony with the law of causes and with the principles of the evolution of species according to Darwin’s theory—did not satisfy my critic. He says: “If the interpretation which Metschnikoff gives of the activity of the leucocytes appears to be rather the product of a rich imagination than the result of the objective observation of the seeker, it matters little that his account of the development of the leucocyte in what he wishes to see in it should be in conformity with the principles of the theory of evolution” (p. 4).