As long as Metchnikoff was but a zoologist, the scientific atmosphere around him remained calm and serene. But everything changed suddenly when he entered the domain of pathology with his theory of phagocytes and phagocytosis.

Here was the realm of secular traditions, deeply rooted, and of theories generally admitted but resting on no biological basis. Attacks and objections against his theories came following upon each other with a rush, only to be compared with the racing clouds of a stormy sky or the hurrying waves of a tempestuous sea. An epic struggle began for Metchnikoff which was to last for twenty-five years, until the moment when the phagocyte theory, his child now grown up, emerged victoriously. To each attack, to each objection, he answered by fresh experiments, fresh observations annihilating objections; his theory was assuming a wider and wider scope, becoming more solid, more convincing.... But only his intimates knew how much the struggle cost him in vital force, what sleepless nights, due to continuous cerebral tension and to the effort to conceive some new and irrefragable experiment, what alternations of hope and depression.... In an ardent, stormy life such as this, each year counted for many.

As soon as he arrived at the Pasteur Institute he undertook active researches with the object of developing and defending the phagocyte theory.

By experiments on the rouget of pigs he refuted the objections of Emmerich, who affirmed that, in that disease, the destruction of the microbes was not due to phagocytes. By experiments on the anthrax of pigeons he answered the attacks of Baumgarten and his pupils. To Behring, who affirmed that immunity was due to the bactericidal power of the serum, he replied by a series of experiments on the anthrax of rats.

By all these researches Metchnikoff proved that recovery and immunity depended on the absorption and digestion of living, virulent microbes by phagocytes. Natural or artificial vaccination by attenuated microbes allows the phagocytes to become gradually accustomed to digest more virulent ones, and this confers immunity upon the organism. That phenomenon is comparable to that by which we can accustom ourselves gradually to doses of poison which would be very harmful if taken at the start (arsenic, opium, nicotine, etc.).

Little by little, the accuracy of Metchnikoff’s observations began to be realised, and, moreover, other scientists supported him by their personal investigations. The part played by phagocytosis was becoming more and more evident and the question was ripening in France and in England, but in Germany it still met with great opposition.

At the Berlin Congress in 1890 the theory was received very favourably by Lister, whilst Koch attacked it, trying to prove that phagocytes played no part in immunity, which, according to him, depended upon the chemical properties of the blood.

Soon after that, Behring discovered antitoxins, and this seemed to favour the chemical or humoral theory of immunity. According to the latter, microbes and their poisons were rendered harmless by the chemical properties of the blood serum, properties similar to those of disinfecting substances.

In spite of his firm conviction of the solidity of the phagocyte theory, this discovery was a shock to Metchnikoff, for it was in apparent contradiction with the cellular theory of immunity. He hastened to undertake a series of researches; his overflowing eagerness infected his whole circle, every one taking the warmest interest in the progress of his experiments.

This was just as preparations were being made to take part in the London Congress, where the question of immunity was to be debated and had indeed been placed at the head of the programme. Many papers were being prepared, and a veritable tourney of opinions was to take place at this Congress.

Metchnikoff had already been to England once, in the spring of 1891, on the occasion of his reception as an Honorary Doctor by the University of Cambridge. This gave him the opportunity of making closer acquaintance with the English, who inspired him with great sympathy; years only increased this feeling. He appreciated the originality of their earnest and generalising spirit, their loyalty and energy; he was grateful to them for the attentive and favourable attitude with which his scientific work and himself had been received.

He was therefore delighted that this Congress, which was to be the scene of his final struggle against his contradictors, should take place in England and not in Germany, a country hostile to his ideas.

In view of the importance of the coming debate, a series of fresh experiments was made. This time Metchnikoff undertook them not only in person, but also in collaboration with M. Roux and with some students. The whole laboratory was in a state of effervescence.

The principal papers to be read at the Congress on the question of immunity were those of Messrs. Roux and BÜchner, the first entirely in favour of the phagocyte theory and the second supporting the humoral theory.

Metchnikoff read an epitome of his researches and of his answers to attacks on his theory. Towards the end of the Congress the latter had visibly acquired the suffrage of numerous scientists. Roux wrote to me from London concerning my husband’s paper:

Thus the researches made in recent years and the results of the London Congress allowed us to consider the phagocyte theory of immunity as being solidly established.

Yet, Behring’s discovery of antitoxins still hung over it like a sword of Damocles; it was imperative that the respective parts played by antitoxins and by phagocytes should be elucidated. With that object in view, Metchnikoff undertook new researches and succeeded in ascertaining once for all the narrow link between immunity and the function of the phagocytes which probably elaborate the antitoxins as a product of their digestion of vaccinal toxins. He drew this conclusion from the fact that, in a rabbit vaccinated against hog-cholera, the exudate devoid of phagocytes[20] is neither bactericidal, nor antitoxic, nor attenuating, while it is so if it contains phagocytes. Therefore a relation of causality exists between cells and the acquired properties of humors. And the resistance of the animal is in visible correlation with the degree of phagocytosis which is manifested by it.

These results having been established, it seemed as if the last rampart of the humoral theory had been taken by storm.

In the meanwhile the persistent and bitter opposition of physicians to the phagocyte theory made a great impression on Metchnikoff, and, while stimulating his energy in defence of his ideas, it maintained him in a state of nervous excitement and even depressed him.

He asked himself why this obstinate opposition to a doctrine based on well-established facts, easily tested and observed throughout the whole animal kingdom? To him, a naturalist, it seemed clear and simple and all the more admissible that it was confirmed by the generality of its application to all living beings.

But, he thought, perhaps the real cause of the attitude of the contradictors lies in the very fact that medical science only concerns itself with the pathological phenomena of higher animals, leaving their evolution entirely out of account, as well as their starting-point in lower animals—whilst it is the very simplicity of the latter which allows us to penetrate to the origin of the phenomena.

Perhaps a general plan of the whole, in the shape of a comparative study, embracing the whole animal scale, would throw light over the generality of phagocytic phenomena and would make their continuity understood through normal and pathological biology. He determined to make this effort. In order to place in a fresh light the biological evolution of phagocytosis phenomena in disease, he chose one of the principal manifestations of pathological phagocytosis, inflammation, and, in 1891, gave a series of lectures on this subject which he afterwards published in a volume. According to his usual method, he began by the most primitive beings, taking as a starting-point the lower organisms which do not yet possess differentiated functions, and whose normal digestion is, if necessary, used as a means of defence against noxious agents. Then, by a comparative study in every grade of the animal kingdom, he proved that the same mode of struggle and defence persists in the mesodermic cells, the phagocytes in all animals in general. In all of them, thanks to a special sensitiveness, Chimiotaxis, phagocytes move towards the intruder, to englobe it and digest it if they can. This reaction for defence by the organism takes place in beings endowed with a vascular system by the migration of the blood-phagocytes which traverse the walls of the blood-vessels in order to betake themselves to the invaded point.

In higher animals, all the symptoms which accompany this phenomenon of defence and which constitute the classical picture of inflammation (a heightened temperature, pain, redness, tumefaction) are due to the complexity of the organism; but the essence, the primum movens of inflammation, with them also, is a digestive action of the phagocytes upon the noxious agent, therefore a salutary reaction of the organism, essentially similar to the normal digestion of inferior beings. Metchnikoff adduced numerous examples giving evidence of the genetic link which exists between inflammation and normal intracellular digestion, and while establishing the evolution of the former on biological and experimental bases, he showed at the same time the close connection which binds normal biology and pathological biology.

This series of lectures formed a volume which appeared in 1892 under the title of LeÇons sur la pathologie comparÉe de l’inflammation, a book which contributed to the acceptation of the phagocyte theory and which showed the importance of Natural History applied to Medicine.