Opposition to the phagocyte theory--Scientific controversies
--Experiments in support of the phagocyte theory--Behring and
antitoxins--The London Congress--Inflammation.
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:
Metchnikoff is busy showing his preparations and, besides, he would
not tell you how great is his triumph. He spoke with such passion
that he carried everybody with him. I believe that, this evening, the
phagocyte theory is the richer by many friends.
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.
[20] Aqueous humor, the exudate of aseptic oedemata.
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.