Messina--Inception of the phagocyte theory--Encouragement from
Virchow and Kleinenberg--First paper on phagocytosis at the Odessa
Congress in 1883--The question of Immunity--Article in Virchow's
_Archiv_, 1884.
At Messina, we settled in a suburb, the Ringo, on the quay of the
Straits, in a small flat with a garden and a splendid view over the
sea. We did not have much room, and the laboratory had to be installed
in the drawing-room, but, on the other hand, Elie only had to cross the
quay in order to find the fisherman who provided him with the material
needed for his researches and with whom we frequently went sailing.
Metchnikoff loved Messina, with its rich marine fauna and beautiful
scenery. The splendid view of the sea and the calm outline of the
Calabrian coast across the Straits delighted him. He enjoyed it all
the more after the many excitements of life at the University, and
eagerly gave himself up to his researches. Often, in later years, he
delighted to recall memories of that period, the more so that this was
connected with the principal phase of scientific activity which led to
the formation of his phagocyte theory. After the earthquake in 1908,
he wrote a few pages on Messina and ended his article by the following
lines:
Thus it was in Messina that the great event of my scientific life
took place. A zoologist until then, I suddenly became a pathologist.
I entered into a new road in which my later activity was to be
exerted.
It is with warm feeling that I evoke that distant past and with
tenderness that I think of Messina, of which the terrible fate has
deeply moved my heart.
They say that Messina will be rebuilt in the same place but in a
different way. Houses will be constructed of light materials, they
will be low, and the streets broad....
The town will be a new Messina, not "my Messina," not that with which
so many dear memories are associated in my mind....
Metchnikoff continued to study intracellular digestion and the origin
of the intestine. He foresaw that the solution of those problems
would lead to general results of great importance. The study of
medusæ and of their mesodermic digestion confirmed him more and more
in the conviction that the mesoderm was a vestige of elements with a
primitive _digestive_ function. In lower beings, such as sponges, this
function takes place without being differentiated, whilst with other
Coelentera and with some Echinoderma the _endoderm_ gives birth to
a digestive cavity; yet, the mobile cells of the _mesoderm_ preserve
their faculty of intracellular digestion. As he studied these phenomena
more closely, he ascertained that mesodermic cells accumulated around
grains of carmine introduced into the organism.
All this prepared the ground for the phagocyte theory, of which he
himself described the inception in the following words:
I was resting from the shock of the events which provoked my
resignation from the University and indulging enthusiastically in
researches in the splendid setting of the Straits of Messina.
One day when the whole family had gone to a circus to see some
extraordinary performing apes, I remained alone with my microscope,
observing the life in the mobile cells of a transparent star-fish
larva, when a new thought suddenly flashed across my brain. It struck
me that similar cells might serve in the defence of the organism
against intruders. Feeling that there was in this something of
surpassing interest, I felt so excited that I began striding up and
down the room and even went to the seashore in order to collect my
thoughts.
I said to myself that, if my supposition was true, a splinter
introduced into the body of a star-fish larva, devoid of
blood-vessels or of a nervous system, should soon be surrounded by
mobile cells as is to be observed in a man who runs a splinter into
his finger. This was no sooner said than done.
There was a small garden to our dwelling, in which we had a few days
previously organised a "Christmas tree" for the children on a little
tangerine tree; I fetched from it a few rose thorns and introduced
them at once under the skin of some beautiful star-fish larvæ as
transparent as water.
I was too excited to sleep that night in the expectation of
the result of my experiment, and very early the next morning I
ascertained that it had fully succeeded.
That experiment formed the basis of the phagocyte theory, to the
development of which I devoted the next twenty-five years of my life.
This very simple experiment struck Metchnikoff by its intimate
similarity with the phenomenon which takes place in the formation of
pus, the diapedesis[15] of inflammation in man and the higher animals.
The white blood corpuscles, or _leucocytes_, which constitute pus, are
mobile mesodermic cells. But, while with higher animals the phenomenon
is complicated by the existence of blood-vessels and a nervous system,
in a star-fish larva, devoid of those organs, the same phenomenon is
reduced to the accumulation of mobile cells around the splinter. This
proves that the essence of inflammation consists in the reaction of
the mobile cells, whilst vascular and nervous intervention has but a
secondary significance. Therefore, if the phenomenon is considered in
its simplest expression, inflammation is merely _a reaction of the
mesodermic cells against an external agent_.
[15] Migration of the white blood corpuscles (leucocytes) through
the walls of blood-vessels.
Metchnikoff then reasoned as follows: In man, microbes are usually
the cause which provokes inflammation; therefore it is against those
intruders that the mobile mesodermic cells have to strive. These mobile
cells must destroy the microbes by digesting them and thus bring about
a cure.
Inflammation is thus a _curative reaction_ of the organism, and morbid
symptoms are no other than the signs of the struggle between the
mesodermic cells and the microbes.
In order to verify these conjectures, he started studying the
englobing of microbes by mesodermic cells in larvæ and in other marine
invertebrates which he inoculated.
At that time, a well-known German scientist, Kleinenberg, was Professor
of Zoology at Messina. Metchnikoff imparted his ideas to him and showed
him his experiments. Kleinenberg encouraged him very much; he looked
upon his theory as "an Hippocratic thought" and advised him to publish
it at once.
Metchnikoff was also greatly encouraged by Virchow, who happened
to pass through Messina and came to see his preparations and his
experiments, which seemed to him conclusive. However, Virchow advised
him to proceed with the greatest prudence in their interpretation, as,
he said, the theory of inflammation admitted in contemporary medicine
was exactly contrary to Metchnikoff's. It was believed that the
leucocytes, far from destroying microbes, spread them by carrying them
and by forming a medium favourable to their growth.
Metchnikoff always preserved a deep gratitude towards Virchow and
Kleinenberg for the moral support which they gave him at that time.
* * * * *
When the hot weather came, we left Messina for Riva, a delicious summer
resort on the shores of the Lake of Garda. There, Metchnikoff wrote
his first memoir on the reaction of inflammation and on the digestion
of microbes by the mesodermic cells of lower invertebrates. On the way
back to Russia through Vienna, he went to see the Professor of Zoology,
Claus; he found other colleagues with him and expounded his theory
to them. They were much interested, and he asked them for a Greek
translation of the words "devouring cells," and that is how they were
given the name of _phagocytes_.
Claus asked him for his memoir for the Review which he edited and in
which it appeared soon afterwards, in 1883.[16] The new-born "phagocyte
theory" was thus very well received by naturalists and by Virchow, the
father of cellular pathology.
[16] _Arbeiten des zool. Inst. zu Wien_, Bd. v. Heft ii. p.
141. "Untersuchung über die intracelluläre Verdauung bei
wirbellosen Tieren," E. Metchnikoff.
Having returned to Russia, we went to the country, where Elie had to
attend to family business; nevertheless, he continued his researches
in every leisure moment. He had observed in Echinoderma that, during
the transformation of their larvæ, the parts becoming atrophied were
englobed by mesodermic mobile cells. In those observations he was
delighted to have found an example of _physiological inflammation_,
_i.e._ one which presented itself in normal and non-morbid conditions.
He thought he might observe it also during the metamorphosis of the
tadpole into a frog, whilst the tail was being atrophied. But he found
that, instead of the leucocytes of the blood, certain cells from the
muscular tissue were those which devoured the enfeebled elements of the
tail; he thus learnt that phagocytes might be, not only the white blood
corpuscles, but other cells of mesodermic origin.[17]
[17] It was only in 1892 that he completed and developed his
observations. He found that the cells of the sarcoplasma
of the muscular tissue devoured its contractile part, the
myoplasma.
In autumn 1883 he read his first paper on phagocytosis to a congress of
physicians and naturalists at Odessa.[18] He compared the phagocytes to
an army hurling itself upon the enemy and looked upon the phagocytic
reaction as a defensive force of the organism.
[18] This paper was entitled "Forces curatives de l'organisme."
In that paper itself and from that moment onwards, the trend of his
ideas towards optimism becomes visible. By discovering the phagocytic
reaction of the organism, he made a first breach in his philosophy
of human nature, hitherto so pessimistic; he discovered within it a
salutary element which could be utilised by science to combat its
discords. He began to have some faith in the power of knowledge, not
only for this struggle, but also for the establishment of a rational
conception of life in general. Thus he said in his paper to the Odessa
Congress:
The theoretical study of Natural History problems (in the largest
sense of the word) alone can provide a critical method for the
comprehension of truth and lead to a definite conception of life, or
at least allow us to approach one.
And yet, until then, the theory of phagocytosis as a curative force
of the organism was but a hypothesis, for he had not yet observed
_spontaneous phagocytosis in diseases_ and did not know pathogenic
microbes. He therefore sought to study them in lower animals, whose
simple structure made the observation easier. He found some small,
transparent, fresh-water crustaceans, called _daphniæ_, which were
diseased and easy to place alive under a microscope. These crustaceans
are often infected by a parasite fungus (_Monospora bicuspidata_), of
which the spores, shaped like sharp needles, are introduced with food
into the digestive tube, traverse the walls of it, and thus penetrate
into the general cavity of the body. They are immediately attacked by
mobile phagocytes, which either singly or in groups englobe them; if
the phagocytes succeed in digesting the spores, the daphnia recovers;
in the contrary case, the spores germinate and develop into small
fungi which invade the organism and kill it. The recovery or death of
the daphnia depends therefore on the issue of the struggle.[19] This
observation gave final confirmation to the hypothesis of the curative
forces of the organism.
[19] Virchow's _Archiv_, vol. 96, p. 177.
Metchnikoff was not content with observing lower animals but wished to
study the reaction of the organism of mammals in infectious diseases.
At that time, the best-known microbe was the bacillus of anthrax.
He therefore chose that for his researches and ascertained that
phagocytosis varied with the virulence of the microbes; thus, while
phagocytes did not attack virulent bacteria, they attacked and rapidly
digested attenuated bacteria. Moreover, he observed a very active
phagocytosis in refractory animals and the reverse in sensitive ones.
He thus came face to face with the question of _immunity_.
He approached it by a comparative examination of the reaction of
the organism of vaccinated rabbits and of non-vaccinated ones, and
ascertained that an active phagocytosis was only manifested in a
previously vaccinated organism. Metchnikoff explained these facts by
the theory that the phagocytes became accustomed, gradually, through
vaccination, to strive against more and more virulent microbes.
From that moment, immunity appeared to him as being no other than this
progressive hardening. He published his researches in 1884 in Virchow's
_Archiv_, and impatiently awaited medical reviews, hoping to find some
answer, but the memoir passed unnoticed; the full significance of it
had not been grasped.