principles which for twenty years had directed his labours, the
resources and applications of which appeared to him unlimited. 'The
etiology of contagious diseases,' he wrote with a scientific certainty
of conviction, 'is on the eve of having unexpected light shed upon it.'
_VIRULENT DISEASES._
SPLENIC FEVER (CHARBON)--SEPTICÆMIA.
'He that thoroughly understands the nature of ferments and
fermentations,' said the physicist Robert Boyle, 'shall probably be
much better able than he that ignores them, to give a fair account of
divers phenomena of certain diseases (as well fevers as others), which
will perhaps be never properly understood without an insight into the
doctrine of fermentations.'
At all times, medical theories, more particularly those which concern
the etiology of virulent diseases, have had to encounter the opposition
of explanations invented to account for the phenomena of fermentation.
When Pasteur in 1856 began his labours on these subjects, the ideas
of Liebig were everywhere revived. Like the ferments, so the viruses
and processes of disease were considered as the results of atomic
motions proper to substances in course of molecular change, and able to
communicate themselves to the diverse constituents of the living body.
The researches of Pasteur on the part played by microscopic organisms
in fermentation, changed the course of these ideas. The ancient
medical theory of parasites and living contagia was revived. A German
Professor, Dr. Traube, in 1864, put forward, in one of his clinical
lectures, a new doctrine of the ammoniacal fermentation of urine.
'For a long period,' he said, 'the mucus of the bladder was regarded
as the agent of the alkaline decomposition of urine. It was supposed
that, in consequence of the distension produced by the retention
of the liquid, the irritated bladder produced a larger quantity of
mucus, and this mucus was regarded as the ferment which brought about
the decomposition of urea, by an innate chemical force. This opinion
(which was that of Liebig) cannot hold its ground in presence of the
researches of Pasteur. This investigator has demonstrated, in the most
decisive manner, that alkaline fermentation, like alcoholic and acetic
fermentation, is produced by living organisms, the pre-existence of
which in the liquid is the _sine quâ non_ of the process.' And Dr.
Traube, citing some facts which confirmed the doctrine of Pasteur,
concluded thus: 'Notwithstanding the long retention of the urine, its
alkaline fermentation is not produced by an increased secretion of
mucus or of pus; it only begins to develop from the moment when the
germs of vibrios find access to the bladder from without.
The opposite doctrines of Liebig and Pasteur are here brought into
clear juxtaposition; and thus was their mutual and reciprocal influence
established in dealing with the etiology of one of the most serious
diseases of the bladder. So far back as 1862, Pasteur, in his memoir
on spontaneous generation, had announced, contrary to all the notions
then held, that whenever urine becomes ammoniacal, a little microscopic
fungus is the cause of this alteration. Later on he established that
in affections of the bladder ammoniacal urine was never found without
the presence of this fungus; and in order to show how in these studies
therapeutic application often runs hand in hand with scientific
discovery, Pasteur, having proved, with his assistant, M. Joubert,
that boracic acid is antagonistic to the development of the ammoniacal
ferment, advised Dr. Guyon, Clinical Professor of Urinary Diseases in
the Faculty of Paris, to combat the dangerous ammoniacal fermentation
by injection of boracic acid into the bladder. The celebrated surgeon
hastened to follow this advice, and with the most happy results. While
attributing to Pasteur the honour of this discovery, M. Guyon, in one
of his lectures, said:--
'Boracic acid has this immense advantage, that it can be applied in
large doses--3 to 4 per cent.--without causing the slightest pain.
It has therefore become, in our practice, the agent continually and
successfully used for injections. I also have recourse to a solution
of boracic acid to produce large evacuations after the operation of
breaking up stones in the bladder (lithotrity). I never omit to use
this antiseptic agent in operations where breaking up is required,
and I never wash the bladders of lithotritised patients with any
other substance. I have also had good results from copiously washing
the bladders and the wounds of patients on whom lithotomy has been
performed with boracic acid. I always finish the operation by prolonged
irrigations with a solution of from 3 to 4 per cent.'
It was not only into France and Germany that Pasteur's ideas
penetrated; in England, surgery borrowed from Pasteur's researches
important therapeutic applications. In 1865 Dr. Lister began in
Edinburgh the brilliant series of his triumphs in surgery by the
application of his antiseptic method, now universally adopted. In the
month of February 1874 in a letter which does honour to the sincerity
and modesty of the great English surgeon, he wrote to Pasteur as
follows:--
'It gives me pleasure to think that you will read with some interest
what I have written about an organism which you were the first to
study in your memoir on lactic fermentation. I do not know whether you
read the 'British Medical Journal;' if so, you will from time to time
have seen accounts of the antiseptic system which for the last nine
years I have been trying to bring to perfection. Allow me to take this
opportunity of sending you my most cordial thanks, for having, by your
brilliant researches, demonstrated to me the truth of the germ theory
of putrefaction, thus giving me the only principle which could lead to
a happy end the antiseptic system.'
Pasteur followed with lively interest the movement of thought and the
successful applications to which his labours had given rise. It was
a realisation of the hopes he had ventured to entertain. Already,
in 1860, he expressed the wish that he might be able to carry his
researches far enough to prepare the way for a profound study of the
origin of diseases. And, as he gradually advanced in the discovery of
living ferments, he hoped more and more to arrive at the knowledge of
the causes of contagious diseases.
Nevertheless, he hesitated long before definitely engaging himself in
this direction. 'I am neither doctor nor surgeon,' he used to repeat
with modest self-distrust. But the moment came when, notwithstanding
all his scruples, he could no longer be content himself to play the
part of a simple spectator of the labours started by his studies on
fermentation, on spontaneous generation, and on the diseases of wines
and beer. The hopes to which his methods gave rise, the eulogies of
which they were the object, obliged him to go forward. In February
1876 Tyndall wrote to him thus:--
'In taking up your researches relating to infusorial organisms, I have
had occasion to refresh my memory of your labours; they have revived
in me all the admiration which I felt on first reading them. It is my
intention to follow up these researches until I shall have dissipated
every doubt that has been raised as to the unassailable exactitude of
your conclusions.
'For the first time in the history of science we are able to entertain
the sure and certain hope that, in relation to epidemic diseases,
medicine will soon be delivered from empiricism, and placed upon a
real scientific basis. When this great day shall come, humanity will
recognise that it is to you the greatest part of its gratitude is due.'
Pasteur approached the study of viruses by seeking to penetrate into
all the causes of the terrible malady called splenic fever (_charbon_,
Germ. _Milzbrand_). Each year this disease decimates the flocks not
only in France but in Spain, in Italy, in Russia, where it is called
the Siberian plague, and in Egypt, where it is supposed to date back
to the ten plagues of Moses. Hungary and Brazil pay it a formidable
yearly tribute; and to come back to France, the losses have amounted
in certain years to from fifteen to twenty millions of francs. For
centuries the cause of this pest has eluded all research; and further,
as the malady did not always exhibit the same symptoms, but varied
according to the kind of animal that was smitten by it, the disease was
supposed to vary with the species that was attacked by it. The splenic
fever of the horse was distinct from that of the cow; the splenic
fever of horse and cow were again different from that of the sheep. In
the latter, splenic fever was called _sang-de-rate_; in the cow, it
was _maladie du sang_; in the horse, splenic fever; in man, malignant
pustule.
It was not until 1850 that trustworthy data were first collected
regarding the nature of the malady, its identity with and difference
from other maladies. From 1849 to 1852 a commission of the Medical
Association of Eure-et-Loir made a great number of inoculations,
applied other tests, and proved that the splenic fever of the sheep
is communicable to other sheep, to the horse, to the cow, and to
the rabbit; that the splenic fever of the horse is communicable to
the horse and to the sheep; that the splenic fever of the cow is
communicable to the sheep, to the horse, and to the rabbit. As for the
malignant pustule in man, no doubt remained that it must arise from the
same cause as splenic fever in animals. What class of men is it that
the malignant pustule most frequently attacks? Shepherds, cowherds,
cattle breeders, farm servants, dealers in hides, tanners, wool
cleaners, knackers, butchers--all who derive their living from domestic
animals. In handling contaminated subjects the slightest excoriation
or scratch of the skin is sufficient to allow the virus to enter. When
others besides the class that we have named become infected, it is
because they live in the neighbourhood of herds smitten with splenic
fever. There are also certain flies which transport the virus. Suppose
one of these flies to have sucked the blood of an animal which has died
of splenic fever, a person stung by that fly is forthwith inoculated
with the virus.
At the very time (1850) when these first experiments were being made
by the Medical Association of the Eure-et-Loir, Dr. Rayer, giving
an account in the 'Bulletin de la Société de Biologie de Paris' of
the researches he had made, with his colleague, Dr. Davaine, on the
contagion of splenic fever, wrote:--'In the blood are found little
thread-like bodies about twice the length of a blood corpuscle. These
little bodies exhibit no spontaneous motion.'
This is the date of the first observation on the presence of little
parasitic bodies in splenic fever, but, strange to say, no attention
was paid to these minute filaments. Rayer and Davaine also paid no
attention to them. This indifference lasted for thirteen years; it
would have lasted longer still, if the parasitic origin of communicable
diseases had not been brought before the mind by each new publication
of Pasteur's. From 1857 to 1860 it will be remembered that he had
demonstrated lactic fermentation, like alcoholic fermentation, to
be the work of a living ferment; in 1861 he had discovered that the
agent of butyric fermentation consisted of little moving thread-like
bodies, of dimensions similar to those of the filaments discovered by
Davaine and Rayer in the blood of splenic fever patients; in 1861 he
had announced that no ammoniacal urine existed without the presence
of a microscopic organism; in 1863 he had established that the bodies
of animals in full health are sealed against the introduction of the
germs of microscopic organisms; that blood drawn with sufficient
precaution from the veins and the arteries, and urine taken direct
from the bladder, could be exposed to the contact of pure air without
putrefaction, and without the appearance of living thread-like
organisms of any kind whatever, mobile or immobile. It was all these
facts which in 1863 brought back the attention of Davaine, as he
himself has acknowledged, to the observation which he had made in 1850.
'M. Pasteur,' said M. Davaine in a communication made to the Academy
of Sciences, 'published some time ago a remarkable memoir on butyric
fermentation, which consists of little cylindrical rods, possessing
all the characteristics of vibrios or of bacteria. The thread-like
corpuscles which in 1850 I saw in the blood of sheep attacked with
_sang-de-rate_, having a great analogy with these vibrios, I was led
to examine whether filiform corpuscles, analogous to or of the same
kind as those which determined the butyric fermentation, would not,
if introduced into the blood of an animal, equally act the part of a
ferment. Thus would be easily explained the alteration, and the rapid
infection of the mass of the blood, in an animal which had received
accidentally or experimentally into its veins a certain number of these
bacteria--that is to say, of this ferment.'
But two summers passed before M. Davaine was able to procure a sheep
affected with the _sang-de-rate_. It was only in 1863 that he first
recognised the constant presence of a parasite, in the blood of sheep
and rabbits which had died from successive inoculations with blood
taken after death or in the last hours of life. He further proved that
the inoculated animal, in the blood of which no parasites were as yet
visible with the microscope, had every appearance of health, and that
in these conditions the blood could not communicate splenic fever.
'In the present state of science,' Davaine concluded, 'no one would
think of going beyond these corpuscles to seek for the agent of the
contagion. This agent is visible, palpable; it is an organised being,
endowed with life, which is developed and propagated in the same manner
as other living beings. By its presence, and its rapid multiplication
in the blood, it without doubt produces in the constitution of this
liquid, after the manner of ferments, modifications which speedily
destroy the infected animal.' 'For a long time,' he repeated,
'physicians and naturalists have admitted theoretically that contagious
diseases, serious epidemic fevers, the plague, &c., are caused by
invisible animalculæ, or by ferments, but I do not know that these
views have ever been confirmed by any positive observations.'
A few months after the publication of the results obtained by Davaine,
two professors of Val-de-Grâce, MM. Jaillard and Leplat, sought to
refute the preceding conclusions. After having inoculated rabbits and
dogs with various putrefying liquids filled with vibrios, they could
not cause the death of these animals. To bring about this result it was
necessary to introduce into the blood of these dogs and rabbits several
cubic centimeters of very putrid liquid. Again in this case, which only
added another example to the experiments of Gaspard and Magendie upon
the action of putrid liquids, they failed to generate any virulence in
the blood. Davaine had no difficulty in showing that MM. Jaillard and
Leplat's experiments were made under conditions totally different from
his; that he, Davaine, had not made use of the vibrios or bacteria of
unselected infusions, but of bacteria which had been found in the blood
of sheep which had died from _sang-de-rate_.
Jaillard and Leplat returned to the charge, and this time with entirely
new and unexpected experiments. They inoculated some rabbits, as
Davaine desired, with the blood of a cow which had died of splenic
fever. The rabbits died rapidly, but without showing before or after
their death the least trace of bacteria. Other rabbits, inoculated with
the blood of the first, perished in the same manner, but it was still
impossible to discover any parasite in their blood. MM. Jaillard and
Leplat offered Davaine some drops of this blood. Davaine, taking up the
experiments of his opponents, confirmed the exactitude of the facts
they had announced, but concluded by saying that these two professors
had not employed true splenic fever blood, but the blood of a new
disease, unknown up to that time, which Davaine proposed to call the
cow disease.
'The blood which we used,' replied MM. Jaillard and Leplat, 'was
furnished to us by the director of the knacker's establishment of
Sours, near Chartres, and this director is undeniably competent as to
the knowledge of splenic fever.'
Full of sincerity and conviction, MM. Jaillard and Leplat recommenced
their experiments, using this time the blood of a sheep which had
died of splenic fever, and which M. Boutet, the most experienced
veterinary surgeon of the town of Chartres, had procured for them.
Their results were the same as those obtained with the blood of the
cow. Notwithstanding the replies of Davaine, which, however, added
nothing to the facts already adduced on one side or the other, it was
difficult to pronounce decidedly in such a debate. Unprejudiced minds
received from these important discussions the impression that Jaillard
and Leplat, in producing facts the exactitude of which were admitted by
Dr. Davaine himself, had given a blow to the assertions of the latter,
and that the subject required, in every case, new experimental studies.
In 1876, a German physician, Dr. Koch, took up the question. He
confirmed the opinion of Davaine, but without in the least producing
conviction, since he threw no light upon the facts adduced by MM.
Jaillard and Leplat, of which, indeed, he did not even deign to speak.
At the very same moment when the memoir of Koch appeared in Germany,
the eminent physician Paul Bert came forward to corroborate the opinion
of Jaillard and Leplat.
'I can,' said M. Paul Bert, 'destroy the bacteria in a drop of blood
by compressed oxygen, inoculate with what remains, and reproduce the
disease and death without any appearance of bacteria. Therefore, the
bacteria are neither the cause nor the necessary effect of the disease
of splenic fever. It is due to a virus.'
This was indeed the opinion of Jaillard and Leplat. Pasteur, in
obedience to the necessity he felt to get at the fundamental truth of
things, and also in his eager desire to discover some decisive proofs
as to the etiology of this terrible disease, resolved in his turn to
attack the subject.
Dr. Koch had stated in his memoir that the little filiform bodies,
seen for the first time by Davaine in 1850, had two modes of
reproduction--one by fission, which Davaine had observed, and another
by bright corpuscles or spores. The existence of this latter mode of
reproduction Pasteur had already discovered in 1865, reasserted and
illustrated in 1870, as being common to the filaments of the butyric
ferment, and to all the ferments of putrefaction. Was Dr. Koch ignorant
of this important fact, or did he prefer by keeping silence to reserve
to himself the advantage of apparent priority?
In order to solve the first difficulty which presented itself to
his mind--that is to say, the question as to whether splenic fever
was to be attributed to a substance, solid or liquid, associated or
not associated with the filaments discovered by Davaine, or whether
it depended exclusively upon the presence and the life of these
filaments--Pasteur had recourse to the methods which for twenty
years had served him as guides in his studies on the organisms of
fermentation. These methods, delicate as they are, are very simple.
When he wished, for example, to demonstrate that the microbe-ferment
of the butyric fermentation was the very agent of decomposition, he
prepared an artificial liquid formed of phosphates of potash, of
magnesia, and of sulphate of ammonia, added to the solution of the
fermentable matter, and in this medium he caused the microbe-ferments
to be sown in a pure state. The microbe multiplied, and provoked
fermentation. From this liquid he could pass to a second or third
fermentable liquid composed in the same manner, and so on in
succession. The butyric fermentation appeared successively in each.
Since the year 1857 this method was supreme. In this particular
research on the disease of splenic fever Pasteur proposed to isolate
the microbe of the infected blood, to cultivate it in a state of purity
in artificial liquids, and then to come back to the examination of
its action on animals. But as, since his attack of paralysis in 1868,
Pasteur had not recovered the use of his left hand, and consequently
found it impossible to carry on a long series of experiments alone, he
was obliged to seek for a courageous and devoted assistant. He found
one in a former pupil of his at the École Normale, M. Joubert, now
Professor of Physics at the Collège Rollin. If M. Joubert incurred
the danger of these experiments on splenic fever, he also shared with
Pasteur, in the Comptes-rendus of the Academy of Sciences, the honour
of the researches and the triumph of the discoveries.
On April 30, 1877, Pasteur read to the Academy of Sciences, in his own
name and in that of his fellow-worker, a note in which he demonstrated,
this time in a completely unanswerable manner, that the bacilli called
bacteria, bacterides, filaments, rods, in a word the bacilli discovered
by Davaine and Rayer in 1850, constituted the only agent of the malady.
A little drop of splenic fever blood, sown in urine or in the water of
yeast, previously sterilised--that is to say, rendered _un_putrescible
by contact with air free from all suspended germs--produces in a few
hours myriads of bacilli or of bacteria. A little drop of this first
cultivation sown in a second flask containing the same liquid as the
first and prepared with the same precautions as to sterility and
purity, shows itself no less fertile. Finally, after ten or twenty
similar cultures the parasite is evidently freed from the substances
which the initial drop of blood might carry with it; yet, if a very
small quantity of the last culture is injected under the skin of a
rabbit or a sheep, it kills them in two or three days at most, with all
the clinical symptoms of natural splenic fever.
It might be objected that the parasite was associated in the
cultivating liquid with some dissolved substance that it had
produced during its life and which acted as a poison. Pasteur
accordingly transported some cultivating tubes into the cellars of
the Observatory, where a temperature absolutely constant reigned,
a circumstance which permits of the deposit of all the parasitic
filaments at the bottom of the tubes. Inoculating afterwards both with
the clear upper liquid and with the deposit at the bottom, he found
that the latter alone produced disease and death. It is, then, the
bacteria which cause splenic fever. The proof was given and no further
doubt remained.
I.
Yes, splenic fever is no doubt produced by bacteria just as itch is
produced by acaries and trichinosis by trichinæ. The only difference
is that the parasite of splenic fever can only be seen by means of a
rather powerful microscope. Here, then, is a disease in the highest
degree virulent, due in its first cause to the _infinitely little_.
Pasteur laid hold of and isolated this terrible virus. It was in a
microscopic parasite, and in it alone, that the virulence of splenic
fever resided. A great scientific fact had been gained. A virus might
consist not of amorphous matter, but of microscopic beings. The
virulence was due to their life.
Liebig, and all the chemists and doctors who had accepted and
maintained his doctrine, totally repudiated all vital action in
fermentation as well as in contagious and infectious diseases.
Dominated by their hypotheses, they allowed themselves to be deceived
by false assimilations to facts of a purely chemical kind, which
appeared to them to be connected with the phenomena of fermentation and
virulence.
Liebig wrote, 'By the contact of the virus of small-pox the blood
undergoes an alteration, in consequence of which its elements reproduce
the virus, and this metamorphosis is not arrested until after the
complete transformation of all the globules capable of decomposition.'