Every year since 1860 at the University of Montpellier, at the commencement of the course on medical chemistry of the Faculty of Medicine, the assistant wrote on the bulletin board an announcement of the fundamental principles of the instruction which would be given by Prof. A. Bechamp. This announcement is prefixed to "Les Microzymas" (pages XXXVII-XXXVIII) demonstrating that already in 1860 Bechamp's views on the subjects mentioned were settled, and nothing has since occurred to show them to be erroneous.
"There is only one chemistry. Matter is endowed only with chemical and physical activity.
"There is no matter essentially organic, all matter is mineral.
"That which is called organic matter is only mineral matter with carbon as a necessary constituent
"Organic matter, chemically definite, is profoundly distinct from organized matter.
"The chemist can, by synthesis, form organic matter, he is powerless to organize it; he cannot create a single cellule.
"The faculty of organizing matter resides, primordially, in pre-existing living organisms.
"It is in the various mechanisms of the organism of organized beings wherein are accomplished the changes of organic matter, whether organized or not; and these changes are effected according to the ordinary laws of chemistry.
"From the chemical point of view, plants are essentially apparatus of synthesis, animals apparatus of analysis."
The object of this work is the solution of a problem of the first order; it is to show what is the real nature of the blood, and what is the character of its organization it has, besides, a secondary purpose; viz, the solution of a problem long ago stated, but never solved, as to the cause of its coagulation, correctly regarded as spontaneous, after it has issued from the blood-vessels. The conclusion arrived at is, that the blood is a flowing tissue, as such, spontaneously alterable in like manner as are all other tissues withdrawn from the animal, coagulation of the blood being only the first phase of its spontaneous change.
It would be too tedious to give even a summary of what had been written upon the blood before the discovery of Harvey and that of the blood globules; I will merely observe here that both before as well as after these memorable discoveries the blood has been almost exclusively called a liquid by those physiologists who specially studied it. This will appear abundantly from the historical introduction, especially with regard to the attempts at explanation of the phenomena styled its spontaneous coagulation.
INTRODUCTORY AND HISTORICAL
The explanation of the fact of the coagulation of the blood, rightly regarded as spontaneous, has been sought for by physiologists, by physicians and by chemists, but without satisfactory result. The detailed history of the attempts at explanation would only demonstrate the uselessness of the preconceived hypotheses and systems on which they rest. Among all these hypotheses, only one deserves attention, precisely the one which the latest investigators have neglected to consider or to verify. The history of the conception of this hypothesis is of great interest.
From time immemorial, it was known that shed blood soon becomes a concrete mass, red, of a consistency more or less soft and called a clot; the phenomenon was otherwise compared to the coagulation of a homogeneous liquid.
It was not until the 18th century that Haller (in the supplement to the article "Blood," in the Encyclopaedia of Diderot), after correcting some errors of Leuwenhoeck concerning blood globules, asserted absolutely that they were essential elements of the blood, existing only in the red part, and, said he, "perhaps also in milk."
But he recognised that "the figure of the blood globules is constant and that they are not merely a collection of fatty grains ... but circumscribed, bounded and solid."
Haller also first placed the spontaneous coagulation of the blood on its true ground (tracing the theory back to Aristotle):
"An element of the blood, generally so regarded by the ancients, especially by Aristotle, are the fibres which the scholiasts regarded as the foundation of the coagulable matter of the blood; these fibres have been seen in the clot-cake which the blood, left to itself, never fails to form, and which seems to be really a sort of network made of small membranes, which can be separated from the fluid part and can then be plainly seen."
But Haller did not admit that the fibres were really an element of the blood. He said:
"If the authors wish us to understand that these fibres are in the blood as are the globules, they are certainly in error."
In support of his view he cited Borelli, the mathematician, who had been the first to refuse to admit "the fibres among the elements of the blood, as also Boerhave and other great men who have followed him," adding further:
"If the authors wish to say that under certain circumstances fibres and flakes are born in the blood, he did not object thereto, "but observed that these fibres and flakes seemed to have their birth rather in the lymph than in the red particles of the blood. In short, according to Haller, the blood contained nothing solid and figured but the globules in a liquid called lymph, adding that he had recommended as a good way of rendering the globules visible the addition of certain salts to the blood which increased the fluidity and the colour; "nitre being of all salts that which gives the best colour to the blood."
Haller,who derived the fibres of the clot from the lymph of the blood, was the precursor of the savants, who, like him, saw in the blood only globules in suspension in a liquid where everything else was supposed to be in a state of perfect solution.
The circumstances of the formation of the clot, its shape depending on that of the vessel in which it was formed, its progressive contraction and expulsion of the yellow serosity, thence called the serum, were all observed with attentive curiosity. The blood having finished its contraction, the washings in water which dissolved its colouring matter furnished the white matter which was called the fibrous portion of the blood, and, after the reform of chemical nomenclature, fibrin. The fibrin was finally isolated from the blood by whipping, before it coagulated. The great German physiologist, J. Muller, believed with Haller: he wrote:
"By liquor of the blood (liquor, lympha sanguinis) we mean the colourless liquid, such as exists before coagulation, in which the blood globules swim . . . it contains all that is really dissolved in the blood. At the moment of coagulation, the liquor separates itself from the fibrin which had before been dissolved"; and from his microscopic observations upon frog's blood, he thought that his researches "proved that besides the albumen, the fibrin was dissolved in the liquor of the blood."
H.H. Schultze gave the name of plasma to the lymph of Haller, which Muller had called liquor saunguinis.
The conclusion of J. Muller was the more circumspect, seeing that it was a refutation or contradiction of another mode of considering it, already published. W. Hewson had expressed two views, one of which had agreed with that of Muller; the other was original. According to the former, the fibrin exists in the blood in a state of solution; according to the other, it exists in it in suspension in a state of fine granulations; he further admitted that the globules did not contain fibrin.
Milne-Edwards accepted the second opinion of Hew son, maintaining that the fibrin did not exist in solution in the blood, but in a finely divided state as a solid, under the form of fine granulations, which after the blood has been shed and left at rest, united together in the form of the fibres of the clot, or by whipping, to form fibrin.
Dumas, who, with Prevost of Geneva, had first admitted the globular origin of the fibrin to explain coagulation, afterwards accepted, to a certain extent, the opinion of Milne-Edwards.
It is important to explain the point of view of such a genius. He said:
"None of the properties of fibrin give us the means of explaining the state in which it exists in the blood. It has not been possible to bring back the fibrin to this condition by any known process. In fact, the blood contains the fibrin, both liquid and spontaneously coagulable ... Everything leads to the belief that this fibrin of the blood is not in solution in it, but that it exists there in a finely divided state, which it maintains so long as the liquid is in motion, but which, in the liquid at rest, stops all of a sudden as a consequence of the disposition of the fibrin particles to unite in a fibrous and membranous network."
Later he modified this view as follows:
"The blood contains a quantity of spontaneously coagulable fibrin in suspension, or in a state so closely approaching solution, that it seems to be really dissolved in it; it is found there in a peculiar flowing state, analogous to that presented by starch mixed with water in the aqueous solution of starch."
But neither of the views of Hewson, nor that of Milne- Edwards, nor that of the illustrious Dumas regarding the individual state of the fibrin in the blood, which, as will be seen, were the nearest to the truth, received much consideration, and were soon lost to view. Physiologists reverted more and more to the view of Haller adopted by J. Muller and by Schultze. The word "plasma" prevailed over lymph, and it was held that everything except the globules were in a state of complete solution in the blood. They came at last to believe that the blood did not contain fibrin even in a state of solution.
In short, the fibrin which was called the "corps de delit" of the coagulation of the blood was imagined in turn to be the same substance as albumen; and it was further imagined that:
- the albumen of the blood was none other than the fibrin combined with the alkali of the blood, only the part not so combined being coagulable;
- that the plasma contained plasmine, which, when out of the vessels, transformed itself by spontaneous decomposition into concrete fibrin and into dissolved fibrin, called also metalbumen;
- that the fibrin does not exist either in the blood or in the plasma;
but that they contain, in solution, substances called fibrinogen and fibrinoplastin, respectively, which, outside of the vessels, under the influence of a ferment, produced the fibrin with an elimination of alkali, etc.
Chemists agreeing with Thenard came to look upon fibrin as an isolated animal matter, that is to say, a "proximate principle," according to the definition of Chevreul. Glenard, who paid a great deal of attention to the phenomenon of the coagulation of the blood and its causes, wrote upon the subject of fibrin, as follows: "Science has not yet been able to establish the constitution of fibrin, of the "corps de delit" of coagulation; it is not known whether it be derived from albumen, or should be regarded as one of its stages; and the formula of this substance varies with each chemist; it is not known whether it is superfluous (recrementitious) matter, or a product of excretion, a nutriment or an organic waste.
It is, therefore, a legitimate conclusion that after a century of hypothesis on hypothesis, we have gotten back to the point where Haller had left the question. Having neglected the conception of Milne-Edwards and of Dumas, as well as some researches which seemed to be approximately a verification thereof, it is not a matter for surprise that scientists who understand neither the real nature of fibrin nor its origin, had recourse to occult causes for the explanation of the phenomenon of coagulation.
The celebrated English Surgeon, Hunter, thought that:
"blood coagulated by virtue of an impression, that is to say, that its fluidity being inopportune or no longer necessary in its state of rest after issuing from the vessels, it coagulates in reply to the indispensable customs of solidity"; also he said that "the blood possesses in itself the force, by virtue whereof it acts in conformity with the stimulus of necessity, a necessity which is derived from the position in which it finds itself."
And Hunter wrote in the time of Haller.
Long after, Henle, having said that the cause of the coagulation of the blood directly after circulation ceased was unknown, added:
"Coagulation is often regarded as the last act of life, as the death of the blood."
This point of view, which was not that of Henle, has been lately revived and fitted into the system signified by the word plasma. In short, the following propositions can be collected from a work full of interesting observations on the coagulation of the blood:
"The blood is endowed with a life of its own."
"Coagulation is a synonym for the death of the blood ."
"By the fact of spontaneous coagulation, the plasma loses its chief property, that of living, and from the state of an organised humor becomes an inert aggregate of proximate principles."
"Coagulation then is the disorganisation of the plasma."
"It is the fact of this organisation which struggles for some minutes against the fatal influence upon the shed blood of contact with foreign bodies."
Right here, before going further, will be the place to seek for the substance beneath the mask of words.
It is true that the author of the above propositions did not, like Hunter, invoke "an impression" or `the indispensable customs of solidity" nor "the stimulus of necessity" to explain the phenomenon of the spontaneous coagulation of the blood, but has he escaped the shoals of "occult causes ?"
It is true that blood as it issues from a living body is alive. But is it not an "explanation" by the occult causes to say that the blood coagulates because it dies?
But if the chief property of the plasma, an organised humor, is to live, is not the struggle of its organisation against the fatal influence of contact, the loss of its life, also an "explanation" by occult causes?
Also the plasma being an aqueous liquid, in which the materials composing it cannot be other than proximate principles, are by the hypothesis and by definition in a state of perfect solution, is it not an explanation by occult causes to say that the cause of its spontaneous coagulation is its disorganisation, etc.?
And what is the value of explanations by occult causes? Here is the answer given to this question by Newton: "To say that each species of things is endowed with a specific occult quality, by means whereof it has a certain power of action, and can produce sensible effects, is to say nothing at all."
Nevertheless, if in 1875 the author (M. Glenard) was reduced to the extremity of seeking an explanation of the phenomenon in considerations outside of anatomy, physiology and chemistry, it was because the then state of science did not offer anything more satisfactory. There are to be found in the transactions of the Academy of Sciences of the same year, attempts at explanation which compared the so called coagulation of milk to that of the blood.
Still later, M. Frey, returning to the methods of Muller and of Haller, said:
"Studied from the anatomical point of view the blood offers for our consideration a transparent colourless liquid, the plasma or liquor sanguinis, wherein float two kinds of cellular elements, the coloured cellules or red globules and the colourless cellules or lymphatic globules."
And as regards the fibrin, he says:
"It is not known under what form it exists in the liquids of the organism before coagulation, and it is generally supposed to be a derivative of albumen."
That amounts to saying that the red globules and the leukocytes are the only figured elements of the blood, and that the plasma holds the materials composing it in perfect solution, as Muller thought he had demonstrated for his liquor sanguinis, these materials being reducible from the organic point of view to albumen.
Further, Frey so thoroughly believed this that he said:
"The rapid nutritive exchanges which are produced in the nutrient liquid of the organism hinder the formation of fibrin during life."
All of which amounts to saying that at the moment of shedding the blood does not contain fibrin.
And here it may be observed that neither Haller nor Muller had any prejudices on the subject of the innate nature of the lymph or liquor of the blood. On the other hand, when plasma is made a synonym for "liquor sanguinis" the question is prejudged, for the synonym plasma is attached to a particular conception of organisation and of life, in conformity to the system which asserts that: "Life is a special form of the activity of matter," a system which differs greatly from the doctrines of Bichat, according to which life is not attached directly to matter, but to anatomical elements limited as to their form and structure. On this I shall insist further in explaining anatomically and physiologically the spontaneous coagulation of the blood.
But several years before GLenard and Frey wrote, Bechamp and Estor had demonstrated that the blood contains, besides the two species of globules, a third figured element, clearly determined in form and properties, by means whereof the phenomenon of coagulation could be explained without any recourse to occult causes.
In his thesis Glenard referred to our researches in these words:
"For reasons which we shall not fail to develop in a later work, we suppress a chapter having for title,`Theory of Bechamp and Estor on the Microzymas.' "
I do not know whether Glenard has anywhere developed his reasons for suppressing the above entitled chapter from his thesis. For my part I had the great sorrow of not being able to continue and complete with Estor the work we had commenced together. A separation which occurred in 1876, and then the so premature death of Estor, deprived me of my eminent collaborator and devoted friend; I had to pursue alone the complete solution of the problem. My latest researches have been carried on in the laboratory which M. Friedel provided me with at the Sorbonne.
The partial results of my researches have been described in notes which have appeared in various magazines; the last, in 1895, was in the form of a communication to the Congress of the French Association for the Advancement of Science held at Bordeaux; but several portions, and that especially which is the crown and keystone of the work, remained unpublished until the appearance of the present work.
The discovery of the third figured element of the blood was not made during the investigation of the phenomenon of the spontaneous coagulation of the blood; but Estor and I applied it according to the ideas then prevailing to the production of fibrin after phlebotomy, to explain the formation of the clot. When I resumed my study of fibrin from the point of view of blood-coagulation, I had already solved the problem of the coagulation of milk in a sense very different from received ideas, and this was long before the publication of the thesis of Glenard, who said:
"Not only are we ignorant of the first cause of coagulation, but we do not even know its proximate cause; we do not know whether this change in the state of the blood is a physical or chemical phenomenon; whether it is a crystallisation or a precipitation."
Unless I am much mistaken, that implies that the author doubted even what Haller, and, later, Muller, Hewson, Milne-Edwards and Dumas held as certain, viz., that the formation of the clot had the fibrin for its direct and near cause. As to the assertion that coagulation is a variation of the state of the blood, etc.; it proves that its author did not know either the anatomical or chemical constitution of the blood any more than that of milk.
In our note of 1869, the microzymas of the blood were expressly mentioned as being the first cause of the production of fibrin and the proximate cause of coagulation. My new researches further demonstrated that the presence of the microzymas and that of the fibrin in the blood are correlative, the one presupposing the other; it was only necessary to explain this correlation to verify, while completing the conception of Milne-Edwards developed by Dumas.
These new researches were allied to others, both older and newer, regarding the determination of the causes of the changes, reputed spontaneous, of organic matters, even of proximate principles in general, and specially of natural vegetable and animal matters, viz.:
(1).The question of the origin of ferments and the physiological theory of fermentation.
(2). The resolving in the negative the problem of the supposed spontaneous generation of ferments.
(3). The origin of urea in the organism during the act of respiration.
(4). The chemical constitution of albuminoid matters and the demonstration of the definite specificity of their chemical molecules.
(5). The true theory of organisation according to the doctrine of Bichat.
It is thus seen that the complete solution of the problem concerning the spontaneous coagulation of the blood necessitated the previous solution of several other problems very difficult of solution; they are given here nearly in their chronological order.
1. The nature of fibrin, isolated from the clot, or obtained by whipping.
2. The real specific individuality of the albuminoid proximate principles.
3. The state of the fibrin in the blood at the moment of shedding.
4. The real structure of the red globules of the blood.
5. The real constitution of the blood at the moment of shedding.
6. The real chemical and physiological meaning of the coagulation of shed blood.
These will be the captions of the following chapters.
After the developments which are to follow, it will be possible to understand that what is called the phenomenon of the spontaneous coagulation of blood is not at all a coagulation of the blood itself, but of that of a portion of its third anatomical element.
It will then clearly appear, that that which is improperly called a coagulation is only the first phase of a much more complete alteration of the blood, involving the destruction of its blood globules and other changes, even that of its red colouring matter; and further, that this spontaneous alteration of the blood is but a special case of a very general phenomenon, that of the spontaneous alterability of all animal matter, solid or humoral, abstracted from an animal, whether living or dead; an alterability, physiologically spontaneous, necessary, drawing with it the destruction even of the cellular anatomical elements themselves, as the consequence of phenomena of fermentations of a special kind, whereof the microzymas of these matters are the principal agents.