VIVISECTION, literally the cutting (sectio) of living (vivus) animals, a word which might be applied to all surgical operations whether practised upon the lower animals or on man. As conventionally used, however, it has exclusive reference to experiments upon the lower animals undertaken for the advancement of medical sciences. There are a number of people who, calling themselves anti-vivisectionists, strongly object to these experiments on the lower animals; and it must be conceded that the humane reasons which they advance against it can only be set aside as " sentimental " if considerations of a wider humanity can show that the arguments of the antivivisectionists really run counter to human progress. The supporters of vivisection, properly considered, must not be confused with those who would make a barbarous use of this means of research. What is at stake here is the right to use it properly and at all. It would be possible for cruelty of an unnecessary kind to result if the practice of vivisection were unrestricted; and the purpose of this article is to give some account of the method of experiments on animals as sanctioned by law in the United Kingdom, and to justify that method by setting forth the chief historical discoveries that have been made by the help of vivisection. Such experiments have for their object the advancement of the sciences of physiology and pathology. From the earliest periods experimental vivisections have occasionally been practised, but before the days of anaesthetics it was difficult to execute them, and not less difficult to draw conclusions. The invention of anaesthetics has greatly extended the scope of the experimental method, because an animal can be kept unconscious and quiet, without even a quiver of a muscle, during prolonged operations. Further, the introduction of the antiseptic method has made it possible to subject all tissues and regions of the body to surgical interference, and this has also had the effect of increasing the possibilities of experimental research.
In 1906 a British Royal Commission was appointed to inquire into the whole subject under the chairmanship of Lord Selby, on whose death Mr A. J. Ram, K.C., took the chair. The Commission sat from October 1906 to March 1908, and heard no fewer than 21,761 questions and answers. In view of attempts on the part of the anti-vivisectionists to misrepresent the nature of the evidence given before the Commission, in January 1908 the supporters of experiments on animals founded the Research Defence Society, under the presidency of Lord Cromer; by July 1910 this society had some 3500 members. Its official address is 21 Ladbroke Square, London, W.
I. METHODS EMPLOYED. The present act relating to experiments on animals was passed in 1876. At that time the majority of these experiments were physiological. There was, it may be fairly said, no such thing as bacteriology, no general following up of Pasteur's work. A few experiments were made in pathology, for instance in tubercle; and a few in surgery, in pharmacology, and in the action of poisons, especially snake venom. But the chief use of experiments on animals was for the advancement of physiology. The evidence given before the Royal Commission (1875) was almost entirely on physiological matters, on the discoveries of Harvey, Bell, Magendie and Claude Bernard, on the Handbook for the Physiological Laboratory, and so forth. The act, therefore, was drafted with a view to physiology, without much concern for pathology, and without foreknowledge of bacteriology. At the time of writing (1910), 95% of the experiments are inoculations. Every experiment must be made in a registered place open to government inspection. But inoculation experiments are sometimes permitted in non-registered places, for the immediate study of outbreaks of disease, or in circumstances which render it impracticable to use a registered place. Every experiment must be made under a licence; and every application for a licence must be recommended by the signatures of two out of a small body of authorities specified in the act presidents of certain learned societies and professors of certain universities and colleges. The word " experiment " is not allowed to cover the use of more than one animal.
Most experiments are made not under a licence alone, but under a licence plus one or more certificates, and the wording and working of these certificates must be clearly understood, because it is over them that the question arises as to the amount of pain inflicted by these experiments. Under the licence alone, the animal must be kept under an anaesthetic during the whole of the experiment; and " if the pain is likely to continue after the effect of the anaesthetic has ceased, or if any serious injury has been inflicted on the animal," it must be killed forthwith under the anaesthetic. Thus, under the licence alone, it is impossible to make an inoculation; for the experiment consists, not in the introduction of the needle under the skin, but in the observation of the results of the inoculation. A guinea-pig inoculated with tubercle cannot be kept under an anaesthetic till the disease appears. The disease is the experiment, and it is therefore an experiment made without an anaesthetic, and not authorized by the licence alone. Again, under the licence alone it would have been impossible to work out the thyroid treatment of myxoedema, or the facts of cerebral localization. For to remove the thyroid gland, or to remove a portion of the surface of the brain, is to inflict a serious injury on the animal. The operation is done under profound anaesthesia it would be impracticable otherwise; the wound is treated and dressed by the antiseptic method suppuration would invalidate the result. But a serious injury has been inflicted. Nevertheless, the animal must not be killed forthwith: the result must be watched. These and the like experiments cannot therefore be made under the licence alone. For the removal of such disabilities as these, the act empowers the home secretary to allow certain certificates, to be held with the licence. They must be recommended by two signatures, and various restrictions are put upon them by the home secretary. On July n, 1898, the home secretary was asked, in the House of Commons, what were the conditions and regulations attached by the Home Office to licences and certificates; and he answered " The conditions are not always the same, but may vary according to the nature of the investigation. It is hardly possible, therefore, for me to state all the conditions attached to licences and certificates. The most important conditions, however (besides the limitations as to place, time and number of experiments), and the conditions most frequently imposed, are those as to reporting and the use of antiseptics. The latter condition is that the animals are to be treated with strict antiseptic precautions, and if these fail and pain results, they are to be killed immediately under anaesthetics. The reporting conditions are, in brief, that a written record, in a prescribed form, is to be kept of every experiment, and is to be open for examination by the inspector; that a report of all experiments is to be forwarded to the inspector; and that any published account of an experiment is to be transmitted to the secretary of state. Another condition requires the immediate destruction under anaesthetics of an animal in which severe pain has been induced, after the main result of the experiment has been attained."
The home secretary attaches to licences and certificates such endorsements as he thinks fit. The bare text of the act, now thirty-four years old, is a very different thing from the administration of the act ; and the present writer is in a position to say that the act is administered with great strictness, under a careful system of inquiry and reference.
The certificates are distinguished as A, B, C, E, EE and F. Certificate D, which permitted the testing, by experiments, of " former discoveries alleged to have been made," has fallen into disuse. Certificate C permits experiments to be made by way of illustration of lectures. They must be made under the provisions contained in the act as to the use of anaesthetics. Certificates E and EE permit experiments on dogs or cats; certificate F permits experiments on horses, asses or mules.
These certificates are linked with Certificate A or Certificate B. It is round these two certificates, A and B, that the controversy as to the pain caused by experiments on animals is maintained.
Certificate A permits experiments to be made without anaesthesia. It is worded as follows: " Whereas A. B. of [here insert address and profession} has represented to us (i.e. two authorities) that he proposes, if duly authorized under the above-mentioned act, to perform on living animals certain experiments described below: We hereby certify that, in our opinion, insensibility in the animal on which any such experiment may be performed cannot be produced by anaesthetics without necessarily frustrating the object of such experiment." All inoculations under the skin, all feeding experiments and the like, are scheduled under this certificate. They must be scheduled somehow: they cannot legally be made under a licence alone. Though the only instrument used is a hypodermic needle, yet every inoculation is officially returned as an experiment, calculated to give pain, performed without an anaesthetic. It is for inoculations and the like experiments, and for them alone, and for nothing else, that Certificate A is allowed (or A linked with E or F). This want of a special certificate for inoculations, and this wresting of Certificate A for the purpose, have led to an erroneous belief that " cutting operations are permitted by the act without an anaesthetic. But, as the home secretary said in parliament, in March 1897, " Certificate A is never allowed except for inoculations and similar trivial operations, and in every case a condition is attached to prevent unnecessary pain." And again he wrote in 1898, " Such special certificates (dispensing with anaesthetics) are granted only for inoculations, feeding and similar procedures involving no cutting. The animal has to be killed under anaesthetics if it be in pain, so soon as the result of the experiment is ascertained."
Certificate B permits the keeping alive of the animal after the initial operation of an experiment. It is worded as follows: " Whereas A. B. of [here insert address and profession} has represented to us (i.e. two authorities) that he proposes, if duly authorized under the above-mentioned act, to perform on living animals certain experiments described below, such animals being, during the whoie of the initial operation of such experiments, under the influence of some anaesthetic of sufficient power to prevent their feeling pain: We hereby certify that, in our opinion, the killing of the animal on which any such experiment is performed before it recovers from the influence of the anaesthetic administered to it would necessarily frustrate the object of such experiment." Certificate B (or B linked with EE or F) is used for those experiments which consist in an operation plus subsequent observation of the animal. The section of a nerve, the removal of a secretory organ, the establishment of a fistula, the plastic surgery of the intestine, the sub-dural method of inoculation these and the like experiments are made under this certificate. We may take, to illustrate the use of Certificate B, Horsley's observations on the thyroid gland. The removal of the gland was the initial operation; and this was performed under an anaesthetic, and with the antiseptic method. Then the animal was kept under observation. The experiment is neither the operation alone nor the observation alone, but the two together. The purpose of this certificate is set forth in the inspector's report for 1909. " In the experiments performed under Certificate B, or B linked with EE, 1704 in number, the initial operations are performed under anaesthetics from the influence of which the animals are allowed to recover. The operations are required to be performed antiseptically, so that the healing of the wounds shall, as far as possible, take place without pain. If the antiseptic precautions fail, and suppuration occurs, the animal is required to be killed. It is generally essential for the success of these experiments that the wounds should heal cleanly, and the surrounding parts remain in a healthy condition. After the healing of the wounds the animals are not necessarily, or even generally, in pain, since experiments involving the removal of important organs, including portions of the brain, may be performed without giving rise to pain after the recovery from the operation; and after the section of a part of the nervous system, the resulting degenerative changes are painless. In the event of a subsequent operation being necessary in an experiment performed under Certificate B, or E linked with EE, a condition is attached to the licence requiring all operative procedures to be carried out under anaesthetics of sufficient power to prevent the animal feeling pain; and no observations or stimulations of a character to cause pain are allowed to be made without the animals being anaesthetized. In no case has a cutting operation more severe than a superficial venesection (the opening of a vein just under the skin) been allowed to be performed without anaesthetics."
From this brief account of the chief provisions of the act, we come to consider the general method of experiments on animals in the United Kingdom, and the question of the infliction of pain on them. The figures for a representative year may be given. The total number of licensees in 1909, in England and Scotland, was 483: of whom 135 performed no experiments during the year. The total number of experiments was 86,277, being 2357 less than in 1908. They v/ere made as follows :
Under Licence alone 1,980 Certificate C 196 Certificate A 81,566 Certificates A + E . . . . 595 Certificates A+F . . . . 228 Certificate B 1,385 Certificates B + EE ... 319 Certificate F 8 The experiments performed under Certificate A (or A+E, or A+F) were mostly inoculations; but a few were feeding experiments, or the administration of various substances by the mouth or by inhalation, or the abstraction of blood by puncture or by simple venesection. Inoculations into deep parts, involving a preliminary incision, are required to be performed under anaesthetics (Certificate B).
" It will be seen," says the report for 1909, " that the operative procedures in experiments performed under Certificate A, without anaesthetics, are only such as are attended by no considerable, if appreciable, pain. The certificate is, in fact, not required to cover these proceedings, but to allow of the subsequent course of the experiment. ' The animals most used for inoculations are mice, rats, guineapigs and rabbits. It is not once in a thousand times that a dog or a cat is used for inoculation. The act of inoculation is not in itself painful. A small area of the skin is carefully shaved and cleansed, that it may be aseptic, the hypodermic needle is sterilized and the method of hypodermic injection or of vaccination is the same as it is in medical practice. " A guinea-pig that will rest quietly in your hands before you commence to inject it, will remain perfectly quiet during the introduction of the needle under the skin; and the moment it is returned to the cage it resumes its interrupted feeding. Arteries, veins and most of the parts of the viscera are without the sense of touch. We have actual proof of this in what takes place when a horse is bled for the purpose of obtaining curative serum. With a sharp lance a cut may be made in the skin so quickly and easily that the animal does nothing more than twitch the skin-muscle of the neck, or give his head a shake, while of the further proceeding of introducing a hollow needle into the vein, the animal takes not the slightest notice. Some horses, indeed, will stand perfectly quiet during the whole operation, munching a carrot, nibbling at a wisp of hay, or playing with a button on the vest of the groom standing at its head." These sentences, written in the Medical Magazine (June 1898) by Dr Sims Woodhead, Professor of Pathology at Cambridge, are sufficient evidence that inoculations and the like experiments are not painful at the time. In a few instances cultures of micro-organisms have been made in the anterior chamber of the eye, by the introduction of a needle behind the cornea. This might be thought painful, but cocaine renders the surface of the eye wholly insensitive. Many operations of ophthalmic surgery are done under cocaine alone, and the anterior chamber of the eye is so far insensitive that a man may have blood or pus (hypopyon) in it, and hardly be conscious of the fact. The results of inoculation are in some cases negative, in others positive; the positive results are, in the great majority of cases, not a local change, but a general infection which may end in recovery, or in death. The diseases thus induced may, in many cases, fairly be called painless such are septicaemia in a mouse, snake-venom in a rat, and malaria in a sparrow. Rabbits affected with rabies do not suffer in the same way as dogs and some other animals, but become subject to a painless kind of paralysis. It is probable that animals kept for inoculation have, on the whole, less pain than falls to the lot of a like number of animals in a state of nature or in subjection to work: they are well fed and sheltered, and escape the rapacity of larger animals, the inevitable cruelties of sport, and the drudgery and sexual mutilation that man inflicts on the higher domestic animals.
The present writer has, of course, seen the mice that are used for the study of cancer (Imperial Cancer Research Fund), and the guinea-pigs that are used at the Lister Institute for the testing of the London milk-supply, lest the milk should convey tubercle. He did not see, among all the many animals, one that appeared to be suffering: save that a very few of the mice were incommoded, or, if the word be applicable to mice, distressed, by large tumours. Of the guinea-pigs that had been inoculated, not one seemed to be in any pain. A nodule of tubercle, or a tuberculous gland, is painless in us, and therefore cannot be painful in a guinea-pig. It is not denied that the study of some diseases (plague, tetanus) causes some pain to rats and rabbits; but this pain is hardly to be compared with the pain and horror of these diseases in man.
We come now to Certificate B. If it were lawful, under Certificate B, to make an incision under an anaesthetic, to call this the " initial operation," and then, without an anaesthetic, to make painful experiments, through the incision, on the deeper structures, doubtless much pain might be inflicted under this certificate. But experiments of this kind can be, and are, made under the licence alone, the animal being kept under an anaesthetic all the time, and killed under it. " No experiments requiring anything of the nature of a surgical operation, or that would cause the infliction of an appreciable amount of pain, are allowed to be performed without an anaesthetic" (Inspector's Report for 1899). " These certificates (B) are granted on condition that antiseptic precautions are used; and if these fail, and pain continues after the anaesthetics have ceased to operate, the animal is immediately killed painlessly " (Letter from the Home Secretary, 1898).
Of experiments made under this certificate (which must be linked with Certificate EE for any experiment on a dog or a cat) , three instances may be given here: an operation on the brain, a removal of part or the whole of a secreting gland, and the establishment of a fistula. It is to be noted that, for these and the like operations, profound anaesthesia and the strict observance of the antiseptic method are matters of absolute necessity for the success of the experiment: the operation could not be performed without anaesthesia; and the experiment would come to nothing if the wound suppurated. It is to be noted, also, that these operations are such as are performed in surgery for the saving of life or for the relief of pain.
As to operations on the brain, it must be remembered that the surface of the brain is not sensitive. Therefore the removal or destruction of a portion of the surface of the brain, or the division of some tract of central nervous tissue, though it might entail some loss of power or of control, does not cause pain: a wound of the brain is painless. Tension within the cranial cavity, as in cases of cerebral tumour or cerebral abscess, may indeed cause great pain; and, if the aseptic method failed in an experiment, inflammation and tension would ensue: in that case the animal must be killed.
The removal of part or the whole of a secreting gland (e.g. the thyroid, the spleen, the kidney) is performed by the same methods, and with the same precautions, as in human surgery. Profound anaesthesia, and the use of a strict antiseptic procedure, are of absolute necessity. The skin over the part to be removed must be shaved and carefully cleansed for the operation; the instruments, sponges and ligatures must be sterile, not capable of infecting the wound; and when the operation is over, the wound must be carefully closed with sutures, and left to heal under a proper surgical dressing.
The establishment of a fistula, again, is an operation practised, as a matter of course, in large numbers of surgical cases. The stomach, the gall-bladder, the large intestine, are opened for the relief of obstruction, and kept open, either for a time or permanently, according to the nature of the case. Under anaesthesia, the organ that is to be opened is exposed through an incision made through the structures overlying it, and is secured in the wound by means of fine sutures. Then, when it has become adherent there, it is opened by an incision made into it; no anaesthetic is needed for this purpose, because these internal organs are so unlike the skin in sensitiveness that an incision is hardly felt: the patient may say that he " felt a prick," or he may be wholly unconscious that anything has been done. A i 5 6 fistula thus established is not afterward painful, though there may be some discomfort now and again.
The classical instance is the case of Alexis St Martin, who was shot in the stomach in 1822, and recovered, but with a fistula. He let Dr Beaumont make experiments on him for nine years: " During the whole of these periods, from the spring of 1824 to the present time (1833), he has enjoyed general good health . . . active, athletic and vigorous; exercising, eating and drinking like other healthy and active people. For the last four months he has been unusually plethoric and robust, though constantly subjected to a continuous series of experiments on the interior of the stomach; allowing to be introduced or taken out at the aperture different kinds o? food, drinks, elastic catheters, thermometer tubes, gastric juice, chyme, etc., almost daily, and sometimes hourly. Such have been this man's condition and circumstances for several years past; and he now enjoys the most perfect health and constitutional soundness, with every function of the system in full force and vigour " (Beaumont, Experiments and Observations on the Gastric Juice, 1838).
We come now to the question, What anaesthetics are used in these experiments, and are they properly administered ? The anaesthetics used are (i) chloroform, ether, or a mixture containing chloroform and ether; (2) morphia, chloral, urethane. It is sometimes said that morphia is not an anaesthetic. That depends on the quantity given. Not a month passes in this country without somebody killing himself or herself with morphia or chloral. They die profoundly anaesthetized: they cannot be roused; even the pain of a strong electric shock is not enough to rouse them. So it is with animals. The doses given to them are enormous and produce complete insensibility. On this point the evidence given before the Royal Commission of 1906-8 by Mr Thane, Professor Schafer, Sir Lauder Brunton, Sir Henry Morris, Professor Dixon, Dr Dudley Buxton and Professor Starling is absolutely conclusive. " As to the statements," says Sir Lauder Brunton, " that chloral and opium or morphia are not narcotics, and do not remove pain, there is no other word for it, it is simply a lie; you may as well say that chloroform does not remove pain. If you give any animal a sufficiently large dose of chloral or opium, you so completely abolish sensibility that there is nothing you can do that will awaken its sensibility. The animal is as senseless as a piece of board."
With regard to chloroform, ether and the A.C.E. mixture (alcohol, chloroform and ether) it is absolutely certain that animals can be kept, with these anaesthetics, profoundly unconscious for three or four or more hours. Nothing on this point is more worthy of consideration than the evidence in veterinary surgery, given before the Royal Commission by Mr Hobday, one of the very foremost veterinary surgeons in this country (Reports of Evidence, vol. iv. Q. 16284-16523). The opponents of all experiments on animals are apt to believe that dogs and cats must be bound and fastened on boards, and then have the anaesthetic given to them. That is not the case. They can take the anaesthetic first, and then be put in position; just as we 1 , for many of the operations of surgery, are bound in position. And, of course, dogs and cats cannot lie on their backs as we can. " The usual thing we do," said Professor Starling, in his evidence before the Royal Commission, " is to give the animal, half an hour before the experiment, a hypodermic injection of morphia, of about a quarter of a grain from a quarter to a third. The effect of that is, that the dog becomes sleepy and stupid, and then sometimes it will lie down quietly, and if it is very sleepy you can put a mask over its nose containing the chloroform, alcohol and ether mixture, which it takes quite quietly. If, at the time one wants to begin the operation, the animal is not fully under the influence of morphia if it still seems restless it is put in a box, and there it has some wool saturated with the A.C.E. mixture put in the box. The air gradually gets saturated, the dog gets more and more sleepy, and finally subsides at the bottom of the box."
A few words must be said here about curare. It was said, some years ago, by an opponent of experiments on animals, that " curare is used daily throughout England," whereas, it is seldom used at all, and is never used alone in any sort or kind of operation on any animal in this country: in every such case a recognized anaesthetic must be given, and is given. In large doses curare not only abolishes the movement of the voluntary muscles, but also acts as an anaesthetic: in small doses it acts only on the voluntary muscles, i.e. on the endings of the motor nerves going to these muscles. For example, suppose that the object of the experiment is to observe and record the action of a nerve on the contraction of certain blood vessels. The nerve gives off some branches to muscles, and other branches to blood vessels. If the animal be anaesthetized, and the nerve stimulated, muscles and vessels will x>th contract; but, if curare be given, as well as an anaesthetic, the vessels alone will contract, without the muscles: for curare does not act on the endings of motor nerves going to blood vessels. But, as a practical matter, curare is very hard to obtain, and is often impure, and is very seldom used. One of the inspectors said to the Royal Commission that he had once seen it used, fifteen years ago. Professor Gotch said that he had not used it, in his own work, Tor twenty years. Professor Schafer said that he had not used it for years. And Sir Lauder Brunton said that he did not think he had used it at all since the passing of the act of 1876. The fear that, in a case where curare was being used, the effect of the anaesthetic might " pass off," and the animal be left under curare alone, is not reasonable. The dosage and administration of anaesthetics is not left to chance. If, for example, an animal is receiving a definite percentage of chloroform vapour, it is of necessity under the influenc of the chloroform: and the anaesthesia will gradually become no less but more profound. (See the evidence given before the Roya Commission by Professor Langley and Professor Waller.)
It may be interesting to compare the pain, or death, or discomfort among 86,277 animals used for experiments in Grea Britain in 1909, with the pain, or death, or discomfort of an equal number of the same kinds of animals, either in a state of nature, or kept for sport, or used for the service of human profit or amusement. But it would be outside the purpose of this article to describe the cruelties which are inseparable from sport, and from the killing of animals for food, and fron fashion; neither is this the place to describe the millions of mutilations which are practised on domestic animals by farmer and breeders. As one of the Royal Commissioners recently said, the farmyards, at certain times of the year, simply " seeth with vivisection." The number of animals wounded in sport, or in traps, cannot be guessed. Against this vast amount suffering we have to put an estimate of the condition of 86,277 animals used for medical science. Ninety-five per cent, of then were used for inoculation. In many of these inoculations result was negative: the animal did not take any disease, and thus did not suffer any pain. In many more, e.g. cance in mice, tubercle in guinea-pigs, the pain or discomfort, if any, may fairly be called trivial or inconsiderable. It could hardly be said that these small animals suffer much more than an equal number of the same kind of animals kept in little cage to amuse children. There remain 3888 animals which we submitted to operation under an anaesthetic . In the great number of these cases the animal was killed then and ther under the anaesthetic, without recovering consciousness, the remaining cases the animal was allowed to recover, and to be kept for observation; but no further observation of an) kind, which could cause pain, was allowed to be made on it unless it were again placed under an anaesthetic. Many these cases, thus allowed to recover after an operation, may fairly be compared to an equal number of domestic anima" after one of the formal operations of veterinary surgery. Thes observations made under Certificate B form but a very sma proportion of the total number of experiments on animals the United Kingdom; and they have led, in recent years, discoveries of the very utmost importance for human life and health.
II. SCIENTIFIC RESULTS. We come now to consider th results of experiments on animals, but we must remember tha not we alone, but animals also, owe a great debt to them. Gr epizootic diseases like anthrax, swine-fever, chicken choler . silkworm disease, pleuro-pneumonia, glanders, Texas catt fever, blackleg, tuberculosis in cattle, have killed yearly million of animals, and have been brought under better control by these experiments. The advantages that have been obtaine' for man may be arranged under two heads (A) Physiology, (B) Pathology, Bacteriology and Therapeutics.
A. PHYSIOLOGY I. The Blood. Galen (A.D. 131) confuted the doctrine of tratus, that the arteries contained TTWUMO, the breath of life, proviti by experiment that they contain blood. " Ourselves, having tied the exposed arteries above and below, opened them, and showed that they were indeed full of blood." Realdus Columbus (i5S9). though he did not discover the general or " systematic " circulation of the blood, yet seems to have discovered, by experiment, the pulmonary circulation. ' The blood is carried through the pulmonary artery .to the lung, and there is attenuated ; thence, mixed with air, it is carried through the pulmonary vein to the left side of the heart. Which thing no man hitherto has noted or left on record, though it is most worthy of the observance of all men. . . . And this is as true as truth itself; for if you will look not only in the dead body but also in the living animal, you will always find this pulmonary vein full of blood, which assuredly it would not be if it were designed only for air and vapours. . . . Verily I pray you, O candid reader, studious of authority, but more studious of truth, to make experiment on animals. You will find the pulmonary vein full of blood, not air orfuligo, as these men call it, God help them." Harvey's treatise De Motu Cordis et Sanguinis in Animalibus was published at Frankfort in 1621. It begins thus: " When by many dissections of living animals, as they came to hand, Cum multis vivorum disseclionibus, uti ad manum dabantur, I first gave myself to observing how I might discover, with my own eyes, and not from books and the writings of other men, the use and purpose of the movement of the heart in animals, forthwith I found the matter hard indeed and full of difficulty; so that I began to think, with Frascatorius, that the movement of the heart was known to God alone. ... At last, having daily used greater disquisition and diligence, by frequent examination of many and various living amma\s-r-multa frequenter et varia animalia viva introspiciendo I came to believe that I had succeeded, and had escaped and got out of this labyrinth, and therewith had discovered what I desired, the movement and use of the heart and the arteries. And from that time, not only to my friends but also in public in my anatomical lectures, after the manner of the Academy, I did not fear to set forth my opinion in this matter." Here, and again at the end of the Preface, and again in the eighth chapter of the De Motu, he puts his experiments in the very foreground of the argument. Take the headings of his first four chapters: I. Causae, quibus ad scribendum auctor permotus fuerit. 2. Ex vivorum dissectione, qualis fit cordis ntotus. 3. Arteriarum motus qualis, ex vivorum dissectione. 4. Motus cordis et auricularum qualis, ex vivorum dissectione. He had, of course, help from. other sources from anatomy and from physics; but it is certain, from his own words, that he attributed his discovery, in a very great measure, to experiments on animals. Malpighi (1661), professor of medicine at Bologna, by examining with a microscope the lung and the mesentery of the live frog, made out the capillary vessels. He writes to Borelli, professor of mathematics at Pisa, that he has failed in every attempt to discover them by injecting fluids into the larger vessels, but has succeeded by examining the tissues with the microscope: " Such is the divarication of these little vessels coming off from the vein and the artery, that the order in which a vessel ramifies is no longer preserved, but it looks like a network woven from the offshoots of both vessels " (De Pulmonibus, 1661). Stephen Hales (1733), rector of Farringdon and minister of Teddington, and a Fellow of the Royal Society, made the first exact estimates of the blood pressure, the real force of the blood, by inserting one end of a vertical glass tube into the crural artery of a mare, and noting the rise of the blood in the tube (Statical Essays, containing Haemostatic ks, &fc., 1733). John Hunter, born 1738, made many observations on the nature and processes of the blood; and, above all, he discovered the facts of collateral circulation. These facts were fresh in his mind when he first ventured, in December 1785, to tie the femoral artery in " Hunter's canal " for the cure of aneurism in the popliteal space. The experiment that gave him his knowledge of the collateral circulation was made on one of the deer in Richmond Park: he tied its externaj carotid artery, to see what effect would be produced on the shedding of the antler. Some days later he found that the circulation had returned in the antler. He had the buck killed, and found that the artery had been completely closed by the ligature, but the small branches coming from it, between the heart and the ligature, were enlarged and were in communication with others of its branches beyond the ligature; and by this collateral circulation the flow of blood to the antler had been restored. Among later observations on the circulation must be mentioned the use of the mercurial manometer by Poiseuille (1828) and Ludwig (1849), the study of the blood pressure within the heart by Hering (1849) and the permanent tracing of the pressure curves by Chauveau and Marey (1863). Finally came the study of those more abstruse problems of the circulation that the older physiologists had left alone the influences of the central nervous system, the relations between blood pressure and secretion, the automatism of the heart-beat, and the influence of gravitation. Professor Starling, in 1906, writes as follows of this part of physiology: "Among the researches of the last thirty years, those bearing on the circulation of the blood must take an important place, both for their physiological interest and for the weighty influence they have exerted on our knowledge and treatment of disorders of the vascular system, such as heart disease. We have learned to measure accurately the work done by the great heart-pump; and by studying the manner in which this work is affected by different conditions, we are enabled to increase or diminish it, according to the needs of the organ. Experiments in what is often regarded as the most transcendental department of physiology i.e. that which treats of muscle and nerve-^have thrown light on the wonderful process of ' compensation ' by which a diseased heart is able to Keep up a normal circulation." And Dr James Mackenzie, writing in 1910 of certain irregularities of the circulation during pregnancy (venous pulse in the neck and irregular beat of the heart), says, very emphatically, that these conditions in patients have been interpreted by experiments on animals. " The outcome ot these researches [ Wenckebach's clinical studies], as well as those of a great number of other observers, has been to elucidate the nature and meaning of a great number of abnormal conditions of the heart. It might be said with truth that, whereas a few years ago irregular action of the heart was one of the most obscure symptoms in clinical medicine, it is now one of the best understood. It is needless to repeat that this advance would have been absolutely impossible without the knowledge gained by experiment " (Research Defence Society, May 1910).
2. The Lacteals. Asellius (1622) by a single experiment demonstrated the flow of chyle along the lacteals. The existence pt these minute vessels had been known even to Galen and Erastistratus, but they had made nothing of their knowledge. Aselliusays: "I observed that the nerves of the intestines were quite distinct from these white threads, and ran a different course. Struck with this new fact, I was silent for a time, thinking of the bitter warfare of words among anatomists as to the mesenteric veins and their purposes. When I came to myself, to satisfy myself by an experiment, I pierced one of the largest cords with a scalpel. I hit the right point, and at once observed a white liquid like milk flowing from the divided vessel." Jehan Pecquet (1647), in the course of an experiment on the heart, observed the now of chyle into the subclavian vein, and its identity with the chyle in the lacteals; and by further experiment found the thoracic duct, and the chyle flowing up it: "I perceived a white substance, like milk, flowing from the vena cava ascendens into the pericardium, at the place where the right auricle had been I found these vessels (the thoracic duct) all along the dorsal vertebrae, lying on the spine, beneath the aorta. They swelled below a ligature; and when I relaxed it, I saw the milk carried to the orifices that I had observed in the subclavian vein-." The existence of this duct, which is empty and collapsed after death, had been overlooked by Vesalius and all the great anatomists of his time.
3. The Gastric Juice. Our knowledge about digestion dates back to the end of the 17th century, when Valisnieri _first observed that the stomach of a dead animal contained a fluid which acted on certain bodies immersed in it " a kind of aqua forlis." In 1752 Reaumur began his observations on this fluid, making birds swallow fine fenestrated tubes containing grain or meat, or sponges with threads attached; and observed that digestion consists in the dissolution of food, not in any sort of mechanical action or trituration. His observations were extended and perfected by Spallanzani (1777). Then came a period of uncertainty, without further advance; until in 1823 the_ French Academy offered a prize for the best work on the subject, and Tiedemann and Gmelin submitted their observations to them : " The work of Tiedemann and Gmelin is of especial interest to us on account of the great number of their experiments, from which came not only the absolute proof of the existence of the gastric juice, but also the study of the transformation of starch into glucose. Thus the theory of digestion entered a new phase : it was finally recognized, at least for certain substances, that digestion is not simplv dissolution, but a true chemical transformation " (Claude Bernard, Physiologic opfratoire, 1879). Beaumont's experiments on Alexis St Martin (vide supra) were published in 1838. They were, of course, based on the work of the physiologists: " I make no claim to originality in my opinions as respects the existence and operation of the gastric juice. My experiments confirm the doctrine? (with some modifications) taught by Spallanzani and many of the most enlightened physiological writers " (Beaumont's preface to his book). Eberle, in 1834, showed how this knowledge of the gastric juice might be turned to a practical use, by extracting it from the mucous membrane of the stomachs of animals after death : hence came the invention of the various preparations of pepsin. Later, Blondlot of Nancy, in 1842, studied the gastric juice by the method of a fistula, like that of St Martin. More recent observations have been made on the movements of the stomach during digestion, and on the influences of the nervous system on the process.
The stomach is, of course not the only organ of digestion: the liver, the pancreas and the intestinal glands, all are concerned. The recent work of Pawlow and of Starling has greatly advanced our knowledge of the actions of the secretions from these organs. The whole chain of processes, nervous and chemical, psychical and physical, from the taking of food into the mouth to the expulsion of the waste residue, is now viewed in its entirety; and especial study has been given to the influences, nervous or chemical, which i S 8 are exercised, as it were, on a particular tract of the digestive system, at the bidding of another tract. Pawlow, recognizing the importance of keeping the animals under the most normal conditions that were possible, and of studying the different tracts of the digestive system in animals not anaesthetized, yet free from pain or distress, made use of fistulae established at different points of the digestive canal, and was able to study the digestive juices at different stages during digestion, without causing pain to the animals. The work of Pawlow has been further developed by Professor Starling's recent work on the chemical substances produced in the body, during the act of digestion, to promote digestion.
4. Glycogen. Claude Bernard's work on the assimilation and destruction of sugar in the body was begun in 1843. His discovery of the glycogenic action of the liver was made by keeping two dogs on different diets, one with sugar, the other without it, then killing them during digestion, and testing the blood in the veins coming from the liver: " What was my surprise when I found a considerable quantity of sugar in the hepatic veins of the dog that had been fed on meat only, and had been kept for eight days without sugar ! . . . Finally, after many attempts apres beaucoup d'essais el plusieurs illusions que je fus oblige de rectifier par des t&tonnements I succeeded in showing, that in dogs fed on meat the blood passing through the portal vein (from the stomach) does not contain sugar before it reaches the liver; but when it leaves the liver and comes by the hepatic veins into the inferior vena cava, this same blood contains a considerable quantity of a sugary substance (glucose) " (Nouvdle fonction dufoie, Paris, 1853).
5. The Pancreas. The 17th century was a time of very fanciful theories about the pancreas (Lindanus, Wharton, Bartholini), which need not be recalled here. But Sylvius (Francois de Bois) had the wisdom to see that the pancreas must be estimated, not according to its position, but according to its structure, as of the nature of the salivary glands. He urged his pupil, Regnier de Graaf, to study it by experiment, and de Graaf says: " I put my hand to the work; and though many times I despaired of success, yet at last, by the blessing of God on my work and prayers, in the year 1662 I discovered a way of collecting the pancreatic juice." By the method of a fistula he collected and studied the secretion of the pancreas; and by further experiment he refuted Bartholini's theory that the pancreas was a sort of appanage or " biliary vesicle " of the spleen. But he got no help from the chemistry of his time ; he could no more discover the amylolytic action of the pancreatic secretion than Galvani could discover wireless telegraphy. Still, he did good work; and Claude Bernard, 180 years later, went back to de Graaf's method of the fistula. His observations, begun in 1846, received a prize from the French Academy in 1850. Sir Michael Foster says of them: " Valentin, it is true, had in 1844 not only inferred that the pancreatic juice had an action on starch, but confirmed his view by actual experiment with the juice expressed from the gland; and Eberle had suggested that the juice had some action on fat; but Bernard at one stroke made clear its threefold action. He showed that it on the one hand emulsified, and on the other hand split up into fatty acids and glycerine, the neutral fats; he clearly proved that it had a powerful action on starch, converting it into sugar; and lastly, he laid bare its remarkable action on proteid matters." At a later date it was discovered that the pancreas, beside its work in digestion, has an " internal secretion ": that it, like the thyroid gland and the suprarenal capsules, helps to keep the balance of the general chemistry of the whole body. Professor Schafer, writing in 1894, says on this subject: " It was discovered a few years ago by von Mering and Minkowski that if, instead of merely diverting its secretion, the pancreas is bodily removed, the metabolic processes of the organism, and especially the metabolism of carbo-hydrates, are entirely deranged, the result being the production of permanent diabetes. But if even a very small part of the gland is left within the body, the carbo-hydrate metabolism remains unaltered, and there is no diabetes. The small portion of the organ which has been allowed to remain (and which need not even be left in its proper place, but may be transplanted under the skin or elsewhere) is sufficient, by the exchanges which go on between it and the blood generally, to prevent those serious consequences to the composition of the blood, and the general constitution of the body, which result from the complete removal of this organ." This fact, that complete removal of the pancreas, in a cat or a dog, may cause fatal diabetes, is of importance, because the pancreas in some cases of diabetes in man is diseased : but, at present, experiments on animals have not led to any certain or specific cure of diabetes in man.
6. The Growth of Bone. The experiments made by du Hamel (1739-'843) on the growth of bone by deposit from the periosteum (the thin membrane ensheathing each bone) rose out of Belchier's observation (1735) that the bones take up the stain of madder mixed with the food. Du Hamel studied the whole subject very carefully, and discovered this bone-producing power of the periosteum, which is an important fact in all operations on the bones. As he puts it, in the title of one of his own memoirs, Les os croissent en grosscur par I'addition de couches osseuses qui tirent leur origine du perioste, commc le corps ligneux des Arbres augmente en grosseur par I'addition de couches ligneuses qui se forment dans I'ecorce. By feeding pigs at one time with dyed food, at another with und> food, he obtained their bones in concentric layers alternately stain, and unstained. His facts were confirmed by Bazan '.1746) an Boehmer (1751); but his conclusions, unfortunately, v,ere oppos by Haller. Still, he brought men to study the whole subject of : growth of bones, in length as well as in thickness, and the wh___ modelling of the bones, in adult life, by deposit and absorption. Bichat, John Hunter, Troja and Cruveilhier took up his work in physiology and in surgery. Later, from the point of view of surge Syme (1837) and Stanley (1849) made experiments on the grow of bone, and on the exfoliation of dead bone; and, after the_ Oilier, whose influence on this part of surgical practice has been the very highest value.
7. The Nervous System. A. The Nerve-Roots. Through all th centuries between Galen, who lived in the time of Commodus, an Sir Charles Bell, who lived in the time of George III., no grez advance was made in our knowledge of the nervous system. Th way of experiment, which had led Galen far ahead of his age, neglected, and everything was overwhelmed by theories. Bell London and Magendie in Paris took up the experimental study the nervous system about where Galen had left it. The questio of priority of discovery does not concern us here: we may take Sii Michael Foster's judgment, that Magendie brought exact and full proof of the truth which Bell had divined rather than demonstrated, that the anterior and posterior roots of spinal nerves have essentially different functions " a truth which is the very foundation of the physiology of the nervous system." The date of Bell's work is 1811, An Idea of a New Anatomy of the Brain, submitted for the Observativ of the Author's Friends. In it he says: " Considering that the spins nerves have a double root, and being of opinion that the propertie of the nerves are derived from their connexions with the parts e the brain, I thought that I had an opportunity of putting my opinio to the test of experiment, and of proving at the same time tha nerves of different endowments were in the same cord (the sam nerve-trunk) and held together by the same sheath. On layin bare the roots of the spinal nerves I found that I could cut acres the posterior fasciculus of nerves, which took its origin from th spinal marrow, without convulsing the muscles of the back; bu that on touching the anterior fasciculus with the point of the knife the muscles of the back were immediately convulsed. Such we my reasons for concluding that the cerebrum and cerebellum parts distinct in function, and that every nerve possessing a doubl< function obtained that by having a double root. I now saw tl meaning of the double connexion of the nerves with the spin marrow, and also the cause of that seeming intricacy in the con nexions of nerves throughout their course, which were not doubli at their origins." His other work, on the cranial nerves, which ar " not double at their origins," bore fruit at once in surgery. John Erichsen says of it : " Up to the time that Sir Charles made his experiments on the nerves of the face, it was the comn custom of surgeons to divide the facial nerve for the relief neuralgia, tic douleureux; whereas it exercises, and was prove by Sir Charles Bell to exercise, no influence over sensation, and it division consequently for the relief of pain was a useless operation."
B. Reflex Action. The observations made by Sir Robert Boyli Redi, Le Gallois and others on the reflex movements of decapitate vipers, frogs, eels and butterflies were of no great use from tli point of view of physiology; but they led toward the discover that nerve-power is stored in the spinal cord, and is liberated thenc in action independent of the higher cerebral centres. Marshall Ha (1832-1837) discovered, by his experiments, that reflex actions i the work of definite groups of cells, set at certain points or levels in the cord; he proved the segmental structure of the cord, the ex' ence of nerve-centres in it, and thus foreshadowed the discov of the like centres in the brain. In his earlier writings (18323 he extended the principles of the doctrines of reflex action to t larynx, the pharynx and the sphincter muscles; later, in 1837, demonstrated the course of nerve-impulses within the cord, fri one level to another, and the effects of direct stimulation of the co Also he noted the effects of opium and of strychnine on refle action; and the reflex character of the convulsions that occur certain diseases.
C. The Medulla Oblongata and the Cerebellum. Flourens, wh was among the earliest students of the use of chloroform, is known for his experiments on the respiratory centre and the c bellum. He localized the cells in the medulla that govern the refle movement of respiration. Afterward came the discovery of cardia and other centres in the neighbourhood of the respiratory centif He showed also that the cerebellum is concerned with the equilibration and co-ordination of the muscles ; that an animal, a few days ol<" deprived of sensation and consciousness by removal of the cerebn hemispheres, was yet able to stand and to move forward, but whe the cerebellum also was removed, lost all power of co-ordinatio (Recherches experimental , Paris, 1842). And from the observation made by him and by others, it was found that the semicircular can of the internal ears are the terminal organs of the sense of equilibr tion.
D. The Vaso-Motor Nerves. Claude Bernard, studying the sympathetic nervous system, discovered the vaso-motor nerves that control the calibre of the arteries. The question of priority between him and Brown Sequard need not be considered here. His first account of his work was communicated to the Societe de Biologie in December 1851. The following account of it is from his Lemons de physiologie operatoire (1879):
" Let me remind you how I was led to discover the vaso-motor ervcs. Starting from the clinical observation, made long ago, that in paralysed limbs you find at one time an increase of cold and at another an increase of heat, I thought that this contradiction might be explained by supposing that, side by side with the general action of the nervous system, the sympathetic nerve might have the function of presiding over the production of heat ; that is to say, that in the case where the paralysed limb was chilled, I supposed the sympathetic nerve to be paralysed, as well as the motor nerves; while in the paralysed limbs that were not chilled the sympathetic nerve had retained its function, the systematic nerves alone having been attacked. This was a theory, that is to say, an idea, leading me to make experiments; and for these experiments I must find a sympathetic nerve-trunk of sufficient size, going to some organ that was easy to observe; and must divide the trunk to see what would happen to the heat-supply of the organ. You know that the rabbit's car, and the cervical sympathetic of this animal, offered us the required conditions. So I divided this nerve; and, at once, the ex|H:riment gave the lie direct to my theory Je coupai done ce filet el aussitoi I 'experience donna <J man hypothcse le plus eclatant dementi. I had thought that the section of the nerve would suppress the function of nutrition, of calorification, over which the sympathetic system had been supposed to preside, and would cause the hollow of the ear to become chilled; and here was just the opposite, a very warm ear, with great dilatation of its vessels." The experiments of Budge and Waller (1853) and of Schiff (1856) threw light on the action of these vaso-motor nerves, and on the place of the vasomotor centre in the cord; and in 1858 Claude Bernard, by his experiments on the chorda tympani and the submaxillary gland, demonstrated their twofold influence, either to dilate or to constrict the vessels. " It is almost impossible to exaggerate the importance of these labours of Bernard on the vaso-motor nerves, since it is almost impossible to exaggerate the influence which our knowledge of the vaso-motor system, springing as it does from Bernard's researches as from its fount and origin, has exerted, is exerting, and in widening measure will continue to exert, on all pur physiological and pathological conceptions, on medical practice, and on the conduct of human life. There is hardly a physiological discussion of any width in which we do not sooner or later come on vaso-motor questions " (Foster, Life of Claude Bernard).
E. Cerebral Localization. The study of the motor and sensory centres of the cerebral hemispheres began in clinical observation. Observation of cases, and examination of the brain after death (Bouillard, 1825, Dax, 1836, Broca, 1861), led men to believe that a particular area of the left frontal lobe of the brain did indeed govern and permit the use of speech. Physiological experiments had nothing to do with the discovery of the speech centres. " Bouillard in 1825 collected a series of cases to show that the faculty of speech resided in the frontal lobes. In 1861 his views were brought by Aubertin before the notice of the Anthropological Society of Paris. Broca, who was present at the meeting, had a patient under his care who had been aphasic for twenty-one years, and who was in an almost moribund state. The autopsy proved of great interest, as it was found that the lesion was confined to the left side of the brain, and to what we now call the third frontal convolution. ... In a subsequent series of fifteen typical cases examined, it was found .that the lesion had destroyed, among other parts, the posterior part of the third frontal in fourteen " (Hamilton, Text-Book of Pathology). From this clinical fact, that the movements of speech depend on the integrity of a special area of the brain's surface, and from the facts of " Jacksonian epilepsy ," and similar observations in medicine and surgery, began the experimental work of cerebral localization, by Hitzig, Goltz, Schiff, Ferrier, Yeo, Horsley, Beevor and many more. It would be hard to find a more striking instance of the familiar truth that science and practice work hand in hand.
Again, the experimental method has thrown a flood of light on the minute anatomy of the central nervous system. For example, we have what is called Marchi's method; it was described to the Royal Commission (1906-8) by Dr Head and Sir Victor Horsley. It was found, by Professor Waller, that nerve-fibres, separated from the nerve-cells which nourish them, degenerate in a definite way. The application of this law experimentally has been of great value. " Let me," says Dr Head, " just take a simile. Imagine a wall covered with creepers arising from several stems. If we wished to know from which of these stems any one branch takes its origin, we could cut one stem, and every leaf arising from it would die, marking out among the healthy foliage the offshoots of the divided stem. This is the principle that has been used in tracing the paths in the nervous system. Gpwers, by applying this method, discovered the ascending tracts in the lateral columns of the spinal cord." If a microscopic section of a spinal cord, containing some fibres thus degenerate, be treated with osmic acid (Marchi's method), the degenerate fibres show dark: and in this way their course may be traced at all levels of the cord.
Indeed, it may truly be said that, alike in anatomy and in physiology, the whole present knowledge of the brain, the spinal cord and the nerves, is in great measure due to the use of experiments on animals. And this knowledge is daily applied to the diagnosis and treatment of diseases and injuries of the central nervous system. " In the case of operations on the brain, you have to form your opinion as to what is going on entirely from your knowledge of the physiology of the brain : and that we owe, of course, in the greatest measure to the discoveries of Hitzig and Fritsch and Ferrier. That has all happened since 1870; and we are now able to cure epilepsy, we are able to cure abscess of the brain, and we are able to cure tumours of the brain. Then, in operations on the spinal cord, the same thing prevails. In fact, the first operation on the spinal cord I am responsible for, so that I know the history of the subject. The technique of that operation I owe entirely to experiments on animals. As regards operations on the peripheral nerves. Bell's operative treatment of neuralgia was guided entirely by his experiments on animals. Then we come to the great subject of nerve suture. The initial work bearing upon that subject was carried out by Flourens, who was the first, to my knowledge, to make experiments on animals, to suture nerves together, to investigate their function " (Sir Victor Horsley, evidence before the Royal Commission, vol. iv. p. 124).
[These notes cover a part only of the results that have been obtained in physiology by the help of experiments on animals. The work of Boyle, Hunter, Lavoisier, Despretz, Regnault and Haldane, on animal heat and on respiration; of Petit, Dupuy, Breschet and Reid, on the sympathetic system; of Galvani, Volta, Hafler, du Bois-Reymond and Pfluger, on muscular contraction all these subjects have been left out, and many more. In his evidence before the Royal Commission (1875), Mr Darwin said : " I am fully convinced that physiology can progress only by the aid of experiments on living animals. I cannot think of any one step which has been made in physiology without that aid."] B. PATHOLOGY, BACTERIOLOGY AND THERAPEUTICS 1. Inflammation. Pathology is so intimately associated with the work of the microscope that it is a new study, in comparison with physiology. In 1850 the microscope was not in general use as it is now; nor did men have the lenses, microtomes and staining fluids that are essential to modern histology. Bacteriology, again, is even younger than pathology. In 1875 it had hardly begun to_ exist. For example, in the evidence before the Royal Commission (1875) one of the witnesses said that they " believed they were beginning to get an idea of the nature of tubercle." Anthrax was the first disease studied by the methods of bacteriology ; and in his evidence concerning this disease, Sir John Simon speaks of bacteriology as of a discovery wholly new and unexplored. Then, in 1881, came Koch's discovery of the bacillus of tubercle. But a great advance was made, in days before 1875, by the more general use of the microscope. Every change in the tissues during inflammation the slowing of the blood stream in the capillary vessels, the escape of the leucocytes through their walls into the surrounding tissues, the stagnation of the blood in the affected part all these were observed in such transparent structures as the web or the mesentery of the frog, the bat's wing, or the tadpole's tail, irritated by a drop of acid, or a crystal of salt, or a scratch with a needle. It was in the course of observations of this kind that Wharton Jones observed the rhythmical contraction of veins, and Waller and Cohnheim observed the escape of the leucocytes, diapedesis, through the walls of the capillaries. From these simple experiments under the microscope arose all our present knowledge of the minute processes of inflammation. Later came the work of Metschnikoff and others, showing the importance of dicpedesis in relation to the presence of bacteria in the tissues.
2. Suppuration and Wound- Infection. Practically every case of suppuration, wound-infection or " blood-poisoning," all abscesses, boils, carbuncles, and all cases of puerperal fever, septicaemia, or pyaemia, are due to infection, either from without or from within the body, by various forms of micro-organisms. The same is true of every case of erysipelas, or cellulitis, or acute gangrene in short, of the whole multitude of " septic " diseases. The work done on these micrococci, and on other pathogenic micro-organisms, involved the study of the phases, antagonisms and preferences of each kind, their range of variation and of virulence, their products, and the influences on them of air, light, heat and chemical agents. The beginning of Lister's work was in Pasteur's study of the souring of milk, about 1856. Pasteur's discovery, that lactic fermentation was due to a special micro-organism, opened the way for modern surgery. Lister had been long studying the chemical changes in decomposing blood and other animal fluids; now he brought these studies into line with Pasteur's work. Thus, in 1867, in his first published writing on the antiseptic treatment of compound fractures, he speaks as follows: " We find that a flood of light has been thrown upon this most important subject by the philosophic writing of M. Pasteur, who has demonstrated, by thoroughly convincing evidence, that it is not to its oxygen, or to any o? its gaseous constituents, that the air owes this property (of producing decomposition), but to minute particles suspended in it, which are the germs of various low forms of life long since revealed by the microscope, and regarded.
1 60 as merely accidental concomitants of putrescence; but now shown by Pasteur to be its essential cause." The present antiseptic method includes the aseptic method. That is to say, the instru ments and other accessories of an operation are " sterilized " by heat; and, where heat cannot be applied, as to the patient's skin and the surgeon's hands, antiseptics are used. Modern surgery is both antiseptic and aseptic.
3. Anthrax. The bacillus of anthrax (charbon, malignant pustule, wool-sorter's disease) was the first specific micro-organism discovered. Rayer and Davaine (1850) observed the petits bdtonnets in the blood of sheep dead of the disease; and in 1863, when Pasteur's observations on lactic-acid fermentation were published Davaine recognized that the bdtonnets were not blood crystals but living organisms. Koch afterward succeeded in cultivating the bacillus, and in reproducing the disease in animals by inocula tion from these cultures. Pasteur's discovery of preventive inoculation of animals against the disease was communicated to the Academic des Sciences in February 1881; and in May of that year he gave his public demonstration at Pouilly-le-Fort. Two months later, at the International Medical Congress in London, he spoke as follows of this discovery: "... La m&hode que je viens de vous exposer pour obtenir des vaccins du charbon etait a peine connue quelle passait dans la grande pratique pour prevenir 1'affection charbonneuse. La France perd chaque annee pour une valeur de plus de vmgt millions d'animaux frappes du charbon, plus de 30 millions, m'a dit une des personnes autoris^es de notre Ministere de 1'Agriculture; mais des statistiques exactes font encore dgfaut. On me demanda de mettre a 1'epreuve les resultats qui precedent par une grande experience publique, a Pouilly-le-Fort, pres de Melun. . ._ . Je presume en quelques mots; 50 moutons furent mis a ma disposition, nous en vaccin&mes 25, les 25 autres ne subirent aucun traitement. puinze jours apres environ, les 50 moutons furent inocules par le microbe charbonneux le plus virulent. Les 25 vaccine's resisterent; les 25 non-vaccines moururent, tous charbonneux, en cinquante heures. Depuis lors, dans mon laboratoire, on ne peut plus suffire a preparer assez de vaccin pour les demandes des fermiers. En quinze jours, nous avons vaccine^ dans les ddpartements voisins de Paris pres de 20,000 moutons et un grand nombre de boeufs, de vaches et de chevaux." The extent of this preventive vaccination may be judged from the fact that a single institute, the Sero-Therapeutic Institute of Milan, in a single year (1897-98) sent out 165,000 tubes of anti-charbon vaccine, enough to inoculate 33.734 cattle and 98,792 sheep. In France, during the years 1882-93, more than three million sheep and nearly half a million cattle were inoculated. In the Annales de I'lnstitui Pasteur, March 1894, M. Chamberland published the results of these twelve years in a paper entitled " Resultats pratiques des vaccinations contre le charbon et le rouget en France." The mortality from charbon before vaccination, was 10% among sheep and 5% among cattle, according to estimates made by veterinary surgeons all over the country. With vaccination, the whole loss of sheep was about I %; the average for the twelve years was 0-94. The loss of vaccinated cattle was still less; for the twelve years it was 0-34 or about one-third %. The annual reports sent to M. Chamberland by the veterinary surgeons represent not more than half of the work. A certain number of veterinary surgeons neglect to send their reports at the end of the year. The number of reports that come to us even tends to become less each year. The fact is, that many veterinary surgeons who perform vaccinations every year content themselves with writing, 'The results are always very good ; it is useless to send you reports that are always the same.' We have every reason to believe, as a matter of fact, that those who send no reports are satisfied; for if anything goes wrong with the herds, they do not fail to let us know it at once by special letters."
The following tables, from M. Chamberland's paper, give the results of Pasteur's treatment against charbon during 1882-93, and against rouget (swine-measles) during 1886-92. It is to be noted that the mortality from rouget among swine, in years before vaccination, was much higher than that from charbon among sheep and cattle: "It was about 20%; a certain number of reports speak of losses of 60 and even 80%; so that almost all the veterinary surgeons are loud in their praises of the new vaccination." It would be too much to say that every country, in every year has obtained results with this anthrax-vaccine equal to those which have been obtained in France. Nor would it be reasonable to advocate the compulsory or wholesale use of the vaccine in the British Islands, where anthrax is rare. For the general value of the vaccine, however, we have this striking fact, that the use of it has steadily increased year by year. A note from the Pasteur Institute, dated November 29, 1909, says: " Qepuis 1882 jusqu'au i" Janvier 1909, il a ete expedie, pour la France, 8,400,000 doses de vaccin anti-charbonneux pour moutons, 1,300,000 pour boeufs. Pour letranger, 8,500,000 doses pour moutons, 6,200,000 pour boeufs. Le nombre de doses augmente d'annee en annee, de sorte que pour I annee 1908 seule il faut compter en tout 1,500,000 doses pour moutons (France et dtranger) 1,100,000 pour bceufs." (Two doses are used for each animal.) It remains to be added that a serum treatment, introduced by Sclavo, has been found of considerable use in cases of anthrax (malignant pustule) occurring in man.
4. Tubercle. Laennec, who in 1816 invented the stethoscope, recognized the fact that tubercle is a specific disease, not a simple degeneration of the affected tissues. Villemin, in 1865, communicated to the Academic des Sciences the fact that he had produced the disease in rabbits by inoculating them with tuberculous matter; a u 1 appealed to these inoculations en voici les premies to how that La tuberculose est une affection specifique: Sa cause reside dans un agent inoculable: L'inoculation se fait tres-bien de I'homme au lapin: La tuberculose appartient done a la, classe des maladies inrulentes. In 1868 Chauveau produced the disease not by inoculalon but by admixture of tuberculous matter with the animals' ood. In 1880, after a period of some uncertainty and confusion of doctrines, Cohnheim reaffirmed the infectivity of the disease, and even made the proof of tubercle depend on inoculation alone : " everything is tuberculous that can produce tuberculous disease by inoculation in animals that are susceptible to the disease; and nothing is tuberculous that cannot do this." In 1881 Koch discovered the tubercle bacillus, and, in spite of the tragic failure of his uilHTculin in 1890-91, a vast amount of practical advantage has already issued out of Koch's discovery, both by way of cure and by of prevention. It has been proved, by experiment on animals, that the sputa of phthisical patients are infective; and this and the like facts have profoundly influenced the nursing and general care ich cases. Bacteriology has brought about (under the safeguard of modern methods of surgery) a thorough and early surgical ment of all primary tuberculous sores or deposits the excision of tuberculous ulcers, the removal of tuberculous glands and the like. It has helped us to make an early diagnosis, in obscure cases, by finding tubercle bacilli in the sputa, or in the discharges, or in a particle of the tissues. It has proved, past all reasonable doubt, that tabes mesenterica, a disease that kills every year in England alone many thousands of children, may arise from infection of the bowels by the milk of tuberculous cows. And it has helped to bring about the present rigorous control of the milk trade and the meat trade.
The " new tuberculin," now that the use of the opsonic index has guided physicians to a better understanding of the tuberculin treatment, has been found of great value, and is giving excellent results in suitable cases. Moreover, tuberculin is used, tecause of the reaction that it causes in tuberculous animals, as a test for the detection of latent tuberculosis in cattle. An injection of one to two cubic centimetres under the skin of the neck is followed by a hi^h temperature if the animal be tuberculous. If it be not, there is no rise of temperature, or only a very slight rise. For example, in 1899 this test was applied to 270 cows on farms in Lancashire: 180 reacted to the test, 85 did not, 5 were " doubtful." Tuberculous disease was actually found in 175 out of the 180. Eber of Dresden used the test on I?A animals, of whom 136 reacted, 32 did not react and 6 were doubtful. Of the 136, 22 were slaughtered, and were all found to have tubercle; of the 32, 3 were slaughtered, and were found free. The opinion of Professor M'Fadyean, one of the highest authorities on the subject, is as follows: I have most implicit faith in tuberculin as a test for tuberculosis when it is used on animals standing in their own premises and undisturbed. It is not reliable when used on animals in a market or slaughter-house. A considerable number of errors at first were found when I examined animals in slaughter-houses after they had been conveyed there by rail, etc. Since that, using it on animals in their own premises, I have found that it is practically infallible. I have notes of one particula- case where 25 animals in one dairy were tested, and afterwards all were killed. There was only one animal which did not react, and it was the only animal not found to be tuberculous when killed." This test has now been in regular use for many years in many countries, and it is accepted everywhere as of national importance.
5. Diphtheria. The Bacillus diphtheriae (Klebs-Loffler bacillus) was described by Klebs in 1875, and obtained in pure culture by Loffler in 188^. Behring and Kitasato, in 1890, succeeded in immunizing animals against the disease. The first cases treated with diphtheria antitoxin were published in 1893 by Behring, Kossel and Hiibner. In England the antitoxin treatment was begun in the latter part of 1894. Besides its curative use, the antitoxin has also been used as a preventive, to stop an outbreak of diphtheria in a school or institute or hospital or village, and with admirable success. (See DIPHTHERIA.)
6. Tetanus (lock-jaw). Experiments on animals have taught us the true nature of this disease, and have led to the discovery of an antitoxin which has given fairly good results. We possess, moreover, a preventive treatment against the disease; though, unfortunately, the time of latency, when the antitoxin is most needed, cannot be recognized. The old, mischievous doctrine that tetanus was due to acute inflammation of a nerve, tracking up from a wound to the central nervous system, was abolished once and for ever by Sternberg (1880), Carle and Rattone (1884) and Nicolaier (1884), who proved that the disease is due to infection by a specific flagellate organism in superficial soil. " It is said to be present in almost all nch garden soils, and that the presence of horse-dung favours its occurrence. There seems to be no doubt as to the ubiquity of the tetanus germ " (Poore, Milroy Lectures, 1899). The work of discovering and isolating the bacillus was full of difficulty. Nicolaier, starting from the familiar fact that the disease mostly comes from wounds or scratches contaminated with earth, studied the various microbes of the soil, and inoculated rabbits with garden mould. He produced the disease, and succeeded in finding and cultivating the bacillus, but failed to obtain a pure culture. Kitasato, in 1899, obtained a pure culture. Others studied the chemical products of the bacillus, and were able to produce the symptoms of the disease by injection of these chemical products obtained from cultures, or from the tissues in cases of tetanus. It has been proved that the infection tends to remain local; that the bacilli in and near the wound pour thence into the xxvm. 6 blood their chemical products, and that these have a selective action, like strychnine, on the cells of the central nervous system. Therefore the rule that the wounded tissues should be at once excised, in all cases where this can possibly be done, has received confirmation. Before Nicolaier, while men were still free to believe that tetanus was the result of an acute ascending neuritis, this rule was neither enforced nor explained.
As a preventive against tetanus, in man or in animals, the antitoxin has proved of the very utmost value. This has been shown in a striking way in America- " One of the wounds most commonly followed by lock-jaw is the blank-cartridge wound of the hand common on the glorious Fourth of July. The death-rate from these wounds is appalling. An active campaign has been conducted throughout the medical profession to reduce this mortality. All over the country, surgeons and medical journals have advised the injection of tetanus antitoxin in every case of blank-cartridge wound. The American Medical Association has compiled statistics of Fourth of July fatalities for the past six years. In 1903, the Fourth of July tetanus cases numbered 416. Then physicians began a more general use of antitoxin in all cases of blank-cartridge and common cracker wounds. As a result of this campaign of prophylaxis by antitoxin injections, from 416 cases of tetanus in 1903 the number dropped to 105 cases in 1904, 104 cases in 1905, 89 cases in 1906, 73 cases in 1907 and 55 cases in 1908. This reduction in the number of tetanus cases took place while the number of accidents remained practically the same each year, and while the number of deaths from causes other than tetanus was steadily rising from 60 in 1903 to 108 in 1908. It is thus evident that the saving of at least 300 lives from tetanus has been accomplished each year through the prophylactic use of antitoxin in the cases of Fourth of July wounds alone " (James P. Warbasse, M.D., The Conquest of Disease through Animal Experimentation, Appleton & Co., 1910).
The preventive use of the serum in veterinary practice has yielded admirable results. In some parts of the world tetanus is terribly common among horses. Nocard of Lille has reported as follows: " The use of anti-tetanus serum as a preventive has been in force for some years in veterinary practice in cases of wounds or surgical procedures. To this end the Pasteur Institute has supplied 7000 doses of anti-tetanus serum, a dose being 10 cubic centimetres; a quantity which has sufficed to treat preventively 3100 horses in those parts of the country where tetanus is endemic. Among these there has been no death from tetanus. In the case of one horse, injected five days after receiving a wound, tetanus devejoped, but the attack was slight. During the same time that these animals were injected, the same veterinary surgeon observed, among animals not treated by injection, 259 cases of tetanus " (Lancet, August 7, 1897).
7. Rabies (hydrophobia). The date of the first case treated by Pasteur's preventive method Joseph Meister, an Alsatian shepherdboy is July 1885. The existence of a specific micro-organism of rabies was a matter of inference. The incubation period of the disease is so variable that no preventive treatment was possible unless this incubation period could be regulated. Inoculations of the saliva of a rabid animal, introduced under the skin of animals, sometimes failed; and if they succeeded, the incubation period of the disease thus induced was hopelessly variable. Next, Pasteur used not saliva, but an emulsion of the brain or the spinal cord; because the central nervous system is the chief seat of the poison. But this emulsion, introduced under the skin, was also uncertain in action, and gave no fixed incubation period. Therefore, he argued, as the poison has a selective action on the nerve cells of the central nervous system, and a sort of natural affinity with them, it must be introduced directly into them, where it will have its proper environment; the emulsion must be put not under the skin, but under the dura mater (the membrane enveloping the brain). These subdural inoculations were the turning-point of his work. By transmitting the poison through a series of rabbits, by subdural inoculation of each rabbit with a minute quantity of nerve tissue from the rabbit that had died before it, he was able to intensify the poison, to shorten its period of incubation, and to fix this period at six days. Thus he obtained a poison of exact strength, a definite standard of virulence, virus fixe: the next rabbit inoculated would have the disease in six days, neither more nor less. By gradual drying, after death, of the cords of rabid animals, he was able to attenuate the poison contained in them. The spinal cord of a rabbit that has died of rabies slowly loses virulence by simple drying. A cord dried for four days is less virulent than a cord dried for three, and more virulent than a cord dried for five. A cord dried for a fortnight has lost all virulence; even a large dose of it will not produce the disease. By this method of drying, Pasteur was able to keep going one or more series of cords, of known and exactly graduated strengths, according to the length of time they had been dried, ranging From absolute non-virulence through every shade of virulence.
As with fowl cholera and anthrax, so with rabies: the poison, attenuated till it is innocuous, can yet confer immunity against a stronger dose of the same poison. A man, bitten by a rabid animal, has at least some weeks of respite before the disease can break out ; and during that time of respite he can be immunized against the disease, while it is still dormant. He begins with a dose of poison attenuated past all power of doing harm, and advances day by day to more active doses, guarded each day by the dose of the day before, till he has manufactured within himself enough antitoxin to make him proof against any outbreak of the disease. (See HYDROPHOBIA.)
8. Cholera. The specific organism of Asiatic cholera, the "comma-bacillus," was discovered by Koch in 1883; but such a multitude of difficulties arose over it that it was not universally recognized as the real cause of the disease before 1892, the year of the epidemic at Hamburg. The discovery of preventive inoculation was the work of many men, but especially of Haffkine, one of Pasteur's pupils. Ferran's earlier inoculations in Spain (1885) were a failure. Haffkine's first inoculations were made in 1893. At Agra, in April 1893, he vaccinated over 900 persons; and from Agra went to many other cities of India. Altogether, in twentyeight months (April 1893~July 1895) no less than 42,179 persons were vaccinated (many of them twice} in towns, cantonments, gaols, tea estates, villages, schools, etc., " without having to record a single instance of mishap or accident of any kind produced by our vaccines." (See CHOLERA.)
9. Bubonic Plague. The Bacillus pestis was discovered in 1894 by Kitasato and Yersin, working independently. The preventive treatment was worked out by Haffkine in 1896: " Twenty healthy rabbits were put in cages. Ten of them were inoculated with Haffkine's plague vaccine. Then both the vaccinated rabbits and the other ten rabbits that had not been vaccinated were infected with plague. The unprotected rabbits all died of the disease, and in their bodies innumerable quantities of the microbes were found. But the vaccinated rabbits remained in good health. Professor Haffkine then vaccinated himself and his friends. This produced some fever, from which, after a day or two, they recovered. Plague broke out in Byculla Gaol, in Bombay, in January 1897. About half the prisoners volunteered to be inoculated. Of these, 3 developed plague on the day of inoculation, and it is probable that they had already plague before the treatment was carried out. Of the remaining 148 who were inoculated, only 2 were afterwards attacked with plague, and both of them recovered. At the same time, of the 173 who had not been vaccinated, 12 were attacked, and out of these 6 died." (See PLAGUE.)
10. Typhoid Fever. The Bacillus typhosus was discovered by Klebs, Eberth and Koch in 1 880-81. The first protective inoculations in England were made at Netley Hospital in 1896 by Sir Almroth Wright and Surgeon-Major Semple: 1 6 medical men and 2 others offered themselves as subjects. The first use of the vaccine during an actual outbreak of typhoid was in October 1897 at the Kent County Asylum: " All the medical staff and a number of attendants accepted the offer. Not one of those vaccinated 84 in number contracted typhoid fever; while of those unvaccinated, and living under similar conditions, 16 were attacked. This is a significant fact, though it should in fairness be stated that the water was boiled after a certain date, and other precautions were taken, so that the vaccination cannot be said to be altogether responsible for the immunity. Still, the figures are striking " (Lancet, March 1898). In 1899 Wright vaccinated against typhoid more than 3000 of the Indian army, at Bangalore, Rawal Pindi and Lucknow. Government has now sanctioned voluntary inoculation against typhoid, at the public expense, among the British troops. " All regiments leaving for the tropics are offered this inoculation, and each year a larger percentage of the soldiers are accepting it. Here are some of the statistics: In August and September 1905, 150 men of a single regiment were inoculated: of these, 23 refused to accept a second inoculation. The regiment reached India, September 28. A month later, typhoid fever broke out; and during the following few months 63 cases were observed in the regiment. With but two exceptions, the disease attacked only the men who had not been inoculated, and both of these exceptions were men who had refused a second inoculation. Careful experiments were made with the second battalion of Royal Fusiliers in India in 1905 and 1906. The average strength of this regiment was 948 men. During the two years, 284 were inoculated with Wright's anti-typhoid vaccine. The regiment had a total of 46 cases of typhoid. Thirty-five of these were men who had not been inoculated ; 9 had been inoculated. Five of the uninoculated died ; none of the inoculated died. Another Indian regiment, the 17th Lancers, in 1905, 1906 and 1907 inoculated about one-third of its men. During the three years it had 293 cases of typhoid fever. There were 44 deaths, with not a single death of an inoculated man. During the first half of 1908, in the largest seven Indian stations where careful records were kept, out of a total of 10,420 soldiers, 2207 volunteered for inoculation. Typhoid developed in 2% of the uninoculated, and in less than I % of the inoculated men. Forty-five deaths occurred. Five per cent of these deaths were among the uninoculated and I % was among the inoculated men. ... In the United States army, a medical board has strongly recommended anti-typhoid vaccinations, and vaccination is now offered to those who desire it. Already 2000 soldiers have voluntarily received inoculation. The German army has adopted the same means of prophylaxis, and is pushing it vigorously " (Warbasse, loc. tit.).
Beside the preventive treatment, bacteriology has given us " Widal's reaction " for the early diagnosis of the disease a matter of the very highest practical importance. A drop of blood, from the finger of a patient suspected to be suffering from typhoid fever, is diluted fifty or more times, that the perfect delicacy of the test may be ensured; a drop of this dilution is mixed with a nutrient fluid containing living bacilli of typhoid, and a drop of this mixture is observed under the microscope. The motility of the bacilli is instantaneously or very quickly arrested, and in a few minutes the bacilli begin to aggregate together into clumps. This " clumping " is also made visible to the naked eye by the subsidence of the agglutinated bacilli to the bottom of the containing vessel. The amazing delicacy of " Widat's test " is but a part of the wonder. Long after recovery, a fiftieth part of a drop of the blood will still cause clumping: it has even been obtained from an infant whose mother had typhoid shortly before the child was born. A drop of blood from a case suspected to be typhoid can now be sent by post to be tested a hundred miles away, and the answer telegraphed back.
11. Malta Fever (Mediterranean fever). The Micrococcus Melitensis was discovered in 1887 by Sir David Bruce. The work of discovering and preparing an immunizing serum was done at Netley Hospital. In this fever, as in typhoid and some others, Widal's test is of great value: " The diagnosis of Malta fever from typhoid is, of course, a highly important practical matter. It is exceedingly difficult in the early stages" (Manson). Even in a dilution of I in looo, the blood of Malta fever can give the typical reaction with the Micrococcus Melitensis; and this occurred in a case at Netley of accidental inoculation with Malta fever: one of three cases that have happened there. The case is reported in the British Medical Journal, October 16, 1897: " It appears that he had scratched his hand with a hypodermic needle on September 17, when immunizing a horse for the preparation of serum-protective against Malta fever; and his blood, when examined, had a typical reaction with the micrococcus of Malta fever in looo-fold dilution. The horse, which has been immunized for Malta fever for the last eight months, was immediately bled, and we are informed that the patient has now had two injections, each of 30 cub. cm. of the serum. He is doing well, and it is hoped that the attack has been cut short." About 50 cases of the fever, by April 1899, had been treated at Netley. The Lancet, April 15, 1899, says that the treatment was "with marked benefit: whereas they found that all drug treatment failed, the antitoxin treatment had been generally successful." Happily, it has now been proved that the usual source of infection with Malta fever is the drinking of the milk of infected goats: thus, by the avoidance, or by the careful and thorough boiling of the milk, the fever may be prevented: and prevention is better than cure. In 1904 a commission was sent out to Malta by the Royal Society, at the request of our government, to discover how the fever is conveyed to man. They found that it is not conveyed by air, or by drinkingwater, or by pollution of sewage, or by contact; nor are its germs carried, like those of malaria, yellow fever and sleeping sickness, by insects. They found that it might be conveyed in food. Therefore Bruce examined the milch-goats, since goats' milk is universally drunk in Malta. The goats looked healthy enough, but it was found that the blood of 50% of them gave the Widal reaction, and that some 10% of them were actively poisonous: monkeys fed on milk from one of them, even for one day, almost invariably got the disease. On the 1st of July 1906, an official order was issued forbidding the supply of goats' milk to our garrison. The year before, there had been 643 cases among our soldiers alone. In 1906, up to the 1st of July, there were 123 cases. During the rest of the year, including the three worst months for the fever, there were 40 cases. In 1907 there were II cases; in 1908 there were 5 cases; in 1909 there was i case; in 1910, by latest accounts, none.
12. Epidemic Meningitis. The history of the serum treatment of epidemic meningitis affords an admirable example of the place of experiments on arimals in the advancement of medical practice. This form of meningitis is one of the worst ways in which a man can die. Dr Robb, who had charge of the Belfast fever hospitals during an epidemic in Belfast, calls it " the most terrible in its manifestations, and the most disastrous in its death-rate, of all the epidemic diseases met with in Eng'ish-speaking countries." Very little is known as to the way in which it spreads, and the public health authorities cannot prevent its sudden appearance in a town. " Many of those attacked," says Dr Robb, " died within a few hours of the onset, and that after terrible suffering; while many of those who survived the acute attack lingered on for weeks and months, going steadily downhill in spite of every effort to save them. Again, many of those who did survive were left permanently maimed." That is the usual picture of the disease when it is left to the older methods of treatment.
By means of inoculation experiments, Dr Flexner and Dr Jobling, of the Rockefeller Institute, proved that the disease is due to a particular kind of germ, diplococcus intracellularis. They obtained these germs from the bodies of patients who had died of the disease; they cultivated the germs all by themselves, in test tubes, apart from all other kinds of germs; and they were able to reproduce the disease in monkeys by injecting under the skin a minute quantity of this pure culture of the germs. It may be worth noting that the disease in monkeys is less violent and less painful than it is in man. By the help of these experiments, Flexner and Jobling WITI- able to prepare a serum for the treatment of the disease, in the ^.irne way as the serum is prepared which has been such a ing to the world in cases of diphtheria. This serum for the tri'.itment of epidemic meningitis was first used in the spring of 1907.
The contrast between cases without serum treatment and cases ith serum treatment is very plain. We may first give the records fore the use of the serum. Of 4000 cases in New York in 1904, % died; Baker reports from Greater New York 2113 cases with 36 deaths, giving 77-4% mortality; Chalmers reports from _ilasgow (1907) 998 cases with 683 deaths, giving 68-4% mortality; Bailie reports in Belfast (1907) 623 cases with 493 deaths, giving ,, mortality; Ker reports that in the Edinburgh epidemic there -S% mortality; Robertson reports from Leith (1907) 62 cases ith 74-4% mortality; Tumour reports from the Transvaal 200 ~ises with 74% mortality. Amongst patients treated in hospitals Vath-rate was no better. Of 202 cases in Ruchill Hospital, ,ow, 79-2% died; of 108 cases in Edinburgh Fever Hospital, 80-5 % died; of 275 cases in Belfast Fever Hospital, 72-3% died; and Dunn reports that in the Boston Children's Hospital, during the years 1899-1907, the mortality varied from 69% to 80%. ,ist with these the results in cases treated with Flexner's and Jobling's Serum:
-'- s*' cases Cases.
Mortality per cent.
Citv Hospital, Cincinnati.
3I-I Dr Dunn, Boston ....
22-5 Johns Hopkins Hospital, Baltimore . Rhode Island Hospital 22 17 4 6 18-1 35-2 Lakeside Hospital, Cleveland .
37-7 Edinburgh Fever Hospital 1zz 3-3 Mount Sinai Hospital (Children)
13-3 Municipal Hospital, Philadelphia 42-7 Belfast Fever Hospital 1zz 9-6 These figures speak for themselves. Similar results have been obtained with similar treatment in France and Germany. " From these figures," says Dr Robb, " it will be seen that the death-rate in cases not treated with serum averaged some 75%. This has been reduced in cases treated with the serum to less than half, and in many instances much below that figure." " My own experience has been that of 275 cases under my care in hospital, before the use of the serum was commenced, 72-3% died; while of the 98 cases treated with serum 29-6% died. No selection of cases was made: every case sent into hospital since September 1907 has been treated in this way. No change in the severity of the attack was observed : in the three months immediately before the serum arrived with us 45 cases came under treatment, of whom 37, or 82 %, died ; and in the first four months after we began its use in hospital 30 cases were treated, of whom 8 died, a mortality of 26-6%; while of the 34 cases occurring in the city in the same period, but not sent into hospital, and not treated with the serum, over 80% died. Great as this change in the death-rate has been, it is not more striking than the improvement in the course run by the cases; for whereas it was common to have cases running on into weeks and even months, such cases are no longer met with " (R. D. S. pamphlet, 1909).
13. Malaria. Laveran, in 1880, discovered the Plasmodium malariae, an amoeboid organism, in the blood of malarial patients. In 1894 Manson took, as a working theory of malaria, the old belief that the mosquito is the intermediate host of the parasite. In 1895 came MacCullum's observations on an allied organism, Halteridium. In 1897, after two years' work, Ross found bodies, pigmented like the Plasmodium, in the outer coat of the stomach of the grey or " dapple-winged " mosquito, after it had been fed on malarial blood. In February 1898 he started work in Calcutta: "Arriving there at a non-fever season, he took up the study of what may be called ' bird malaria.' In birds, two parasites have become well known (l) the Halteridium, (2) the Proteosoma of Labbe 1 . Both have flagellate forms, and both are closely allied to the Plasmodium malariae. Using grey mosquitoes and protepsoma-infected birds, Ross showed by a large number of observations that it was only from blood containing the proteosoma that pigmented cells in the grey mosquito could be got; therefore that this cell is derived from the proteosoma, and is an evolutionary stage of that parasite " (Manson, 1898). These pigmented cells give issue to innumerable swarms of spindle-shaped bodies, " germinal rods "; and in infected mosquitoes Ross found these rods in the glands of the proboscis. Finally, he completed the circle of development, by infecting healthy sparrows by causing mosquitoes to bite them. It would be hard to surpass Ross's work, and that done in Italy by Grass! and others, for fineness and carefulness. He says, for instance, " out of 245 grey mosquitoes fed on birds with proteosoma, 178, or 72%, contained pigmented cells; out of 249 fed on blood containing halter- idium, immature proteosoma, etc., not one contained a single pigmented cell. . . . Ten mosquitoes fed on the sparrow with numerous proleosoma contained 1009 pigmented cells, or an average of 101 each. Ten mosquitoes fed on the sparrow with moderate proteosoma contained 292 pigmented cells, or an average of 29 each. Ten mosquitoes fed on the sparrow with no proteosoma contained no pigmented cells."
By these and the like observations it was made practically certain that malaria is transmitted from man to man by a special kind of mosquito. Then came the final experiments on man. In 1900 Sambon, Low and Terzi made their famous experiment on themselves in the neighbourhood of Ostia. They put up a little mosquitoproof hut in a neighbourhood " saturated with malaria." In this little hut they lived through the whole of the malaria season, without taking a grain of quinine, and not one of them had a touch of the fever. Then another experiment was made. A consignment of mosquitoes containing blood from a case of malaria was sent from Rome to the London School of Tropical Medicine. Dr Manson and Dr Warren then submitted themselves to being bitten by these mosquitoes, and in due time suffered malarial fever. On these proven facts was founded the whole plan of campaign against malaria. The nature, habits and breeding-places of the mosquito of malaria (Anopheles maculipennis) have been studied with infinite care, and are now thoroughly recognized. The task is to destroy its eggs and its larvae, to break the cycle of its life, and to do away with its favourite breeding-places.
14. Yellow Fever. A special mosquito (Slegomyia) conveys yellow fever from man to man. The germ, like the germ of rabies, has not yet been made visible under the microscope. It is probably a very minute spirochaete, which undergoes a slow evolution in the body of the mosquito told off for that purpose. The earlier experiments (1810-20) made on themselves by Chervin, Potter, Firth and others were truly heroic, but provecf nothing. Finlay (1880- 1900) experimented with mosquitoes on himself and other volunteers, and certainly proved the transmissibility of the fever through mosquitoes. Sanarelli (1898) prepared an immunizing serum which gave good results: but the germ which he took to be the specific cause of the fever, having found it in cases cf the fever, is not now accepted by bacteriologists as specific. But the great work, which proved to the world the way of infection of yellow fever, was done by the Army Commission of the United States (1900). This Commission was sent to Havana, and the experiments were carried out by Drs Walter Reed, Carrol, Lazear and Agrampnte in the Army Camp in Havana. A hut was constructed with two compartments, divided from each other by a wire mosquito-proof screen. In one compartment they placed infected mosquitoes, which had bitten a yellow fever patient within the first three days of the fever. More than twenty volunteers offered themselves for experiment. In one set of experiments, clothing and other material, soiled by the vomit or blood or excretions from cases of the fever, were placed in one of the rooms, and some of the experimenters slept for 21 consecutive nights in contact with these materials, and in some cases in the very sheets on which yellow fever patients had died. Not one of these experimenters took the fever. In another set of experiments, 22 of the experimenters submitted themselves to be bitten by the infected mosquitoes, and in each instance they took the disease. It was thus proved, past all reasonable doubt, that yellow fever cannot be conveyed by ordinary infection, but must be transmitted from man to man through the agency of the mosquito. It might be said, by the opponents of all experiments on animals, that the discovery of these facts has nothing to do with " vivisection." But, as Professor Osier said in his evidence before the Royal Commission (vol. iv. p. 158), these experiments would never have been thought of if it had not been for previous experiments on animals. " The men who made these investigations spent their lives in laboratories, and their whole work has been based on experimentation on animals. They could not otherwise, of course, have ventured to devise a series of experiments of this sort." Out of this work came the wiping out of yellow fever (q.v.) from Cuba after the Spanish- American War, and from the area of the Panama Canal.
15. Sleeping-Sickness. Experiments on animals have proved that sleeping-sickness is due to specific germs carried by tse-tse flies from man to man. By measures taken to prevent this way of infection, legions of human lives have been saved or safeguarded.
16. Infantile Paralysis. Flexner, of the Rockefeller Institute, has proved, by experiments on animals, the infective nature of this disease, and its transmissibility by inoculation: a discovery of the very utmost value and significance.
17. Myxoedema. Our knowledge of myxoedema, like our knowledge of cerebral localization, began not in experimental science but in clinical observation (Gull, 1873; Ord, 1877). In 1882- 1883 Reverdin and Kocher published cases where removal of the thyroid gland for disease (goitre) had been followed by symptoms such as Gull and Ord had (described. In 1884 Horsley, by removal of the thyroid gland of monkeys, . produced in them a chronic myxoedema, a cretinoid state, the exact image of the disease in man: the same symptoms, course, tissue-changes, mental and physical hebetude, the same alterations of the excretions, the temperature and the voice. In 1888 the Clinical Society of London published an exhaustive report, of 215 pages, on 119 cases of th disease, giving all historical, clinical, pathological, chemical an< experimental facts; but out of 215 pages there is but half a pag about treatment, of the useless old-fashioned sort. In 1890 Horslej published the suggestion that a graft of thyroid gland from a newly killed animal should be transplanted beneath the skin in cases of myxoedema: " The justification of this procedure rested on the remarkable experiments of Schiff and von Eisselsberg. I onlbecame aware in April 1890 that this proposal had been in fac forestalled in 1889 by Dr Bircher in Aarau. Kocher had tried t( do the same thing jn 1883, but the graft was soon absorbed; bu early in 1889 he tried it again in five cases, and one greatly im proved." In 1891 George Murray published his Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract of th Thyroid Gland of a Sheep. Later, the gland was administered in food At the present time tabloids of thyroid extract are given. We coulc not have a better example how experiments on animals are necessary for the advancement of medicine. Now, with little bottles of tabloids men and women are restored to health who had become degenerati in body and mind, disfigured and debased. The same treatmen has given back mental and bodily growth to countless cases o sporadic cretinism. Moreover, the action of the thyroid gland has been made known, and the facts of " internal secretion " have been in part elucidated. (Claude Bernard, speaking of the thyroid the thymus anc 1 the suprarenal capsules, said : " We know abso lutely nothing about the functions of these organs; we have not so much as an idea what use and importance they may possess because experiments have told us nothing about them, and anatomy left to itself, is absolutely silent on the subject.")
18. The Action of Drugs. Even in the 18th century medicine was still tainted with magic and with gross superstition: the 1721 Pharmacopoeia contains substances that were the regular stock-in-trade of witchcraft. Long after 1721 neither clinica observation, nor anatomy, nor pathology brought about a reasonable understanding of the action of drugs: it was the physiologists, more than the physicians, who worked the thing out Bichat, Magendie, Claude Bernard. Magendie's study of upas and strychnine, Bernard's study of curare and digitalis, revealed the selective action of drugs: the direct influence of strychnine on the central nerve-cells, of carare on the terminal filaments of motor nerves.
Two instances may be given how experiments on animals have elucidated the action of drugs. A long list might be made aconite, belladonna, chloride of calcium, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics all these and many more have been studied to good purpose by this method; but it must suffice to quote here (i) Sir Thomas Eraser's account of digitalis, and (2) Sir Thomas Lauder Brunton's account of nitrite of amyl :
" i. Digitalis was introduced as a remedy for dropsy; and on the applications which were made of it for the treatment of that disease, a slowing action upon the cardiac movements was observed, which led to its acquiring the reputation of a cardiac sedative. . . . It was not until the experimental method was applied in its investigation, in the first instance by Claude Bernard, and subsequently by Dybkowsky, Pelikan, Meyer, Bohm and Schmiedeberg, that the true action of digitalis upon the circulation was discovered. It was shown that the effects upon the circulation were not in any exact sense sedative, but, on the contrary, stimulant snd tonic, rendering the action of the heart more powerful, and increasing the tension of the blood vessels. The indications for its use in disease were thereby revolutionized, and at the same time rendered more exact; and the striking benefits which are now afforded by the use of this substance in most (cardiac) diseases were made available to humanity."
" 2. In the spring of 1867 I had opportunities of constantly observing a patient who suffered from angina pectoris, and of obtaining from him numerous sphygmographic tracings, both during the attack and during the interval. These showed that during the attack the pulse became quicker, the blood-pressure rose and tne arterioles contracted. ... It occurred to me that if it was possible to diminish the tension by drugs instead of by bleeding, the pain would be removed. I knew from unpublished experiments on animals by Dr A. Gamgee that nitrite of amyl had this power, and therefore tried it on the patient. My expectations were perfectly answered."
19. Snake Venom. Sewall (1887) showed that animals could be immunized, by repeated injection of small doses of rattlesnake's yenom,_ against a sevenfold fatal dose. Kanthack (1891) immunized animals against cobra venom : afterward Fraser, Calmette and many others worked at the subject. Eraser's work on the antidotal properties of the bile of serpents is of the very highest interest and value, both _ in physiology and in serp-therapy. Calmette's work is an admirable instance of the delicacy and accuracy of the experimental method. The different venoms were measured in decimal milligrammes, and their action was estimated by the body-weights of the animals inoculated ; but of course this estimate of _ virulence was checked according to the susceptibility of the animals; guinea-pigs, rabbits and especially rats being more susceptible than dogs.
" The following table gives^the relative toxicity, for i kilogramme of rabbit, of the different venoms that I have tested " :
1. Venom of Naja . . . . 0-25 milligramme per kilogramme of rabbit. One gramme of this venom kills 4000 kilogrammes of raBbit: activity = 4,000,000.
2. Venom of Hoplocephalus . . 0-29 . 3,450 ooo 3. Venom of Pseudechis . . .1-25 '. 'gooiooo' 4. Venom of Pelias herus . . 4-00 . 250,000.
By experiments in vitro Calmette studied the influence of heat and chemical agents on these venoms; and, working by various methods, was able to immunize animals:
I have got to immunizing rabbits against doses of venom that are truly colossal. 1 have several, vaccinated more than a year ago, that take without the least discomfort so much as forty milligrammes of venom of Naja tripudians at once. Five drops of serum from these rabbits wholly neutralize in vitro the toxicity of one milligramme of Naja venom. ... It is not even necessary that the serum should come from an animal vaccinated against the same sort of venom as that in the mixture. The serum of a rabbit immunized against the venom of the cobra or the viper acts it differently on all the venoms that I have tested."
In 1895 he had prepared a curative serum: " If you first inoculate a rabbit with such a dose of venom as kills the control-animals in three hours; and then, an hour after injecting the venom, inject under the skm of the abdomen four to five cubic centimetres of serum, recovery is the rule. When you interfere later than this, the results are uncertain; and out of all my experiments the delay of an hour and a half is the most that I have been able to reach."
In 1896 four successful cases were reported in the British Medical Journal. In 1898 Calmette reports:
"It is now nearly two years since the use of my anti venomous serum was introduced in India, in Algeria, in Egypt, on the West Coast of Africa, in America, in the West Indies, Antilles, etc. It has been very often used for men and domestic animals (dogs, horses, oxen), and up to now none of those that have received an injection of serum have succumbed. A great number of observations have been communicated to me, and not one of them refers to a case of failure " (Brit. Med. Journ., May 14, 1898; see also Boston Medical and Surgical Journal, April 7, 1898).
It is of course impossible that " antivenene " should be always at hand, or that it should bring about any great decrease in the number of deaths from snake-bite, which in India alone are 30,000 annually ; but at least something has been accomplished with it.
The account given above of the chief discoveries that have been made by the help of experiments on animals, in physiology, pathology, bacteriology and therapeutics, might easily have been lengthened if we added to it other methods of treatment that owe less, but yet owe something, to these experiments. Nevertheless the facts quoted in this article are sufficient to indicate the great debt that medicine owes to the employment of vivisection. (S. P.)
Note - this article incorporates content from Encyclopaedia Britannica, Eleventh Edition, (1910-1911)