"There is a perfect water supply, and people can get their water fresh from the standpipes at their doors. Old wells ought to be filled up; no water-barrels or tubs should be allowed, or, if kept, they should be emptied every week or so. Tanks and collections of water in gardens should all be periodically treated with kerosene, or be furnished with closely-fitting covers to prevent mosquitoes getting in. These methods are simple and inexpensive, and each householder should see that they are applied in his garden and grounds. The difficulty begins when one has to take into account the inability of the negro to grasp anything of a hygienic nature. The only way to get over this, would be a system of sanitary inspection by a few competent men. For individual prophylaxis, mosquito-nets ought always to be used; but many, even educated people, still persist in sleeping without them; of course, nothing in this line can be expected of the native population."If such means were adopted for Barbadoes, the presence of filarial disease, which at present is quite alarming, could easily, with little trouble and expense, be greatly diminished, and thus save much suffering, as well as loss of time, hideous deformity, and doubtless in not a few instances loss of life."
"There is a perfect water supply, and people can get their water fresh from the standpipes at their doors. Old wells ought to be filled up; no water-barrels or tubs should be allowed, or, if kept, they should be emptied every week or so. Tanks and collections of water in gardens should all be periodically treated with kerosene, or be furnished with closely-fitting covers to prevent mosquitoes getting in. These methods are simple and inexpensive, and each householder should see that they are applied in his garden and grounds. The difficulty begins when one has to take into account the inability of the negro to grasp anything of a hygienic nature. The only way to get over this, would be a system of sanitary inspection by a few competent men. For individual prophylaxis, mosquito-nets ought always to be used; but many, even educated people, still persist in sleeping without them; of course, nothing in this line can be expected of the native population.
"If such means were adopted for Barbadoes, the presence of filarial disease, which at present is quite alarming, could easily, with little trouble and expense, be greatly diminished, and thus save much suffering, as well as loss of time, hideous deformity, and doubtless in not a few instances loss of life."
Thus, in a few years, from experiments on mosquitoes, sparrows, and men, has come the present plan of campaign against malaria, yellow fever, and filariasis; that is, againstAnophelesandCulex. He who would know what is being done to check these diseases in Italy, India, China, Africa, and America, must read Prof. Ross'Malarial Fever, its Cause, Prevention, and Treatment(1902), andMosquito Brigades, and how to organise them(1902). There has been nothing like it since Pasteur died. Far and wide, from Staten Island to Cuba, from Hong Kong to Lagos, the work of keeping down the larvæ ofAnophelesandCulexis going on.Henceforth we have to reckon not with a nameless something, but with a definite parasite, whose conditions of life are known. Before all things, we must shut off the sources of the infection.For centuries, men had believed in exhalations and miasmata lying all over the land: and, behold, the agents of malaria are in the puddles round a man's house, and the agents of yellow fever are in the water-butt and the broken bottles and old sardine-tins. Science has given the word, and now there areAnophelesbrigades andCulexbrigades set going; labourers with brooms and rubbish-carts, sweeping out the stagnant pools, draining the surface soil, and carrying off the odd receptacles that serve to hold mosquito eggs and larvæ. The job, like all sanitary jobs, must be steady, year in, year out: it must be limited to infected places, a whole continent cannot be treated. But there the work is, and will grow; and saves, by unskilled labour, and at a trivial expense, those "non-acclimatised" lives that have hitherto been thrown away as recklessly as the larvæ that are now swept out of the puddles and ditches round African settlements.
The foregoing chapters are concerned with bacteriology alone, and with those curative or preventive methods of treatment that have come out of inoculation-experiments on animals. The lives that are saved, or safeguarded, by these methods, even in one year, must be many thousands in each country of the civilised world. And, beside human lives, there is the protection of sheep and cattle against anthrax, swine against rouget, horses against tetanus, cattle against rinderpest. In Cape Colony alone, so far back as 1899, about half a million cattle had received preventive treatment against rinderpest; and the sum total of human and animal lives saved or safeguarded, in all parts of the world, must be reckoned in millions by this time.
The present chapter, and the next two chapters, are concerned with methods that have come out of experiments on animals, but not out of bacteriology.
It is plain that the grosser parasites of the human body, tapeworms and the like, could not be explained or understood without the help of feeding-experiments on animals. By this method, and by this alone, their life-history was discovered. They were known to Aristotle and to Hippocrates; but nothing was understood about them. They were never studied, for this among other reasons, that men believed in spontaneousgeneration; and the presence of lower forms of life inside human bodies was attributed to the fault of the patient, or the work of the devil. Then, at last, Redi (1712), and Swammerdam (1752) in hisBibel der Natur, struck at the doctrine of spontaneous generation, saying that it did not apply to insects; and in 1781 Pallas boldly declared that the internal parasites of man came out of eggs, like insects, and not "of themselves." It would be a good theme for an essay—The paralysing effect, on medicine and surgery, of the doctrine of spontaneous generation. Rudolphi (1808) and Bremser (1819) opposed Pallas; and von Siebold (1835) and Eschricht (1837) supported him. Then came the great students of this part of biology—Cobbold, Busk, Davaine, van Beneden, Leuckart, Küchenmeister. In 1842, Steenstrup had discovered, in certain insects, the alternation of generations; in 1852, Küchenmeister proved that the generations of internal parasites are similarly alternate. By feeding carnivorous animals with "measly" meat, he produced tapeworms in them; and by feeding herbivorous animals with the ova of tapeworms, he made their muscles "measly."
The feeding of animals was the only possible way to understand the bewildering transformations and transmigrations of the thirty or more entozoa to which flesh is heir. This chapter of pathology makes up in tragedy what it lacks in romance; for these animal parasites have killed whole hosts of people. Take, for instance, thetrichina spiralis, a minute worm discovered in 1835 encysted in countless numbers in the muscles of the human body; it was studied by Virchow, Leuckart, and others, by feeding-experiments on animals, and was proved to come from infectedhalf-cooked ham and pork, and to make its way from the alimentary canal all over the body. The name of trichiniasis or trichina-fever was given to the acute illness that came of the sudden dissemination of these myriad parasites into the tissues. Trichiniasis had killed hundreds of people by a most painful death; outbreaks of it, in Germany and elsewhere, had swept through villages like cholera or plague: then Leuckart and Virchow traced it to its source, and it was stopped there—Above all things, we must shut off the sources of the infection—the butchers' shops were kept under sanitary inspection, people were warned against half-cooked ham and pork, and there was an end of it.
Or take hydatid disease, which occurs in all parts of the world, and in some countries (Australia, Iceland) is terribly common. The nature of this disease—that it is an animal parasite transmissible between men and dogs—was proved by feeding-experiments on animals. In Iceland, where men and dogs live crowded together in huts, there is an appalling number of deaths from hydatid disease; Leuckart, in 1863, of it:—
"At present, almost the sixth part of all the inhabitants annually dying in Iceland fall victims to the echinococcus epidemic."
Before Küchenmeister's experiments in 1852, there was no general knowledge of the exact pathology of entozoic disease. The advance was not made by the experimental method alone; other things helped: but among them was neither clinical experience, nor what Sir Charles Bell called "the observation of the just facts of anatomy and of natural motions."
Beside the entozoa, there are also vegetable parasites. Of these, the most important is thestreptothrix actinomyces, the cause of actinomycosis in man and cattle. Israel, in 1877, gave the first accurate account of it in man; and Böllinger, the same year, studied it in cattle. Ponfick, in 1882, recognised the identity of the disease in man and animals. In 1885, Israel published the collected records of 37 cases in man, tabulated according to the site of the primary infection. Boström, about this time, made cultures of the fungus: but all the earlier attempts at inoculation failed; and it was not till 1891 that Wolff and Israel published their successful inoculations, and thus completed the evidence that actinomycosis is a parasitic infection, a growth of vegetable threads and spores, transmissible between men and animals, and able to keep its vitality outside its host; so that men who are employed with cattle, or have the habit of chewing straws or ears of corn, incur some slight risk of infection. Before 1877, the disease was hardly suspected in man, and was not understood in cattle.
On 4th October 1873, Sir William Gull read a short paper before the Clinical Society of London, "On a Cretinoid State supervening in Adult Life in Women." This famous first account of myxœdema was based on five cases: it is less than five pages long, it does not suggest a name for the disease, and it says nothing about the thyroid gland. Four years later (23rd October 1877), Dr. Ord read a paper before the Medico-Chirurgical Society of London, "On Myxœdema; a term proposed to be applied to an essential condition in the 'Cretinoid' Affection occasionally observed in Middle-aged Women." His work had begun so far back as 1861; and in this 1877 paper he gave not only clinical observations, but also pathological and chemical facts; and he noted, as one among many changes, wasting of the thyroid gland. He also pointed out the close resemblance between cases of myxœdema and cases of sporadic cretinism.
In 1882, Reverdin stated before the Medical Society of Geneva that signs like those of myxœdema had been observed in some cases of removal of the thyroid gland on account of disease (goître). In April 1883, Kocher of Berne read a paper on this subject, before the Congress of German Surgeons; but he attributed this myxœdema after removal of the gland (cachexiastrumipriva) not directly to the loss of thyroid-tissue, but rather to some sort of interference with free respiration, due to operation. On 23rd November, Sir Felix Semon brought the subject again before the Clinical Society; and on 14th December 1883, the Society appointed a Committee of Investigation to study the whole question.
Their report, 215 pages long, with tabulated records of 119 cases of myxœdema, was published in 1888. It is a monument of good work, historical, clinical, pathological, chemical, and experimental. Twenty years ago, the purpose of the thyroid gland was unknown: a few experiments had been made on it, by Sir Astley Cooper and others, and had failed; and Claude Bernard, in hisPhysiologie Opératoire(published in 1879, soon after his death), makes it clear that nothing was known in his time about it. He is emphasising the fact that anatomy cannot make the discoveries of physiology:—
"The descriptive anatomy, and the microscopic characters, of the thyroid gland, the facts about its blood-vessels and its lymphatics—are not all these as well known in the thyroid gland as in other organs? Is not the same thing true of the thymus gland, and the suprarenal capsules?Yet we know absolutely 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."
Therefore, in 1882-83, things stood at this point—that the removal of a diseased thyroid gland had been followed, in some cases, by a train of symptoms such as Sir William Gull had recorded in 1873. Would the same symptoms follow removal of the healthy gland? The answer was given by Sir Victor Horsley's experiments,begun in 1884. He was able, by removal of the gland, to produce in monkeys a chronic myxœdema, a cretinoid state, the facsimile of the disease in man: the same symptoms, course, tissue-changes, the same physical and mental hebetude, the same alterations of the excretions, the temperature, and the voice. It was now past doubt that myxœdema was due to want of thyroid-tissue, and to that alone; and that "cachexia strumipriva" was due to the loss, by operation, of such remnants of the gland as had not been rendered useless by disease.
The advance had still to be made from pathology to treatment. Here, so far as England is concerned, honour is again due to Sir Victor Horsley. On 8th February 1890, he published the suggestion that thyroid-tissue, from an animal just killed, should be transplanted beneath the skin of a myxœdematous patient:—
"The justification of this procedure rested on the remarkable experiments of Schiff and von Eisselsberg. I only became aware in April 1890, that this proposal had been in fact forestalled in 1889 by Dr. Bircher, in Aarau. (The date of Dr. Bircher's operation was 16th January 1889.) Kocher had tried to do the same thing in 1883, but the graft was soon absorbed; but early in 1889 he tried it again, in five cases, and one greatly improved."
The importance of this treatment, by transplantation of living thyroid-tissue, must be judged by the fact that in 1888 no practical use had yet been made of the scientific work that had been done. The Clinical Society's Report, published that year, gives but half a page to treatment, of the old-fashioned sort; and not a word of hope.
Then, at last, in 1891, came Dr. George Murray's paper in theBritish Medical Journal, "Note on the Treatment of Myxœdema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep." Later, hypodermic injections of thyroid-extract gave way to sandwiches, made with thyroid gland (Dr. Hector Mackenzie, and Dr. Fox of Plymouth), and these in their turn were eclipsed by tabloids.
It is a strange sequence, from 1873 onward: clinical observation,post-mortemwork, calamities of surgery, experimental physiology, transplantation, hypodermic injections, sandwiches, and tabloids. And far more has been achieved than the cure of myxœdema. Even if the discovery stopped here, it would still be a miracle that little bottles of tabloids should bring men and women back from myxœdema to what they were before they became thick-witted, slow, changed almost past recognition, drifting toward idiocy. But it does not stop here. The same treatment has given good results in countless cases of sporadic cretinism, restoring growth of body and of mind to children that were hopelessly imbecile. It is of great value also for certain diseases of the skin. Moreover, physiology has gained knowledge of the purpose of the thyroid gland, and a clearer insight into the facts relating to internal secretion.
Long after the Renaissance, the practice of medicine was still under the influence of magic. Whatever things were rare and precious were held to be good against disease—gold, amber, coral, pearls, and the dust of mummies; whatever took strange forms of life—toads, earthworms, and the like; whatever looked like the disease, after the doctrine of signatures—pulmonaria for the lungs, because the spots on its leaves were like tubercle, a kidney-shaped fruit for the kidneys, a heart-shaped fruit for the heart, and yellow carrots for the yellow jaundice. Among the drugs in the 1618 Pharmacopœia arecranium humanum,mandibula lucii,nidus hirundinum,sericum crudum,linum vivum, andpilus salamandræ. In the Pharmacopœia of 1667 areexuviæ serpentis,telæ aranearum,saliva jejuni,cranium hominis violentâ morte extincti, and worse obscenities.
Soon after the publication of this Pharmacopœia, on 14th February 1685, King Charles II. died; and in the Library of the Society of Antiquaries there is a manuscript account in Latin, by Dr. Scarbrugh, how the case was treated. The King had sixteen physicians, and nine consultations in five days; and to say "everything was done that was possible" gives no idea of the vigour of the treatment. Finally, the day he died, theygave him, eleven of them in consultation—totus medicorum chorus ab omni spe destitutus—they gave him, asmore generous cardiacs, thelapis Goæ, and theBezoar-stone. Thelapis Goæwas a dust of topaz, jacinth, sapphire, ruby, pearl, emerald, bezoar, coral, musk, ambergris, and gold, all made into a pill and polished; and thebezoaris a calculus found in the intestines of herbivorous animals. Half a century later, the Pharmacopœia of 1721 still included ants' eggs, teeth,lapis nephriticus, and other horrors; and in the Pharmacopœia of 1746, though the dust of Egyptian mummies was ruled out, vipers and wood-lice were retained.
Certainly these "last enchantments of the Middle Ages" were slow to depart. Clinical observation, anatomy, and pathology, had all failed to bring about a right understanding of the actions of drugs. It was the physiologists, not the doctors, who first formulated the exact use of drugs; it was Bichat, Magendie, and Claude Bernard. That is the whole meaning of Magendie's work on the upas-poison and on strychnine, and Claude Bernard's work on curari and digitalis. Of these four substances, two only are of any use in practice; yet Magendie's study of strychnine[41]was of immeasurable value, not so much because it gave the doctors a "more generous cardiac," though that was a great gift, but because it revealed theselectiveaction of drugs. Contrast his account of strychnine with Ambroise Paré's story how they tested the bezoar-stone on the thief instead of hanging him; contrast Bernard's chapter on curari with Dr. Scarbrugh's notes on the King's death, withall the Crown jewels inside him: you are in two different worlds. Theselectiveaction of drugs—the affinity between strychnine and the central nerve-cells, between curari and the terminal filaments of the motor nerves—that was the revolutionary teaching of science: and it came, not by experience, but by experiment.
Take Professor Fraser's address on "The Action of Remedies, and the Experimental Method" at the International Medical Congress in London, 1881:—
"The introduction of this method is due to Bichat; and, by its subsequent application by Magendie, pharmacology was originated as the science we now recognise. Bichat represents a transition state, in which metaphysical conceptions were mingled with the results of experience. Magendie more clearly recognised the danger of adopting theories, in the existing imperfections of knowledge; and devoted himself to the supplementing of these imperfections by experiments on living animals. The advantages of such experiments he early illustrated by his investigation on the upas-poison; and afterwards by a research on the then newly-discovered alkaloid, strychnia.... He demonstrated the action of this substance upon the spinal cord, by experiments upon the lower animals, so thoroughly, that subsequent investigations have added but little to his results."
Or take Professor Fraser's account of digitalis:—
"It 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. Numerous observations were made on man by the originators of its application, by Dr. Sanders and many other physicians, in which special attention was paid to its effects upon the circulation; but no further light was thrown upon its remarkableproperties, with the unimportant exception that in some cases it was found to excite the circulation. 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, Boehm, 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 and tonic, rendering the action of the heart more powerful, and increasing the tension in the blood-vessels. The indications for its use in disease were thereby revolutionised, 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."
Or take Sir T. Lauder Brunton's account of the action of nitrite of amyl in angina pectoris:—
"The action of nitrite of amyl in causing flushing was first observed by Guthrie, and Sir B. W. Richardson recommended it as a remedy in spasmodic conditions, from the power he thought it to possess of paralysing motor nerves. 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 the arterioles contracted.... It seemed probable that the great rise in tension was the cause of the pain, and 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. The pain usually disappeared in three-quarters of a minute after the inhalation began,and at the same time the pulse became slower and much fuller, and the tension diminished."
"The action of nitrite of amyl in causing flushing was first observed by Guthrie, and Sir B. W. Richardson recommended it as a remedy in spasmodic conditions, from the power he thought it to possess of paralysing motor nerves. 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 the arterioles contracted.... It seemed probable that the great rise in tension was the cause of the pain, and 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. The pain usually disappeared in three-quarters of a minute after the inhalation began,and at the same time the pulse became slower and much fuller, and the tension diminished."
Of course it would be easy to lengthen out the list. Aconite, adrenalin, belladonna, calcium chloride, colchicum, cocain, chloral, ergot, morphia, salicylic acid, strophanthus, the chief diuretics, the chief diaphoretics—all these drugs, and many more, have been studied and learned by experiments on animals. Then comes the answer, that drugs act differently on animals and on men. The few instances, that give a wise air to this foolish answer, were known long ago to everybody: they do not so much as touch the facts of daily practice:—
"The action of drugs on man differs from that on the lower animals chiefly in respect to the brain, which is so much more greatly developed in man. Where the structure of an organ or tissue is nearly the same in man and in the lower animals, the action of drugs upon it is similar. Thus we find that carbonic oxide, and nitrites, produce similar changes in the blood of frogs, dogs, and man, that curare paralyses the motor nerves, alike in them all, and veratria exerts upon the muscles of each its peculiar stimulant and paralysing action. Where differences exist in the structure of the various organs, we find, as we would naturally expect, differences in their reaction to drugs. Thus the heart of the frog is simpler than that of dogs or men, and less affected by the central nervous system; we consequently find that while such a drug as digitalis has a somewhat similar action upon the hearts of frogs, dogs, and men, there are certain differences between its effect upon the heart of a frog and on that of mammals."Belladonna offers another example of apparent difference in action—a considerable dose of belladonna will produce almost no apparent effect upon a rabbit, while a smaller dose in a dog or a man would cause the rapidityof the pulse to be nearly doubled. Yet in all three—rabbits, dogs, and men—belladonna paralyses the power of the vagus over the heart. The difference is that in rabbits the vagus normally exerts but little action on the heart, and the effect of its paralysis is consequently slight or hardly appreciable." (Professor Fraser.)
"The action of drugs on man differs from that on the lower animals chiefly in respect to the brain, which is so much more greatly developed in man. Where the structure of an organ or tissue is nearly the same in man and in the lower animals, the action of drugs upon it is similar. Thus we find that carbonic oxide, and nitrites, produce similar changes in the blood of frogs, dogs, and man, that curare paralyses the motor nerves, alike in them all, and veratria exerts upon the muscles of each its peculiar stimulant and paralysing action. Where differences exist in the structure of the various organs, we find, as we would naturally expect, differences in their reaction to drugs. Thus the heart of the frog is simpler than that of dogs or men, and less affected by the central nervous system; we consequently find that while such a drug as digitalis has a somewhat similar action upon the hearts of frogs, dogs, and men, there are certain differences between its effect upon the heart of a frog and on that of mammals.
"Belladonna offers another example of apparent difference in action—a considerable dose of belladonna will produce almost no apparent effect upon a rabbit, while a smaller dose in a dog or a man would cause the rapidityof the pulse to be nearly doubled. Yet in all three—rabbits, dogs, and men—belladonna paralyses the power of the vagus over the heart. The difference is that in rabbits the vagus normally exerts but little action on the heart, and the effect of its paralysis is consequently slight or hardly appreciable." (Professor Fraser.)
It would be strange indeed, if experts who work in micromillimetres and decimal milligrammes, and study the vanishing-point of microscopic structures, and measure and ordain infinitesimal changes in invisible organisms, were blind to such gross and palpable differences as exist between men and pigeons in their susceptibility to a dose of opium.
Anæsthetics must be reckoned among the drugs that have been studied on animals: but, for the discovery of them, men experimented on themselves. The first use of nitrous oxide (laughing gas) in surgery was 11th December 1844, when Horace Wells, of Connecticut, had it administered to himself for the removal of a tooth. The first use of ether was made by Dr. Long, of Athens, Georgia; but he did not publish the case, or follow up the work: and the honour of the discovery of ether went to Morton, of Boston, who made repeated experiments, both on animals and on himself. The date when he first rendered himself absolutely unconscious for seven or eight minutes, is 30th September 1846; and the first operation under ether was done on 16th October, in the Massachusetts General Hospital. The first use of chloroform was 4th November 1847, that famous evening when Simpson, George Keith, and Matthews Duncan took it together. The whole history of anæsthesia is to be found in thePractitioner, Oct. 1896.
It is sometimes said that the men who make experiments on animals ought to make them on themselves.But they do, hundreds of them, and suffer for it: Heaven knows the list is long enough—the discoverers of anæsthesia, Hunter, Garré, Koch, Klein, Moor, Haffkine, Grassi, Bochefontaine, Quesada, Sanarelli, Pettenkofer—these and hosts more, here or abroad, have done it, as part of the day's work; and some—by accidental infection, like Chabry and Villa, or by deliberate self-inoculation, like Carrion—have been killed:—
"Dr. Angelo Knorr,Privat-docentin the Veterinary School of Munich, died on 22nd February from acute glanders, contracted in the course of an experimental research on mallein. Helmann, the Russian investigator who discovered mallein, himself fell a victim to accidental inoculation of the glanders virus. Some time afterwards another Russian, Protopopow, died of glanders contracted in a French laboratory. An Austrian physician, Dr. Koffman-Wellenhof, died of the same disease, contracted in the Institute of Hygiene at Vienna. On 17th January of the present year Dr. Guiseppe Bosso, of the University of Turin, died of infection contracted in the course of cultivations of tubercle-bacilli made in his laboratory. Not long before, Dr Lola, assistant in the maternity department of the Czech University Hospital of Prague, died of tetanus caused by an experimental inoculation made on himself. Some fourteen or fifteen years ago, a medical student of Lima proved that 'verruga Peruana' is an infectious disease by inoculating himself with it, an act of scientific devotion which cost him his life.[42]Besides those who have died, there are many who have only escaped with their lives after long and painful illness. Professor Kourloff contracted anthrax in a laboratory at Munich, and was saved only by vigorous surgery. Dr. Nicolas supplied, in his own person, the first example of tetanus produced in man by inoculation of the pure toxinof the bacillus of Nicolaier." (Brit. Med. Journal, 18th March 1899.)
This list is seven years old now; it is twice the length by this time. Typhoid, malaria, yellow fever, have all taken toll of those who study them. It is a long record of the men who fell ill, or died, or killed themselves over their work; and the deaths of Barisch, Dr. Müller, and Nurse Pecha, from plague at Vienna (October 1898) are another instance that there is danger in the constant handling of cultures. But these deaths at Vienna were due to the great carelessness of one man. In laboratories in all parts of the world there are stored cultures of all sorts of organisms, yet no harm comes of it. "More cases of infection occur amongst young medical men attending fever cases, whether in private practice or hospital wards, in a single month, than have occurred in the whole of the laboratories in the world since they were established." (British Medical Journal, 29th October 1898.) Outside the laboratory, outside the fever hospitals, the risk is something less than a negligible quantity:—
"Apart from plague and cholera, in all the big laboratories studies are uninterruptedly pursued, from one end of the year to the other, upon anthrax, glanders, influenza, Malta fever, various tropical diseases which do not exist at all or are rare in the countries where they are being studied. The laboratories in question are situated in the largest and most important towns of their respective countries; and, within those towns, very often in the most fashionable or most populous centres.... On no occasion was there even a suspicion aroused of an epidemic having been produced by any of the above-mentioned institutes, or by those tens of thousands of operations against cholera performed in India." (Haffkine,Madras Mail, 8th December 1898.)
The Report of the 1875 Commission said:—
"It is not possible for us to recommend that the Indian Government should be prohibited from pursuing its endeavours to discover an antidote for snake-bites; or that, without such an effort, your Majesty's Indian subjects should be left to perish in large numbers annually from the effects of these poisons."
Certainly it was not possible; and the numbers are large indeed. During 1897, 4227 persons were killed by wild animals in India, and 20,959 by snakes. (British Medical Journal, 5th November 1898.)
Sir Joseph Fayrer's name must be put in the highest place of all those who have studied the venomous snakes of India.
Sewell, in 1887, showed that animals could be rendered immune, by repeated inoculation with minute quantities of rattlesnake-venom, to a dose seven times as large as would kill an unprotected animal. Kanthack, in 1891, immunised animals in the same way against cobra-venom. He also made experiments to ascertain whether the blood-serum of these animals acted as an antidote to the venom. Then came the work of Calmette, Fraser, Phisalix, Bertrand, Martin (Australia), Stephens, and Meyers. Professor Fraser's observations on the antidotal properties of the bile are,of course, of the utmost importance; not only in preventive medicine, but also in physiology. The results obtained by Calmette are a good instance of the fineness and accuracy of the experimental method. It is to be noted that the animals were inoculated with a fine needle, not thrust into cages with snakes, as at zoological gardens; and that an animal thus poisoned has a painless death. The different venoms were measured in decimal milligrammes, and their potency was estimated according to the body-weight of the animal inoculated. As with tetanus, so with snake-venom, there must be a standard, or "unit of toxicity."
"The following table gives the relative toxicity, for 1 kilogr. of rabbit, of the different venoms that I have tested. To denote this toxicity I use terms such as Behring, Roux, and Vaillard used for the toxin of tetanus, taking the number of grammes of animal killed by one gramme of toxin:—1.Venom ofnaja0.25 mgr. per kilogr.of rabbit.One gramme of this venom kills 4000 kilogrammesof rabbit; it has, therefore, an activity of4,000,0002.Venom ofhoplocephalus0.29 mgr.3,450,0003.Venom ofpseudechis1.25 mgr800,0004.Venom ofpelias berus4.00 mgr250,000"Of course, this estimation of virulence is not absolute; it varies considerably according to the species of animal tested. Thus the guinea-pig, and still more the rat, are extremely sensitive. For instance, 0.15 mgr. of viper-venom is enough to kill, in less than 12 hours, 500 grammes of guinea-pig; so that the activity of this venom with a guinea-pig is 3,333,000, but with a rabbit is not more than 650,000. With more resistant animals, the opposite result is obtained; about 10 mgr. of cobra-venom are necessary to kill a dog of 6.50 kilogrm. weight; but to kill the same weight of rabbit 1.65 mgr. is enough. Thus the virulence of this venom with the rabbit is 4,000,000; but with the dog not more than 650,000."
"The following table gives the relative toxicity, for 1 kilogr. of rabbit, of the different venoms that I have tested. To denote this toxicity I use terms such as Behring, Roux, and Vaillard used for the toxin of tetanus, taking the number of grammes of animal killed by one gramme of toxin:—
"Of course, this estimation of virulence is not absolute; it varies considerably according to the species of animal tested. Thus the guinea-pig, and still more the rat, are extremely sensitive. For instance, 0.15 mgr. of viper-venom is enough to kill, in less than 12 hours, 500 grammes of guinea-pig; so that the activity of this venom with a guinea-pig is 3,333,000, but with a rabbit is not more than 650,000. With more resistant animals, the opposite result is obtained; about 10 mgr. of cobra-venom are necessary to kill a dog of 6.50 kilogrm. weight; but to kill the same weight of rabbit 1.65 mgr. is enough. Thus the virulence of this venom with the rabbit is 4,000,000; but with the dog not more than 650,000."
By experiments in test-tubes, Calmette studied these venoms under the influences of heat and various chemical agents. He found how to attenuate their virulence, and how to diminish the local inflammation round the point of inoculation; and it was in the course of these test-tube experiments and inoculations that he discovered the value of calcium hypochlorite as a local application. Working, by various methods, with attenuated venoms, he was able to immunise animals:—
"I have come to immunise rabbits against quantities of venom that are truly colossal. I have got several, vaccinated more than a year ago, which take, without the least discomfort, so much as 40 mgr. of venom ofnaja tripudiansat a single injection; that is to say, enough to kill 80 rabbits of 2 kilogr. weight, or 5 dogs."Five drops of serum from these rabbits wholly neutralisein vitro(in a glass test-tube) the toxicity of 1 mgr. ofnaja-venom."
"I have come to immunise rabbits against quantities of venom that are truly colossal. I have got several, vaccinated more than a year ago, which take, without the least discomfort, so much as 40 mgr. of venom ofnaja tripudiansat a single injection; that is to say, enough to kill 80 rabbits of 2 kilogr. weight, or 5 dogs.
"Five drops of serum from these rabbits wholly neutralisein vitro(in a glass test-tube) the toxicity of 1 mgr. ofnaja-venom."
By 1894 he had found that the serum of an animal, thus immunised by graduated doses of one kind of venom, neutralised other kinds of venom:—
"If 1 mgr. of cobra-venom, or 4 mgr. of viper-venom, be mixed, in a test-tube, with a small quantity of serum from an immunised rabbit, and a fresh rabbit be inoculated with this mixture, it does not suffer any discomfort. 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 immunised against the venom of the cobra or the viper acts indifferently on all the venoms that I have tested."
In 1894 he had prepared enough serum for the treatment to be tried by his own countrymen practising in some of the French colonies. In April 1895, he gave the following account of his work:—
"I have immunised two asses, one having received 220 mgr. ofnaja-venom from 25th September to 31st December 1894, and the other 160 mgr. from 15th October to 31st December. The serum of the first of these two animals has now reached this point, that half a cubic centimetre destroys the toxicity of 1 mgr. ofnaja-venom. Four cubic centimetres of this serum, injected four hours before the inoculation of a dose of venom enough to kill twice over, preserve the animal in every case. It is also therapeutic, under the conditions that I have already defined; that is to say, 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 skin of the abdomen 4 to 5 cubic centimetres of serum, recovery is the rule. When you interfere later than this the results are uncertain; and in all my experiments the delay of an hour and a half is the most that I have been able to reach."This antivenomous serum of asses has these same antitoxic properties with all kinds of snake-venom; it is equally activein vitro, preventive, and therapeutic, with the venoms ofcerastes, oftrigonocephalus, ofcrotalus, and of four kinds of Australian snakes that Mr. MacGarvie Smith has sent to M. Roux. I am still injecting these two animals with venom, and I hope to give to their serum at last a much greater antitoxic power."
"I have immunised two asses, one having received 220 mgr. ofnaja-venom from 25th September to 31st December 1894, and the other 160 mgr. from 15th October to 31st December. The serum of the first of these two animals has now reached this point, that half a cubic centimetre destroys the toxicity of 1 mgr. ofnaja-venom. Four cubic centimetres of this serum, injected four hours before the inoculation of a dose of venom enough to kill twice over, preserve the animal in every case. It is also therapeutic, under the conditions that I have already defined; that is to say, 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 skin of the abdomen 4 to 5 cubic centimetres of serum, recovery is the rule. When you interfere later than this the results are uncertain; and in all my experiments the delay of an hour and a half is the most that I have been able to reach.
"This antivenomous serum of asses has these same antitoxic properties with all kinds of snake-venom; it is equally activein vitro, preventive, and therapeutic, with the venoms ofcerastes, oftrigonocephalus, ofcrotalus, and of four kinds of Australian snakes that Mr. MacGarvie Smith has sent to M. Roux. I am still injecting these two animals with venom, and I hope to give to their serum at last a much greater antitoxic power."
In 1896 four successful cases of this treatment in the human subject were reported in theBritish Medical Journal. In 1898 Calmette made the following statement of his results:—
"It is now nearly two years since the use of my antivenomous serum was introduced in India, in Algeria, in Egypt, on the West Coast of Africa, in America, in the West Indies, Antilles, &c. 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 ofobservations have been communicated to me, and not one of them refers to a case of failure." (British Medical Journal, 14th May 1898.)
Good accounts of Fraser's and Calmette's work are given by Dr. Stone in theBoston Medical and Surgical Journal, 7th April 1898, and by Staff-Surgeon Andrews, R.N., in theBritish Medical Journal, 9th September 1899. For other cases see thePioneer, 10th August 1899, theLancet, 25th November 1899, and theBritish Medical Journal, 23rd December 1899. In one of these cases, recorded by Dr. Rennie, the patient was, literally, at the point of death, but recovered after the serum had been injected. Two cases have also been recorded of cobra-bite during work in the laboratory: both of them recovered after injection. "Every Government or private dispensary," says Surgeon Beveridge, "should be supplied with antivenene, which is certainly the best remedy for snake-bite available." The cases are few at present; but it does not appear that the treatment has failed in any case; and, with a new remedy of this kind, it is fairly certain that failures would be published.
From all these instances in physiology, pathology, bacteriology, and therapeutics, we come to consider the Act relating to experiments on animals in the United Kingdom. Many subjects have been left out; among them, the work of the last few years on the suprarenal glands and adrenalin, and Dr. William Hunter's admirable work on pernicious anæmia. No attempt has been made to describe the researches of experts in many countries into the nature of malignant disease, or to guess what may come of the discovery that mice can be immunised against that form of cancer which occursin mice and is inoculable from mouse to mouse. Nothing has been said of the discovery that the African sleeping-sickness is due to a blood-parasite carried by flies from man to man. Nothing has been said about those discoveries in bacteriology that have not yet been applied to practice, or of the many inventions of medical and surgical practice that owe only an indirect debt to experiments on animals. Artificial respiration, the transfusion of saline fluid, the hypodermic administration of drugs, the use of oxygen for inhalation, the torsion of arteries, the grafting of skin, the transplantation of bone, the absorbable ligature, the diagnostic and therapeutic uses of electricity, the rational employment of blood-letting—all these good methods have been left out of the list; only some facts have been presented, those that mark most clearly the advance of knowledge and of practice, and stand up even above the rest of the work. There they will stand, when we are all dead and gone: and by them, as by landmarks, all further advance will be guided.
The Royal Commission "On the Practice of subjecting Live Animals to Experiments for Scientific Purposes," was appointed on 22nd June 1875. Its members were—Lord Cardwell (chairman), Lord Winmarleigh, Mr. W. E. Forster, Sir John Karslake, Mr. Huxley, Mr. (Sir John) Erichsen, and Mr. Hutton. Between 5th July and 30th December, 53 witnesses were examined, and 6551 questions were put and answered. The report of the Commission bears date 8th January 1876, and in that year the present Act received the Royal Assent.
The evidence before the Commission was all, or nearly all, concerned with physiology, with the work of Magendie, Claude Bernard, and Sir Charles Bell, the action of curare, theHandbook of the Physiological Laboratory, the teaching of physiology, and so forth. Very little was said of pathology; and of bacteriology next to nothing. Practically, physiology alone came before the Commissioners; and such experiments in physiology as are now, the youngest of them, more than thirty years old.
Bacteriology, at the time of the passing of the Act, had hardly made a beginning. Therefore the Act made no special provision for inoculations, injections, and the whole study of immunisation of animals and men against disease. Experiments of this kind have to be scheduled under one of the existing certificates, to bring them under an Act that was drafted without foreknowledgeof them. Certificate A or Certificate B has to be used for this purpose:—
Certificate A."We hereby certify that, in our opinion, insensibility in the animal on which any such experiment may be performed cannot be produced by anæsthetics without necessarily frustrating the object of such experiment."Certificate B."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 anæsthetic administered to it, would necessarily frustrate the object of such experiment."
Certificate A.
"We hereby certify that, in our opinion, insensibility in the animal on which any such experiment may be performed cannot be produced by anæsthetics without necessarily frustrating the object of such experiment."
Certificate B.
"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 anæsthetic administered to it, would necessarily frustrate the object of such experiment."
Under one or other of these certificates must be scheduled all inoculations, injections, feeding-experiments, transplantations of particles of disease, immunisations, and the like. They must be scheduled somehow; and that is the only way of doing it. Where the act of inducing the disease would itself give any pain, if an anæsthetic were not administered—as in the subdural inoculation of a rabbit, or the intra-peritoneal inoculation of an animal with a particle of cancerous tissue—there the licensee must hold, together with the license, Certificate B, because the act of inducing the disease is itself an operation, done under an anæsthetic. If the animal be a dog or a cat, he must hold Certificates B and EE; if it be a horse, ass, or mule, Certificates B and F.
Where the act of inducing the disease is not itself painful—as in ordinary inoculation, and in feeding-experiments—the licensee must hold, together with hislicense, Certificate A, because the animal is not anæsthetised. It is not a painful operation; the experiment consists not in the act of putting the hypodermic needle under the animal's skin, but in the subsequent observation of the course of the disease. Take, for instance, the inoculation of a guinea-pig with tubercle-bacilli: the experiment is the production of tubercle; the experiment lasts till the animal is killed and found to be infected; it is therefore scheduled under Certificate A. Or take the testing, on an animal, of an antitoxin; the experiment is not the injection, but the observation of the result; the animal may not suffer, but the injection must still be done under Certificate A. And, if the animal be a dog or a cat, the licensee must hold Certificates A and E; or, if it be a horse, ass, or mule, Certificates A and F.
This want of a special certificate for inoculations is an important matter, because it has led to the belief that painful operations are performed, without anæsthesia, in cases where the only instrument used is a needle. It is hardly reasonable, for instance, that the inoculation of a mouse should be scheduled as a painful operation performed without anæsthesia. The disease, thus painlessly induced, may in many cases be called painless; for instance, snake-venom in the rat, septicæmia in the mouse, malaria in small birds. In other cases, there are such pain and fever as are part of the disease. The form that rabies take in rabbits may fairly be called painless. Inoculations not under the skin, but into the anterior chamber of the eye, are very seldom made; they sound cruel, but cocain renders the surface of the eye wholly insensitive, and the anterior chamber is so far insensitive that a man with blood or pus (hypopyon) in the anterior chamber of the eye maysuffer no pain from it. A horse or an ass kept for the giving of an antitoxic serum has a more comfortable life than an omnibus horse; and this preparation of the antitoxins, since it is not an experiment, but a direct use of animals in the recognised service of man, does not require a license or certificates under the Act. But the testing of an antitoxin is an experiment, and must be made under a license and Certificate A.
It is not the business of this book to consider whether the sensitiveness of a dog, a rabbit, or a guinea-pig can fairly be stated in terms of the physical and mental sensitiveness of men and women. In the world of animals, as in the world of humanity, there are differences of sensitiveness. Anyhow, the pain inflicted on animals may in some cases be measured:—