THE LABORAT ORY | Kickoff

THE LABORAT ORY

17 May

Experiments on animals have, we have seen, been central to the development of modern medicine, but some have always found them repugnant, and many have refused to engage in them. The more I have thought about this subject the less sympathetic I have become to all animal experiments conducted before 1877, when Pasteur began work on anthrax. Samuel Johnson said in 1758: Among the inferior professors of medical knowledge is a race of wretches, whose lives are only varied by varieties of cruelty . . . What is alleged in defence of these hateful practises everyone knows, but the truth is that by knives, fire, and poison knowledge is not always sought and is very seldom attained. The experiments that have been tried are tried again . . . I know not that by living dissections any discovery has been made by which a single malady is more easily cured. And if knowledge of physiology has been somewhat increased, he surely buys knowledge dear, who learns the use of the lacteals at the expense of his humanity. It is time that universal resentment should arise against these horrid operations . . . But animal experimentation was absolutely central to the new science of physiology as it developed in the nineteenth century.

According to Claude Bernard, the man generally acknowledged as the greatest of all the nineteenth-century physiologists, without vivisection ‘neither physiology nor scientific medicine is possible’. Moreover, Bernard was quite explicit in his determination to pay no attention to the pain his animals suffered: A physiologist is not a man of fashion, he is a man of science, absorbed by the scientific idea which he pursues: he no longer hears the cry of animals, he no longer sees the blood that flows, he sees only his idea and perceives only organisms concealing problems which he intends to solve. Similarly, no surgeon is stopped by the most moving cries and sobs, because he sees only his idea and the purpose of his operation. Similarly again, no anatomist feels himself in a horrible slaughter house; under the influence of a scientific idea, he delightedly follows a nervous filament through stinking livid flesh, which to any other man would be an object of disgust and horror. Bernard was quite right: surgery and anatomy require the overcoming of normal human responses and the substitution of a professional detachment. But Bernard’s argument was also a form of special pleading. By the time he wrote this, in 1865, anaesthetics were com- monplace.

Surgeons no longer had to brace themselves against cries and sobs. As for Bernard he was genuinely indifferent to the sufferings of his animals. One of his research programmes was directed at under- standing how curare worked as a poison. Having discovered that it paralysed but did not anaesthetize, Bernard frequently used it to immobilize animals in his experiments, knowing full well that it pro- vided no pain relief. He also understood perfectly that some people found these experiments unbearable to contemplate. His wife left him in 1870, citing his cruelty to animals as a major reason for the break-up of the marriage. Bernard’s famous book An Introduction to the Study of Experimental Medicine, from which I have been quoting, was directed at two distinct groups opposed to the new physiology. On the one hand there were the exponents of the statistical method of Louis, who thought that medicine would progress, not by experimenting on animals, but by studying what actually happened to patients. Bernard could scarcely conceal his impatience with such people: ‘A great surgeon performs operations for stone by a single method; later he makes a statistical summary of deaths and recoveries, and he concludes from these statistics that the mortality law for this operation is two out of five. Well, I say that this ratio means literally nothing . . .’ But Bernard had misrepresented the statistical method: any surgeon announcing a mortality rate of 40 per cent was inviting others to compare their method with his; if their results were worse, they should adopt his method, and if better, he should adopt theirs.

Bernard’s other imagin- ary interlocutor was an antivivisectionist. To this person he both presented the arguments for vivisection, and insisted that it was a waste of time doing so, for ‘we shall deem all discussion of vivisection futile or absurd’. It is hard not to think that Bernard is here addressing his wife. Johnson made three charges against vivisection: that it was cruel, that experiments were repeated unnecessarily, and that little of value was learnt from them. For most of the nineteenth century, these remained for many British men and, more frequently, women the key charges against vivisection: I say British, because opposition to vivi- section was far stronger in Britain than anywhere else in the world. Even some British vivisectionists were acutely aware of the pain they inflicted on animals in their work. In 1809 Sir Charles Bell conducted pioneering experiments on rabbits to try to establish the function of different nerves in the body –– some, it seemed, were primarily employed to convey sensation, others to control movement. The easi- est sensation to generate, of course, was pain, but Bell was reluctant to work on conscious rabbits, and stunned his creatures first. ‘I cannot perfectly convince myself’, he said, ‘that I am authorized in nature or religion to do these cruelties –– for what? –– for anything else than a little egotism or self-aggrandizement; and yet, what are my experi- ments in comparison with those which are daily done? And done daily for nothing.’ As a direct result of this squeamishness he reached the wrong conclusions. In 1822, the leading French physiologist of the day, François Magendie, repeated Bell’s experiments with fully conscious rabbits. He showed that ‘the posterior (dorsal) roots of the nerves proceeding from the spinal cord are primarily associated with sensation, whereas the anterior (ventral) roots of the same nerves are primarily associated with motion’.

This has been described as the most important single discovery of Magendie’s career. It could have been Bell’s, but Bell had refused to do the equivalent of learning the use of the lacteals at the expense of his humanity. At this point, I fear we need to think about actual operations. Sometimes they were straightforwardly elegant, and were not neces- sarily associated with a great deal of pain. Bernard, who had been Magendie’s assistant, developed Magendie’s work on the functions of the nerves. One of his studies was of a major nerve in the face, the facial nerve: ‘In the first experiment’, John Lesch tells us, Bernard anaesthetized and immobilized an adult dog with a strong dose of opium extract. He introduced a small hook with a double cutting edge into the skull on the left side via the orifice of the mastoid vein situated above and within the mastoid apophysis. As soon as the instrument had penetrated, Bernard directed it obliquely down and inside, following the posterior face of the petrosal bone. As soon as contractions were visible on the left side of the face, he knew the instrument had reached the facial nerve. Turning the hook upward, and without leaving the petrosal bone, he carefully withdrew the instru- ment, thereby pulling at and sectioning the nerve. The completion of this operation was signalled by the immediate and complete paralysis of the left side of the face. Within six days the wound had healed and the effects of the opium had dissipated. Bernard was able to confirm that, apart from the facial paralysis, there was a considerable diminution of the gustatory faculty in the left anterior half of the tongue, without any corresponding alteration of movement or of the tactile sense in the same region. When the animal was sacrificed after thirty-three days, autopsy confirmed that the seventh pair, and only the seventh pair, of cranial nerves had been sectioned. He obtained the same results in experiments on two other dogs. Bernard’s study of dogs helped make sense of some cases of facial paralysis in humans: it proved possible to find damage to the facial nerve in an autopsy of a patient whose symptoms were similar to those of the vivisected dogs. But some operations involved slashing and gashing that caused horrible damage to the dog.

Thus Magendie’s work on the nerves of the spinal column was conducted on small young dogs. ‘He was able to lay bare the membranes of the posterior half of the spinal cord with a single stroke of a very sharp scalpel.’ But the shock and blood loss associated with operations such as this were so great that others had difficulty repeating his findings: it turned out that one had to allow the dogs time to recover before manipulating their nerves if one wanted to find what passed for ‘normal’ physiological responses. And there is something grotesque about some of the experiments conducted by the French physiologists. Magendie did a good deal of work on the operation of poisons such as strychnine and prussic acid em;Bernard was to extend this into studies of curare and carbon monoxide. One question was how poisons such as strychnine, which appeared to work directly on the central nervous system, were absorbed into the body. Was it via the veins, the lacteals, or the nerves? The great eighteenth-century Scottish surgeon John Hunter had done experiments on absorption where he had cut out a small section of a dog’s small intestine, leaving it still connected to the blood system and the lacteals, in order to study whether milk was absorbed into the veins or lacteals –– he thought he could show that absorption was into the lacteals. Magendie would later seek to disprove this experiment, and show that absorption was into the veins: I’m told by a physiolo- gist that both were right, for the milk’s fat would have been absorbed into the lacteals, and the protein and carbohydrates into the veins. Magendie developed Hunter’s experiment: he stripped from the portion of intestine all the vessels until only a single artery and vein were left –– strychnine was absorbed into the blood, evidently through the veins in the wall of the gut. He then took this experiment a step further. He severed a dog’s leg, leaving it connected to the body by only a single artery and vein. And then he severed these, placing a hollow quill between the two ends –– thus the dog and his leg were now connected through an entirely artificial connection, so that no one could argue that there were hidden lacteals that had not been severed. If strychnine was injected into the paw of the severed leg, the dog was poisoned. Conceptually, this experiment was merely a logical development of Hunter’s and Magendie’s own previous experiments, and yet it seems to me absolutely grotesque, while the other experi- ments seem merely gruesome. The outcome is the same in both cases: the dog is dead (‘sacrificed’ is the term of art employed by vivi- sectionists). It is, I think, the heightened artificiality involved in the severed leg experiment that makes it both perverse and perverted. In 1824 Magendie visited London where he gave public lectures combined with vivisections. There was what the London Medical Gazette called ‘a violent clamour’, one with which even a medical journal could sympathize: its word for Magendie’s experiments was ‘appalling’. In 1837 James Macaulay, an antivivisectionist doctor, attended Magendie’s Paris lectures with some friends: ‘

The whole scene was revolting, not the cruelty only, but the “tiger–monkey” spirit visible in the demoralized students. We left in disgust, and felt thankful such scenes would not be tolerated in England by public opinion.’ The issue of vivisection eventually came to a head in Britain with the publication in 1873 of a book edited by John Burdon Sanderson and entitled Handbook for the Physiological Laboratory. This described classic physiological experiments, and was illustrated by numerous photographs. It was clearly intended to bring about a more wide- spread practice of French-style physiological experimentation in Britain. The book provided immediate evidence in support of the claim that vivisectionists constantly repeated experiments, for it was after all a handbook telling you how to perform experiments that had been performed many times before. Worse, it contained no reference to anaesthesia. Burdon Sanderson later claimed that this was merely an oversight, and the use of anaesthetics was so routine that there had been no need to mention it, but this defence was disingenuous. We now know that Burdon Sanderson and another Englishman, Rutherford, had both performed vivisections using curare and without painkillers. The furore provoked by the Handbook was redoubled when a French physiologist, Eugene Magnan, gave a lecture to the annual meeting of the British Medical Association in August 1874. Magnan had promised to induce the symptoms of epilepsy in dogs by injecting them with absinthe. There were scenes of disorder, and magistrates were called. In February 1875, George Hoggan, who had spent four months working in Bernard’s laboratory in Paris, wrote a letter to the Morning Post describing the horrors of what he had seen. The result was the establishment of a Royal Commission in 1875. This heard much remarkable testimony. Sir Henry Acland, Regius Professor of Medicine at Oxford and President of the General Medical Council, for example, testified as to the dangers associated with the unprincipled pursuit of knowledge for its own sake. But the star witness turned out to be Emanuel Klein, a German who was working in Britain and was one of the contributors to Burdon Sanderson’s handbook. Klein testified that when vivisecting cats and dogs he never bothered with anaesthetics in order to relieve pain; he only employed them when there was risk that he might be bitten or scratched by the suffering animals. After Klein’s testimony legislation became inevitable, though what Klein had said was little different from what Bernard had said in his Introduction. The outcome, after much negotiation, was the Cruelty to Animals Act of 1876, the first legislation anywhere in the world to restrict vivisection.

The Act provided that anyone experimenting upon liv- ing vertebrate animals must have a licence from the Home Secretary; in order to apply for such a licence they must have the support of a president of a major scientific or medical society and of a professor of medicine. The experiments must be performed at a registered location and be open to inspection, and must have as their purpose the acquisition of new knowledge. They must be performed under anaesthesia, and the animal experimented upon must not be revived afterwards. Special licences had to be sought by anyone who intended to experiment without anaesthesia, to repeat experiments that had already been performed, or to use vivisection to illustrate a lecture. Cats, dogs, horses, and donkeys were singled out for particular protection. In its detail the Act was a commentary on the charges laid against the Handbook and the French physiologists. Curare was explicitly ruled not to be an anaesthetic. Obstacles were placed in the way of the repetition of experiments. Many French physiologists had conducted experiments at the Parisian veterinary school of Alfort. There horses that had been condemned to be put down were handed over to students so that they could practise their operative skills upon them, and in Bernard’s laboratory animals that still had life in them when the experiments were finished were presented to the students so that they could practise on them.

The Act specifically forbade such vivi- section to develop manual dexterity. The use of animals in public lectures had caused particular offence in England, and again particular restrictions were placed upon this by the Act. The Act was an initial success for a strong antivivisection movement which had developed in Britain, and which continued to campaign (indeed continues to campaign) for the complete abolition of vivisection. It was clear from the beginning that the Act would mean whatever the Home Secretary decided it should mean. At first, the Home Secretary acted independently, rejecting a significant number of applications that had the support of the scientific estab- lishment. But in 1881 the International Medical Congress met in London and this meeting was used by the physiologists to mount a campaign against the restrictions being placed upon their work. The timing was perfect. Koch, the discoverer of the life cycle of the anthrax bacillus, was there. So was his rival and enemy Pasteur, who had just demonstrated at Pouilly-Le-Fort the success of his anthrax vaccine: on 31 May fifty sheep, of whom half had previously been vaccinated, were injected with anthrax; on 2 June a large audience (including the correspondent of the London Times) could see that all the sheep that had not been vaccinated were either dead or dying, while all but one of the sheep that had been vaccinated were in good health. For the first time, it looked as though experiments on animals might soon open the way to the conquest of human diseases. In 1882, British physiologists formed the Association for the Advancement of Medicine by Research. At first this was probably envisaged as a campaigning organization to counter the various anti- vivisectionist societies. But it quickly became something quite differ- ent: the Home Secretary agreed that in future the AAMR would inspect all applications for licences to experiment on animals, and that none would be approved without their support; the tacit implication was naturally that applications they supported would be approved.

This agreement was reached in private and never publicized. From 1882 the physiologists were in effect allowed to regulate themselves. The Act may have provided some restrictions on their activities and may have required the exercise of a certain caution on their part; but at the same time they were now in a decisive position to control the interpretation of the Act. What one thinks of this depends in part on whether you think the end justifies the means. In Britain, antivivisectionists and antivac- cinationists continued to campaign vigorously against Pasteur’s work until the end of the nineteenth century and beyond. But this time the animal experimenters really could point to advances that benefited human beings. And there can be no doubt that the new bacteriology (unlike Jenner’s discovery of the smallpox vaccine, which had not involved the death of any animals) was entirely dependent on animal experimentation. Pasteur’s work on rabies involved not only infect- ing dogs with rabies; it also involved infecting rabbits, guinea pigs, and monkeys, in the first two cases to develop virulent strains of rabies, and in the third case to develop an attenuated strain. Dogs that had been rendered immune to rabies were routinely, as Pasteur put it, ‘sacrificed’ (by injections of strychnine) simply because his laboratory was short of cages and space had to be made for new experimental subjects. Pasteur’s work on rabies provided the model for a younger gener- ation of researchers. In 1894, for example, Yersin published his researches on bubonic plague in Hong Kong.

Carrying his ‘labora- tory’ in a small suitcase, working in a tent, in a few weeks he had established that the plague was a disease of rats as well as humans; he had isolated and cultivated the bacillus; he had infected mice, rats, and guinea pigs in the laboratory; and he had learnt how to produce strains of greater and lesser virulence by passing the disease from animal to animal and species to species. Yersin was soon on the track of a vaccine against bubonic plague, a plague that had killed some- thing like 30 per cent of the population of Europe when it had first arrived on the continent in 1348. Triumphs of this sort were impossible without animal experimentation. Exactly the same argument applies to the first discoveries of effective chemotherapy. Ehrlich’s discovery of salvarsan in 1910 –– the first ‘magic bullet’ chemical therapy, effective against syphilis –– was the result of injecting hundreds of substances into thousands and thousands of infected animals. Salvarsan was the 606th substance on which Ehrlich had carried out animal trials. So too prontosil, the first drug effective against a truly dreadful killer, puerperal fever, which killed women soon after childbirth, was discovered in the Bayer laboratories in 1935 as the result of extensive animal testing. As it happens prontosil was lethal to puerperal fever in the body, but totally ineffective in the test tube, and so could only have been discovered by animal testing –– it was later established that prontosil only works because it is broken down in the body into other substances. English scientists, visiting the Bayer laboratories, were horrified by the numbers of animals killed, and it is significant that early work in England on penicillin involved animal testing on a much smaller scale –– the key experiments in Oxford in 1940 involved first eight and then ten mice. In this case the experiments were crucial not in order to show that penicillin was effective against bacteria (that could be shown in the test tube), but to show that it could survive long enough in the body to destroy an infection. Since the production of penicillin was complex and difficult, this knowledge was essential before decid- ing to scale up production in order to produce sufficient quantities to treat human beings (who are 3,000 times larger than mice). In defence of the animal experimentalists, one may also say that they were prepared when necessary to experiment upon themselves. The pioneers of anaesthetics had inhaled all sorts of gases to test their effects, and now the bacteriologists followed in their footsteps. When Koch claimed to have identified the cholera vibrio (the name refers to its comma like shape) in 1884 Max von Pettenkofer swallowed a flask full of them –– with the intention, it must be said, of proving Koch wrong. (Since he survived, and suffered only from diarrhoea not cholera, he succeeded in casting doubt on Koch’s claim.) In 1897 Almroth Wright injected himself and many members of his staff with dead typhoid bacilli to see if they would develop antibodies, which they did. And a volunteer was injected with live bacilli to see if the theoretical immunity worked in practice. In 1928 Alexander Fleming’s assistant Stuart Craddock ate penicillin mould to confirm it was not toxic. It ought to be impossible to discuss vivisection without pausing to ask if it is justified. Can one draw a line, a line which separates the experiments of Bichat, Magendie, and Bernard, who displayed the most callous indifference to animal suffering, from those of Bell, who conscientiously sought to minimize pain, or those of Pasteur and Yersin, of Ehrlich and Domagk (the discoverer of prontosil) which really did save human lives? I’d like to think one can, but who can be trusted, without the benefit of hindsight, to make such distinctions?

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