Animal Experimentation in a Large Research Institute
THE PRESIDENT, THE EARL OF HALSBURY, in opening the proceedings welcomed the Members of the Society and their guests who were present to hear Sir Peter Medawar deliver the 34th Stephen Paget Memorial Lecture entitled "Animal experimentation in a large Research Institute".
In introducing the lecturer, he said that Sir Peter was a Fellow of the Royal Society and Director of the National Institute for Medical Research, Mill Hill. If he were to take the audience through "Who's Who" on the subject of Sir Peter it would take longer than the Stephen Paget Lecture so he proposed at once to ask Sir Peter to deliver his lecture.
Animal Experimentation in a Large Research Institute
By SIR PETER MEDAWAR. C.B.E., M.A., D.Sc, F.R.S.
My Lord Chairman, Ladies and Gentlemen:
It is a very great honour to be asked to give the Stephen Paget Memorial Lecture, and a particular pleasure for me to have this opportunity to re-visitUniversityCollegeto give it.
The Stephen Paget Lecture has as its particular theme a defence of the use of experimental animals to enlarge medical knowledge. You may well wonder why in the year 1966 such a defence should be thought necessary, and, conversely, why the general public should demand repeated assurances that medical research is being humanely and properly conducted. I myself believe it is entirely right that the public should ask for these assurances. When I say "properly conducted" I do not only mean properly conducted in respect of experiments on animals (although that happens to be the particular theme of this lecture), but properly conducted in respect of every research activity that could reasonably cause misgivings. For example, the possible dangers of clinical experimentation; the endeavour to keep people alive beyond what is thought to be their natural span by the use of medical contrivances of one kind or another—or, alternatively, the morality of not keeping them alive when it is in principle possible to do so. Then there are the possible dangers of our great and ever growing dependence on medical supplies and medical services, a dependence so great as to tempt people to say that one day the whole world will turn into a kind of hospital in which even the best of us will be no more than ambulatory patients; and the dangers, real or imagined, of the genetic deterioration brought about by the propagation of the genetically unfit.
Some of these dangers are illusory, and can be shown to be so; but the fears and misgivings they give rise to are not illusory, and they must be allayed—by public discussion, by making the truth of these matters widely known, and by such methods as the delivery of Stephen Paget Memorial Lectures.
In saying that medical research workers should be required to give a fair account of themselves to the general public, I am talking as if the general public were a sort of all-wise body into whose care the well-being of animals could perfectly safely be entrusted. Alas—this is very far from being the case. The general public is by no means qualified to judge whether or not our human wardenship of animals is being satisfactorily discharged.
Some years ago I had the privilege of serving on a Home Office Committee "to enquire into practices or activities which may involve cruelty to British wild mammals, whether at large or in captivity". We took great pains to hear evidence from all interested parties, but the amount of evidence that bore on the welfare of unattractive animals, or on pests like rats, was negligible.
It is difficult not to despise the sentimental ignorance about animals that is so widely thought of as a traditional part of the British character—the kind of ignorant sentimentality that finds expression in the fatuous cry that a caged bird should be "given its freedom". Somebody should make the general public familiar with modern research on the dynamics of natural populations of animals: for example, the work in which Professor Lack has shown that the annual adult mortality of the European robin is as high as 60 per cent, of the starling 50 per cent and of the sparrow no less than 45 per cent. The concern of the British public for the welfare of animals is, as a matter of fact, a rattier new thing: it does not lie deep in our traditions. I think I am right in saying that the common law takes no cognizance of the rights of animals, and I do not know if it even concedes that animals can have rights. At all events, the first legislation protecting animals dates from the I820's (the R.S.P.C.A. was founded in 1824). The reason given for introducing new legislation to prohibit cock fighting was that it tended to corrupt the general public—not that it inflicted cruelty on the wretched animals themselves. Although I disapprove of pop sociology, a good case can be made for arguing that ignorant sentimentality about animals and how they live in nature grew up in proportion as people ceased to know anything about animals at first hand. The literature personalising animals has grown up in the past hundred years. "Alice in Wonderland" was published in 1865 and "Black Beauty" in 1877, and soon the nursery came to be populated with animal familiars—Brer Rabbit and Peter Rabbit, Piglet and Donald Duck have been the conditioning stimuli of our childhood; but we must allow ourselves to grow up if we are to get any sensible conception of the nature and life of animals as they really are.
The opposite of ignorant sentimentality is humane understanding. Just how far the public has yet to go to achieve humane understanding is made very clear by the world of pet dogs and the Dog Shows.
During the past ten years or so, The British Veterinary Association—in particular the Small Animals Veterinary Association—and the Animal Health Trust have been fighting an uphill but in the main successful battle to educate dog breeders and their clients, show judges and the 650 odd Breed Societies, into some understanding of, and some determination to cope with, the problems raised by the occurrence in many breeds of dogs of distressing or painful congenital deformities. I remember being stirred by a Presidential Address on this very theme at the Annual Meeting of the British Veterinary Association in 1954.
The Kennel Club has co-operated with the veterinary profession in the exposure and analysis of these abnormalities, and the fruits of their co-operation can be read in a series of important papers in the Journal of Small Animal Practice. They make sorry reading. The gist of them is that most breeds of dogs carry a cruel load of abnormalities which are the primary or secondary consequences of hereditary defects. Among them are dislocation of the knee cap or hip, gross skeletal deformities, undescended testes, deafness, retinal atrophy, chronic dermatitis, ingrowing eyelashes and chronic respiratory distress; they extend even to hyperexcitability, mental deficiency, or downright idiocy.
Now these deformities are of two kinds. Some are quite unwanted, and are indeed accidental. They have been unluckily fixed by inbreeding, and they remain in the stocks because breeders have been more anxious to sell than to cull. These abnormalities are not approved of, but they are condoned. Other congenital abnormalities are deliberately bred for: they are show points: they are among the defining characters of the breed. I do not understand how anyone of educated sensibility can admire the bow legs and poor crumpled face of the bulldog, the spinal deformity that gives him his gay twirly tail, the palatal abnormalities that make it so difficult for him to breathe. No one with a real understanding of animals could applaud a show stance made possible by a congenital dislocation of the hip. We should all applaud the British Veterinary Association and the Animal Health Trust for the stand they have taken; and let me add that their criticism of breeders and of show judges was very much more warmly expressed than my own.
The welfare of animals must depend on an understanding of animals, and one does not come by this understanding intuitively: it must be learned. I once knew a little girl, who having been told that frogs were rather engaging creatures, befriended a frog. Her first thought was that it needed warming up, because it felt so cold. Her first lesson in the humane understanding of animals was that frogs do not like being warmed up and prefer to remain at the temperature of their environment. Fortunately, some humane and learned organisations do exist to promote the welfare of animals and to educate the public to understand animals as they really are, so that they need no longer rely on some supposedly intuitive understanding of what animals think or feel. One of the most important of these organisations is UFAW, the Universities Federation for Animal Welfare. I had the pleasure of being the Chairman of its Scientific Advisory Committee for some few years. Among these organisations I include that Department of the Home Office which authorises and supervises all experimentation on animals in Institutes such as my own. Not everyone realises what a high proportion of medical research workers in this country do warmly approve of the restriction of animal experimentation to people who are qualified to carry it out. This is not to say that the existing Home Office regulations are flawless or that certain administrative changes in its working are not now widely thought to be desirable.
After this long preamble—I intended it to be so—let me now say something about the care of and the use of animals in the National Institute for Medical Research, the largest research institute of its kind in the Commonwealth.
The NIMR is a sort of microcosm of basic medical research.
So far as is possible or practicable, the animals used in the Institute are bred within its precincts. We like to think of ourselves as the pioneers in this country of the careful and the scientifically-informed husbandry of laboratory animals. The animals are in charge of a scientific division of the Institute headed by a veterinary scientist. Dr. A. W. Gledhill. The Superintendent of the Division is responsible not only for its day to day running, but also for the training of animal technicians—educating them for a career which, thanks to Mr. D. J. Short's efforts as much as to anybody's, now offers the prospect of a rewarding and interesting life in what has come to be thought of as a profession ancillary to medical science. The establishment of animal technicians as a recognised profession and the regulation of examination standards by an Institute were projects in which the National Institute is proud to have played a leading part.
This was a revolution, for in the old days the care of animals was too often entrusted to kindly and well meaning, but often not very bright old men. There have been two other such revolutions in laboratory animal husbandry. The second was the provision and use of animals of known genetic composition and history— notably of inbred animals and of first generation hybrids between inbred strains. This innovation met with a good deal of opposition from the medical profession. It was contended that pure bred animals were in some way artificial and unnatural, and that the results secured by using them would be misleading or unrepresentative. This criticism is, of course, based on a misunderstanding of the nature and purposes of medical research; one might with equal justice reproach the chemist for basing his researches on the use of pure compounds.
The third revolution, which is still in progress, is the control of infectious disease. The animals in Research Institutes are of necessity kept at a population density which makes them an easy prey to epidemics. To control these epidemics— or rather, to prevent their occurrence in the first instance—is essentially a problem in medical or sanitary engineering. The same is true of the control of epidemics in human populations. Indeed, the actuarial status of the experimental animals bred in almost all laboratories today is still too much like that of a human population in the 16th century: a grievously high proportion of the animals still die from intercurrent infection, and without the consolation of believing that they go to heaven. The principle of protecting animal colonies from the attacks of pathogenic organisms had also to be fought for, but the battle has been won, and within the next few years all major biological Research Institutions will re-found their animal colonies on what is called a 'specific pathogen free' (S.P.F.) basis.
In the National Institute for Medical Research, as in the country generally, the largest single users of experimental animals are those responsible for the standardisation and safety control of drugs and vaccines. The National institute is in fact an agent of the World Health Organisation for defining international standards for those drugs and biological products which can only be assayed and tested by biological methods; and we are also agents of the Ministry of Health for checking the safety of vaccines and other agents of an immunological nature used in general medical practice. The two scientific divisions of the Institute responsible for this work make use of about 25,000 experimental animals a year; the control of polio vaccines makes use of some 2.000 monkeys a year. It is a large number in any absolute sense, but very small in proportion to the number of children at risk. Of course, no one is satisfied with the use of experimental animals for these purposes. The most determined efforts are constantly being made to find improved substitutes for the use of animals in standardisation and control.
To describe the directions that research is taking, I cannot improve on Dr. W. M. S. Russell's "3 R's" of humane laboratory practice; Reduction, Refinement, and Replacement. The number of animals used may be reduced only by increasing the amount of information to be secured from the study of any one. One method of doing so is to use genetically standardised animals—not necessarily inbreds. "Refinement" is essentially a matter of increasing the precision of individual assays. Our ultimate goal, however, is the replacement of animals altogether. For drugs, we look forward ultimately to chemical assays, or at least to the adoption of in vitro methods, such as the immunological assays now being developed for the standardisation of protein hormones. For the safety control of virus vaccines, e.g. polio vaccine, everyone hopes that the cytopathic changes produced in cells in tissue cultures will prove to be sufficiently discriminating and reliable. Slowly but progressively all these ambitions are being achieved.
These activities of the Institute are services, though they are services underpinned by research. Turning now to the researches of the Institute generally, I obviously cannot describe the dozens of projects undertaken in this past year by 180 scientists supported by perhaps twice that number of qualified technicians, but I shall choose some special examples to give you some idea of their variety and range of purposes.
Some people believe that the greatest task of modern medicine is to extend to the world generally the standards of medicine and hygiene that today obtain only in the advanced industrial countries. Let me therefore first mention the Institute's researches into malaria and leprosy in collaboration with research stations in West Africa and inMalayarespectively. Malaria is still, in a numerical sense, the world's gravest disease: some two and a half million people die every year of malaria and perhaps two hundred and fifty million are afflicted by it at any one time: it is not unreasonable that less than one-thousandth of that number of animals should be used in experimental malarial research. Rats and monkeys are each susceptible to their own kind of malarial infection, and the study of rats and monkeys has already taken us a long way towards elucidating the mechanism of the cyclical recurrence of malarial illness. Our understanding of leprosy is still backward, because the organism that causes it—it belongs to the same family as the tubercle bacillus— cannot yet be grown in cell-free cultures, and grows impossibly slowly when caused to infect cells in tissue culture; but rodents can be infected with their own leprosy organism, and now at last it has become possible to grow the human organism in mice. Now, for the first time, critical experimental tests on the chemotherapy of leprosy can be undertaken.
My own special research interest is in the field of transplantation, and our ambition is to overcome the immunological barriers that normally prohibit the transplantation of tissues and organs between two different human beings or, for that matter, two different mice. The transplantation of kidneys in medical practice has already enjoyed greater success than any of us dared to believe possible even as recently as five years ago. All the methods used in clinical practice to prolong the life of homografts have been founded upon experiments carried out in mice, rabbits, rats and dogs, and thanks to them, surgery will one day enter into that new dimension of accomplishment which the transplantation of organs seems to promise.
The transplantation problem is a problem in immunology. Our Institute has been described as the greatest centre of immunological research in the world, and I shall not challenge this description. A high proportion of immunological research is now directed towards inhibiting and controlling the immunological response. When that control has been achieved, as it certainly will be, its rewards will be diffused far more widely than over the domain of transplantation itself. It will become possible to relieve that huge diffuse burden of human suffering imposed upon us by the allergies, hypersensitivities, auto-immune diseases, and many other miscarriages of the immunological process.
Research at the Institute is by no means confined to the use of lower animals; perhaps no Institute makes greater use of human volunteers for those researches in which only human beings will do. The complex of viruses responsible for the common cold—viruses first denned and cultivated in the National Institute— cause their characteristic symptoms only in man. Human volunteers are therefore used at the Common Cold Research Unit, our famous outpost nearSalisbury. Human volunteers are also, of necessity, used to study the adaptation of human beings to climatic stresses. The Hampstead campus of the Institute is equipped with the complex instrumentation that makes it possible to create climatic conditions even more disagreeable than those which prevail out-of-doors. One of our most distinguished human physiologists in Hampstead is studying the athletic performance of human beings at an altitude of 7,415 ft. above sea level—the height of Mexico City, where the Olympic Games are to be held in 1968. It would not be very informative to simulate the Olympic Games with mice.
You may think that in choosing malaria, leprosy, and transplantation as examples of the Institute's research, I am cheating—at least in the sense that 1 am directing your attention to research of obvious practical utility, where there is no doubting the ultimate benefit to mankind. But what about the moral credentials of so called "pure" research—for example on the mechanisms of protein synthesis, one of our major preoccupations?
In terms of their ultimate relevance to mankind, the difference between research into protein synthesis and on malaria is a difference of immediacy, and in the degree of diffusion of their effects. The work on protein synthesis stands further from practical application than work on malaria, but its results illuminate almost the whole of biology and medicine; they illuminate normal and abnormal growth, regeneration, reproduction, the synthesis of hormones, the production of antibodies, the multiplication of viruses and bacteria—surely a big enough dividend for any scholarly investment. You may disapprove of all experiments using animals, but it is scientifically and medically ruinous to approve only those with obvious practical uses and to reprobate all others.
To conclude: the use of experimental animals in medical research requires justification, and I think that the general public is right to demand repeated assurances that such a justification exists. The justification lies in the advancement of human welfare, but I myself interpret '"welfare" more widely than in terms of material benefits or the conquest of disease. Human beings are so constituted that they seem temperamentally obliged to explore the world around them, to enlarge their grasp and understanding of nature. It is to this restless and insistent exploratory process that human beings owe their present place in the world. It is too late now to adopt an intellectually pastoral existence—to adopt a molluscan solution of the problems of living. To invert an epigram of Thomas Browne's, it is too late to cease to be ambitious. The use of experimental animals in laboratories to enlarge our understanding of nature is part of a far wider exploratory process, and one cannot assay its value in isolation—as if it were an activity which, if prohibited, would deprive us only of the material benefits that grow directly out of its use. Any such prohibition of learning or confinement of the understanding would have widespread and damaging consequences: but this does not imply that we are for evermore, and in increasing numbers, to enlist animals in the scientific service of man. 1 think that the use of experimental animals on the present scale is a temporary episode in biological and medical history, and that its peak will be reached in ten years time, or perhaps even sooner. In the meantime we must grapple with the paradox that nothing but research on animals will provide us with the knowledge that will make it possible for us, one day, to dispense with the use of them altogether.
The Chairman thanked Sir Peter for giving a most fascinating lecture and called upon Professor D. G. Evans to propose a vote of thanks.
Professor Evans said it gave him great pleasure to propose a vote of thanks on behalf of the Research Defence Society. He was sure everyone agreed they had had an outstanding exposition of the difficulties surrounding experimentation using animals. Some of the people who did not like experimentation were amongst those who benefited from it and they could do well to read Sir Peter's lecture as they might then be very much more sympathetic to the work being done than at present. There was no doubt that medical research had been benefited by the use of experimental animals and he was sure the National Institute would go on and remain the leader in their field.
The Chairman then asked all those who were not Members of the Research Defence Society to withdraw, so that the Society could hold its Annual General Meeting.