Animals and Medicine offers a detailed, scholarly historical review of the critical role animal experiments have played in advancing medical knowledge. Laboratory animals have been essential to this progress, and the knowledge gained has saved countless lives—both human and animal. Unfortunately, those opposed to using animals in research have often employed doctored evidence to suggest that the practice has impeded medical progress. This volume presents the articles Jack Botting wrote for the Research Defence Society News from 1991 to 1996, papers which provided scientists with the information needed to rebut such claims. Collected, they can now reach a wider readership interested in understanding the part of animal experiments in the history of medicine—from the discovery of key vaccines to the advancement of research on a range of diseases, among them hypertension, kidney failure and cancer.This book is essential reading for anyone curious about the role of animal experimentation in the history of science from the nineteenth century to the present.
The Biomedical Research Education Trust has generously contributed towards the publication of this volume.
Animals and Medicine: The Contribution of Animal Experiments to the Control of Disease
Jack Botting | April 2015
xx + 224 | 56 colour illustrations | 6.14" x 9.21" (234 x 156 mm)
ISBN Paperback: 9781783741175
ISBN Hardback: 9781783741182
ISBN Digital (PDF): 9781783741199
ISBN Digital ebook (epub): 9781783741205
ISBN Digital ebook (mobi): 9781783741212
BIC subject codes: MBX (History of medicine), MBN (Public health and preventive medicine)
List of Illustrations
Adrian R. Morrison
I. Treatment of Infectious Diseases
Although smallpox had been known and feared since biblical times, Louis Pasteur nineteenth-century development of vaccination eradicated the disease by the nineteen seventies. He used animals such as horses, goats and rabbits to generate the virus antibodies, but calves became the most common source of vaccine. Antivivisectionists argued that improvements in public health were responsible for the reduction in deaths from smallpox, but statistics demonstrated clearly that wherever vaccination was introduced, smallpox was eradicated. Pasteur also developed vaccines to chicken cholera and anthrax based on the use of animal experiments.
Rabies is transmitted from the bite of a rabid dog or wolf. The typical symptoms of hydrophobia, hallucinations and fever appear some time later, after the virus has travelled to the central nervous system. Rabies is still endemic in most parts of the world, but the strict quarantine laws have kept it under control in the UK. In the nineteenth century, Pasteur produced a vaccine by inoculating rabbits with the virus and using their tissues to vaccinate other animals. Human rabies can be treated with post-exposure vaccination before the virus has produced the central symptoms. Antivivisectionists are critical of Pasteur’s work, but many lives were saved by vaccination at the Pasteur Institute in Paris.
3. Lockjaw: Prevalent but Preventable
4. Pertussis Vaccine, Unfairly Maligned – At What Cost?
6. The Conquest of Polio and the Contribution of Animal Experiments
7. Diphtheria: Understanding, Treatment and Prevention
II. Development of Life-saving Procedures
8. Development of Dialysis to Treat Loss of Kidney Function
9. The Contribution of Animal Experiments to Kidney Transplantation
10. Cardiopulmonary Bypass: Making Surgery on the Heart Possible
11. Artificial Heart Valves: From Caged Ball to Bioprosthesis
12. Animals and Blood Transfusion
III. Drugs for Organic Diseases
13. Animal Experiments and the Production of Insulin
14. Animals and Humans: Remarkably Similar
15. Early Animal Experiments in Anaesthesia
16. The Control of Malignant Hypertension
17. Penicillin and Laboratory Animals: The Animal Rights Myth
18. The History of Thalidomide
19. Misleading Research or Misleading Statistics: Animal Experiments and Cancer Research
Though tetanus was described 2,000 years ago, its cause was discovered in the nineteenth century when it was shown to be due to a bacterial infection. The anaerobic organism thrives in well-manured soil and produces a potent toxin that, after one to three days, causes spasm of the muscles at the site of infection. Tetanus antitoxin could be produced in animals by injection of the bacilli, for example, into horses. The antitoxin could only neutralise toxin that had not yet entered the motor nerves, so prophylaxis with antitoxin was established to prevent tetanus first in animals and then in humans. Many deaths from tetanus were prevented by immunisation with antitoxin during the 1914-18 war.
5. Vaccination: The Present and FutureWhooping cough is a distressing and potentially lethal disease. It is characterised by an intractable cough, followed by vomiting and lack of oxygen to the brain. The causative organism, present in sputum, was described in 1900. This bacillus produced a toxin which was lethal to rabbits. Vaccines were developed from the killed bacillus and the immunisation of infants was recommended. The triple vaccine of diphtheria/tetanus/pertussis became a routine vaccination procedure. However, the vaccine acceptance rate dropped due to reports that the pertussis vaccine caused brain damage. Subsequent studies established the safety of pertussis vaccine, but antivivisectionists question the benefit of this vaccination and claim that the disease had ceased to be a problem before vaccination began.
New vaccines are still needed to reduce morbidity and mortality from communicable diseases. In 1992 vaccination against infection by Haemophilus influenzae type B (Hib), a major cause of meningitis, was included in the childhood immunisation programme in the UK. Before vaccination, Hib infection killed 65 children and caused brain damage and deafness in a further 150 each year. Malaria, in terms of actual numbers, is one of the most serious infectious diseases. A recent estimate suggests that malaria causes 3 million deaths per year. A malaria vaccine is actively being sought, as is a vaccine to hantaviruses. Hantavirus infections causing haemorrhagic fever and nephropathy are virtually untreatable.
Supporters of the animal rights movement assert that animal experiments have contributed nothing to the reduction in death and paralysis from poliomyelitis. Epidemics of ‘infantile paralysis’ began to occur in developed countries in the early twentieth century. The polio virus was studied in monkeys and ultimately grown in human tissue culture. Animal experiments were crucial in testing whether the virus had replicated in tissue culture. The ability to grow the virus in tissue culture ensured the rapid development of a vaccine, and widespread vaccination was introduced in 1955 in the USA and Europe. The WHO programme of polio vaccination has now spread to developing countries.
Diphtheria has long been known but was not formally described until 1826. Children died either from suffocation or, as the disease progressed, from paralysis and heart failure. The bacillus from diphtheria patients was isolated and cultured on mucous membranes of various animals. Bacteria grown on broth released an exudate which was toxic to rabbits and other animals. The antiserum to the toxin was then produced in horses and standardised in guinea pigs. This serum reduced child mortality from diphtheria if administered early after the onset of the infection. Formalin-inactivated toxin has been used to immunise pre-school children against diphtheria from 1940 onwards. Antivivisectionists and the National Anti-Vaccination League are opposed to immunisation against diphtheria.
II. Development of Life-saving Procedures
8. Development of Dialysis to Treat Loss of Kidney Function
The kidney regulates the water and ion balance of the body and removes toxic substances. Acute and chronic renal failure can be corrected by dialysis. Colloids and crystalloids can be separated by dialysis through a semipermeable membrane. Collodion tubes allow small molecules to pass through, but they retain colloids. These tubes form the basis of artificial kidney machines. Thus, long lengths of cellophane tubing were manufactured and the anticoagulant, heparin, extracted from animal tissues for use in dialysis for kidney failure. Peritoneal dialysis is also a means of removing toxic metabolites from the blood with the peritoneum acting as a semipermeable membrane.
Human kidney transplantation would not have been possible without the initial experiments on animals. The first requirement for a successful transplant was to connect the donor kidney to the artery and vein of the recipient. This was done with a special suturing technique first attempted in the dog and cat. Rejection of the transplanted kidney was another problem which occurred when the kidney of one animal was transplanted into another. The pathological changes taking place in the kidney during rejection were the same in humans as in animals. Rejection of a donor kidney could be prevented by administering immunosuppressant drugs both in dogs and in humans.
Surgery on the heart has been made possible by the development of the cardiopulmonary bypass technique, whereby the patient’s heart and lungs are temporarily replaced by a mechanical pump and an oxygenator. This was first successfully performed on an anaesthetised cat and is now a routine procedure for heart surgery. Open heart surgery was also performed on anaesthetised dogs using this technique. Experiments on rat hearts then examined whether it was possible to stop the heart completely during the surgical procedure with the help of a cardioplegic solution. An effective cardioplegic solution, which is also used to preserve human hearts prior to transplantation, was developed at St Thomas’ Hospital in London.
Much research has been carried out to develop heart valves as replacements for valves damaged by disease. The caged ball valve was the first successful prosthesis for the replacement of the mitral valve, tested in dogs. Then the caged disc valve was developed. It was smaller and more suitable as a replacement for aortic valves. The manufactured prosthesis of choice at present is the tilting disc valve, successfully implanted both in dogs and in patients. Heart valves removed from pigs and other species have also been transplanted into dogs and humans after chemical treatment to remove antigenicity.
Animal experiments were crucial to the development of techniques for carrying out blood transfusion. Successful transfusion of blood was achieved in the nineteenth century, first between dogs and then from one human to another. However, transfusion was practiced only as a last resort until the studies of Landsteiner established the ABO blood group system. This had great significance for the transfusion of compatible blood and explained the failure of some early transfusions. Prevention of blood coagulation was also intensively investigated. A breakthrough came with the discovery that citrate could prevent clotting, when added immediately to freshly collected blood, and that citrated blood was relatively non-toxic.
III. Drugs for Organic Diseases
13. Animal Experiments and the Production of Insulin
Before 1922, the diagnosis of what was then called ‘juvenile onset diabetes’ meant a long, lingering death within months. In that year, however, a team of scientists in the physiological laboratories at the University of Toronto isolated and purified from the pancreas the hormone called insulin. The purified insulin was shown to control not only the symptoms induced by removal of the pancreas in dogs, but also those of diabetes mellitus in patients. The production of insulin on a large scale from pig and cattle pancreases was achieved fairly rapidly, but the story of the discovery of insulin has been subjected to vehement attacks from animal rights adherents.
The assertion that animal experimentation is a ‘failed technology’ is the linchpin of the pseudoscientific attack on animal-based biomedical research that has been waged over the last four decades by the animal rights lobby. William Harvey’s conclusion that the movements of the heart caused the blood to circulate around the body was derived from observations in the living snake and toad as well as in the pig. Today, the rodent is the most widely used species for experimental work. It is evident that there is no difference in the way the conducting tissue in the heart of the rat or of the human triggers the sequential contraction of the individual muscle fibres.
Fifty years before an anaesthetic was administered to patients, Humphrey Davy had demonstrated that nitrous oxide produced a state of unconsciousness in animals that was reversible if the animal was returned to air. He described the administration of nitrous oxide to a ‘stout and healthy cat’ and the effect of breathing a mixture of 1 part oxygen and 3 parts nitrous oxide on a guinea pig. Twenty years later the dentist Horace Wells had a wisdom tooth removed under nitrous oxide. By 1846, however, major operations both in the USA and the UK were being performed under ether anaesthesia. Subsequently, Simpson at Edinburgh University used chloroform in midwifery and described its effects in 1847.
Malignant hypertension was characterised by very high blood pressure accompanied by changes in the optic fundi. It could occur at any age and was generally fatal within one year of diagnosis. Drugs for its treatment were discovered serendipitously in 1948 during experiments on anaesthetised cats. These ganglion blocking drugs reduced the activity of the sympathetic nervous system and lowered the blood pressure. More drugs with a similar mechanism of action were then developed, the adrenergic neurone blocking drugs and the beta receptor antagonists. More recently, the very effective angiotensin converting enzyme inhibitors were discovered in studies on anaesthetised rats. The synthesis of angiotensin receptor antagonists further refined the treatment of hypertension.
The fact that penicillin, whilst being relatively innocuous for most species, appeared to be toxic to guinea pigs, has served as a sheet anchor for the claims of antivivisectionists that species differences render animal experiments redundant and possibly dangerous. However, the apparent sensitivity of this species to penicillin and indeed to other antibiotics, is certainly not evidence of the futility of animal experimentation. It is in fact a good example of the usefulness of the right model in biomedical research. Prolonged treatment with high doses of antibiotics causes toxic symptoms in patients like those in the guinea pig. With such treatment, the normally harmless gut bacteria are replaced by the toxin-producing clostridium difficile.
No drug has had a greater effect than thalidomide on the extent and intensity of the preclinical investigation of potential medicines required by the regulatory authorities. Indeed, the establishment of thalidomide as the cause of the apparent epidemic of children born with horrific deformities was responsible for the institution of some regulatory bodies, such as the Committee on the Safety of Drugs in the UK, and for the strengthening of others such as the FDA in the US. Thalidomide was never administered to pregnant animals before it was given to humans and five months after the drug was withdrawn, the embryopathic actions of thalidomide were demonstrated in rabbits, in rats and in other species such as newts.
Those devoted to attacking the scientific credibility of researchers who use animals, and to abolishing animal experiments, look to cancer research to provide evidence to support their campaign. They claim that despite the continued use of animals there is a rise in cancer mortality. In fact, the prognosis for some cancers has improved markedly. 95% of patients with cancer of the testis are now cured and in the treatment of childhood cancers, 5 year survival rates have shown a striking increase over the past 30 years. Numerous in vitro systems have been examined for the investigation of potential drugs with anti-tumour activity. However, the results have indicated that no in vitro method can replace a whole animal tumour model such as that of the mouse.
© 2015 Regina Botting
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Jack Botting, ed. Regina Botting, Animals and Medicine: The Contribution of Animal Experiments to the Control of Disease. Cambridge, UK: Open Book Publishers, 2015. http://dx.doi.org/10.11647/OBP.0055
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Please see the list of illustrations below for attribution relating to individual images. Whenever a license is not specified, images have been released under the same license as the book. Every effort has been made to identify and contact copyright holders and any omission or error will be corrected upon notification to the publisher.
List of Illustrations:
1.1) Smallpox deaths in Sweden, 1774-1900.
1.2) Smallpox deaths in England, 1838-1900.
1.3) Smallpox incidence in Indonesia, 1966-1971.
1.4) Louis Pasteur (1822-1895), microbiologist. Wellcome Library, London, CC BY.
2.1) Study of a rabid dog from an oil painting by J.T. Nettleship. Wellcome Library, London, CC BY.
2.2) Slaying of a rabid dog. Wellcome Library, London, CC BY.
3.1) Incidence of tetanus per 1,000 wounded in the British Army, 1914-1918.
4.1) Studies on pertussis immunisation, 1937-1942.
4.2) Whooping cough notifications in England and Wales, 1940-1990.
4.3) Whooping cough in Fiji, 1950-1980.
5.1) Hib meningitis in Helsinki. Actual cases, 1970-1990.
5.2) Decline of Hib Meningitis in USA children under 5 years, 1980-1993.
6.1) The iron lung before vaccination, 1952? Image in the public domain.
6.2) Comparison of infant mortality rates and the incidence of poliomyelitis.
6.3) Deaths from poliomyelitis in the USA, 1948-1967. Data from Vital statistics of the USA; US Dept of Health, Educ. & Welfare.
6.4) Deaths from poliomyelitis in England and Wales. Data from A.M. Ramsey and R.T.D. Emond, Infectious Diseases, London: Heinemann, 1978.
6.5) Polio in Latin America, confirmed cases per year, 1969-1989. Data from Medical & Health Annual, 1991, Chicago: Encycl. Britannica Inc.
7.1) 1909 photo of Emil von Behring (1854-1917). Wellcome Library, London, CC BY.
7.2) Effect of antitoxin on case mortality.
7.3) Diphtheria death rate in New York, 1920-1930.
7.4) Incidence of diphtheria in Birmingham (children 5-14 years), 1920-1935.
7.5) Diphtheria death rate in Great Britain, 1925-1955.
8.1) Kidney dialysis machine. © Science Photo Library, all rights reserved.
9.1) Alexis Carrel, 1912 Nobel Laureate in Physiology or Medicine. Wellcome Library, London, CC BY.
9.2) Carrel’s vascular anastamosis. From A. Carrel (1902), ‘La Technique operatoire des anastomoses vasculaire et la transplantation des visceres’, Medecine de Lyon, 98, 859.
9.3) Sir Peter Medawar, painting by Sir Roy Calne. All right reserved.
9.4) The first long-surviving dog, Lollypop, treated with the immunosuppressant azathioprine following a kidney graft. All right reserved.
9.5) A donor human kidney is perfused with saline prior to transplantation. © Science Photo Library, all rights reserved.
9.6) Surgeons performing a kidney transplant operation. © Science Photo Library, all rights reserved.
10.1) The recently transplanted heart of a baby boy, showing the tubing still connecting it to the heart-lung machine. © Science Photo Library, all rights reserved.
10.2) Heart-lung machine. © Science Photo Library, all rights reserved.
10.3) Effect of additives on recovery of rat heart from ischemia. Data from D. Hearse (1988) ‘The protection of the ischaemic myocardium: surgical success v clinical failure?’, Progress in Cardiovascular Diseases, 30, 6, 381.
10.4) Hypothermia and ischaemic injury. Data from Hearse (1988).
11.1) Diagrams from: ‘On Breathlessness, especially in relation to cardiac disease?’ An address given by Lauder Brunton to the Willesden and District Medical Society and published in The Practitioner in June, 1905. Image in the public domain.
11.2) Surgery to replace a mitral valve. © Science Photo Library, all rights reserved.
11.3) Artificial heart valves were successfully developed in animals.
11.4) The tilting disc aortic heart valve, with the tilting action shown in cross sectional profile. Picture courtesy of Medtronic, all rights reserved.
11.5) Tilting disc aortic heart valve. © Science Photo Library, all rights reserved.
12.1) Engravings showing transfusion in the neck and leg of a dog, from animal to man, and from man to man, by J. S. Elsholtz, 1667. Wellcome Library, London, CC BY.
12.2) Attempt at blood transfusion from lamb to man, depicted in an illustration dating from 1705. Wellcome Library, London, CC BY.
12.3a) Drawing of Blundell’s impellor. Wellcome Library, London, CC BY.
12.3b) Blundell’s apparatus in use. From J. Blundell (1828). ‘Observations on the transfusion of blood’, The Lancet, 2, 321. Wellcome Library, London, CC BY.
12.4) Today, the storage and transfusion of sterile compatible blood or blood constituents is a routine and life saving procedure. © Science Photo Library.
13.1) Photo of Frederick Banting, Charles Best and the dog Marjory, an early depancreatised dog treated with insulin, 1921. Wellcome Library, London, CC BY.
13.2) The effect of Collip’s highly-purified extract on the first patient to be successfully treated. Data adapted from F. Banting, C. Best, J. Collip, et al. (1922), ‘The effect produced on diabetes by extracts of pancreas.’ Transactions of the Association of American Physicians, 1-11.
13.3) Photographed in 1922, this diabetic girl, aged 13, weighed just 45lb before treatment with insulin. A few months later she had made a dramatic recovery. Wellcome Library London, CC BY.
14.1) Aspirin causes birth defects in rats, but not in people.
15.1) Watercolour of Henry Hickman by Richard Cooper, painted in 1912. Wellcome Library, London, CC BY.
15.2) Drawing of Sir James Young Simpson and friends by unknown artist, representing Simpson’s discovery of the anaesthetic properties of chloroform in humans. Wellcome Library, London, CC BY.
16.1) Deaths from hypertensive disease. Annual deaths per million population. Data from Paton et al. (1978) Highlights of British Science, Silver Jubilee Exhibition, Royal Society, and Compendium of Health Statistics, 8th edition, 1992 (Office of Health Economics).
16.2) Treatment of malignant hypertension with ganglionic blocking drugs. Comparison between 140 treated and 105 untreated patients, percent surviving against time after diagnosis. Data from Paton et al. (1978).
17.1) Effect of penicillin in normal and germ-free guinea pigs. Figures are number of animals per group. Data from S.B. Formal, G.D. Abrams, H. Schneider, and R. Laundy (1963), ‘Penicillin in germ-free guinea pigs.’ Nature, 198:712.
18.1) Columns represent the monthly incidence in Germany of births of children deformed because of ingestion of thalidomide by the mother. Data from W. Lenz (1988), ‘A short history of thalidomide embryopathy.’ Teratology, 38, 203-15.
19.1) Trends in cancer survival in the USA (male and female white), 1960-1963 and 1983-1988.
19.2) Trends in cancer mortality in England and Wales (males), 1950-1990.
19.3) Trends in survival of children under 15 in the USA, 1960-1963 and 1983-1988.