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Animals and Medicine: The Contribution of Animal Experiments to the Control of Disease

Animals and Medicine: The Contribution of Animal Experiments to the Control of Disease Jack Botting
Paperback ISBN: 978-1-78374-117-5 £18.95
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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
DOI: 10.11647/OBP.0055
BIC subject codes: MBX (History of medicine), MBN (Public health and preventive medicine); BISAC subject codes: MED000000 (MEDICAL / General), MED022000 (MEDICAL / Diseases), MED076000 (MEDICAL / Preventive Medicine); OCLC Number: 916465166.

Jack Howard Botting
(1932-2012) received his B.Pharm at Chelsea College in 1954 and his PhD in Pharmacology, under the supervision of Professor Mary Lockett, in 1957.
After marrying fellow Chelsea student, Renia Mrozowska, in 1958 and completing his National Service, Jack Botting returned to Chelsea in 1959 to teach in the Department of Pharmacology, which he did until 1990. Over this period, he was a mentor to many students, who then had and continue to have, significant careers in the field of Pharmacology all over the world.
Following his retirement from teaching, Jack Botting was Scientific Director of the Research Defence Society until 1995, producing articles and papers on the significance of animal experimentation to the discovery of new drugs. He also edited a number of books, some with Sir John Vane, including Animal Experimentation and the Future of  Medical Research (1992), Improved Steroid Anti-Inflammatory Drugs (1996), Selective COX-2 Inhibitors (1998) and Leukotrienes (1998).

Regina (Renia) Maria Botting (née Mrozowska) was born in Warsaw, Poland in 1932 and arrived in the UK as a refugee with her family in June 1940. She graduated from Chelsea College with a B.Pharm degree in 1953 and completed her PhD in 1957 going on to teach the Pharmacology programme at North East Surrey College of Technology, in addition to doing research and publishing papers throughout this period.
In 1986, Renia Botting joined the William Harvey Research Institute at St Bartholomew’s Hospital Medical College, working with the 1982 Nobel Laureate in Physiology or Medicine, Sir John Vane. While there, she wrote more than 100 articles and co-edited books with Sir John including Aspirin and Other Salicylates (1992) and Therapeutic Roles of Selective COX-2 Inhibitors (2001).

1. Smallpox and After: An Early History of the Treatment and Prevention of Infections
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.

2. Rabies
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
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.

4. Pertussis Vaccine, Unfairly Maligned – At What Cost?
Whooping 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.

5. Vaccination: The Present and Future
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.

6. The Conquest of Polio and the Contribution of Animal Experiments
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.

7. Diphtheria: Understanding, Treatment and Prevention
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.

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.

9. The Contribution of Animal Experiments to Kidney Transplantation
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.

10. Cardiopulmonary Bypass: Making Surgery on the Heart Possible
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.

11. Artificial Heart Valves: From Caged Ball to Bioprosthesis
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.

12. Animals and Blood Transfusion
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.

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.

14. Animals and Humans: Remarkably Similar
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.

15. Early Animal Experiments in Anaesthesia
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.

16. The Control of Malignant Hypertension
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.

17. Penicillin and Laboratory Animals: The Animal Rights Myth
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.

18. The History of Thalidomide
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.

19. Misleading Research or Misleading Statistics: Animal Experiments and Cancer Research
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.