History of animal testing

The history of animal testing goes back to the writings of the Greeks in the third and fourth centuries BCE, with Aristotle (384-322 BCE) and Erasistratus (304-258 BCE) among the first to perform experiments on living animals. [Cohen and Loew 1984.] Galen, a physician in second-century Rome, dissected pigs and goats, and is known as the "father of vivisection." [http://www.lpag.org/layperson/layperson.html#history "History of nonhuman animal research"] , Laboratory Primate Advocacy Group.]

Early debate

For philosophical issues relating history of ethics in animal rights see Animal Rights.

In 1655, physiologist Edmund O'Meara is recorded as saying that "the miserable torture of vivisection places the body in an unnatural state."Ryder, Richard D. "Animal Revolution: Changing Attitudes Towards Speciesism". Berg Publishers, 2000, p. 54.] [http://www.adelaide.edu.au/ANZCCART/resources/AnimalExperimentation.pdf "Animal Experimentation: A Student Guide to Balancing the Issues"] , Australian and New Zealand Council for the Care of Animals in Research and Teaching (ANZCCART), retrieved December 12, 2007, cites original reference in Maehle, A-H. and Tr6hler, U. 1987. Animal experimentation from antiquity to theend of the eighteenth century: attitudes and arguments. In N. A. Rupke (ed.) Vivisection in Historical Perspective. Croom Helm, London, p. 22] O'Meara thus expressed one of the chief scientific objections to vivisection: that the pain that the subject endured would interfere with the accuracy of the results.

On the other side of the debate, those in favor of animal testing held that experiments on animals were necessary to advance medical and biological knowledge. Claude Bernard, known as the "prince of vivisectors"Croce, Pietro. "Vivisection or Science? An Investigation into Testing Drugs and Safeguarding Health". Zed Books, 1999, p. 11.] and the father of physiology — whose wife, Marie Françoise Martin, founded the first anti-vivisection society in France in 1883 [Rudacille, Deborah. "The Scalpel and the Butterfly: The Conflict", Farrar Straus Giroux, 2000, p. 19.] — famously wrote in 1865 that "the science of life is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen". [http://www.telegraph.co.uk/health/main.jhtml?xml=/health/2003/11/24/hsick23.xml "In sickness and in health: vivisection's undoing"] , "The Daily Telegraph, November 2003.] Arguing that "experiments on animals ... are entirely conclusive for the toxicology and hygiene of man...the effects of these substances are the same on man as on animals, save for differences in degree,"Bernard, Claude "An Introduction to the Study of Experimental Medicine", 1865. First English translation by Henry Copley Greene, published by Macmillan & Co., Ltd., 1927; reprinted in 1949, p125] Bernard established animal experimentation as part of the standard scientific method.LaFollette, H., Shanks, N., Animal Experimentation: the Legacy of Claude Bernard, "International Studies in the Philosophy of Science" (1994) pp. 195-210.] In 1896, the physiologist and physician Dr. Walter B. Cannon said “The antivivisectionists are the second of the two types Theodore Roosevelt described when he said, ‘Common sense without conscience may lead to crime, but conscience without common sense may lead to folly, which is the handmaiden of crime.’ ” [http://www.the-aps.org/publications/tphys/legacy/1991/issue6/303.pdf The Physiologist at the-aps.org A Physiologist’s Viewson the Animal Rights/Liberation Movement] by Charles S. Nicoll "The Physiologist" 34(6): Dec 1991] These divisions between pro- and anti- animal testing groups first came to public attention during the brown dog affair in the early 1900s, when hundreds of medical students clashed with anti-vivisectionists and police over a memorial to a vivisected dog.Mason, Peter. [http://www.london-books.co.uk/books/browndog.html "The Brown Dog Affair"] . Two Sevens Publishing, 1997.]

In 1822, the first animal protection law was enacted in the British parliament, followed by the Cruelty to Animals Act (1876), the first law specifically aimed at regulating animal testing. The legislation was promoted by Charles Darwin, who wrote to Ray Lankester in March 1871: "You ask about my opinion on vivisection. I quite agree that it is justifiable for real investigations on physiology; but not for mere damnable and detestable curiosity. It is a subject which makes me sick with horror, so I will not say another word about it, else I shall not sleep to-night." [ [http://www.fullbooks.com/The-Life-and-Letters-of-Charles-Darwinx29407.html "The Life and Letters of Charles Darwin, Volume II"] , "fullbooks.com".] [Bowlby, John. "Charles Darwin: A New Life", W. W. Norton & Company, 1991. p. 420.] Opposition to the use of animals in medical research first arose in the United States during the 1860s, when Henry Bergh founded the American Society for the Prevention of Cruelty to Animals (ASPCA), with America's first specifically anti-vivisection organization being the American AntiVivisection Society (AAVS), founded in 1883. Antivivisectionists of the era generally believed the spread of mercy was the great cause of civilization, and vivisection was cruel. However, in the USA the antivivisectionists' efforts were defeated in every legislature, overwhelmed by the superior organization and influence of the medical community. The early antivivisectionist movement in the USA dwindled greatly in the 1920s, potentially caused by a variety of factors including opposition of the medical community, improvement in medicine through the use of animals, and the tendency of the antivivisectionists to misrepresentation and exaggeration, and their use of inaccurate, vague and outdated references. Overall, this movement had no US legislative success until the passing of the Laboratory Animal Welfare Act, in 1966. [Buettinger, Craig [http://www.encyclopedia.com/doc/1G1-13506650.html Antivivisection and the charge of zoophil-psychosis in the early twentieth century.] "The Historian" 1 January 1993]

Basic science advances

In the 1600s, William Harvey described the movement of blood in mammals. In the 1700s, Antoine Lavoisier, used a guinea pig in a calorimeter to prove that respiration was a form of combustion, and Stephen Hales measured blood pressure in the horse. In the 1880s, Louis Pasteur convincingly demonstrated the germ theory of medicine by giving anthrax to sheep. In the 1890s, Ivan Pavlov famously used dogs to describe classical conditioning.

In 1921 Otto Loewi provided the first strong evidence that neuronal communication with target cells occurred via chemical synapses. He extracted two hearts from frogs and left them beating in an ionic bath. He stimulated the attached Vagus nerve of the first heart, and observed its beating slowed. When the second heart was placed in the ionic bath of the first, it also slowed. [ [http://www.springerlink.com/media/hb5c1xjkyj5xwgb1va6q/contributions/x/0/1/3/x01314653605h385.pdf] O. Loewi (1921) "Uber humorale Ubertragbarkeit der Herznervenwirkung. I." "Pflugers Archiv", 189, pp. 239-242]

In the 1920s, Edgar Adrian formulated the theory of neural communication that the frequency of action potentials, and not the size of the action potentials, was the basis for communicating the magnitude of the signal. His work was performed in an isolated frog nerve-muscle preparation. Adrian was awarded a Nobel Prize for his work. [ [http://nobelprize.org/nobel_prizes/medicine/laureates/1932/adrian-bio.html] Adrian Nobel Prize]

In the 1960s David Hubel and Torsten Wiesel demonstrated the macrocolumnar organization of visual areas in cats and monkeys, and provided physiological evidence for the critical period for the development of disparity sensitivity in vision (ie: the main cue for depth perception), and were awarded a Nobel Prize for their work.

In 1996 Dolly the sheep was born, the first mammal to be cloned from an adult cell.

Medical advances

In the 1880s and 1890s, Emil von Behring isolated the diphtheria toxin and demonstrated its effects in guinea pigs. He went on to demonstrate immunity against diphtheria in animals in 1898 by injecting a mix of toxin and antitoxin. This work constituted in part the rationale for awarding von Behring the 1901 Nobel Prize in Physiology and Medicine. Roughly 15 years later, Behring announced such a mix suitable for human immunity which largely banished the diphtheria from the scourges of mankind. [ [http://nobelprize.org/nobel_prizes/medicine/laureates/1901/behring-bio.html Bering Nobel Biography] ] The antitoxin is famously commemorated each year in the Iditarod race, which is modeled after the delivery of diphtheria antitoxin to Nome in the 1925 serum run to Nome. The success of the animal studies in producing the diphtheria antitoxin are attributed by some as a cause in the decline of the early 1900s antivivisectionist movement in the USA. [ [http://www.amphilsoc.org/library/mole/c/cannon.htm Walter B. Cannon Papers, American Philosophical Society] ]

In 1921, Frederick Banting tied up the pancreatic ducts of dogs, and discovered that the isolates of pancreatic secretion could be used to keep dogs with diabetes alive. He followed up these experiments with chemical isolation of insulin in 1922 with John Macleod. These experiments used bovine sources instead of dogs to improve the supply. [ [http://www.discoveryofinsulin.com/Experiments.htm Experiments in discovery of insulin] ] The first person treated was Leonard Thompson, a 14 year old diabetic who only weighed 65 pounds and was about to slip into a coma and die. After the first dose, the formulation had to be re-worked, a process that took 12 days. The second dose was effective. [ [http://www.mta.ca/faculty/arts/canadian_studies/english/about/study_guide/doctors/insulin.html Discovery of Insulin] ] These two won the Nobel Prize in Physiology or Medicine in 1923 for their discovery of insulin and its treatment of diabetes mellitus. Thompson lived 13 more years taking insulin. Before insulin's clinical use, a diagnosis of diabetes mellitus meant death; Thompson had been diagnosed in 1919. [ [http://www.dlife.com/dLife/do/ShowContent/inspiration_expert_advice/famous_people/leonard_thompson.html Thompson bio ref] ]

In the 1943, Selman Waksman's laboratory discovered streptomycin using a series of screens to find antibacterial substances from the soil. Waksman coined the term antibiotic with regards to these substances. Waksman would win the Nobel Prize in Medicine in 1952 for his discoveries in antibiotics. Corwin Hinshaw and William Feldman took the streptomycin samples and cured tuberculosis in four guinea pigs with it. Hinshaw followed these studies with human trials that provided a dramatic advance in the ability to stop and reverse the progression of tuberculosis. [ [http://www.rawbw.com/~hinshaw/cgi-bin/id?1375] Hinshaw obituary] [ [http://www.discoveriesinmedicine.com/Ra-Thy/Streptomycin.html] Streptomycin] Mortality from tuberculosis in the UK has diminished from the early 20th century due to better hygiene and improved living standards, but from the moment antibiotics were introduced, the fall became much steeper, so that by the 1980s mortality in developed countries was effectively zero. [Is Science Necessary
Author: Max Perutz
Page: 37-41
Published 1989
Publisher E.P. Dutton/NAL Penguin Inc
ISBN 0-525-24673-8]

In the 1940s, Jonas Salk used Rhesus monkey cross-contamination studies to isolate the three forms of the polio virus that affected hundreds of thousands yearly. [ [www.post-gazette.com/pg/05093/481117.stm] Virus-typing of polio by Salk] Salk's team created a vaccine against the strains of polio in cell cultures of Rhesus monkey kidney cells. The vaccine was made publicly available in 1955, and reduced the incidence of polio 15-fold in the USA over the following five years. [ [http://www.post-gazette.com/pg/05094/482468.stm] Salk polio virus ] Albert Sabin made a superior "live" vaccine by passing the polio virus through animal hosts, including monkeys. The vaccine was produced for mass consumption in 1963 and is still in use today. It had virtually eradicated polio in the USA by 1965. [ [http://americanhistory.si.edu/polio/virusvaccine/vacraces2.htm] History of polio vaccine] It has been estimated that 100,000 Rhesus monkeys were killed in the course of developing the polio vaccines, and 65 doses of vaccine were produced for each monkey.

Also in the 1940s, John Cade tested lithium salts in guinea pigs in a search for pharmaceuticals with anticonvulsant properties. The animals seemed calmer in their mood. He then tested lithium on himself, before using it to treat recurrent mania. [ [http://www.adb.online.anu.edu.au/biogs/A130374b.htm] John Cade and Lithium ] The introduction of lithium revolutionized the treatment of manic-depressives by the 1970s. Prior to Cade's animal testing, manic-depressives were treated with lobotomy or electro-convulsive therapy.

In the 1950's the first safer, non-volatile anaesthetic halothane was developed through studies on rodents, rabbits, dogs, cats and monkeys.Raventos J (1956) "Brit J Pharmacol" 11, 394] This paved the way for a whole new generation of modern general anaesthetics - also developed by animal studies - without which modern, complex surgical operations would be virtually impossible.Whalen FX, Bacon DR & Smith HM (2005) "Best Pract Res Clin Anaesthesiol" 19, 323]

In 1960, Albert Starr pioneered heart valve replacement surgery in humans after a series of surgical advances in dogs. [ [http://blog.oregonlive.com/breakingnews/2007/09/starr_receives_nations_most_pr.html Portland surgeon receives top medical prize - OregonLive.com: Breaking News Updates ] ] He received the Lasker Medical Award in 2007 for his efforts, along with Alain Carpentier. In 1968 Carpentier made heart valve replacements from the heart valves of pigs, which are pre-treated with gluteraldehyde to blunt immune response. Over 300,000 people receive heart valve replacements derived from Starr and Carpentier's designs annually. Carpentier said of Starr's initial advances "Before his prosthetic, patients with valvular disease would die". [ [http://www.the-scientist.com/blog/display/53590/ The Scientist : Blogs ] ]

In the 1970s, leprosy multi-drug antibiotic treatments were refined using leprosy bacteria grown in armadillos, and were then tested in human clinical trials. Today, the nine-banded armadillo is still used to culture the bacteria that causes leprosy, for studies of the proteomics and genomics (the genome was completed in 1998) of the bacteria, for the purposes of improving therapy and developing vaccines. Leprosy is still prevalent in Brazil, Madagascar, Mozambique, Tanzania, India and Nepal, with over 400,000 cases at the beginning of 2004. [ [http://www.spectroscopynow.com/coi/cda/detail.cda?id=1682&type=Feature&chId=10&page=1 Armadillos enlisted in leprosy research] ] The bacteria has not yet been cultured "in vitro" with success necessary to develop drug treatments or vaccines, and mice and armadillos have been the sources of the bacteria for research. [ [http://www.everwonder.com/david/armadillo/research.html Armadillos in research] ]

The non-human primate models of AIDS, using HIV-2, SHIV, and SIV in macaques, have been used as a complement to ongoing research efforts against the virus. The drug tenofovir has had its efficacy and toxicology evaluated in macaques, and found longterm-highdose treatments had adverse effects not found using shortterm-highdose treatment followed by longterm-lowdose treatment. This finding in macaques was translated into human dosing regimens. Prophylactic treatment with anti-virals has been evaluated in macaques, because introduction of the virus can only be controlled in an animal model. The finding that prophylaxis can be effective at blocking infection has altered the treatment for occupational exposures, such as needle exposures. Such exposures are now followed rapidly with anti-HIV drugs, and this practice has resulted in measurable transient virus infection similar to the NHP model. Similarly, the mother-to-fetus transmission, and its fetal prophylaxis with antivirals such as tenofovir and AZT, has been evaluated in controlled testing in macaques not possible in humans, and this knowledge has guided antiviral treatment in pregnant mothers with HIV. "The comparison and correlation of results obtained in monkey and human studies is leading to a growing validation and recognition of the relevance of the animal model. Although each animal model has its limitations, carefully designed drug studies in nonhuman primates can continue to advance our scientific knowledge and guide future clinical trials." [ [http://www.aidsreviews.com/files/2005_7_2_67_83.pdf AIDS Reviews 2005;7:67-83 Antiretroviral Drug Studies in Nonhuman Primates: a Valid Animal Model for Innovative Drug Efficacy and Pathogenesis Experiments] ] [ [http://www.thebody.com/cdc/tb165.html PMPA blocks SIV in monkeys] ] [ [http://www.thebody.com/bp/dec99/medical.html PMPA is tenofovir] ]

Throughout the twentieth century, research that used live animals has led to many other medical advances and treatments for human diseases, such as: organ transplant techniques and anti-transplant rejection medications,Carrel A (1912) "Surg. Gynec. Obst." 14: p. 246] Williamson C (1926) "J. Urol." 16: p. 231] Woodruff H & Burg R (1986) in "Discoveries in Pharmacology" vol 3, ed Parnham & Bruinvels, Elsevier, Amsterdam] Moore F (1964) "Give and Take: the Development of Tissue Transplantation". Saunders, New York] the heart-lung machine,Gibbon JH (1937) "Arch. Surg." 34, 1105] antibiotics like penicillin,Fleming A (1929) "Brit J Exper Path" 10, 226] and whooping cough vaccine.Medical Research Council (1956) "Br. Med. J." 2: p. 454]

Presently, animal experimentation continues to be used in research that aims to solve medical problems from Alzheimer's disease,Geula C, Wu C-K, Saroff D, Lorenzo A, Yuan M, Yankner BA (1998) Aging renders the brain vulnerable to amyloid β protein neurotoxicity, "Nature Medicine" 4: p. 827] multiple sclerosisJameson BA, McDonnell JM, Marini JC & Korngold R (1994) A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis, "Nature" 368: p. 744] spinal cord injury,Lyuksyutova AL, Lu C-C, Milanesio N (2003) Anterior-posterior guidance of commissural axons by Wnt-Frizzled signaling. "Science" 302, 1984.] and many more conditions in which there is no useful "in vitro" model system available.

Veterinary advances

Animal testing for veterinary studies accounts for around five per cent of research using animals. Treatments to each of the following animal diseases have been derived from animal studies: rabies,"A reference handbook of the medical sciences". William Wood and Co., 1904, Edited by Albert H. Buck.] anthrax, glanders, Feline immunodeficiency virus (FIV),Pu R, Coleman J, Coisman J, Sato E, Tanabe T, Arai M, Yamamoto JK. btype FIV vaccine (Fel-O-Vax FIV) protection against a heterologous subtype B FIV isolate. "J Feline Med Surg." (2005) 7(1):65-70, PMID 15686976] tuberculosis, Texas cattle fever, Classical swine fever (hog cholera), Heartworm and other parasitic infections.Dryden MW, Payne PA. Preventing parasites in cats. "Vet Ther" (2005) 6:260-267, PMID 16299672]

Basic and applied research in veterinary medicine continues in varied topics, such as searching for improved treatments and vaccines for feline leukemia virus and improving veterinary oncology.

See also

* History of model organisms
* Animal testing
* Alarik Frithiof Holmgren

Notes

Further reading

* [http://www.fbresearch.org/Education/nobels.htm Nobel Prizes for animal research]
* [http://vivisection-absurd.org.uk/menun.html Full History of Absurdity of Animal Research]