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module 1_advances preclinical research.pptx
- 1. Animals in biomedicalresearch
- 2. • BSc Zoology •PhD Gastroenterology and Endocrinology • Post Doc Gastroenterology and Endocrinology • Post Doc Neurosciences • Post Doc Regenerative Medicine • >20 years experience working with animals • Multiple project license holder (UOM) About me
- 3. So what isPreclinical resarch? • the study of specific diseases and conditions • the design of methods, drugs and devices used to diagnose, support and maintain the individual during and after treatment for specific diseases or conditions • the scientific investigation required to understand the underlying life processes which affect disease and human well-being
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- 6. Global projections forselective causes 0 2 4 6 8 10 12 2000 2005 2010 2015 2020 2025 2030 Deaths (millions) Updated from Mathers and Loncar, PLoS Medicine, 2006 Cancers Stroke Acute respiratory infections Road traffic accidents Perinatal HIV/AIDS TB Malaria Ischaemic HD
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- 8. 1875 Creation of“Society for Prevention of Cruelty to Animals” 1875 Ms Francis Powers Cobbe forms Victoria Street Society 1876 “Cruelty to Animals” laws in the UK 1884 London Society for the Prevention of Cruelty to Children founded 1897 National Anti-Vivisection Society & British Union for Abolition of Vivisection founded 1908 Research Defence Society (RDS) founded Early 20th century slow increase in use of animals Post WWII – chemical industry boom & increased science funding huge increase in animal experiments 1959 1975 1980s 1990s 2009 Russell and Burch publish the 3 ‘Rs’ Singer publishes “Animal Liberation” Increase in alternatives e.g. in vitro Significant increase in use of transgenics RDS and Coalition for Medical Progress merge Historical perpsective
- 9. What are thestatistics? Collected by Home Office UK Published Annually
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- 11. Animals in society Eachyear in the UK how many animals are: • used for research? • used for food? • killed as vermin? • abandoned pets? • killed by domestic cats? 3.2 million 2.5 billion 2 million 117,000 220 million
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- 14. What advances havebeen made?
- 15. 1910s-1920s Blood transfusions (dogs, guineapigs, rabbits) Insulin (dogs, rabbits, mice)
- 16. 1930s-1940s Penicillin and streptomycin (mice) Diphtheriavaccine (guinea pigs, rabbits, horses, monkeys) Kidney dialysis (guinea pigs, rabbits, dogs, monkeys)
- 17. 1950s-1960s Polio vaccine (mice, monkeys) Kidneytransplants (dogs) Cardiac pacemakers (dogs) Heart transplants (dogs)
- 18. 1970s-1980s Chemotherapy (mice) Asthma inhalers (guinea pigs,rabbits) MRI scanning (rabbits, pigs) Treatment for river blindness (rodents, cattle) Treatment for leprosy (armadillos, monkeys)
- 19. 1990s-2000s Combined therapy forHIV (mice, monkeys) Meningitis vaccines (mice) Deep brain stimulation for Parkinson’s (monkeys) Cervical cancer vaccine (rabbits, cattle)
- 20. Turning off hisbrain stimulator Mike Robins, Parkinson’s patient https://www.youtube.com/watch?v=h8tWlYv1Ykc
- 21. J Royal SocMed 2008: 101: 95–98
- 22. Myths and facts Relatedto Vernon Coleman’s “10 biggest vivisector lies”
- 23. • Humans biologicallyvery similar to other mammals – descended from common ancestors • Most human diseases exist in at least one other species • Vitamins and hormones identified by animal experiments have similar functions in people • Many veterinary medicines used in animals are the same or similar to those for patients Research on animals not relevant to people
- 24. • Misunderstands rationalefor testing in animals Animal testing unreliable – drugs have different effects in animals & people
- 25. ‘Thalidomide - about10,000 birth defects world wide, and effects do not appear in most laboratory animals - so the human tragedy would probably still occur’ • Prescribed in pregnancy to overcome morning sickness with dreadful effects on developing embryo • Not tested on pregnant animals during pre-clinical studies, as this was not a legal requirement at the time • After the effects of thalidomide had been established and the drug withdrawn, the same effects were shown to occur in many different species (e.g. mice, rats, rabbits, macaques, marmosets, baboons and rhesus monkey) • FDA refused to approve thalidomide for use in pregnant women, as they felt insufficient testing had been done Thalidomide
- 26. • ASPA doesnot allow animals to be used where the information could be gained by other means • Trivial or repetitive work will likely not be approved • All animal experiments go through ethical review at local level • Animal experiments are expensive • Funds are limited, so each proposal rigorously assessed Many pointless, unnecessary animal experiments are carried out
- 27. Animal research iscarried out for profit “If researchers were motivated by the desire for profit, rather than the desire to establish scientific fact, then animal experimentation is the last technique they would adopt, since it is much more expensive than other, non-animal methods.”
- 28. • 60% ofall procedures carried out without anaesthesia – Breeding, simple injections, blood collection (e.g. rabbits ears), dietary or behavioural studies • In majority of remainder anaesthetics or pain-killing drugs are used to prevent discomfort • Invasive procedures without anaesthesia very rigorously scrutinised and extremely rare Laboratory animals suffer great pain and distress
- 29. Use of animalsunnecessary because equivalent information can be obtained by alternative methods ‘computer simulations, cell, tissue or organ cultures, complex artificial systems, epidemiology, QSARs or brain imaging” (BUAV FAQ) • Many of these “alternatives” provide initial leads, but still need animal experiments to verify efficacy • Alternatives ARE used wherever possible • Animal experiments are expensive • Around 10% of medical research funding is spent on animals • Most tissue culture and all organ culture uses serum, invariably derived from animals
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- 31. GM animals • Insertionof human genes associated with disease into mice (and other animals) • Can ‘mimic’ aspects of the human condition – Dystrophin (muscular dystrophy); Amyloid/tau (dementia) etc • Allows potential treatments to be tested • Does not have to be disease related – e.g. can visualise synaptic circuits (‘Brainbow mice’)
- 32. Stem cells • Stemcells have capacity to differentiate into any cell type - can stimulate production of endogenous factors • Isolated from humans and other sources and placed into animals to study effects • Potential to treat a whole range of diseases from paralysis to blindness e.g. – Stem cells from nose grown in vitro – Transplant into rats with spinal cord injury – Improves recovery • Several clinical studies
- 33. Imaging • Non-invasive meansof monitoring anatomy, function and neurochemistry – Positron emission tomography (PET) – Magnetic resonance imaging (MRI) – Computed tomography (CT) – Bioluminescence – Fluorescence • Can monitor same animal over time • Correlate findings with behaviour
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- 35. ARRIVE guidelines • AnimalResearch: Reporting In Vivo Experiments • Intended to improve reporting of animal experiments • Developed by NC3Rs National Centre 3Rs • Published by and adopted by many journals • Guidelines consist of a 20-point checklist of the essential information that should be included in publications reporting animal research
- 36. The 3Rs –Russell and Burch William Russell and Rex Burch, Principles of Humane Experimental Technique ;1959 • Reduction • Refinement • Replacement
- 37. Reduction • use asfew animals as possible • maximise each one’s usefulness – share tissues between groups – employ experimental design to maximise power – use pilot studies to assess general efficacy prior to full study
- 38. Refinement • Adopt experimentaland husbandry techniques that minimise animal suffering and promote wellbeing • provide environmental enrichment • enhanced experimental technique; training and performance – ethical and scientific benefits • experimental design and effective reporting – ARRIVE Guidelines from NC3Rs
- 39. Replacement • replacing protectedanimals in experimental and scientific procedures • can be divided into 6 categories: – information mining – in silico (computer modelling) – physico-chemical techniques – lower organisms or embryonic stages – in vitro (cell, tissue and organ based assays) – human studies
- 40. Humane Methods ofKilling • Animals may have to be killed at points during scientific studies • Must be done with care and competence to reduce stress to the animal
- 41. Schedule 1 ofASPA 1986 (amended 2012) A. Methods for animals other than foetal, larval and embryonic forms Animals for which appropriate 1.Overdose of an anaesthetic using a route and an anaesthetic agent appropriate for the size and species of animal All animals 2.Exposure to carbon dioxide gas in a rising concentration Rodents, Rabbits and Birds up to 1.5kg (but not neonatal rodents) 3.Dislocation of the neck (with the prior use of a sedative or anaesthetic in the case of rodents and rabbits over 150 g and birds over 250 g) Rodents up to 500g Rabbits up to 1kg Birds up to 1kg 4.Concussion of the brain by striking the cranium Rodents and Rabbits up to 1kg Birds up to 250g Amphibians and reptiles (with destruction of the brain before the return of consciousness) up to 1kg Fishes (with destruction of the brain before the return of consciousness) 5.One of the recognised methods of slaughter set out below which is appropriate to the animal and is performed by a registered veterinary surgeon, or, in the case of the methods described in paragraph (ii) below, performed by the holder of a current licence granted under the Welfare of Animals (Slaughter or Killing) Regulations 1995 (a) i) Destruction of the brain by free bullet, or ii) captive bolt or electrical stunning followed by destruction of the brain or exsanguination before return of consciousness. Ungulates B. Methods for foetal, larval and embryonic forms Animals for which appropriate 1. Overdose of an anaesthetic using a route and anaesthetic agent appropriate for the size, stage of development and species of animal All animals 2. Refrigeration, or disruption of membranes, or maceration in apparatus approved under appropriate slaughter legislation, or exposure to carbon dioxide in near 100% concentration until they are dead Birds Reptiles 3. Cooling of foetuses followed by immersion in cold tissue fixative Mice, Rats and Rabbits 4. Decapitation Mammals and Birds up to 50g
- 42. Confirmation of death •permanent cessation of circulation • destruction of the brain • dislocation of the neck • exsanguation • rigor mortis • mechanical disruption
- 43. Recognition of Wellbeing,Pain and Distress.
- 44. 1. Why youneed to know the difference.
- 45. Animals may bein pain or distress due to:
- 46. Ill health /disease.
- 47. Ill health /disease.
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- 50. Recognition of thehealthy, well animal.
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- 58. Recognition of theanimal which is stressed, ill or in pain
- 59. Recognition of theanimal which is stressed, ill or in pain.
- 60. Recognition of theanimal which is stressed, ill or in pain.
- 61. Recognition of theanimal which is stressed, ill or in pain.
- 62. Recognition of theanimal which is stressed, ill or in pain.