Animal Models 24 25 BIO217 PDF

ANIMAL MODELS  DEFINITION ❑ According to Wessler, “an animal model is a living organism in which a spontaneous or induced pathological process can be investigated, and in which the phenomenon in one or more respects resembles the same phenomenon in humans or other...

ANIMAL MODELS  DEFINITION ❑ According to Wessler, “an animal model is a living organism in which a spontaneous or induced pathological process can be investigated, and in which the phenomenon in one or more respects resembles the same phenomenon in humans or other species of animal” ❑ They serve as tools that researchers use to study diseases and test treatments in cases where human experimentation is not possible or unethical ❑ Analogy is a key word that is essential for understanding the concept of animal models – analogy refers to resemblance of the physiological mechanisms of model animals to humans or other species ❑ Animal models have been very critical to the development, evaluation and trials of many new vaccines and treatments ❑Animal models are used in research because they share very similar biology with humans and that diseases that affect humans also affect other animal species ❑For example infectious diseases and other common conditions such as hypertension, cancer, diabetes etc ❑Many veterinary drugs used to treat animals are very similar or analogous to those used to treat humans ❑At anatomical and physiological levels, animals and humans are remarkably similar ❑Animals, from mice to monkeys, have the same organs (heart, lungs, brain etc.) and organ systems (respiratory, cardiovascular, nervous systems etc.) which perform the same functions in pretty much the same way ❑A lot of vaccines which saved many human and animal lives were successfully developed using animal models ❑The treatment of Type I diabetes with insulin was first demonstrated in dog by Banting and McLeod ❑Tissue engineering for the regeneration of tissues, replacement of damaged or diseased tissue was first tested in animals ❑Many surgical procedures before being applied to humans were first tested in various animal models  CRITERIA FOR SELECTING ANIMAL MODELS ❑ For an animal to be selected as a model, it must meet the following conditions ▪ Accurately mimic the desired function or disease ▪ Data extrapolatable to man ▪ Be available to multiple investigators ▪ Be handled easily by most investigators ▪ Survive long enough to be functional ▪ Fit available animal housing facilities ▪ Be of sufficient size to provide multiple samples ▪ Be polytococous (multiparous) so that multiple offspring are produced for each gestation  CLASSIFICATION OF ANIMAL DISEASE MODELS Disease models may be grouped into one of the following five categories: 1. Induced (experimental) models 2. Spontaneous (genetic, mutant) models 3. Genetically modified/ “knock-in” / “knock-out” models 4. Negative or non-reactive models 5. Orphan models ❑INDUCED MODELS are healthy animals in which the disease condition to be investigated is induced experimentally ▪ For example, the induction of diabetes milletus using the antibacterial agent streptozotocin (STZ) or alloxan SPONTANEOUS MODELS models of human diseases that have been bred to conserve phenotypical characteristics that were due to spontaneous genetic mutations ▪ Example is the athymic nude mouse which lacks a thymus (an organ that is crucial to the immune system which serves as the body's defense mechanism by providing surveillance and protection against different tumors, antigens, pathogens and molecules that bring about tissue damage) ▪ Athymic mice are unable to produce T-cells and are therefore immunodeficient ▪ Athymic mice was first used to demonstrate cytotoxic activity of natural killer (NK) cells to heterotransplanted tumors ▪ Most spontaneous models involve rat and mice models Athymic mice: Jax.org ❑ GENETICALLY ENGINEERED/ “KNOCK-IN”/ ”KNOCK-OUT” MODELS ▪ models in which an existing gene is turned off or inactivated by disrupting or replacing it with an artificial piece of DNA is called a “knockout” model ▪ By turning off a gene, researchers are able to understand the function of that gene ▪ Humans share several genes with mice ▪ As such, observing the characteristics of knockout mice, researchers gain insights into how a similar gene can contribute or cause diseases in humans ▪ For example, knockout mice have been used model obesity, various kinds of cancers, Parkinson disease, arthritis etc p53 knockout mice (in which the p53 gene has been turned off or inactivated) is a model for bone, blood and breast cancers "Methuselah" is a knockout mouse model for investigating longevity, while "Frantic" is a model for studying anxiety disorders p53 knockout mice used to study cancer and tumour suppression: genetageting.com ▪ Models in which an exogenous gene is inserted at a targeted locus in their genome are called “knockin” models ▪ Many knockin mouse have been developed to study various diseases such as Huntington’s disease and Huntington’s disease Knockin mice: genetargeting.com ❑ NEGATIVE OR NON-REACTIVE MODELS These are animal models in which the disease causing agent that affects humans does not cause the disease in the animal ▪ Negative models thus include animals that exhibit a lack of reactivity to a particular stimulus that would typically cause a disease in humans ▪ Such models are applied to study the mechanism of disease resistance. This can provide insights into why certain organisms are resistant to diseases that affect humans and can help in developing new treatments or vaccines ▪ Example tuberculosis (TB) caused by Mycobacterium tuberculosis is serious condition in humans, but certain rodents, like the naked mole-rat does not develop TB when exposed to the bacteria ❑ ORPHAN MODELS These are animal models with diseases that have not been recognized in humans. When a comparable human disease is discovered, these models become invaluable for studying the human condition Examples ▪ Papillomatosis: a viral disease that causes benign tumours (warts) in animals like dogs and cattle. Once similar conditions were identified in humans, research on papillomatosis in animals helped in understanding human papillomavirus (HPV) and its link to cancers ▪ Bovine Spongiform Encephalopathy (BSE): Also known as mad cow disease, BSE is a neurodegenerative disease in cattle. The discovery of variant Creutzfeldt-JaKob Disease (vCJD) in humans, which is linked to consuming BSE-infected meat, transformed BSE into a model for studying human prion disease  EXTRAPOLATION OF DATA FROM ANIMAL MODELS ❑After experimental results have been generated in an animal model, they have to be subjected to validation with respect to their applicability to the target species, which normally is the human ❑The term extrapolation is often used to describe how data obtained from animal studies can be translated into therapy to improve human health ❑Validation is important as animal studies sometimes do not predict with certainty the outcomes in humans due to undesirable effects, toxicity, low efficacy, off targets and problematic dosing  ETHICAL CONCERNS ON THE USE OF ANIMAL MODELS IN RESEARCH ❑ Experimentation using animal models has sparked global debates on animal welfare, leading the British Parliament to introduce the cruelty to Animals Act in 1876, pioneering regulatory frameworks for animal experimentation ❑The cruelty to animal act emphasized the following three main points: 1. Animal experiments should only be conducted when there is absolute need of knowledge that will be useful for saving or prolonging life or alleviate suffering”; 2. The animals must be anesthetized during experiment; and 3. The animals must be euthanized immediately if after the experimental procedure they would be injured or in pain as a result of the experiment ❑ William Russell (Zoologist and Psychologist) and Rex Burch (Microbiologist) in 1959 developed the “3R’s Principle” that guides the ethical use of animals in research ❑ The 3 Rs are: 1. Reduction 2. Refinement 3. Replacement ▪ REPLACEMENT animals must not be used whenever other, non-animal-based, experimental approaches are available, with similar relevance and reliability ▪ This principle advances the substitution of animals with alternative models such as cell cultures, organs, micro-organisms and other invertebrates. An ideal replacement would be an experimentation conducted without the use of animals ▪ REDUCTION the number of animals used must be reduced to the minimum needed to reach a conclusion ▪ REFINEMENT efforts must be taken throughout the experiment/research to minimize any harm/suffering animals are subjected to ▪ This principle advances the use of non-invasive strategies, housing conditions that offers a safe and conducive environment, the use of anaesthesia during a procedure and analgesics for pain relief during recovery ▪ The 3R’sare now universal and guide animal experimentation in several countries