Animal disease model

Last updated

An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of harming a human. Although biological activity in an animal model does not ensure an effect in humans, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models. [1] [2] Animal models representing specific taxonomic groups in the research and study of developmental processes are also referred to as model organisms. [2] There are three main types of animal models: Homologous, Isomorphic and Predictive. Homologous animals have the same causes, symptoms and treatment options as would humans who have the same disease. Isomorphic animals share the same symptoms and treatments, only. Predictive models are similar to a particular human disease in only a couple of aspects. However, these are useful in isolating and making predictions about mechanisms of a set of disease features. [3]

Contents

Phylogeny and genetic similarity

Although scientific study of animals predates Charles Darwin by several hundred years, the primary justification for the use of animals in research is based on the evolutionary principle that all organisms share some degree of relatedness and genetic similarity due to common ancestry. The study of taxonomic human relatives, then, can provide a great deal of information about mechanism and disease within the human body that can be useful in medicine.[ citation needed ]

Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics as well as the geochemical and fossil record. [4] These estimations tell us that humans and chimpanzees last shared a common ancestor about 6 million years ago (mya). As our closest relatives, chimpanzees have a lot of potential to tell us about mechanisms of disease (and what genes may be responsible for human intelligence). However, chimpanzees are rarely used in research and are protected from highly invasive procedures. The most common animal model is the rodent. Phylogenic trees estimate that humans and rodents last shared a common ancestor ~80-100mya. [5] [6] Despite this distant split, humans and rodents have far more similarities than they do differences. This is due to the relative stability of large portions of the genome; making the use of vertebrate animals particularly productive.[ citation needed ]

Recently, genomic data has been added to techniques to make close comparisons between species and determine relatedness. Humans share about 99% of our genome with chimpanzees [7] [8] (98.7% with bonobos) [9] and over 90% with the mouse. [6] With so much of the genome conserved across species, it is relatively impressive that the differences between humans and mice can be accounted for in approximately six thousand genes (of ~30,000 total). Scientists have been able to take advantage of these similarities in generating experimental and predictive models of human disease.[ citation needed ]

Disease models

Animal models serving in research may have an existing, inbred or induced disease or injury that is similar to a human condition. These test conditions are often termed as animal models of disease. The use of animal models allows researchers to investigate disease states in ways which would be inaccessible in a human patient, performing procedures on the non-human animal that imply a level of harm that would not be considered ethical to inflict on a human.

As in noted the introduction, animal models can be classified as homologous, isomorphic or predictive. Animal models can also be more broadly classified into four categories: 1) experimental, 2) spontaneous, 3) negative, 4) orphan. [10]

Experimental models are most common. These refer to models of disease that resemble human conditions in phenotype or response to treatment but are induced artificially in the laboratory. Some examples include:

Spontaneous models refer to diseases that are analogous to human conditions that occur naturally in the animal being studied. These models are rare, but informative.

Negative models essentially refer to control animals, which are useful for validating an experimental result.

Orphan models refer to diseases for which there is no human analog and occur exclusively in the species studied.

The increase in knowledge of the genomes of non-human primates and other mammals that are genetically close to humans is allowing the production of genetically engineered animal tissues, organs and even animal species which express human diseases, providing a more robust model of human diseases in an animal model.

The best models of disease are similar in etiology (mechanism of cause) and phenotype (signs and symptoms) to the human equivalent. However complex human diseases can often be better understood in a simplified system in which individual parts of the disease process are isolated and examined. For instance, behavioral analogues of anxiety or pain in laboratory animals can be used to screen and test new drugs for the treatment of these conditions in humans. A 2000 study found that animal models concorded (coincided on true positives and false negatives) with human toxicity in 71% of cases, with 63% for nonrodents alone and 43% for rodents alone. [24]

In 1987, Davidson et al. suggested that selection of an animal model for research be based on nine considerations. These include "1) appropriateness as an analog, 2) transferability of information, 3) genetic uniformity of organisms, where applicable, 4) background knowledge of biological properties, 5) cost and availability, 6) generalizability of the results, 7) ease of and adaptability to experimental manipulation, 8) ecological consequences, and 9) ethical implications." [25]

Behavioral sciences

Animal models observed in the sciences of psychology and sociology are often termed animal models of behavior. It is difficult to build an animal model that perfectly reproduces the symptoms of depression in patients. Animals lack self-consciousness, self-reflection and consideration;[ citation needed ] moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans.[ citation needed ] However, depression, as other mental disorders, consists of endophenotypes [26] that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between genetic or environmental alterations and depression can be examined, which would afford a better insight into pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.[ citation needed ]

Challenges and criticisms

Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively sedentary, obese and glucose intolerant. This may confound their use to model human metabolic processes and diseases as these can be affected by dietary energy intake and exercise. [27]

Animal models of psychiatric illness give rise to other concerns. Qualitative assessments of behavior are too often subjective. This would lead the investigator to observe what they want to observe in subjects, and to render conclusions in line with their expectations. Also, the imprecise diagnostic criteria for psychiatric illnesses inevitably lead to problems modeling the condition; e.g., since a person with major depressive disorder may experience weight loss or weight gain, insomnia or hypersomnia, we cannot with any certainty say that a rat with insomnia and weight loss is depressed. Furthermore, the complex nature of psychiatric conditions makes it difficult/impossible to translate human behaviors and deficits; e.g., language deficit plays a major role in autistic spectrum disorders, but – since rodents do not have language – it is not possible to develop a language-impaired "autistic" mouse.[ citation needed ]

Ethics

Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament enacted the first law for animal protection preventing cruelty to cattle see text. This was followed by the Cruelty to Animals Act of 1835 and 1849, which criminalized ill-treating, over-driving, and torturing animals. In 1876, under pressure from the National Anti-Vivisection Society, the Cruelty to Animals Act was amended to include regulations governing the use of animals in research. This new act stipulated that 1) experiments must be proven absolutely necessary for instruction, or to save or prolong human life; 2) animals must be properly anesthetized; and 3) animals must be killed as soon as the experiment is over (see text). Today, these three principles are central to the laws and guidelines governing the use of animals and research. In the U.S., the Animal Welfare Act of 1970 (see also Laboratory Animal Welfare Act) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care program see AWA policies.

In academic settings in which NIH funding is used for animal research, institutions are governed by the NIH Office of Laboratory Animal Welfare (OLAW). At each site, OLAW guidelines and standards are upheld by a local review board called the Institutional Animal Care and Use Committee (IACUC). All laboratory experiments involving living animals are reviewed and approved by this committee. In addition to proving the potential for benefit to human health, minimization of pain and distress, and timely and humane euthanasia, experimenters must justify their protocols based on the principles of Replacement, Reduction and Refinement. [28]

Replacement refers to efforts to engage alternatives to animal use. This includes the use of computer models, non-living tissues and cells, and replacement of "higher-order" animals (primates and mammals) with "lower" order animals (e.g. cold-blooded animals, invertebrates, bacteria) wherever possible (list of common model organisms approved for use by the NIH).

Reduction refers to efforts to minimize number of animals used during the course of an experiment, as well as prevention of unnecessary replication of previous experiments. To satisfy this requirement, mathematical calculations of statistical power are employed to determine the minimum number of animals that can be used to get a statistically significant experimental result. Reduction involves methods to maximize information provided while minimizing the number of animals applied. [29]

Refinement refers to efforts to make experimental design as painless and efficient as possible in order to minimize the suffering of each animal subject.[ citation needed ]

While significant advances have been made in the care and treatment of animals, this is an ever-evolving debate. Animal rights and protection groups such as the ASPCA, PETA and BUAV continue to advocate for the best laboratory conditions, and experimental protocols possible for animals in research. Pressure from these groups has also led to novel modes of experimentation, which does not involve the sacrifice of live animals.[ citation needed ]

One aspect of this debate; however, continues to be difficult to resolve: the classification of animals according to a hierarchy, which protects some species more than others. Next to humans, primates are the most protected species in experimentation. The rationale for this has both evolutionary and philosophical underpinnings. Because chimpanzees and other non-human primates can demonstrate intelligence, and social structure that they have a life experiences that is more cognitively complex than lower species. Conversely, this kind of moralizing of complexity of interaction and thought could be considered "specieisism." Ultimately, this is an argument not likely to be resolved, however most people are more comfortable with the idea of experimentation that involves worms or flies than mice, dogs, or monkeys.[ citation needed ]

Alternatives

Ethical concerns, as well as the cost, maintenance and relative inefficiency of animal research has encouraged development of alternative methods for the study of disease. Cell culture and in vitro studies provide an alternative that preserves the physiology of the living cell, but does not require the sacrifice of an animal for mechanistic studies. [30] [31] Human induced pluripotent stem cells can also elucidate new mechanisms for understanding cancer and cell regeneration. [32] Imaging studies (such as MRI or PET scans) enable non-invasive study of human subjects. [33] Recent advances in genetics and genomics can identify disease-associated genes, which can be targeted for therapies. [31]

See also

Related Research Articles

<span class="mw-page-title-main">Zebrafish</span> Species of fish

The zebrafish is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio.

<span class="mw-page-title-main">Model organism</span> Organisms used to study biology across species

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Model organisms are widely used to research human disease when human experimentation would be unfeasible or unethical. This strategy is made possible by the common descent of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution.

<span class="mw-page-title-main">Phenotype</span> Composite of the organisms observable characteristics or traits

In genetics, the phenotype is the set of observable characteristics or traits of an organism. The term covers the organism's morphology, its developmental processes, its biochemical and physiological properties, its behavior, and the products of behavior. An organism's phenotype results from two basic factors: the expression of an organism's genetic code and the influence of environmental factors. Both factors may interact, further affecting the phenotype. When two or more clearly different phenotypes exist in the same population of a species, the species is called polymorphic. A well-documented example of polymorphism is Labrador Retriever coloring; while the coat color depends on many genes, it is clearly seen in the environment as yellow, black, and brown. Richard Dawkins in 1978 and then again in his 1982 book The Extended Phenotype suggested that one can regard bird nests and other built structures such as caddisfly larva cases and beaver dams as "extended phenotypes".

Gene knockouts are a widely used genetic engineering technique that involves the targeted removal or inactivation of a specific gene within an organism's genome. This can be done through a variety of methods, including homologous recombination, CRISPR-Cas9, and TALENs.

<span class="mw-page-title-main">Animal testing</span> Use of animals in experiments

Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals, such as model organisms, in experiments that seek to control the variables that affect the behavior or biological system under study. This approach can be contrasted with field studies in which animals are observed in their natural environments or habitats. Experimental research with animals is usually conducted in universities, medical schools, pharmaceutical companies, defense establishments, and commercial facilities that provide animal-testing services to the industry. The focus of animal testing varies on a continuum from pure research, focusing on developing fundamental knowledge of an organism, to applied research, which may focus on answering some questions of great practical importance, such as finding a cure for a disease. Examples of applied research include testing disease treatments, breeding, defense research, and toxicology, including cosmetics testing. In education, animal testing is sometimes a component of biology or psychology courses.

<span class="mw-page-title-main">House mouse</span> Species of mammal

The house mouse is a small mammal of the order Rodentia, characteristically having a pointed snout, large rounded ears, and a long and almost hairless tail. It is one of the most abundant species of the genus Mus. Although a wild animal, the house mouse has benefited significantly from associating with human habitation to the point that truly wild populations are significantly less common than the semi-tame populations near human activity.

<span class="mw-page-title-main">Laboratory mouse</span> Mouse used for scientific research

The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Mice used in laboratories are usually of the species Mus musculus. They are the most commonly used mammalian research model and are used for research in genetics, physiology, psychology, medicine and other scientific disciplines. Mice belong to the Euarchontoglires clade, which includes humans. This close relationship, the associated high homology with humans, their ease of maintenance and handling, and their high reproduction rate, make mice particularly suitable models for human-oriented research. The laboratory mouse genome has been sequenced and many mouse genes have human homologues. Lab mice are sold at pet stores for snake food and can also be kept as pets.

<i>Plasmodium berghei</i> Single celled parasite, rodent malaria

Plasmodium berghei is a single-celled parasite causing rodent malaria. It is in the Plasmodium subgenus Vinckeia.

A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the phenotype of an organism. Transgene describes a segment of DNA containing a gene sequence that has been isolated from one organism and is introduced into a different organism. This non-native segment of DNA may either retain the ability to produce RNA or protein in the transgenic organism or alter the normal function of the transgenic organism's genetic code. In general, the DNA is incorporated into the organism's germ line. For example, in higher vertebrates this can be accomplished by injecting the foreign DNA into the nucleus of a fertilized ovum. This technique is routinely used to introduce human disease genes or other genes of interest into strains of laboratory mice to study the function or pathology involved with that particular gene.

<span class="mw-page-title-main">Animal testing on rodents</span> Overview article

Rodents have been employed in biomedical experimentation from the 1650s. Currently, rodents are commonly used in animal testing, particularly mice and rats, but also guinea pigs, hamsters, gerbils and others. Mice are the most commonly used vertebrate species, due to their availability, size, low cost, ease of handling, and fast reproduction rate.

A humanized mouse is a genetically modified mouse that has functioning human genes, cells, tissues and/or organs. Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.

<span class="mw-page-title-main">Genetically modified mouse</span> Mouse with altered genomes

A genetically modified mouse, genetically engineered mouse model (GEMM) or transgenic mouse is a mouse that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases and are also used for research on genes. Together with patient-derived xenografts (PDXs), GEMMs are the most common in vivo models in cancer research. Both approaches are considered complementary and may be used to recapitulate different aspects of disease. GEMMs are also of great interest for drug development, as they facilitate target validation and the study of response, resistance, toxicity and pharmacodynamics.

The diet-induced obesity model is an animal model used to study obesity using animals that have obesity caused by being fed high-fat or high-density diets. It is intended to mimic the most common cause of obesity in humans. Typically mice, rats, dogs, or non-human primates are used in these models. These animals can then be used to study in vivo obesity, obesity's comorbidities, and other related diseases. Users of such models must take into account the duration and type of diet as well as the environmental conditions and age of the animals, as each may promote different bodyweights, fat percentages, or behaviors.

<span class="mw-page-title-main">Genetically modified animal</span> Animal that has been genetically modified

Genetically modified animals are animals that have been genetically modified for a variety of purposes including producing drugs, enhancing yields, increasing resistance to disease, etc. The vast majority of genetically modified animals are at the research stage while the number close to entering the market remains small.

<span class="mw-page-title-main">Neurogenomics</span> Part of the study of the genome

Neurogenomics is the study of how the genome of an organism influences the development and function of its nervous system. This field intends to unite functional genomics and neurobiology in order to understand the nervous system as a whole from a genomic perspective.

<span class="mw-page-title-main">Tail flick test</span> Pain response test

The tail flick test is a test of the pain response in animals, similar to the hot plate test. It is used in basic pain research and to measure the effectiveness of analgesics, by observing the reaction to heat. It was first described by D'Amour and Smith in 1941.

<span class="mw-page-title-main">Animal models of depression</span> Research tools for understanding depressive symptoms in non-human animals

Animal models of depression are research tools used to investigate depression and action of antidepressants. They are used as a simulation to investigate the symptomatology and pathophysiology of depressive illness and to screen novel antidepressants. These models provide insights into molecular, genetic, and epigenetic factors associated with depression. Criteria for valid animal models include face, construct, and predictive validity. Endophenotypes, such as anhedonia, behavioral despair, changes in appetite, neuroanatomical alterations, neuroendocrine disturbances, alterations in sleep architecture, and anxiety-related behaviors, are evaluated in these models. Antidepressant screening tests are employed to assess the effects of genetic, pharmacological, or environmental manipulations. Stress models including learned helplessness, chronic mild stress, and social defeat stress simulate the impact of stressors on depression. Early life stress models, psychostimulant withdrawal models, olfactory bulbectomy, and genetically engineered mice contribute to a comprehensive understanding of depression's etiology and potential therapeutic interventions.

A knockout mouse, or knock-out mouse, is a genetically modified mouse in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be caused by genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.

<span class="mw-page-title-main">Experimental models of Alzheimer's disease</span>

Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive neurodegenerative disorder associated with aging, which occurs both sporadically or due to familial passed mutations in genes associated with Alzheimer's pathology. Common symptoms associated with Alzheimer's disease include: memory loss, confusion, and mood changes.

References

  1. ↑ Chakraborty C, Hsu CH, Wen ZH, Lin CS, Agoramoorthy G (February 2009). "Zebrafish: a complete animal model for in vivo drug discovery and development". Current Drug Metabolism. 10 (2): 116–24. doi:10.2174/138920009787522197. PMID   19275547.
  2. 1 2 Kari G, Rodeck U, Dicker AP (July 2007). "Zebrafish: an emerging model system for human disease and drug discovery". Clinical Pharmacology and Therapeutics. 82 (1): 70–80. doi:10.1038/sj.clpt.6100223. PMID   17495877. S2CID   41443542.
  3. ↑ "Pinel Chapter 6 - Human Brain Damage & Animal Models". Academic.uprm.edu. Archived from the original on 2014-10-13. Retrieved 2014-01-10.
  4. ↑ Hedges SB (November 2002). "The origin and evolution of model organisms". Nature Reviews. Genetics. 3 (11): 838–49. doi:10.1038/nrg929. PMID   12415314. S2CID   10956647.
  5. ↑ Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS, Haussler D (May 2004). "Ultraconserved elements in the human genome". Science. 304 (5675): 1321–5. Bibcode:2004Sci...304.1321B. doi:10.1126/science.1098119. PMID   15131266. S2CID   2790337.
  6. 1 2 Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, et al. (December 2002). "Initial sequencing and comparative analysis of the mouse genome". Nature. 420 (6915): 520–62. Bibcode:2002Natur.420..520W. doi: 10.1038/nature01262 . PMID   12466850.
  7. ↑ Kehrer-Sawatzki H, Cooper DN (February 2007). "Understanding the recent evolution of the human genome: insights from human-chimpanzee genome comparisons". Human Mutation. 28 (2): 99–130. doi: 10.1002/humu.20420 . PMID   17024666. S2CID   42037159.
  8. ↑ Kehrer-Sawatzki H, Cooper DN (February 2007). "Structural divergence between the human and chimpanzee genomes". Human Genetics. 120 (6): 759–78. doi:10.1007/s00439-006-0270-6. PMID   17066299. S2CID   6484568.
  9. ↑ Prüfer K, Munch K, Hellmann I, Akagi K, Miller JR, Walenz B, et al. (June 2012). "The bonobo genome compared with the chimpanzee and human genomes". Nature. 486 (7404): 527–31. Bibcode:2012Natur.486..527P. doi:10.1038/nature11128. PMC   3498939 . PMID   22722832.
  10. ↑ Hughes HC, Lang CM (December 1978). "Basic principles in selecting animal species for research projects". Clinical Toxicology. 13 (5): 611–21. doi:10.3109/15563657808988266. PMID   750165.
  11. ↑ White HS (1997). "Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs". Epilepsia. 38 (Suppl 1): S9-17. doi:10.1111/j.1528-1157.1997.tb04523.x. PMID   9092952. S2CID   46126941.
  12. ↑ Bolton C (October 2007). "The translation of drug efficacy from in vivo models to human disease with special reference to experimental autoimmune encephalomyelitis and multiple sclerosis". Inflammopharmacology. 15 (5): 183–7. doi:10.1007/s10787-007-1607-z. PMID   17943249. S2CID   8366509.
  13. ↑ Leker RR, Constantini S (2002). "Experimental Models in Focal Cerebral Ischemia: Are we there yet?". Research and Publishing in Neurosurgery. Acta Neurochirurgica Supplements. Vol. 83. pp. 55–9. doi:10.1007/978-3-7091-6743-4_10. ISBN   978-3-7091-7399-2. PMID   12442622.
  14. ↑ Wang J, Fields J, Doré S (July 2008). "The development of an improved preclinical mouse model of intracerebral hemorrhage using double infusion of autologous whole blood". Brain Research. 1222: 214–21. doi:10.1016/j.brainres.2008.05.058. PMC   4725309 . PMID   18586227.
  15. ↑ Rynkowski MA, Kim GH, Komotar RJ, Otten ML, Ducruet AF, Zacharia BE, et al. (2008). "A mouse model of intracerebral hemorrhage using autologous blood infusion". Nature Protocols. 3 (1): 122–8. doi:10.1038/nprot.2007.513. PMID   18193028. S2CID   22553744.
  16. ↑ Korneev KV (18 October 2019). "[Mouse Models of Sepsis and Septic Shock]". Molekuliarnaia Biologiia. 53 (5): 799–814. doi: 10.1134/S0026893319050108 . PMID   31661479. S2CID   204758015.
  17. ↑ Eibl RH, Kleihues P, Jat PS, Wiestler OD (March 1994). "A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen". The American Journal of Pathology. 144 (3): 556–64. PMC   1887088 . PMID   8129041.
  18. ↑ Radner H, el-Shabrawi Y, Eibl RH, Brüstle O, Kenner L, Kleihues P, Wiestler OD (1993). "Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose". Acta Neuropathologica. 86 (5): 456–65. doi:10.1007/bf00228580. PMID   8310796. S2CID   2972931.
  19. ↑ Homo-Delarche F, Drexhage HA (May 2004). "Immune cells, pancreas development, regeneration and type 1 diabetes". Trends in Immunology. 25 (5): 222–9. doi:10.1016/j.it.2004.02.012. PMID   15099561.
  20. ↑ Yousefzadeh N, Kashfi K, Jeddi S, Ghasemi A (2020-01-10). "Ovariectomized rat model of osteoporosis: a practical guide". EXCLI Journal. 19: 89–107. doi:10.17179/excli2019-1990. PMC   7003643 . PMID   32038119.
  21. ↑ Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, Kishihara K, et al. (January 2004). "Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells". Nature Medicine. 10 (1): 29–30. doi:10.1038/nm975. PMID   14702631. S2CID   2111178.
  22. ↑ Coppi A, Cabinian M, Mirelman D, Sinnis P (May 2006). "Antimalarial activity of allicin, a biologically active compound from garlic cloves". Antimicrobial Agents and Chemotherapy. 50 (5): 1731–7. doi:10.1128/AAC.50.5.1731-1737.2006. PMC   1472199 . PMID   16641443.
  23. ↑ Frischknecht F, Martin B, Thiery I, Bourgouin C, Menard R (March 2006). "Using green fluorescent malaria parasites to screen for permissive vector mosquitoes". Malaria Journal. 5: 23. doi: 10.1186/1475-2875-5-23 . PMC   1450296 . PMID   16569221.
  24. ↑ Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, et al. (August 2000). "Concordance of the toxicity of pharmaceuticals in humans and in animals". Regulatory Toxicology and Pharmacology. 32 (1): 56–67. doi:10.1006/rtph.2000.1399. PMID   11029269. S2CID   17158127.
  25. ↑ Davidson MK, Lindsey JR, Davis JK (June 1987). "Requirements and selection of an animal model". Israel Journal of Medical Sciences. 23 (6): 551–5. PMID   3312096.
  26. ↑ Hasler G, Drevets WC, Manji HK, Charney DS (October 2004). "Discovering endophenotypes for major depression". Neuropsychopharmacology. 29 (10): 1765–81. doi: 10.1038/sj.npp.1300506 . PMID   15213704.
  27. ↑ Martin B, Ji S, Maudsley S, Mattson MP (April 2010). ""Control" laboratory rodents are metabolically morbid: why it matters". Proceedings of the National Academy of Sciences of the United States of America. 107 (14): 6127–33. Bibcode:2010PNAS..107.6127M. doi: 10.1073/pnas.0912955107 . PMC   2852022 . PMID   20194732.
  28. ↑ "What Investigators Need to Know About the Use of Animals" (PDF). National Institutes of Health. April 2016. Retrieved 2020-04-26.
  29. ↑ Kendall LV, Owiny JR, Dohm ED, Knapek KJ, Lee ES, Kopanke JH, et al. (December 2018). "Replacement, Refinement, and Reduction in Animal Studies With Biohazardous Agents". ILAR Journal. 59 (2): 177–194. doi: 10.1093/ilar/ily021 . PMID   30668740.
  30. ↑ "Alternatives to animal testing". Unilever . Retrieved 2021-05-03.
  31. 1 2 Doke SK, Dhawale SC (July 2015). "Alternatives to animal testing: A review". Saudi Pharmaceutical Journal. 23 (3): 223–9. doi:10.1016/j.jsps.2013.11.002. PMC   4475840 . PMID   26106269.
  32. ↑ Kim TW, Che JH, Yun JW (July 2019). "Use of stem cells as alternative methods to animal experimentation in predictive toxicology". Regulatory Toxicology and Pharmacology. 105: 15–29. doi:10.1016/j.yrtph.2019.03.016. PMID   30930176. S2CID   89618750.
  33. ↑ Heindl C, Hess A, Brune K (2008). "Refinement and reduction in animal experimentation: options for new imaging techniques". Altex. 25 (2): 121–5. doi: 10.14573/altex.2008.2.121 . PMID   18551236.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.