A model organism is a non-human species that is extensively studied to understand particular biology phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms.Griffiths, E. C. (2010) What is a model? Model organisms are widely used to research human disease when human experimentation would be unfeasible or bioethics. 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.
Research using animal models has been central to most of the achievements of modern medicine. It has contributed most of the basic knowledge in fields such as human physiology and biochemistry, and has played significant roles in fields such as neuroscience and infectious disease. The results have included the near-eradication of polio and the development of organ transplantation, and have benefited both humans and animals. From 1910 to 1927, Thomas Hunt Morgan's work with the fruit fly Drosophila melanogaster identified as the vector of inheritance for genes, and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science". Research in model organisms led to further medical advances, such as the production of the diphtheria antitoxin and the 1922 discovery of insulin and its use in treating diabetes, which had previously meant death. Modern general anaesthetics such as halothane were also developed through studies on model organisms, and are necessary for modern, complex surgical operations. Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,Williamson C (1926) J. Urol. 16: p. 231 the heart-lung machine, , and the whooping cough vaccine.
In researching human disease, model organisms allow for better understanding the disease process without the added risk of harming an actual human. The species of the model organism is usually chosen so that it reacts to disease or its treatment in a way that resembles human physiology, even though care must be taken when generalizing from one organism to another. However, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models. Treatments for animal diseases have also been developed, including for rabies, anthrax, glanders, feline immunodeficiency virus (FIV), tuberculosis, Texas cattle fever, classical swine fever (hog cholera), heartworm, and other parasitic infections. Animal experimentation continues to be required for biomedical research, and is used with the aim of solving medical problems such as Alzheimer's disease, AIDS, multiple sclerosis, spinal cord injury, many headaches, and other conditions in which there is no useful in vitro model system available.
Model organisms are drawn from all three domains of life, as well as . One of the first model systems for molecular biology was the bacterium Escherichia coli ( E. coli), a common constituent of the human digestive system. The mouse ( House mouse) has been used extensively as a model organism and is associated with many important biological discoveries of the 20th and 21st centuries. Other examples include baker's yeast ( Saccharomyces cerevisiae), the T4 phage virus, the Drosophilidae Drosophila melanogaster, the flowering plant Arabidopsis thaliana, and ( Cavia porcellus). Several of the bacterial viruses (bacteriophage) that infect Escherichia coli also have been very useful for the study of gene structure and gene regulation (e.g. phages Lambda phage and T4). Disease models are divided into three categories: 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, and predictive models are similar to a particular human disease in only a couple of aspects, but are useful in isolating and making predictions about mechanisms of a set of disease features.
Research using animal models has been central to most of the achievements of modern medicine.
In the late 19th century, Emil von Behring isolated the diphtheria toxin and demonstrated its effects in guinea pigs. He went on to develop an antitoxin against diphtheria in animals and then in humans, which resulted in the modern methods of immunization and largely ended diphtheria as a threatening disease. Bering Nobel Biography The diphtheria antitoxin is famously commemorated in the Iditarod race, which is modeled after the delivery of antitoxin in the 1925 serum run to Nome. The success of animal studies in producing the diphtheria antitoxin has also been attributed as a cause for the decline of the early 20th-century opposition to animal research in the United States. Walter B. Cannon Papers, American Philosophical Society
Subsequent research in model organisms led to further medical advances, such as Frederick Banting's research in dogs, which determined that the isolates of pancreatic secretion could be used to treat dogs with diabetes. This led to the 1922 discovery of insulin (with John Macleod) Discovery of Insulin and its use in treating diabetes, which had previously meant death. Thompson bio ref John Cade's research in guinea pigs discovered the anticonvulsant properties of lithium salts, John Cade and Lithium which revolutionized the treatment of bipolar disorder, replacing the previous treatments of lobotomy or electroconvulsive therapy. Modern general anaesthetics, such as halothane and related compounds, were also developed through studies on model organisms, and are necessary for modern, complex surgical operations.Raventos J (1956) Br J Pharmacol 11, 394Whalen FX, Bacon DR & Smith HM (2005) Best Pract Res Clin Anaesthesiol 19, 323
In the 1940s, Jonas Salk used rhesus monkey studies to isolate the most virulent forms of the polio virus, Virus-typing of polio by Salk which led to his creation of a polio vaccine. The vaccine, which was made publicly available in 1955, reduced the incidence of polio 15-fold in the United States over the following five years. Salk polio virus Albert Sabin improved the vaccine by passing the polio virus through animal hosts, including monkeys; the Sabin vaccine was produced for mass consumption in 1963, and had virtually eradicated polio in the United States by 1965.[7] History of polio vaccine It has been estimated that developing and producing the vaccines required the use of 100,000 rhesus monkeys, with 65 doses of vaccine produced from each monkey. Sabin wrote in 1992, "Without the use of animals and human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans, but also among animals." "the work on [polio] prevention was long delayed by... misleading experimental models of the disease in monkeys" | ari.info
Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,Carrel A (1912) Surg. Gynec. Obst. 14: p. 246Williamson C (1926) J. Urol. 16: p. 231Woodruff H & Burg R (1986) in Discoveries in Pharmacology vol 3, ed Parnham & Bruinvels, Elsevier, AmsterdamMoore F (1964) Give and Take: the Development of Tissue Transplantation. Saunders, New York the heart-lung machine,Gibbon JH (1937) Arch. Surg. 34, 1105 ,[9] Hinshaw obituary[10] StreptomycinFleming A (1929) Br J Exp Path 10, 226 and the whooping cough vaccine.Medical Research Council (1956) Br. Med. J. 2: p. 454 Treatments for animal diseases have also been developed, including for rabies, A reference handbook of the medical sciences. William Wood and Co., 1904, Edited by Albert H. Buck. anthrax, glanders, feline immunodeficiency virus (FIV), tuberculosis, Texas cattle fever, classical swine fever (hog cholera), heartworm, and other parasitic infections. Animal experimentation continues to be required for biomedical research,Sources:
Often, model organisms are chosen on the basis that they are amenable to experimental manipulation. This usually will include characteristics such as short life-cycle, techniques for genetic manipulation (inbreeding strains, stem cell lines, and methods of transformation) and non-specialist living requirements. Sometimes, the genome arrangement facilitates the sequencing of the model organism's genome, for example, by being very compact or having a low proportion of junk DNA (e.g. yeast, arabidopsis, or pufferfish).
When researchers look for an organism to use in their studies, they look for several traits. Among these are size, generation time, accessibility, manipulation, genetics, conservation of mechanisms, and potential economic benefit. As comparative molecular biology has become more common, some researchers have sought model organisms from a wider assortment of lineages on the tree of life.
Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics, as well as the geochemical and fossil record. 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. Rodents are the most common animal models. Phylogenetic trees estimate that humans and rodents last shared a common ancestor ~80-100mya.
Genomic data is used to make close comparisons between species and determine relatedness. Humans share about 99% of their genome with chimpanzees (98.7% with bonobos) and over 90% with the mouse. 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 a few thousand genes, less than 1% (of ~19,000 total). Scientists have been able to take advantage of these similarities in generating experimental and predictive models of human disease.Frankish, A., Diekhans, M., Ferreira, A.-M., Johnson, R., Jungreis, I., Loveland, J., Mudge, J. M., Sisu, C., Wright, J., Armstrong, J., Barnes, I., Berry, A., Bignell, A., Carbonell Sala, S., Cunningham, F., Di Domenico, T., Donaldson, S., Fiddes, I. T., García-García, J., … Harrow, J. (2022). GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Research. (GENCODE / annotation review).
In , several yeasts, particularly Saccharomyces cerevisiae ("baker's" or "budding" yeast), have been widely used in genetics and cell biology, largely because they are quick and easy to grow. The cell cycle in a simple yeast is very similar to the cell cycle in and is regulated by homologous proteins. The fruit fly Drosophila melanogaster is studied, again, because it is easy to grow for an animal, has various visible congenital traits and has a polytene (giant) chromosome in its salivary glands that can be examined under a light microscope. The roundworm Caenorhabditis elegans is studied because it has very defined development patterns involving fixed numbers of cells, and it can be rapidly assayed for abnormalities.
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 where 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 medication 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 non-rodents alone and 43% for rodents alone.
In 1987, Davidson et al. suggested that the selection of an animal model for research be based on nine considerations. These include
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.
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 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.
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 of depression in patients. Depression, as other mental disorders, consists of that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetics and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between Heredity or environmental alterations and depression can be examined, which would afford a better insight into the pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.
Simple model include baker's yeast ( Saccharomyces cerevisiae) and fission yeast ( Schizosaccharomyces pombe), both of which share many characters with higher cells, including those of humans. For instance, many cell division genes that are critical for the development of cancer have been discovered in yeast. Chlamydomonas reinhardtii, a unicellular green alga with well-studied genetics, is used to study photosynthesis and motility. C. reinhardtii has many known and mapped mutants and expressed sequence tags, and there are advanced methods for genetic transformation and selection of genes. Dictyostelium discoideum is used in molecular biology and genetics, and is studied as an example of cell communication, differentiation, and programmed cell death.
Among invertebrates, the Drosophilidae Drosophila melanogaster is famous as the subject of genetics experiments by Thomas Hunt Morgan and others. They are easily raised in the lab, with rapid generations, high fecundity, few , and easily induced observable mutations. The nematode Caenorhabditis elegans is used for understanding the genetic control of development and physiology. It was first proposed as a model for neuronal development by Sydney Brenner in 1963, and has been extensively used in many different contexts since then. C. elegans was the first multicellular organism whose genome was completely sequenced, and as of 2012, the only organism to have its connectome (neuronal "wiring diagram") completed.
Arabidopsis thaliana is currently the most popular model plant. Its small stature and short generation time facilitates rapid genetic studies, About Arabidopsis on The Arabidopsis Information Resource page (TAIR) and many phenotypic and biochemical mutants have been mapped. A. thaliana was the first plant to have its genome DNA sequencing.
Among , ( Cavia porcellus) were used by Robert Koch and other early bacteriologists as a host for bacterial infections, becoming a byword for "laboratory animal", but are less commonly used today. The classic model vertebrate is currently the mouse ( House mouse). Many inbred strains exist, as well as lines selected for particular traits, often of medical interest, e.g. body size, obesity, muscularity, and voluntary wheel-running behavior.
The rat ( Rattus norvegicus) is particularly useful as a toxicology model, and as a neurological model and source of primary cell cultures, owing to the larger size of organs and suborganellar structures relative to the mouse, while eggs and embryos from Xenopus tropicalis and Xenopus laevis (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience. Likewise, the zebrafish ( Danio rerio) has a nearly transparent body during early development, which provides unique visual access to the animal's internal anatomy during this time period. Zebrafish are used to study development, toxicology and toxicopathology, specific gene function and roles of signaling pathways.
Other important model organisms and some of their uses include: T4 phage (viral infection), Tetrahymena thermophila (intracellular processes), maize (), hydras (regeneration and morphogenesis), (neurophysiology), (development), (respiratory and cardiovascular systems), Nothobranchius furzeri (aging), non-human primates such as the rhesus macaque and chimpanzee (hepatitis, HIV, Parkinson's disease, cognition, and ), and (SARS-CoV-2)
The of all model species have been sequenced, including their /
Mice differ from humans in several immune properties: mice are more resistant to some toxins than humans; have a lower total neutrophil fraction in the blood, a lower neutrophil enzymatic capacity, lower activity of the complement system, and a different set of pentraxins involved in the inflammatory process; and lack genes for important components of the immune system, such as IL-8, IL-37, TLR10, ICAM-3, etc. Laboratory mice reared in specific-pathogen-free (SPF) conditions usually have a rather immature immune system with a deficit of memory T cells. These mice may have limited diversity of the microbiota, which directly affects the immune system and the development of pathological conditions. Moreover, persistent virus infections (for example, Herpesviridae) are activated in humans, but not in SPF mice, with Sepsis complications and may change the resistance to bacterial coinfections. "Dirty" mice are possibly better suitable for mimicking human pathologies. In addition, inbred mouse strains are used in the overwhelming majority of studies, while the human population is heterogeneous, pointing to the importance of studies in interstrain hybrid, outbred, and nonlinear mice.
Many biomedical researchers argue that there is no substitute for a living organism when studying complex interactions in disease pathology or treatments.
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. NIH need-to-know
"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) wherever possible. list of common model organisms approved for use by the NIH)
History
For example, the results have included the near-eradication of polio and the development of organ transplantation, and have benefited both humans and animals. From 1910 to 1927, Thomas Hunt Morgan's work with the fruit fly Drosophila melanogaster identified as the vector of inheritance for genes. Drosophila became one of the first, and for some time the most widely used, model organisms,Kohler, Lords of the Fly, chapter 5 and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science".Kandel, Eric. 1999. "Genes, Chromosomes, and the Origins of Modern Biology", Columbia Magazine D. melanogaster remains one of the most widely used eukaryotic model organisms. During the same time period, studies on mouse genetics in the laboratory of William Ernest Castle in collaboration with Abbie Lathrop led to generation of the DBA ("dilute, brown and non-agouti") inbred mouse strain and the systematic generation of other inbred strains. The mouse has since been used extensively as a model organism and is associated with many important biological discoveries of the 20th and 21st centuries.
and is used with the aim of solving medical problems such as Alzheimer's disease, AIDS, PMPA blocks SIV in monkeys PMPA is tenofovir multiple sclerosis, spinal cord injury, many headaches, and other conditions in which there is no useful in vitro model system available.
Selection
Phylogeny and genetic relatedness
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Use
Disease models
Important model organisms
Selected model organisms
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Phi X 174 ΦX174 Bacteriophage evolution Escherichia coli E. coli Bacteria bacterial genetics, metabolism Pseudomonas fluorescens P. fluorescens Bacteria evolution, adaptive radiation Dictyostelium discoideum Amoeba immunology, host–pathogen interactions Saccharomyces cerevisiae Brewer's yeast
Baker's yeastYeast cell division, organelles, etc. Schizosaccharomyces pombe Fission yeast Yeast Fission Yeast GO slim terms >PomBase Chlamydomonas reinhardtii Green algae hydrogen production Tetrahymena thermophila, T. pyriformis Ciliate education, Emiliania huxleyi Phytoplankton surface sea temperature Arabidopsis thaliana Thale cress Flowering plant population genetics Physcomitrella patens Spreading earthmoss Moss molecular farming Populus trichocarpa Balsam poplar Tree drought tolerance, lignin biosynthesis, wood formation, plant biology, morphology, genetics, and ecology Caenorhabditis elegans Nematode, Roundworm Worm differentiation, development Drosophila melanogaster Fruit fly Insect developmental biology, human brain degenerative disease Callosobruchus maculatus Cowpea Weevil Insect developmental biology Danio rerio Zebrafish Fish embryonic development Mummichog Mummichog Fish effect of hormones on behavior Nothobranchius furzeri Turquoise killifish Fish aging, disease, evolution Oryzias latipes Japanese rice fish Fish fish biology, sex determination Anolis carolinensis Carolina anole Reptile reptile biology, evolution Mus musculus House mouse Mammal disease model for humans Gallus gallus / G. g. domesticus Red junglefowl / chicken Bird embryological development and organogenesis Taeniopygia guttata Australian zebra finch Bird vocal learning, neurobiology Xenopus laevis
Xenopus tropicalisAfrican clawed frog
Western clawed frogAmphibian embryonic development
Limitations
Unintended bias
Alternatives
/ref> Imaging studies (such as MRI or PET scans) enable non-invasive study of human subjects. Recent advances in genetics and genomics can identify disease-associated genes, which can be targeted for therapies.
Ethics
See also
Further reading
External links
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