Model organism
A model organism (often shortened to model) is a
Studying model organisms can be informative, but care must be taken when generalizing from one organism to another.[5][page needed]
In researching human disease, model organisms allow for better understanding the disease process without the added risk of harming an actual human. The species chosen will usually meet a determined taxonomic equivalency[clarification needed] to humans, so as to react to disease or its treatment in a way that resembles human physiology as needed. Although biological activity in a model organism 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.[6][7]
There are three main types of disease 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. 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.[8]
There are many model organisms. One of the first model systems for
Model organisms are drawn from all three
History
The use of animals in research dates back to ancient Greece, with Aristotle (384–322 BCE) and Erasistratus (304–258 BCE) among the first to perform experiments on living animals.[10] Discoveries in the 18th and 19th centuries included Antoine Lavoisier's use of a guinea pig in a calorimeter to prove that respiration was a form of combustion, and Louis Pasteur's demonstration of the germ theory of disease in the 1880s using anthrax in sheep.[citation needed]
Research using animal models has been central to many 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.[24] 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.[25]
Subsequent research in model organisms led to further medical advances, such as
In the 1940s, Jonas Salk used rhesus monkey studies to isolate the most virulent forms of the polio virus,[31] 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.[32] 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.[33] 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."[34]
Other 20th-century medical advances and treatments that relied on research performed in animals include
Selection
Models are those organisms with a wealth of biological data that make them attractive to study as examples for other
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 (inbred 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).[citation needed]
When researchers look for an organism to use in their studies, they look for several traits. Among these are size,
The primary reason for the use of model organisms in research is the evolutionary principle that all organisms share some degree of relatedness and genetic similarity due to
Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics as well as the geochemical and fossil record.[56] 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.[57][58] 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]
Genomic data is used to make close comparisons between species and determine relatedness. Humans share about 99% of their genome with chimpanzees[59][60] (98.7% with bonobos)[61] and over 90% with the mouse.[58] 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]
Use
There are many model organisms. One of the first model systems for
In
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.
The best models of disease are similar in
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.[65]
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.[66]
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:
- The use of
- Induction of mechanical brain injury as an animal model of post-traumatic epilepsy[68]
- Injection of the 6-hydroxydopamine to dopaminergic parts of the basal ganglia as an animal model of Parkinson's disease.[69]
- autoimmune diseases such as Experimental autoimmune encephalomyelitis[70]
- Occlusion of the animal model of ischemic stroke[71]
- Injection of blood in the
- toxins[74]
- Infecting animals with infectious diseases
- Injecting animals with
- Using tumors
- Using gene transfer to cause
- Implanting animals with tumors to test and develop treatments using ionizing radiation
- Various animal models for screening of drugs for the treatment of glaucoma
- The use of the ovariectomized rat in osteoporosis research
- Use of Plasmodium yoelii as a model of human malaria[78][79][80]
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.[66]
The increase in knowledge of the
Animal models observed in the sciences of
Important model organisms
Model organisms are drawn from all three
Simple model
Among invertebrates, the fruit fly 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 chromosomes, and easily induced observable mutations.[86] 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.[87][88] 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.[89][90]
Arabidopsis thaliana is currently the most popular model plant. Its small stature and short generation time facilitates rapid genetic studies,[91] and many phenotypic and biochemical mutants have been mapped.[91] A. thaliana was the first plant to have its genome sequenced.[91]
Among
Other important model organisms and some of their uses include:
Selected model organisms
The organisms below have become model organisms because they facilitate the study of certain characters or because of their genetic accessibility. For example, E. coli was one of the first organisms for which genetic techniques such as transformation or genetic manipulation has been developed.
The
Model Organism | Common name | Informal classification | Usage (examples) | |
---|---|---|---|---|
Virus | Phi X 174 | ΦX174 | Virus | evolution[99] |
Prokaryotes | Escherichia coli | E. coli | Bacteria | bacterial genetics, metabolism |
Pseudomonas fluorescens | P. fluorescens | Bacteria | evolution, adaptive radiation[100] | |
Eukaryotes, unicellular | Dictyostelium discoideum | Amoeba | immunology, host–pathogen interactions[101] | |
Saccharomyces cerevisiae | Brewer's yeast Baker's yeast |
Yeast | cell division, organelles, etc. | |
Schizosaccharomyces pombe | Fission yeast | Yeast | cell cycle, cytokinesis, chromosome biology, telomeres, DNA metabolism, cytoskeleton organization, industrial applications[102][103] | |
Chlamydomonas reinhardtii | Algae | hydrogen production[104] | ||
Tetrahymena thermophila, T. pyriformis | Ciliate | education,[105] biomedical research[106] | ||
Emiliania huxleyi | Plankton | surface sea temperature[107] | ||
Plants | Arabidopsis thaliana | Thale cress | Flowering plant | population genetics[108] |
Physcomitrella patens | Spreading earthmoss | Moss | molecular farming[109] | |
Populus trichocarpa | Balsam poplar | Tree | drought tolerance, lignin biosynthesis, wood formation, plant biology, morphology, genetics, and ecology[110] | |
Animals, nonvertebrate | Caenorhabditis elegans | Nematode, Roundworm | Worm | differentiation, development |
Drosophila melanogaster | Fruit fly | Insect | developmental biology, human brain degenerative disease[111][112] | |
Callosobruchus maculatus | Cowpea Weevil | Insect | developmental biology | |
Animals, vertebrate | Danio rerio
|
Zebrafish | Fish | embryonic development |
Fundulus heteroclitus | Mummichog | Fish | effect of hormones on behavior[113] | |
Nothobranchius furzeri | Turquoise killifish | Fish | aging, disease, evolution | |
Oryzias latipes | Japanese rice fish | Fish | fish biology, sex determination[114] | |
Anolis carolinensis | Carolina anole | Reptile | reptile biology, evolution | |
Mus musculus
|
House mouse | Mammal | disease model for humans | |
Gallus gallus
|
Red junglefowl | Bird | embryological development and organogenesis | |
Taeniopygia castanotis | Australian zebra finch | Bird | vocal learning, neurobiology[115] | |
African clawed frog Western clawed frog |
Amphibian | embryonic development |
Limitations
Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively
Mice differ from humans in several immune properties: mice are more resistant to some
Unintended bias
Some studies suggests that inadequate published data in animal testing may result in irreproducible research, with missing details about how experiments are done omitted from published papers or differences in testing that may introduce bias. Examples of hidden bias include a 2014 study from McGill University in Montreal, Canada which suggests that mice handled by men rather than women showed higher stress levels.[123][124][125] Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research.[126]
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, or 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. Human, inducible
Many biomedical researchers argue that there is no substitute for a living organism when studying complex interactions in disease pathology or treatments.[127][128]
Ethics
Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament under pressure from British and Indian intellectuals enacted the first law for animal protection preventing cruelty to cattle.
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.[131]
"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.[132]
"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.
"Refinement" refers to efforts to make experimental design as painless and efficient as possible in order to minimize the suffering of each animal subject.
See also
- Animals in space
- Animal testing
- Animal testing on invertebrates
- Animal testing on rodents
- Cellular model (numerical), e.g., Mycoplasma genitalium.
- Ensemblgenome database of model organisms
- Generic Model Organism Database
- Genome project
- History of animal testing
- History of model organisms
- History of research on Arabidopsis thaliana
- History of research on Caenorhabditis elegans
- Mouse models of breast cancer metastasis
- Mouse model of colorectal and intestinal cancer
- RefSeq - the Reference Sequence database
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Further reading
- Marx, Vivien (June 2014). "Models: stretching the skills of cell lines and mice". Nature Methods. 11 (6): 617–620. S2CID 11798233.
- Goldstein, Bob; King, Nicole (November 2016). "The Future of Cell Biology: Emerging Model Organisms". Trends in Cell Biology. 26 (11): 818–824. PMID 27639630.
- Lloyd, Kent; Franklin, Craig; Lutz, Cat; Magnuson, Terry (June 2015). "Reproducibility: Use mouse biobanks or lose them". Nature. 522 (7555): 151–153. PMID 26062496.
External links
- Wellcome Trust description of model organisms
- National Institutes of Health Comparative Medicine Program Vertebrate Models
- NIH Using Model Organisms to Study Human Disease
- National Institutes of Health Model Organism Sharing Policy
- Why are Animals Used in NIH Research
- Disease Animal Models – BSRC Alexander Fleming
- Emice – National Cancer Institute
- Knock Out Mouse Project – KOMP
- Mouse Biology Program
- Mutant Mouse Resource & Research Centers, National Institutes of Health, supported Mouse Repository
- Rat Resource & Research Center – National Institutes of Health, supported Rat Repository
- NIH Model Organism Research Reproducibility and Rigor