Model organism

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Animal models
)
Escherichia coli is a gram-negative prokaryotic model organism
Drosophila melanogaster, one of the most famous subjects for genetics experiments
Saccharomyces cerevisiae, one of the most intensively studied eukaryotic model organisms in molecular and cell biology

A model organism (often shortened to model) is a

genetic material over the course of evolution.[4]

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

T4). However, it is debated whether bacteriophages should be classified as organisms, because they lack metabolism and depend on functions of the host cells for propagation.[9]

Model organisms are drawn from all three

T4 phage virus, the fruit fly Drosophila melanogaster, the flowering plant Arabidopsis thaliana, guinea pigs (Cavia porcellus), and the mouse (Mus musculus
).

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.

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.[21][22] 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.[23]

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

diabetes. This led to the 1922 discovery of insulin (with John Macleod)[26] and its use in treating diabetes, which had previously meant death.[27] John Cade's research in guinea pigs discovered the anticonvulsant properties of lithium salts,[28] 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.[29][30]

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

heartworm, and other parasitic infections.[46] Animal experimentation continues to be required for biomedical research,[47] and is used with the aim of solving medical problems such as Alzheimer's disease,[48] AIDS,[49][50][51] multiple sclerosis,[52] spinal cord injury, many headaches,[53] and other conditions in which there is no useful in vitro
model system available.

Selection

Models are those organisms with a wealth of biological data that make them attractive to study as examples for other

genomic parsimony models, investigating pivotal position in the evolutionary tree.[54] Historically, model organisms include a handful of species with extensive genomic research data, such as the NIH model organisms.[55]

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,

tree of life
.

Phylogeny and genetic relatedness

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

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.[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

T4). However, it is debated whether bacteriophages should be classified as organisms, because they lack metabolism and depend on functions of the host cells for propagation.[62]

In

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.[63]

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

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.[64]

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:

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

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

therapies for depression.[82][83]

Important model organisms

Model organisms are drawn from all three

host organism for the majority of work with recombinant DNA.[84]

Simple model

.

Laboratory mice, widely used in medical research

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

wheel-running behavior.[92]
The rat (
Xenopus laevis (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience.[93][94] 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,[95]
specific gene function and roles of signaling pathways.

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 databases
exist to provide researchers with a portal from which to download sequences (DNA, RNA, or protein) or to access functional information on specific genes, for example the sub-cellular localization of the gene product or its physiological role.

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

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.[117] Similarly, there are differences between the immune systems of model organisms and humans that lead to significantly altered responses to stimuli,[118][119][120] although the underlying principles of genome function may be the same.[120] The impoverished environments inside standard laboratory cages deny research animals of the mental and physical challenges are necessary for healthy emotional development.[121] Without day-to-day variety, risks and rewards, and complex environments, some have argued that animal models are irrelevant models of human experience.[122]

Mice differ from humans in several immune properties: mice are more resistant to some

outbred, and nonlinear mice.[74]

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

pluripotent stem cells can[citation needed
] also elucidate new mechanisms for understanding cancer and cell regeneration. 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.

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.

Laboratory Animal Welfare Act) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care program.[130]

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

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Further reading

External links