A model organism (often shortened to model) is a

non-human Non-human (also spelled nonhuman) is any entity displaying some, but not enough, human characteristics to be considered a human. The term has been used in a variety of contexts and may refer to objects that have been developed with human intelligen ...

species In biology, a species is the basic unit of Taxonomy (biology), classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of ...

that is extensively studied to understand particular

biological Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...

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 Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. All living beings are in fact descendants of a unique ancestor commonly referred to as the last universal comm ...

of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution. Studying model organisms can be informative, but care must be taken when generalizing from one organism to another. 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 Taxonomy is the practice and science of categorization or classification. A taxonomy (or taxonomical classification) is a scheme of classification, especially a hierarchical classification, in which things are organized into groups or types. A ...

equivalency to humans, so as to react to disease or its treatment in a way that resembles human physiology as needed. Although

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or p ...

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. 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. There are many model organisms. One of the first model systems for molecular biology was the bacterium ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...

'', a common constituent of the human digestive system. Several of the bacterial viruses (

bacteriophage A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...

) that infect '' E. coli'' also have been very useful for the study of gene structure and

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products ( protein or RNA). Sophisticated programs of gene expression are w ...

(e.g. phages Lambda and 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. Model organisms are drawn from all three domains of life, as well as viruses. Examples include ''

'' (''E. coli''), baker's yeast (''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been ...

''), the T4 phage virus, the fruit fly '' Drosophila melanogaster'', the flowering plant ''

Arabidopsis thaliana ''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land. A winter a ...

'', guinea pigs (''Cavia porcellus''), and the mouse ('' Mus musculus'').

History

The use of animals in research dates back to

ancient Greece Ancient Greece ( el, Ἑλλάς, Hellás) was a northeastern Mediterranean civilization, existing from the Greek Dark Ages of the 12th–9th centuries BC to the end of classical antiquity ( AD 600), that comprised a loose collection of cult ...

, with Aristotle (384–322 BCE) and

Erasistratus Erasistratus (; grc-gre, Ἐρασίστρατος; c. 304 – c. 250 BC) was a Greek anatomist and royal physician under Seleucus I Nicator of Syria. Along with fellow physician Herophilus, he founded a school of anatomy in Alexandria, where th ...

(304–258 BCE) among the first to perform experiments on living animals. Discoveries in the 18th and 19th centuries included

Antoine Lavoisier Antoine-Laurent de Lavoisier ( , ; ; 26 August 17438 May 1794),
CNRS (

guinea pig in a

calorimeter A calorimeter is an object used for calorimetry, or the process of measuring the heat of chemical reactions or physical changes as well as heat capacity. Differential scanning calorimeters, isothermal micro calorimeters, titration calorimete ...

to prove that respiration was a form of combustion, and Louis Pasteur's demonstration of the

germ theory of disease The germ theory of disease is the currently accepted scientific theory for many diseases. It states that microorganisms known as pathogens or "germs" can lead to disease. These small organisms, too small to be seen without magnification, invade ...

in the 1880s using

anthrax Anthrax is an infection caused by the bacterium '' Bacillus anthracis''. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The s ...

in sheep. Research using animal models has been central to many of the achievements of modern medicine. It has contributed most of the basic knowledge in fields such as human physiology and

biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...

, and has played significant roles in fields such as neuroscience and infectious disease.Hau and Shapiro 2011: * * For example, the results have included the near-

eradication of polio The word "Eradication" is derived from Latin word "radix" which means "root". It may refer to: *Eradication of infectious diseases (human), the reduction of the global incidence of an infectious disease in humans to zero *Eradication of infectiou ...

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 chromosomes as the vector of inheritance for genes. ''Drosophila'' became one of the first, and for some time the most widely used, model organisms, and

Eric Kandel Eric Richard Kandel (; born Erich Richard Kandel, November 7, 1929) is an Austrian-born American medical doctor who specialized in psychiatry, a neuroscientist and a professor of biochemistry and biophysics at the College of Physicians and Surge ...

wrote that Morgan's discoveries "helped transform biology into an experimental science." ''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 William Ernest Castle (October 25, 1867 – June 3, 1962) was an early American geneticist. Early years William Ernest Castle was born on a farm in Ohio and took an early interest in natural history. He graduated in 1889 from Denison Universit ...

in collaboration with

Abbie Lathrop Abbie E. C. Lathrop (1868 – 1918) was a rodent fancier who bred fancy mice and inbred strains for animal models, particularly for research on development and hereditary properties of cancer. Biography Lathrop was born in 1868 in Illinois to scho ...

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. In the late 19th century,

Emil von Behring Emil von Behring (; Emil Adolf von Behring), born Emil Adolf Behring (15 March 1854 – 31 March 1917), was a German physiologist who received the 1901 Nobel Prize in Physiology or Medicine, the first one awarded in that field, for his discover ...

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. 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 1925 serum run to Nome, also known as the Great Race of Mercy and The Serum Run, was a transport of diphtheria antitoxin by dog sled relay across the U.S. territory of Alaska by 20 mushers and about 150 sled dogs across in days, saving th ...

. 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. Subsequent research in model organisms led to further medical advances, such as

Frederick Banting Sir Frederick Grant Banting (November 14, 1891 – February 21, 1941) was a Canadian medical scientist, physician, painter, and Nobel laureate noted as the co-discoverer of insulin and its therapeutic potential. In 1923, Banting and Joh ...

'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) and its use in treating diabetes, which had previously meant death.

John Cade John Frederick Joseph Cade AO (18 January 1912 – 16 November 1980) was an Australian psychiatrist who in 1948 discovered the effects of lithium carbonate as a mood stabilizer in the treatment of bipolar disorder, then known as manic depres ...

's research in guinea pigs discovered the anticonvulsant properties of lithium salts, which revolutionized the treatment of

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

, 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 Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe sy ...

virus, 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.

Albert Sabin Albert Bruce Sabin ( ; August 26, 1906 – March 3, 1993) was a Polish-American medical researcher, best known for developing the oral polio vaccine, which has played a key role in nearly eradicating the disease. In 1969–72, he served as the ...

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. 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." 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

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

s,Fleming A (1929) ''Br J Exp Path'' 10, 226 and the

whooping cough Whooping cough, also known as pertussis or the 100-day cough, is a highly contagious bacterial disease. Initial symptoms are usually similar to those of the common cold with a runny nose, fever, and mild cough, but these are followed by two or ...

vaccine.Medical Research Council (1956) ''Br. Med. J.'' 2: p. 454 Treatments for animal diseases have also been developed, including for

rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, vi ...

,''A reference handbook of the medical sciences''. William Wood and Co., 1904, Edited by Albert H. Buck.

glanders Glanders is a contagious zoonotic infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals, such as dogs, cats, pigs, goats, and humans. It is caused by infection with the bacterium ''Burkhold ...

, feline immunodeficiency virus (FIV), tuberculosis, Texas cattle fever,

classical swine fever Classical swine fever (CSF) or hog cholera (also sometimes called pig plague based on the German word ) is a highly contagious disease of swine (Old World and New World pigs). It has been mentioned as a potential bioweapon. Clinical signs Sw ...

(hog cholera),

heartworm ''Dirofilaria immitis'', also known as heartworm or dog heartworm, is a parasitic roundworm that is a type of filarial worm, a small thread-like worm, that causes dirofilariasis. It is spread from host to host through the bites of mosquitoes. ...

, and other parasitic infections. Animal experimentation continues to be required for biomedical research,Sources: * * * * 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.

Selection

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

and/or natural phenomena that are more difficult to study directly. Continual research on these organisms focuses on a wide variety of experimental techniques and goals from many different levels of biology—from ecology,

behavior Behavior (American English) or behaviour (British English) is the range of actions and mannerisms made by individuals, organisms, systems or artificial entities in some environment. These systems can include other systems or organisms as we ...

and

biomechanics Biomechanics is the study of the structure, function and motion of the mechanical aspects of biological systems, at any level from whole organisms to organs, cells and cell organelles, using the methods of mechanics. Biomechanics is a branch of ...

, down to the tiny functional scale of individual tissues,

organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...

s and proteins. Inquiries about the DNA of organisms are classed as genetic models (with short generation times, such as the fruitfly and

nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant- parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a bro ...

worm),

experimental An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs when a ...

models, and genomic parsimony models, investigating pivotal position in the evolutionary tree. Historically, model organisms include a handful of species with extensive genomic research data, such as the NIH model organisms. 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 Inbreeding is the production of offspring from the mating or breeding of individuals or organisms that are closely related genetically. By analogy, the term is used in human reproduction, but more commonly refers to the genetic disorders and o ...

strains,

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...

lines, and methods of

transformation Transformation may refer to: Science and mathematics In biology and medicine * Metamorphosis, the biological process of changing physical form after birth or hatching * Malignant transformation, the process of cells becoming cancerous * Trans ...

) 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 Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regula ...

(e.g. yeast,

arabidopsis ''Arabidopsis'' (rockcress) is a genus in the family Brassicaceae. They are small flowering plants related to cabbage and mustard. This genus is of great interest since it contains thale cress (''Arabidopsis thaliana''), one of the model organis ...

, or pufferfish). When researchers look for an organism to use in their studies, they look for several traits. Among these are size,

generation time In population biology and demography, generation time is the average time between two consecutive generations in the lineages of a population. In human populations, generation time typically ranges from 22 to 33 years. Historians sometimes use thi ...

, 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.

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 Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. All living beings are in fact descendants of a unique ancestor commonly referred to as the last universal comm ...

. 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. Various phylogenetic trees for vertebrates have been constructed using comparative

proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. I ...

, 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. 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. 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 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.

Use

There are many model organisms. One of the first model systems for molecular biology was the bacterium ''

'', a common constituent of the human digestive system. Several of the bacterial viruses (

) that infect '' E. coli'' also have been very useful for the study of gene structure and

'' ("baker's" or "budding" yeast), have been widely used in genetics and

cell biology Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living a ...

, largely because they are quick and easy to grow. The

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

in a simple yeast is very similar to the cell cycle in humans 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 ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

'' is studied because it has very defined development patterns involving fixed numbers of cells, and it can be rapidly assayed for abnormalities.

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

etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...

(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 Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

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. In 1987, Davidson et al. suggested that 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: * The use of

metrazol Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convul ...

(pentylenetetrazol) as an animal model of epilepsy * Induction of mechanical brain injury as an animal model of

post-traumatic epilepsy Post-traumatic epilepsy (PTE) is a form of acquired epilepsy that results from brain damage caused by physical trauma to the brain ( traumatic brain injury, abbreviated TBI). A person with PTE experiences repeated post-traumatic seizures (PTS, s ...

* Injection of the neurotoxin

6-hydroxydopamine Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a neurotoxic synthetic organic compound used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. The main use for o ...

to dopaminergic parts of the basal ganglia as an animal model of Parkinson's disease. * Immunisation with an auto-

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

to induce an immune response to model

autoimmune diseases An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

such as

Experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with ro ...

* Occlusion of the middle cerebral artery as an animal model of ischemic stroke * Injection of blood in the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

of mice as a model for

hemorrhagic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioni ...

Sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

and septic shock induction by impairing the integrity of barrier tissues, administering live

pathogens In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...

toxins A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

* Infecting animals with

to reproduce human infectious diseases * Injecting animals with

agonists An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of various neurotransmitters to reproduce human mental disorders * Using ionizing radiation to cause tumors * Using gene transfer to cause tumors * Implanting animals with tumors to test and develop treatments using ionizing radiation *

Genetically Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar working ...

selected (such as in

diabetic Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

mice also known as NOD mice) * Various animal models for

screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), ...

of drugs for the treatment of

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

* The use of the

ovariectomized rat An ovariectomized rodent (OVX) is a female rat or mouse whose ovaries have been removed. Currently there is no single animal model that identically represents the stages of osteoporosis in humans although there are some animals that are relatively ...

in osteoporosis research * Use of ''

Plasmodium yoelii ''Plasmodium yoelii'' is a parasite of the genus ''Plasmodium'' subgenus '' Vinckeia''. As in all ''Plasmodium'' species, ''P. yoelii'' has both vertebrate and insect hosts. The vertebrate hosts for this parasite are mammals. Taxonomy This spe ...

'' as a model of human malaria 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 Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including ...

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 symptoms of depression in patients. Depression, as other mental disorders, consists of

endophenotype In genetic epidemiology, endophenotype (or intermediate phenotype) is a term used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 pap ...

s that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic and

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...

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.

Important model organisms

Model organisms are drawn from all three domains of life, as well as viruses. The most widely studied prokaryotic model organism is ''

'' (''E. coli''), which has been intensively investigated for over 60 years. It is a common, gram-negative gut bacterium which can be grown and cultured easily and inexpensively in a laboratory setting. It is the most widely used organism in

molecular genetics Molecular genetics is a sub-field of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the ...

, and is an important species in the fields of

biotechnology Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services. The term ''biotechnology'' was first used by ...

and microbiology, where it has served as the

host organism In biology and medicine, a host is a larger organism that harbours a smaller organism; whether a parasitic, a mutualistic, or a commensalist ''guest'' (symbiont). The guest is typically provided with nourishment and shelter. Examples include a ...

for the majority of work with

recombinant DNA Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be fou ...

. Simple model eukaryotes include baker's yeast (''

'') and fission yeast (''

Schizosaccharomyces pombe ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measur ...

''), both of which share many characters with higher cells, including those of humans. For instance, many

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there a ...

genes that are critical for the development of cancer have been discovered in yeast. ''

Chlamydomonas reinhardtii ''Chlamydomonas reinhardtii'' is a single-cell green alga about 10 micrometres in diameter that swims with two flagella. It has a cell wall made of hydroxyproline-rich glycoproteins, a large cup-shaped chloroplast, a large pyrenoid, and an eyes ...

'', a unicellular

green alga The green algae (singular: green alga) are a group consisting of the Prasinodermophyta and its unnamed sister which contains the Chlorophyta and Charophyta/Streptophyta. The land plants (Embryophytes) have emerged deep in the Charophyte alga as ...

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 In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular ...

, differentiation, and

programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...

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. The

'' is used for understanding the genetic control of development and physiology. It was first proposed as a model for neuronal development by

Sydney Brenner Sydney Brenner (13 January 1927 – 5 April 2019) was a South African biologist. In 2002, he shared the Nobel Prize in Physiology or Medicine with H. Robert Horvitz and Sir John E. Sulston. Brenner made significant contributions to wor ...

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 A connectome () is a comprehensive map of neural connections in the brain, and may be thought of as its "wiring diagram". An organism's nervous system is made up of neurons which communicate through synapses. A connectome is constructed by t ...

(neuronal "wiring diagram") completed. ''

'' 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

sequenced In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succi ...

. Among vertebrates, guinea pigs (''Cavia porcellus'') were used by

Robert Koch Heinrich Hermann Robert Koch ( , ; 11 December 1843 – 27 May 1910) was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera (though the bacteri ...

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 ('' Mus musculus''). 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 ''Rattus'' is a genus of muroid rodents, all typically called rats. However, the term rat can also be applied to rodent species outside of this genus. Species and description The best-known ''Rattus'' species are the black rat (''R. rattus'' ...

'') 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 The western clawed frog (''Xenopus tropicalis'') is a species of frog in the family Pipidae, also known as tropical clawed frog. It is the only species in the genus ''Xenopus'' to have a diploid genome. Its genome has been sequenced, making it a ...

'' and ''

Xenopus laevis The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws o ...

'' (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience. Likewise, the

zebrafish The zebrafish (''Danio rerio'') 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 (and thus often ...

(''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 ''Tetrahymena thermophila'' is a species of Ciliophora in the family Tetrahymenidae. It is a free living protozoa and occurs in fresh water. There is little information on the ecology and natural history of this species, but it is the most wide ...

'' (intracellular processes), maize ( transposons), '' hydras'' ( regeneration and morphogenesis),

cat The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...

s (neurophysiology), chickens (development),

dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. ...

s (respiratory and cardiovascular systems), ''

Nothobranchius furzeri ''Nothobranchius furzeri'', the turquoise killifish, is a species of killifish from the family Nothobranchiidae native to Africa where it is only known from Zimbabwe and Mozambique. This annual killifish inhabits ephemeral pools in semi-arid ...

'' (aging), and non-human primates such as the rhesus macaque and

chimpanzee The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close relative the ...

( hepatitis,

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

, Parkinson's disease,

cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, though ...

, and vaccines).

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

genetic manipulation Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including ...

has been developed. The genomes of all model species have been

, including their mitochondrial/

chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...

genomes.

Model organism databases Model organism databases (MODs) are biological databases, or knowledgebases, dedicated to the provision of in-depth biological data for intensively studied model organisms. MODs allow researchers to easily find background information on large sets ...

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.

Limitations

Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively

sedentary Sedentary lifestyle is a lifestyle type, in which one is physically inactive and does little or no physical movement and or exercise. A person living a sedentary lifestyle is often sitting or lying down while engaged in an activity like soci ...

, 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. Similarly, there are differences between the immune systems of model organisms and humans that lead to significantly altered responses to stimuli, although the underlying principles of genome function may be the same. The impoverished environments inside standard laboratory cages deny research animals of the mental and physical challenges are necessary for healthy emotional development. Without day-to-day variety, risks and rewards, and complex environments, some have argued that animal models are irrelevant models of human experience. Mice differ from humans in several immune properties: mice are more resistant to some

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 Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

. 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, herpesviruses) are activated in humans, but not in SPF mice, with septic complications and may change the resistance to bacterial

coinfections Coinfection is the simultaneous infection of a host by multiple pathogen species. In virology, coinfection includes simultaneous infection of a single cell by two or more virus particles. An example is the coinfection of liver cells with hepatiti ...

. “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 Out-crossing or out-breeding is the technique of crossing between different breeds. This is the practice of introducing distantly related genetic material into a breeding line, thereby increasing genetic diversity. Outcrossing can be a useful ...

, and nonlinear mice.

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. Another study in 2016 suggested that gut

microbiomes A microbiome () is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps ''et al.'' as "a characteristic microbial community occupying a reasonably wel ...

in mice may have an impact upon scientific research.

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 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.

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. 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 National Anti-Vivisection Society (NAVS) is an international not-for-profit animal protection group, based in London, working to end animal testing, and focused on the replacement of animals in research with advanced, scientific techniques. S ...

, 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. 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. 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. "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
"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.

References

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

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
{{DEFAULTSORT:Model Organism Animal testing