An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human
disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
, for the purpose of better understanding the disease process without the risk of harming a human. Although biological activity in an animal model does not ensure an effect in humans, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models.
Animal models representing specific taxonomic groups in the research and study of
developmental processes are also referred to as
model organism
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...
s.
[ There are three main types of animal models: Homologous, Isomorphic and Predictive.
Homologous animals have the same causes, symptoms and treatment options as would humans who have the same disease.
Isomorphic animals share the same symptoms and treatments, only.
Predictive models are similar to a particular human disease in only a couple of aspects. However, these are useful in isolating and making predictions about mechanisms of a set of disease features.
]
Phylogeny and genetic similarity
Although scientific study of animals predates Charles Darwin
Charles Robert Darwin ( ; 12 February 1809 – 19 April 1882) was an English naturalist, geologist, and biologist, widely known for his contributions to evolutionary biology. His proposition that all species of life have descended ...
by several hundred years, the primary justification for the use of animals in research is based on the evolutionary principle that all organisms share some degree of relatedness and genetic similarity due to common ancestry. The study of taxonomic human relatives, then, can provide a great deal of information about mechanism and disease within the human body that can be useful in medicine.
Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics as well as the geochemical and fossil record. These estimations tell us that humans and chimpanzees last shared a common ancestor about 6 million years ago (mya). As our closest relatives, chimpanzees have a lot of potential to tell us about mechanisms of disease (and what genes may be responsible for human intelligence). However, chimpanzees are rarely used in research and are protected from highly invasive procedures. The most common animal model is the rodent. Phylogenic 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.
Recently, genomic data has been added to techniques to make close comparisons between species and determine relatedness. Humans share about 99% of our genome with chimpanzees (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.
Disease models
Animal models serving in research may have an existing, inbred or induced disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
or injury that is similar to a human condition. These test conditions are often termed as animal models of disease. The use of animal models allows researchers to investigate disease states in ways which would be inaccessible in a human patient, performing procedures on the non-human animal that imply a level of harm that would not be considered ethical to inflict on a human.
As in noted the introduction, animal models can be classified as homologous, isomorphic or predictive. Animal models can also be more broadly classified into four categories: 1) experimental, 2) spontaneous, 3) negative, 4) orphan.
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) as an animal model of epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...
* 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 respon ...
to induce an immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which coul ...
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 r ...
* Occlusion of the middle cerebral artery
The middle cerebral artery (MCA) is one of the three major paired cerebral arteries that supply blood to the cerebrum. The MCA arises from the internal carotid artery and continues into the lateral sulcus where it then branches and projects to ma ...
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 ext ...
of mice
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
as a model for hemorrhagic stroke
A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
* 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
Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International C ...
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 ...
or 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 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 ...
to reproduce human infectious diseases
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
* Injecting animals with agonists or antagonists of various neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
s to reproduce human mental disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
s
* Using ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
to cause tumors
* Using gene transfer to cause tumors
* Implanting animals with tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s to test and develop treatments using ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
* Genetically 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
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
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 aqueous humor, fluid withi ...
* 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
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
research
* Use of Plasmodium yoelii 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 genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
s of non-human primates
Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter including ...
and other mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
that are genetically close to humans is allowing the production of genetically engineered animal tissues, organs and even animal species which express human diseases, providing a more robust model of human diseases in an animal model.
The best models of disease are similar in etiology
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, ...
(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
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
in laboratory animals can be used to screen and test new drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalati ...
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 "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."
Behavioral sciences
Animal models observed in the sciences of psychology
Psychology is the science, scientific study of mind and behavior. Psychology includes the study of consciousness, conscious and Unconscious mind, unconscious phenomena, including feelings and thoughts. It is an academic discipline of immens ...
and sociology
Sociology is a social science that focuses on society, human social behavior, patterns of social relationships, social interaction, and aspects of culture associated with everyday life. It uses various methods of empirical investigation an ...
are often termed animal models of behavior. It is difficult to build an animal model that perfectly reproduces the symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
s of depression in patients. Animals lack self-consciousness
Self-consciousness is a heightened sense of awareness of oneself. It is not to be confused with consciousness in the sense of qualia. Historically, "self-consciousness" was synonymous with "self-awareness", referring to a state of awareness that ...
, self-reflection and consideration; moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans. However, depression, as other mental disorders
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...
, 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
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...
, 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 ...
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
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.
Challenges and criticisms
Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively sedentary, obese and glucose intolerant. This may confound their use to model human metabolic processes and diseases as these can be affected by dietary energy intake and exercise
Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness.
It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
.
Animal models of psychiatric illness give rise to other concerns. Qualitative assessments of behavior are too often subjective. This would lead the investigator to observe what they want to observe in subjects, and to render conclusions in line with their expectations. Also, the imprecise diagnostic criteria for psychiatric illnesses inevitably lead to problems modeling the condition; e.g., since a person with major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
may experience weight loss or weight gain, insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
or hypersomnia
Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...
, we cannot with any certainty say that a rat with insomnia and weight loss is depressed. Furthermore, the complex nature of psychiatric conditions makes it difficult/impossible to translate human behaviors and deficits; e.g., language deficit plays a major role in autistic spectrum disorder
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
s, but – since rodents do not have language – it is not possible to develop a language-impaired "autistic" mouse.
Ethics
Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament enacted the first law for animal protection preventing cruelty to cattl
see text
This was followed by the Cruelty to Animals Act of 1835 and 1849, which criminalized ill-treating, over-driving, and torturing animals. In 1876, under pressure from the National Anti-Vivisection Society, the Cruelty to Animals Act was amended to include regulations governing the use of animals in research. This new act stipulated that 1) experiments must be proven absolutely necessary for instruction, or to save or prolong human life; 2) animals must be properly anesthetized; and 3) animals must be killed as soon as the experiment is over (see text). Today, these three principles are central to the laws and guidelines governing the use of animals and research. In the U.S., the Animal Welfare Act of 1970 (see also Laboratory Animal Welfare Act) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care progra
see AWA policies
In academic settings in which NIH funding is used for animal research, institutions are governed by the NIH Office of Laboratory Animal Welfare (OLAW). At each site, OLAW guidelines and standards are upheld by a local review board called the Institutional Animal Care and Use Committee (IACUC). All laboratory experiments involving living animals are reviewed and approved by this committee. In addition to proving the potential for benefit to human health, minimization of pain and distress, and timely and humane euthanasia, experimenters must justify their protocols based on the principles of Replacement, Reduction and Refinement.
Replacement refers to efforts to engage alternatives to animal use. This includes the use of computer models, non-living tissues and cells, and replacement of "higher-order" animals (primates and mammals) with "lower" order animals (e.g. cold-blooded animals, invertebrates, bacteria) wherever possible
list of common model organisms approved for use by the NIH
.
Reduction refers to efforts to minimize number of animals used during the course of an experiment, as well as prevention of unnecessary replication of previous experiments. To satisfy this requirement, mathematical calculations of statistical power are employed to determine the minimum number of animals that can be used to get a statistically significant experimental result. Reduction involves methods to maximize information provided while minimizing the number of animals applied.
Refinement refers to efforts to make experimental design as painless and efficient as possible in order to minimize the suffering of each animal subject.
While significant advances have been made in the care and treatment of animals, this is an ever-evolving debate. Animal rights and protection groups such as the ASPCA, PETA and BUAV continue to advocate for the best laboratory conditions, and experimental protocols possible for animals in research. Pressure from these groups has also led to novel modes of experimentation, which does not involve the sacrifice of live animals.
One aspect of this debate; however, continues to be difficult to resolve: the classification of animals according to a hierarchy, which protects some species more than others. Next to humans, primates are the most protected species in experimentation. The rationale for this has both evolutionary and philosophical underpinnings. Because chimpanzees and other non-human primates can demonstrate intelligence, and social structure that they have a life experiences that is more cognitively complex than lower species. Conversely, this kind of moralizing of complexity of interaction and thought could be considered "specieisism." Ultimately, this is an argument not likely to be resolved, however most people are more comfortable with the idea of experimentation that involves worms or flies than mice, dogs, or monkeys.
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
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This tec ...
and ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'' 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 induced 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.
See also
* Animal models of autism
* Animal models of schizophrenia
* Animal testing on invertebrates
Most animal testing involves invertebrates, especially ''Drosophila melanogaster'', a fruit fly, and ''Caenorhabditis elegans'', a nematode. These animals offer scientists many advantages over vertebrates, including their short life cycle, simple ...
* Animal testing on rodents
* Animal testing
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
* Britches (monkey)
In 1985, a raid took place at a laboratory belonging to the University of California, Riverside (UCR) that resulted in the removal of a monkey by the Animal Liberation Front (ALF). This monkey, called Britches (born March 1985), was a stump-tail ...
* Ensembl
Ensembl genome database project is a scientific project at the European Bioinformatics Institute, which provides a centralized resource for geneticists, molecular biologists and other researchers studying the genomes of our own species and other v ...
genome database
* History of animal testing
The history of animal testing goes back to the writings of the Ancient Greeks in the 4th and 3rd centuries BCE, with Aristotle (384–322 BCE) and Erasistratus (304–258 BCE) one of the first documented to perform experiments on nonhuman animal ...
* History of model organisms
The history of model organisms began with the idea that certain organisms can be studied and used to gain knowledge of other organisms or as a control (ideal) for other organisms of the same species. Model organisms offer standards that serve a ...
* ''In vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
''
* Knockout rat
* Mouse models of colorectal and intestinal cancer
References
{{Reflist, 30em
External links
Transgenic Animal Models – Biomedcode
Knock Out Rat Consortium – KORC
Emice
– National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. T ...
Animal testing