Model organism

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

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms.[1] Model organisms are in vivo models and are widely used to research human disease when human experimentation would be unfeasible or unethical.[2] This strategy is made possible by the common descent of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution.[3] Studying model organisms can be informative, but care must be taken when extrapolating 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 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 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.[4][5] 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.[6]

Selecting a model organism

Models are those organisms with a wealth of biological data that make them attractive to study as examples for other species and/or natural phenomena that are more difficult to study directly. Continual research on these organisms focus on a wide variety of experimental techniques and goals from many different levels of biology—from ecology, behavior, and biomechanics, down to the tiny functional scale of individual tissues, organelles, and proteins. Inquiries about the DNA of organisms are classed as genetic models (with short generation times, such as the fruitfly and nematode worm), experimental models, and genomic parsimony models, investigating pivotal position in the evolutionary tree.[7] Historically, model organisms include a handful of species with extensive genomic research data, such as the NIH model organisms.[8]

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).

When researchers look for an organism to use in their studies, they look for several traits. Among these are size, generation time, accessibility, manipulation, genetics, conservation of mechanisms, and potential economic benefit. As comparative molecular biology has become more common, some researchers have sought model organisms from a wider assortment of lineages on the tree of life.

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.

Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics as well as the geochemical and fossil record.[9] 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. Phylogenetic trees estimate that humans and rodents last shared a common ancestor ~80-100mya.[10][11] 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 our genome with chimpanzees[12][13] (98.7% with bonobos)[14] and over 90% with the mouse.[11] 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 of model organisms

There are many model organisms. One of the first model systems for molecular biology was the bacterium Escherichia coli, a common constituent of the human digestive system. Several of the bacterial viruses (bacteriophage) that infect E. coli also have been very useful for the study of gene structure and gene regulation (e.g. phages Lambda and T4). However, bacteriophages are not organisms because they lack metabolism and depend on functions of the host cells for propagation.

In eukaryotes, several yeasts, particularly Saccharomyces cerevisiae ("baker's" or "budding" yeast), have been widely used in genetics and cell biology, largely because they are quick and easy to grow. The cell cycle in a simple yeast is very similar to the cell cycle in 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 is studied because it has very defined development patterns involving fixed numbers of cells, and it can be rapidly assayed for abnormalities.

Electron microphotograph of tobacco mosaic virus (TMV) particles

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.

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.[15]

Experimental models are most common. These refer to models of disease that resemble human conditions in phenotype or response to treatment but are induced artificially in the laboratory. Some examples include:

Spontaneous models refer to diseases that are analogous to human conditions that occur naturally in the animal being studied. These models are rare, but informative.

Negative models essentially refer to control animals, which are useful for validating an experimental result.

Orphan models refer to diseases for which there is no human analog and occur exclusively in the species studied.

The increase in knowledge of the genomes of non-human primates and other mammals that are genetically close to humans is allowing the production of genetically engineered animal tissues, organs and even animal species which express human diseases, providing a more robust model of human diseases in an animal model.

The best models of disease are similar in etiology (mechanism of cause) and phenotype (signs and symptoms) to the human equivalent. However complex human diseases can often be better understood in a simplified system in which individual parts of the disease process are isolated and examined. For instance, behavioral analogues of anxiety or pain in laboratory animals can be used to screen and test new 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.[27]

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.”[28]

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. Animals lack self-consciousness, 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, consists of endophenotypes [29] that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic and epigenetic 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

Sporulating Bacillus subtilis

Model organisms are drawn from all three domains of life, as well as viruses. The most widely studied prokaryotic model organism is Escherichia coli (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, and is an important species in the fields of biotechnology and microbiology, where it has served as the host organism for the majority of work with recombinant DNA.[30] Simple model eukaryotes include Chlamydomonas reinhardtii, a unicellular green alga with well-studied genetics, used to study photosynthesis and motility, among many other topics. C. reinhardtii has many known and mapped mutants and expressed sequence tags, and there are advanced methods for genetic transformation and selection of genes.[31] Dictyostelium discoideum is used in molecular biology and genetics, and is studied as an example of cell communication, differentiation, and programmed cell death.

Caenorhabditis elegans
Laboratory mice

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.[32] 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.[33][34] 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.[35][36] Arabidopsis thaliana is currently the most popular model plant. Its small stature and short generation time facilitates rapid genetic studies,[37] and many phenotypic and biochemical mutants have been mapped.[37] Arabidopsis was the first plant to have its genome sequenced.[37] Among vertebrates, guinea pigs (Cavia porcellus) were used by Robert Koch and other early bacteriologists as a host for bacterial infections, becoming a byword for "laboratory animal," but are less commonly used today. The classic model vertebrate is currently the mouse (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.[38]

The rat (Rattus norvegicus) is particularly useful as a toxicology model, and as a neurological model and source of primary cell cultures, owing to the larger size of organs and suborganellar structures relative to the mouse, while eggs and embroys from Xenopus tropicalis and Xenopus laevis (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience[39][40] 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,[41] specific gene function and roles of signaling pathways.

Other important model organisms and some of their uses include: T4 phage (viral infection), Tetrahymena thermophila (intracellular processes), budding yeast, fission yeast (cell cycle, cell polarity, RNAi, centromeres, and transcription), maize (transposons), hydras (regeneration and morphogenesis),[42] cats (neurophysiology), chickens (development), dogs (respiratory and cardiovascular systems), and non-human primates such as the rhesus macaque and chimpanzee (hepatitis, HIV, Parkinson's disease, cognition, and vaccines).

Table of model genetic organisms

This table indicates the status of the genome sequencing project for each organism.

Organism Genome Sequenced Mitochondrial Genome Sequenced
Prokaryote
Escherichia coli Yes -
Eukaryote, unicellular
Dictyostelium discoideum Yes
Saccharomyces cerevisiae Yes
Schizosaccharomyces pombe Yes
Chlamydomonas reinhardtii Yes
Tetrahymena thermophila Yes Yes
Emiliania huxleyi Yes
Eukaryote, multicellular
Caenorhabditis elegans Yes
Drosophila melanogaster Yes
Arabidopsis thaliana Yes Yes
Physcomitrella patens Yes
Vertebrate
Danio rerio Yes Yes
Fundulus heteroclitus Yes
Mus musculus Yes
Xenopus laevis (Note: and X. tropicalis)[43] Yes
Homo sapiens (Note:not a model organism) Yes

Limitations of model organisms

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.[44]

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 may experience weight loss or weight gain, insomnia or hypersomnia, 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 disorders, but – since rodents do not have language – it is not possible to develop a language-impaired "autistic" mouse.

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.

Ultimately, however, 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 enacted the first law for animal protection preventing cruelty to cattle 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 program 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.[45]

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.

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

References

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  45. ↑ http://grants.nih.gov/grants/olaw/investigatorsneed2know.pdf

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