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

A model organism 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 workings of other organisms.[1][2] Model organisms are widely used to research human disease when human experimentation would be unfeasible or unethical.[3] 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.[4]

Research using animal models has been central to most of the achievements of modern medicine.[5][6][7] It has contributed most of the basic knowledge in fields such as human physiology and biochemistry, and has played significant roles in fields such as neuroscience and infectious disease.[8][9] The results have included the near-eradication of polio and the development of organ transplantation, and have benefited both humans and animals.[5][10] From 1910 to 1927, Thomas Hunt Morgan's work with the fruit fly Drosophila melanogaster identified chromosomes as the vector of inheritance for genes,[11][12] and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science".[13] Research in model organisms led to further medical advances, such as the production of the diphtheria antitoxin[14][15] and the 1922 discovery of insulin[16] and its use in treating diabetes, which had previously meant death.[17] Modern general anaesthetics such as halothane were also developed through studies on model organisms, and are necessary for modern, complex surgical operations.[18] Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,[19][20][21][22] the heart-lung machine,[23] antibiotics,[24][25][26] and the whooping cough vaccine.[27]

In researching human disease, model organisms allow for better understanding the disease process without the added risk of harming an actual human. The species of the model organism is usually chosen so that it reacts to disease or its treatment in a way that resembles human physiology, even though care must be taken when generalizing from one organism to another.[28] However, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models.[29][30] Treatments for animal diseases have also been developed, including for rabies,[31] anthrax,[31] glanders,[31] feline immunodeficiency virus (FIV),[32] tuberculosis,[31] Texas cattle fever,[31] classical swine fever (hog cholera),[31] heartworm, and other parasitic infections.[33] Animal experimentation continues to be required for biomedical research,[34] and is used with the aim of solving medical problems such as Alzheimer's disease,[35] AIDS,[36] multiple sclerosis,[37] spinal cord injury, many headaches,[38] and other conditions in which there is no useful in vitro model system available.

Model organisms are drawn from all three domains of life, as well as viruses. One of the first model systems for molecular biology was the bacterium Escherichia coli (E. coli), a common constituent of the human digestive system. The mouse (Mus musculus) has been used extensively as a model organism and is associated with many important biological discoveries of the 20th and 21st centuries.[39] Other examples include baker's yeast (Saccharomyces cerevisiae), the T4 phage virus, the fruit fly Drosophila melanogaster, the flowering plant Arabidopsis thaliana, and guinea pigs (Cavia porcellus). 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).[40] Disease models are divided into three categories: 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, and 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.[41]

History

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The use of animals in research dates back to ancient Greece, with Aristotle (384–322 BCE) and Erasistratus (304–258 BCE) among the first to perform experiments on living animals.[42] Discoveries in the 18th and 19th centuries included Antoine Lavoisier's use of a guinea pig in a calorimeter to prove that respiration was a form of combustion, and Louis Pasteur's demonstration of the germ theory of disease in the 1880s using anthrax in sheep.[43]

Research using animal models has been central to most of the achievements of modern medicine.[5][6][7] It has contributed most of the basic knowledge in fields such as human physiology and biochemistry, and has played significant roles in fields such as neuroscience and infectious disease.[8][9] For example, the results have included the near-eradication of polio and the development of organ transplantation, and have benefited both humans and animals.[5][10] From 1910 to 1927, Thomas Hunt Morgan's work with the fruit fly Drosophila melanogaster identified chromosomes as the vector of inheritance for genes.[11][12] Drosophila became one of the first, and for some time the most widely used, model organisms,[44] and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science".[13] 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 in collaboration with Abbie Lathrop led to generation of the DBA ("dilute, brown and non-agouti") inbred mouse strain and the systematic generation of other inbred strains.[45][46] 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.[39]

In the late 19th century, Emil von Behring isolated the diphtheria toxin and demonstrated its effects in guinea pigs. He went on to develop an antitoxin against diphtheria in animals and then in humans, which resulted in the modern methods of immunization and largely ended diphtheria as a threatening disease.[14] The diphtheria antitoxin is famously commemorated in the Iditarod race, which is modeled after the delivery of antitoxin in the 1925 serum run to Nome. The success of animal studies in producing the diphtheria antitoxin has also been attributed as a cause for the decline of the early 20th-century opposition to animal research in the United States.[15]

Subsequent research in model organisms led to further medical advances, such as Frederick Banting'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)[16] and its use in treating diabetes, which had previously meant death.[17] John Cade's research in guinea pigs discovered the anticonvulsant properties of lithium salts,[47] which revolutionized the treatment of bipolar disorder, replacing the previous treatments of lobotomy or electroconvulsive therapy. Modern general anaesthetics, such as halothane and related compounds, were also developed through studies on model organisms, and are necessary for modern, complex surgical operations.[18][48]

In the 1940s, Jonas Salk used rhesus monkey studies to isolate the most virulent forms of the polio virus,[49] 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.[50] Albert Sabin improved the vaccine by passing the polio virus through animal hosts, including monkeys; the Sabin vaccine was produced for mass consumption in 1963, and had virtually eradicated polio in the United States by 1965.[51] 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."[52]

Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,[19][20][21][22] the heart-lung machine,[23] antibiotics,[24][25][26] and the whooping cough vaccine.[27] Treatments for animal diseases have also been developed, including for rabies,[31] anthrax,[31] glanders,[31] feline immunodeficiency virus (FIV),[32] tuberculosis,[31] Texas cattle fever,[31] classical swine fever (hog cholera),[31] heartworm, and other parasitic infections.[33] Animal experimentation continues to be required for biomedical research,[34] and is used with the aim of solving medical problems such as Alzheimer's disease,[35] AIDS,[36][53][54] multiple sclerosis,[37] spinal cord injury, many headaches,[38] and other conditions in which there is no useful in vitro model system available.

Selection

[edit]

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 focuses 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.[55] Historically, model organisms include a handful of species with extensive genomic research data, such as the NIH model organisms.[56]

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).[57]

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

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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 mechanisms and diseases within the human body that can be useful in medicine.[58]

Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics, as well as the geochemical and fossil record.[59] 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.[60][61] 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.[62]

Genomic data is used to make close comparisons between species and determine relatedness. Humans share about 99% of their genome with chimpanzees[63][64] (98.7% with bonobos)[65] and over 90% with the mouse.[61] 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 a few thousand genes, less than 1% (of ~19,000 total). Scientists have been able to take advantage of these similarities in generating experimental and predictive models of human disease.[66]

Use

[edit]

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, it is debated whether bacteriophages should be classified as organisms, because they lack metabolism and depend on functions of the host cells for propagation.[67]

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.[68]

Disease models

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Main article: Animal disease model

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.[69]

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 where 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 non-rodents alone and 43% for rodents alone.[70]

In 1987, Davidson et al. suggested that the 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.[71]

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.[72]

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.[72]

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.

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 endophenotypes[87] 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 the pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.[88][89]

Important model organisms

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See also: List of model organisms

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.[90]

Simple model eukaryotes include baker's yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe), both of which share many characters with higher cells, including those of humans. For instance, many cell division genes that are critical for the development of cancer have been discovered in yeast. Chlamydomonas reinhardtii, a unicellular green alga 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.[91] Dictyostelium discoideum is used in molecular biology and genetics, and is studied as an example of cell communication, differentiation, and programmed cell death.

Laboratory mice, widely used in medical research

Among invertebrates, the fruit fly Drosophila melanogaster is famous as the subject of genetics experiments by Thomas Hunt Morgan and others. They are easily raised in the lab, with rapid generations, high fecundity, few chromosomes, and easily induced observable mutations.[92] 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.[93][94] 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.[95][96]

Arabidopsis thaliana is currently the most popular model plant. Its small stature and short generation time facilitates rapid genetic studies,[97] and many phenotypic and biochemical mutants have been mapped.[97] A. thaliana was the first plant to have its genome sequenced.[97]

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.[98] 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 embryos from Xenopus tropicalis and Xenopus laevis (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience.[99][100] 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,[101] 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), maize (transposons), hydras (regeneration and morphogenesis),[102] cats (neurophysiology), chickens (development), dogs (respiratory and cardiovascular systems), Nothobranchius furzeri (aging),[103] non-human primates such as the rhesus macaque and chimpanzee (hepatitis, HIV, Parkinson's disease, cognition, and vaccines), and ferrets (SARS-CoV-2)[104]

Selected model organisms

[edit]

The organisms below have become model organisms because they facilitate the study of certain characteristics or because of their genetic accessibility. For example, E. coli was one of the first organisms for which genetic techniques such as transformation or genetic manipulation has been developed.[105]

The genomes of all model species have been sequenced, including their mitochondrial/chloroplast genomes. Model organism databases exist to provide researchers with a portal from which to download sequences (DNA, RNA, or protein) or to access functional information on specific genes, for example the sub-cellular localization of the gene product or its physiological role.[106]

Model Organism Common name Informal classification Usage (examples)
Virus Phi X 174 ΦX174 Bacteriophage evolution[107]
Prokaryotes Escherichia coli E. coli Bacteria bacterial genetics, metabolism
Pseudomonas fluorescens P. fluorescens Bacteria evolution, adaptive radiation[108]
Eukaryotes, unicellular Dictyostelium discoideum Amoeba immunology, host–pathogen interactions[109]
Saccharomyces cerevisiae Brewer's yeast
Baker's yeast 		Yeast cell division, organelles, etc.
Schizosaccharomyces pombe Fission yeast Yeast cell cycle, cytokinesis, chromosome biology, telomeres, DNA metabolism, cytoskeleton organization, industrial applications[110][111]
Chlamydomonas reinhardtii Green algae hydrogen production[112]
Tetrahymena thermophila, T. pyriformis Ciliate education,[113] biomedical research[114]
Emiliania huxleyi Phytoplankton surface sea temperature[115]
Plants Arabidopsis thaliana Thale cress Flowering plant population genetics[116]
Physcomitrella patens Spreading earthmoss Moss molecular farming[117]
Populus trichocarpa Balsam poplar Tree drought tolerance, lignin biosynthesis, wood formation, plant biology, morphology, genetics, and ecology[118]
Animals, nonvertebrate Caenorhabditis elegans Nematode, Roundworm Worm differentiation, development
Drosophila melanogaster Fruit fly Insect developmental biology, human brain degenerative disease[119][120]
Callosobruchus maculatus Cowpea Weevil Insect developmental biology
Animals, vertebrate Danio rerio Zebrafish Fish embryonic development
Fundulus heteroclitus Mummichog Fish effect of hormones on behavior
Nothobranchius furzeri Turquoise killifish Fish aging, disease, evolution
Oryzias latipes Japanese rice fish Fish fish biology, sex determination[121]
Anolis carolinensis Carolina anole Reptile reptile biology, evolution
Mus musculus House mouse Mammal disease model for humans
Gallus gallus / G. g. domesticus Red junglefowl / chicken Bird embryological development and organogenesis
Taeniopygia guttata Australian zebra finch Bird vocal learning, neurobiology[122]
Xenopus laevis
Xenopus tropicalis[123] 		African clawed frog
Western clawed frog 		Amphibian embryonic development

Limitations

[edit]

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.[124] Similarly, there are differences between the immune systems of model organisms and humans that lead to significantly altered responses to stimuli,[125][126][127] although the underlying principles of genome function may be the same.[127] The impoverished environments inside standard laboratory cages deny research animals of the mental and physical challenges are necessary for healthy emotional development.[128] Without day-to-day variety, risks and rewards, and complex environments, some have argued that animal models are irrelevant models of human experience.[129]

Mice differ from humans in several immune properties: mice are more resistant to some toxins 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.[80] Laboratory mice reared in specific-pathogen-free (SPF) conditions usually have a rather immature immune system with a deficit of memory T cells. 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. "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, and nonlinear mice.[80]

Unintended bias

[edit]

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.[130][131][132] Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research.[133]

Alternatives

[edit]

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.[134] 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.[135][136]

Ethics

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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.[137] This was followed by the Cruelty to Animals Act 1835 and the Cruelty to Animals Act 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 1849 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.[138]

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.[139]

"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.[140]

"'Reduction' refers to efforts to minimize the number of animals used in experiments, including avoiding unnecessary replication, and determining sample size via statistical power calculations so that the smallest number of animals necessary yields scientifically valid results.[141]

Refinement refers to efforts to make experimental design as painless and efficient as possible—to minimize pain, suffering, distress or lasting harm—by improving procedures, husbandry, analgesia, humane endpoints, and animal care.[142]

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Model organism

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from Grokipedia

A model organism is a non-human species or strain chosen for biological research owing to attributes like short generation times, small size, ease of cultivation, well-characterized genomes, and conserved genetic or physiological mechanisms that permit extrapolation to more complex systems, including humans.
These organisms enable controlled experimentation on fundamental processes such as gene function, development, and disease pathology, with common examples encompassing the bacterium Escherichia coli for molecular genetics, the yeast Saccharomyces cerevisiae under differential interference contrast microscopy for eukaryotic cell cycle studies, the fruit fly Drosophila melanogaster for developmental genetics, the nematode Caenorhabditis elegans for neurobiology, and the mouse Mus musculus for mammalian physiology and immunology.
Historically rooted in early 20th-century genetics research—such as Thomas Hunt Morgan's work with Drosophila establishing chromosomal inheritance—model organisms have driven pivotal achievements, including the mapping of metabolic pathways, identification of oncogenes, and Nobel-recognized insights into RNA interference and programmed cell death.
Despite these contributions, limitations persist: interspecies differences often hinder direct applicability to human biology, with animal models exhibiting poor predictive accuracy for clinical toxicity and efficacy, as evidenced by high drug failure rates in translation from preclinical to human trials.
Ethical debates over animal suffering and the push for reductionist alternatives like in vitro systems or computational simulations further underscore ongoing controversies in their selection and use.

Definition and Selection Criteria

Core Characteristics of Model Organisms

Model organisms are species chosen for research due to inherent traits that enable efficient, reproducible experimentation on biological processes. These traits prioritize practicality in laboratory settings, such as ease of cultivation and manipulation, over direct physiological of humans unless relevant to the question at hand. Empirical selection favors organisms where causal mechanisms can be isolated and tested rapidly, often through genetic interventions that reveal underlying principles applicable across taxa. A primary characteristic is short , which permits observation of multiple generations within months, accelerating studies of , , and effects. For instance, completes its life cycle in about 3 days at 25°C, while requires roughly 10 days, allowing researchers to track phenotypic changes across dozens of generations in under a year. This trait underpins genetic mapping and selection experiments, as slower-reproducing species like mice (21-day plus maturation) demand longer timelines and higher resource investment for equivalent data. Genetic tractability is equally central, encompassing the organism's susceptibility to targeted modifications via , transgenesis, or tools like CRISPR-Cas9. This enables causal inference by knocking out or overexpressing specific genes to dissect pathways, as seen in (Saccharomyces cerevisiae), where facilitates precise replacement with efficiencies exceeding 80% in optimized strains. Extensive mutant collections, often numbering thousands of strains, further support this by providing pre-characterized variants for phenotyping, reducing de novo engineering needs. Without such amenability, verifying gene function or epistatic interactions becomes infeasible at scale. Small physical size and low maintenance demands minimize costs and logistical barriers, enabling high-throughput assays in confined spaces. Organisms like nematodes or fruit flies require minimal housing—e.g., C. elegans thrives in agar plates with bacterial food sources—contrasting with larger vertebrates that necessitate specialized facilities compliant with ethical and standards. This scalability supports parallel experiments, such as screening thousands of compounds for , where space and feed costs for mice could multiply expenses by orders of magnitude. Complementing these are high fecundity and well-characterized genomes, which supply abundant experimental material and foundational reference data. Model organisms typically produce hundreds to thousands of offspring per cycle, ensuring statistical power in assays, while fully sequenced genomes (e.g., E. coli since 1997) with annotated orthologs to eukaryotic genes allow cross-species validation of conserved mechanisms. These features collectively enable first-principles dissection of causality, from molecular interactions to organismal phenotypes, though applicability to humans hinges on verified homology rather than assumed universality.

Factors Guiding Selection

Selection of model organisms balances scientific relevance to the research question with practical constraints, ensuring mechanisms can be dissected causally while minimizing experimental barriers. Key factors include genetic tractability, which enables precise interventions like gene knockouts or editing; organisms such as and excel here due to well-characterized genomes and vast mutant strain repositories, allowing attribution of phenotypes to specific genetic loci. Short generation times facilitate high-throughput studies; yeast, for example, reproduces in 1-2 days, enabling multi-generational experiments that would take years in vertebrates like mice, which require 10 weeks per cycle. Conservation of molecular pathways across taxa supports mechanistic inference; eukaryotic models like conserve core processes such as and regulation with humans, permitting foundational discoveries translatable to higher organisms, though tissue-level coordination demands vertebrate models like Danio rerio for vertebrate-specific . Practicality encompasses low maintenance costs and ease of scaling; microbial and models require minimal space and media compared to , which demand vivaria and veterinary oversight, influencing choices for budget-limited labs. Ethical and regulatory feasibility favors invertebrates over vertebrates; C. elegans and fruit flies face fewer oversight hurdles than mammals, reducing approval timelines from months to days and avoiding welfare concerns tied to sentience. Tradeoffs arise in phenotyping scope: population-level analysis suits genetically diverse strains in yeast recombinant inbred lines (e.g., 100+ lines for mapping), while individual-level resolution favors mice for complex traits involving neural or metabolic integration. Established research infrastructure, including genomic databases and community tools, reinforces selections; the Mouse Genome Informatics database, active since 1994, provides annotated data accelerating murine studies over nascent systems. These criteria interact contextually—for instance, high genetic similarity to humans prioritizes mice for modeling (sharing 85-95% orthologous genes), but overrides in microbial models when causal at the molecular level is paramount. Selection thus involves iterative refinement, weighing pathway-level fidelity against systemic complexity to optimize validity without assuming direct equivalence.

Historical Evolution

Pre-Modern and Early Scientific Use

The systematic study of living organisms for insights into biological processes predates the modern concept of model organisms, originating in ancient observational practices. In ancient Greece, Alcmaeon of Croton around the 6th century BCE employed dissections of dogs to identify the brain as the organ of sensation and intelligence. Aristotle (384–322 BCE) conducted extensive comparative anatomy and embryological observations on diverse species, including chickens for developmental stages, fish for reproduction, and insects for metamorphosis, classifying animals into those with blood (vertebrates) and without (invertebrates) while emphasizing empirical dissection over 500 species. These efforts laid foundational taxonomic and functional understandings, prioritizing accessible, abundant local fauna for reproducible observations of anatomy, behavior, and life cycles. In the Roman era and medieval period, such practices continued with experimental elements. (c. 129–c. 216 CE) performed vivisections on monkeys, dogs, and pigs to map and cardiovascular function, influencing physiological models for centuries despite inaccuracies like assuming production in the liver. By the , Islamic scholar Avenzoar tested tracheotomy and other surgeries on animals prior to human application, bridging observation and intervention. Early in the , pioneered by (1632–1723), revealed microbial life through examinations of pond water, , and animal fluids, documenting and as "animalcules" in letters from 1674 onward, though these served descriptive rather than standardized experimental roles. The early scientific era, from the Renaissance to the 19th century, shifted toward controlled experiments using select organisms to infer broader principles. William Harvey (1578–1657) utilized cold-blooded animals like eels, fish, snakes, and warm-blooded species such as chicks and pigeons in ligature and observational studies, demonstrating unidirectional blood flow and valvular function in his 1628 work De Motu Cordis, quantifying heart output via volume calculations (e.g., estimating 540 grams of blood circulated per heartbeat in larger animals). Chick embryos proved particularly valuable for tracing epigenesis, the sequential development from egg to organism. In botany, Gregor Mendel (1822–1884) selected pea plants (Pisum sativum) for their short generation time, self-pollinating nature, and discrete traits, conducting hybridization experiments from 1856 to 1863 on over 28,000 plants to establish laws of inheritance, presented in 1865 and published in 1866. These precedents highlighted criteria like ease of maintenance, observability, and manipulability, foreshadowing modern model selection without the genetic or genomic frameworks of later centuries.

20th Century Establishment and Expansion

The establishment of model organisms in the 20th century began with the fruit fly , pioneered by at . In January 1910, Morgan identified a white-eyed male mutant fly, which led to experiments demonstrating sex-linked inheritance and supporting the chromosomal theory of heredity. This work, building on Mendelian principles, positioned as a key system for genetic mapping and mutation studies due to its short of about 10 days, large number of , and ease of maintenance in laboratories. By the , Morgan's fly room had generated extensive genetic data, influencing the shift toward experimental over descriptive . Concurrently, the laboratory mouse Mus musculus emerged as a mammalian model in the early 1900s, valued for its short generation interval of 9-10 weeks and genetic tractability. Clarence Little developed the first inbred strain, DBA, through 20+ generations of sibling matings starting around 1909, enabling controlled genetic studies particularly in . The founding of in 1929 further standardized mouse strains, such as , facilitating reproducible experiments in and pathology. These strains reduced genetic variability, allowing precise linkage analysis and phenotypic consistency essential for in . In the 1940s, microbial models expanded the toolkit. and Edward Tatum's 1941 experiments with the bread mold established the one gene-one enzyme hypothesis by inducing mutations via X-rays and observing auxotrophic phenotypes requiring specific nutrients. This fungus's haploid life cycle and linear asci enabled direct gene-enzyme correlations, advancing biochemical genetics. Similarly, gained prominence in the 1940s for blending biochemical and genetic approaches, with its rapid growth (doubling every 20 minutes) and plasmid conjugation facilitating DNA transfer studies. Post-World War II expansion was driven by increased funding, technological advances like radiation mutagenesis, and the rise of , making model organisms indispensable for dissecting cellular mechanisms. By mid-century, these systems enabled scalable experiments yielding empirical data on function, far surpassing ad hoc species use in prior eras. mitigated variables, promoting causal realism in biological inference, though critiques later emerged regarding translatability to non-model species.

Genomic Revolution and Contemporary Shifts (2000s–2025)

The completion of sequences for major model organisms in the early 2000s facilitated and functional annotation efforts. The genome was fully sequenced and published in March 2000, revealing approximately 13,600 and enabling systematic identification of orthologs to human disease . The mouse (Mus musculus) genome followed in December 2002, with initial assembly covering 96% of and highlighting conserved synteny with the , which accelerated the development of libraries for . These milestones, contemporaneous with the Human Genome Project's draft completion in 2000, shifted research paradigms from classical to genome-wide association and prediction of functions across . Subsequent advances in next-generation sequencing (NGS) technologies from the mid-2000s onward democratized genomic data generation, enabling high-throughput transcriptomics, , and population-level variation studies in model organisms. By 2007, NGS platforms like Illumina's Genome Analyzer reduced sequencing costs dramatically, allowing projects such as modENCODE (for and ) to map regulatory elements and non-coding RNAs, which comprised over 80% of the fly genome. In (zebrafish), the genome assembly improved iteratively, with the GRCz11 version in 2017 incorporating long-read sequencing to resolve complex regions, supporting large-scale screens for developmental genes. Saccharomyces cerevisiae benefited from resequencing efforts revealing structural variants, informing applications like genome-scale metabolic modeling. These tools enhanced by linking variants directly to phenotypes, bypassing limitations of earlier microarray-based approaches. The 2012 introduction of CRISPR-Cas9 gene editing marked a pivotal shift, enabling precise, multiplexed modifications in model organisms with efficiencies far surpassing prior zinc-finger nucleases or TALENs. Initial demonstrations in human cells were rapidly adapted: knockouts in achieved 25-80% efficiency by 2013, facilitating rapid disease modeling such as orthologs; in mice, it enabled conditional alleles and humanized strains by 2014, reducing breeding times from years to months. In C. elegans and , supported pooled screens interrogating thousands of genes simultaneously, as in 2015 studies identifying essentiality under stress conditions. By the 2020s, refinements like base editing (2016) and (2019) minimized double-strand breaks, improving precision for modeling point mutations in cancer or neurodegeneration, with applications exceeding 10,000 edited loci in mouse models by 2023. These innovations promoted causal realism in , allowing direct testing of genetic hypotheses rather than correlative associations, though off-target effects necessitated validation via whole-genome sequencing. Contemporary trends toward integrative multi-omics and non-traditional models reflect -driven diversification, addressing translational gaps in traditional systems. Single-cell sequencing, scaled in models like the atlas (2018 onward), revealed cellular heterogeneity, informing human validation. Efforts to sequence emerging models, such as historical specimens in 2023, enabled evolutionary , tracing changes over decades. However, critiques highlight over-reliance on a few species, prompting genomic enablement of alternatives like rats via (post-2013), which better mimic human physiology in . By 2025, AI-augmented analysis of these datasets predicts interactions, but empirical validation remains essential to avoid biases from incomplete annotations.

Research Applications

Fundamental Mechanisms in Biology

Model organisms facilitate the investigation of core biological processes such as genetic inheritance, , , and developmental patterning through genetic manipulation, genomic sequencing, and high-resolution observation. These systems enable controlled experiments that reveal causal mechanisms, often leveraging short generation times and simple anatomies to isolate variables unattainable in more complex species. In genetics, has been instrumental since Thomas Hunt Morgan's 1910 discovery of a white-eyed , which demonstrated sex-linked and established the theory of heredity. Subsequent work in fruit flies elucidated rates, , and , with over a century of yielding insights into eukaryotic mechanics and transposon activity. For , Escherichia coli provided the foundational model for , where studies confirmed semi-conservative replication and identified key enzymes like , informing universal prokaryotic and eukaryotic mechanisms. Research in this bacterium, including density-gradient centrifugation experiments in the 1950s, quantified replication fidelity and origin-specific initiation at oriC, establishing paradigms for duplication control. Cell cycle regulation has been dissected primarily in budding yeast (Saccharomyces cerevisiae), where Leland Hartwell's identification of cell division cycle (CDC) mutants in the 1970s pinpointed checkpoints ensuring orderly progression from G1 to mitosis. Comprehensive transcriptomic analyses revealed over 800 periodically expressed genes, linking cyclin-dependent kinases to growth control and DNA damage responses, with models integrating these into robust network dynamics. Developmental biology benefits from , whose invariant —959 somatic cells in the adult hermaphrodite—allows precise tracking of lineage decisions and from to maturity over three days. Genetic screens uncovered heterochronic genes regulating temporal patterning and vulval induction pathways, revealing conserved signaling cascades like Wnt and Notch operative across metazoans. In vertebrates, Mus musculus supports gene function studies via targeted knockouts, with the mouse genome (sequenced 2002) sharing 80-90% orthology with humans, enabling dissection of mammalian-specific processes like Hox-mediated axial patterning and signaling in . These approaches, combined with editing since 2013, have causally linked thousands of genes to embryonic viability and tissue specification.

Modeling Human Diseases

Model organisms replicate aspects of human diseases through genetic manipulations that introduce disease-causing mutations or environmental stressors, exploiting conserved pathways across species to study , progression, and potential interventions. In vertebrates like mice, genetically engineered models (GEMMs) incorporate human-specific alterations, such as activations or tumor suppressor knockouts, to mimic tumorigenesis; for example, gene inactivation in mice induces intestinal polyps analogous to in humans. Transgenic mice expressing mutant human s, including APP and PSEN1 for , exhibit -beta plaques and tau tangles, enabling dissection of neuronal loss and synaptic dysfunction. These models have elucidated causal roles of genetic variants in chronic conditions, with mouse studies revealing APOE ε4's contribution to deposition and neurodegeneration. Invertebrate models, particularly Drosophila melanogaster, facilitate of disease mechanisms due to short generation times and genetic tractability. Expression of human α-synuclein in flies recapitulates Lewy body-like inclusions and dopaminergic neuron loss seen in , uncovering pathways like and mitochondrial dysfunction that inform therapeutic targets. Similarly, Caenorhabditis elegans models polyglutamine expansion disorders by inducing aggregation-prone proteins, demonstrating toxicity modulation via screens that identified over 100 modifier genes with human orthologs. Unicellular organisms like Saccharomyces cerevisiae probe cellular-level defects, such as protein misfolding, where yeast prions share conformational propagation mechanisms with mammalian counterparts, aiding understanding of transmissible spongiform encephalopathies. Zebrafish (Danio rerio) models offer optical transparency for real-time imaging of disease processes, with over 80% of human disease-associated genes conserved, supporting studies in congenital heart defects and via targeted mutations like BRAF V600E. Syngeneic tumor implants assess immune-tumor interactions, as in models of or , where checkpoint inhibitors demonstrate efficacy predictive of clinical responses. These approaches have accelerated gene discovery; for instance, functional assays in model organisms validated variants in undiagnosed cases, linking them to phenotypes like ciliopathies. Despite species differences, empirical validation through phenotypic rescue or orthologous pathway conservation substantiates causal inferences transferable to humans.

Pharmacological and Toxicological Testing

Model organisms facilitate pharmacological testing by enabling the evaluation of drug efficacy, pharmacokinetics, and mechanisms of action in vivo systems that mimic aspects of human physiology. In early-stage drug discovery, invertebrates such as Drosophila melanogaster and Caenorhabditis elegans support high-throughput screening for bioactive compounds targeting conserved pathways, including those involved in aging and neurotransmission. For instance, serotonergic drugs that enhance oocyte quality in C. elegans and Drosophila highlight the translational potential of these models for reproductive pharmacology. Toxicological assessments leverage model organisms to predict adverse effects, with rodents like mice and rats serving as primary models for regulatory safety evaluations, including acute toxicity, genotoxicity, and carcinogenicity studies. These mammals provide data on absorption, distribution, metabolism, and excretion (ADME) profiles that inform dosing in higher species. Zebrafish (Danio rerio) embryos offer a vertebrate alternative for developmental toxicity screening, demonstrating concordance with rodent data; one study of 18 toxic compounds found zebrafish toxicity values correlated with rodent outcomes, supporting their use in prioritizing compounds for mammalian testing. In predictive toxicology, C. elegans has emerged as a rapid, cost-effective model for assessing chemical hazards, with the FDA exploring its application to expedite safety evaluations beyond traditional animal models. Drosophila contributes to understanding gut microbiota modulation by drugs and biogenic amine signaling disruptions, aiding in neurotoxicology. While these models accelerate preclinical pipelines—reducing the need for initial rodent exposure in some screens—they complement, rather than replace, mammalian validation to bridge species-specific differences in metabolism and response.

Prominent Model Organisms

Microbial and Unicellular Models

stands as the archetypal prokaryotic model organism, pivotal for advancing understandings of bacterial , , and molecular processes. The K-12 laboratory strain, isolated in 1922, supports axenic growth on minimal media with a generation time of 20-30 minutes at 37°C, facilitating high-throughput and selection experiments. Its genetic tractability, including facile plasmid transformation and conjugation, enabled foundational discoveries such as operon structure by François Jacob and in the 1960s. The complete of E. coli K-12 MG1655, spanning 4.64 million base pairs and encoding 4,288 protein-coding genes, was sequenced in 1997, providing a reference for and applications like recombinant protein production. Saccharomyces cerevisiae, or budding yeast, exemplifies unicellular eukaryotic models, bridging prokaryotic simplicity with eukaryotic complexity in studies of cell division, signaling, and aging. Culturable on defined media with a 90-minute doubling time, it shares conserved pathways with humans, including homologous recombination and mitotic checkpoints, making it ideal for dissecting conserved mechanisms via targeted knockouts. The S288C strain's genome, the first fully sequenced eukaryote at 12.1 million base pairs with 5,918 open reading frames, was completed in 1996 through an international consortium, catalyzing functional genomics via systematic gene disruption libraries. Applications extend to modeling human diseases, such as amyloid aggregation in neurodegeneration, leveraging its haploid-diploid life cycle for rapid phenotype screening. Other unicellular models complement these, addressing specialized eukaryotic processes. Dictyostelium discoideum, a amoeba with a unicellular vegetative phase transitioning to multicellular fruiting bodies under starvation, models , , and host-pathogen interactions due to its conserved actin cytoskeleton and endocytic machinery. Its 34-megabase , sequenced in 2005, supports via . Chlamydomonas reinhardtii, a flagellated green alga, elucidates , ciliary motility, and bioenergy pathways, with mutants revealing chloroplast and flagellar assembly dynamics; its 121-megabase nuclear aids organelle-nuclear crosstalk studies. These organisms' advantages—rapid reproduction, genetic tools, and low maintenance—underpin their enduring utility despite limitations in mimicking multicellularity.

Invertebrate Models

Invertebrate model organisms, lacking backbones, offer advantages in research due to their small size, short generation times, ease of genetic manipulation, and lower ethical concerns compared to vertebrates. These traits enable high-throughput studies of fundamental biological processes, including , development, and behavior, with mechanisms often conserved across eukaryotes. Prominent examples include the fruit fly Drosophila melanogaster and the Caenorhabditis elegans, which have facilitated key discoveries while minimizing resource demands. Drosophila melanogaster, established as a model around 1900–1901 by , revolutionized through observations of sex-linked via white-eyed mutants in 1910. Its utility stems from a 10-day , production of hundreds of per female, and giant polytene chromosomes for cytogenetic analysis. Applications span —elucidating homeotic genes like Hox clusters—neurobiology, and human disease modeling, such as Parkinson's via expression. Over 60% of human disease-associated genes have orthologs in , supporting its role in screening therapeutics and studying cancer pathways. Caenorhabditis elegans, selected by in 1965 for its invariant 959 lineage and hermaphroditic reproduction, permits precise tracking of cell fate and , earning Nobel recognition in 2002 for mechanisms. With a fully mapped neural of 302 neurons and the first sequenced metazoan in 1998, it excels in aging research—doubling lifespan via insulin signaling mutants—and , modeling and Alzheimer's. Its transparency and RNAi susceptibility enable genome-wide functional screens, revealing conserved pathways like TOR in nutrient sensing. Other invertebrates, such as the sea slug Aplysia californica, contribute to neuroscience by dissecting synaptic plasticity in gill-withdrawal reflexes, foundational to understanding habituation and sensitization. The cnidarian Hydra vulgaris serves regeneration studies due to its stem cell-driven body renewal, while insects like honeybees model social behavior. These niche models complement broader systems but lack the genetic tractability of Drosophila or C. elegans.

Vertebrate Models

Vertebrate model organisms offer physiological and genetic features more akin to humans than , facilitating research into mammalian-specific processes such as immune responses, neural development, and . Among these, the (Mus musculus) stands as the predominant mammalian model, with its sharing approximately 85% homology with humans and a reproductive cycle enabling sexual maturity in 6-8 weeks. Established as a key system over a century ago, mice have enabled foundational genetic studies, including the creation of strains via targeted , which recapitulate human genetic disorders like . Their small size, ease of housing, and susceptibility to induced cancers have made them indispensable for and , though differences in and lifespan necessitate cautious extrapolation. The zebrafish (Danio rerio), a teleost fish, gained prominence since the 1960s for developmental genetics due to its transparent embryos allowing real-time imaging of organ formation. With a fully sequenced genome exhibiting 70-85% orthology to human genes and high fecundity—females producing 200-300 eggs every 7-10 days—it supports large-scale forward genetic screens. Zebrafish regenerate fins, heart tissue, and spinal cords, providing insights into regenerative medicine absent in mammals, while their rapid 3-month generation time accelerates transgenerational studies. Applications extend to modeling metabolic disorders and neurotoxicity, leveraging CRISPR/Cas9 for precise edits mirroring human mutations. Amphibian models like the (Xenopus laevis) excel in embryological research, with embryos reaching fertilization to hatching in 1-2 days and supporting for . Historically pivotal in discovering cell cycle regulators like cyclins, Xenopus oocytes enable expression studies due to their large size (1-2 mm). As an allotetraploid species, it permits pseudotetraploid analysis but introduces challenges in genetic mapping; nonetheless, it models defects and function via transgenesis. Its aquatic lifecycle aids hypoxia studies relevant to human birth defects. Avian models, particularly the domestic chicken (Gallus gallus domesticus), provide accessible extra-embryonic development, with eggs incubating externally for 21 days to yield manipulable embryos. Used since the 19th century for gastrulation studies, chickens reveal conserved signaling pathways in limb and heart formation, with 60-70% gene conservation to humans. Their large embryo size (up to 50 mm) facilitates surgical interventions like quail-chick chimeras to trace cell lineages, informing congenital anomalies. Chickens also model viral infections and immunology via inbred lines, though ethical constraints limit adult use compared to rodents.

Limitations and Scientific Critiques

Translational Gaps to

Translational gaps between model organisms and manifest prominently in the high attrition rates of preclinical outcomes when applied to clinical settings, with over 90% of candidates that succeed in animal models failing in human trials due to inefficacy or . This discrepancy arises from fundamental species-specific differences in , , and disease pathology, as animal models often inadequately recapitulate responses. For instance, in , only about 5% of agents demonstrating anticancer activity in preclinical models advance successfully to human efficacy. Genetic and genomic divergences exacerbate these gaps; while model organisms like share conserved pathways, their gene regulation, expression profiles, and inflammatory responses diverge significantly from , leading to mismatched phenotypes. In mouse models of such as or trauma, genomic signatures show poor congruence with counterparts, with mice exhibiting muted inflammatory thresholds compared to the hyper-responsive human state. Similarly, simpler models like or C. elegans excel in elucidating core mechanisms but falter in capturing complex traits influenced by long lifespans, environmental interactions, and polygenic factors absent in short-lived . Disease-specific modeling reveals further limitations, as seen in neurodegenerative disorders where amyloid-beta accumulation in transgenic mice does not fully replicate Alzheimer's pathology, including tangles and neuronal loss, resulting in limited predictive value for therapeutic interventions. In pharmacological testing, metabolize compounds more rapidly and via distinct pathways, yielding false positives for safety and efficacy; for example, thalidomide's teratogenicity was missed in mice but evident in closer to s. An of systematic studies confirms that merely 5% of interventions promising in animal models translate effectively to treatments across various conditions. These gaps underscore the need for cautious interpretation of model organism data, with critiques highlighting overreliance on inbred strains that lack and fail to account for epigenetic and influences prevalent in . Recent analyses emphasize that while models inform mechanistic insights, their translational fidelity remains low, prompting shifts toward human-relevant alternatives like organoids to bridge these divides without assuming equivalence.

Inherent Biases and Model-Specific Flaws

Lab strains of model organisms, such as mice and fruit flies, are typically derived from inbred lines to ensure genetic uniformity, which minimizes experimental variability but introduces a profound bias against the observed in human populations. This homogeneity, where strains like mice exhibit near-identical genotypes across >99% of loci, fails to recapitulate the diverse genetic backgrounds that influence disease susceptibility and treatment responses in humans, leading to overestimation of reproducibility at the expense of real-world applicability. Studies using such strains often overlook population-level variation, as seen in models where uniform outcomes in inbred mice diverge sharply from heterogeneous human infections. Sex bias compounds these issues, with preclinical research disproportionately favoring animals—up to 70-80% in some fields like —ignoring sex-specific physiological differences in immune responses, , and that affect progression and therapeutic efficacy. Age biases similarly persist, as models rarely account for lifespan disparities; for instance, mice reach in months while diseases like neurodegeneration unfold over decades, distorting temporal dynamics of . These systemic choices prioritize experimental tractability over biological fidelity, contributing to translational gaps where findings from homogeneous models falter in diverse cohorts. In models, species-specific divergences exacerbate flaws: genomic responses to , a core driver of many diseases, correlate poorly with humans, with only ~50% overlap in profiles between mouse and human endotoxemia. models, reliant on transgenic strains like APP/PS1 mice, inadequately replicate human amyloid-beta aggregation, , or neuronal loss, yielding quantitative mismatches in plaque burden and cognitive decline that hinder drug validation. Cancer models suffer from accelerated tumor growth in mice due to shorter telomeres and distinct immune microenvironments, resulting in false positives for therapies that succeed in but fail clinically, as evidenced by <10% translation success for candidates. Drosophila melanogaster, while genetically tractable, harbors anatomical and physiological limitations: its lacks the layered cortex and myelinated axons central to , rendering it unsuitable for modeling complex behaviors like or psychiatric disorders beyond basic circuits. Approximately 40% of disease-associated genes have no clear orthologs or divergent functions in flies, limiting applicability to conserved pathways while overlooking tissue-specific mechanisms, such as adaptive immunity absent in . Unicellular models like and exhibit foundational flaws from lacking multicellularity: yeast cannot simulate tissue interactions or organ-level , biasing insights toward isolated molecular events that ignore emergent properties like gradients in metazoans. High-throughput annotations in yeast are skewed toward well-studied functions, underrepresenting novel or context-dependent roles, which propagates errors when extrapolating to human systems. These organism-specific constraints, rooted in evolutionary divergence—e.g., over 500 million years between humans and arthropods—underscore how favors logistical ease, often yielding mechanistic knowledge that resists causal translation to .

Alternatives and Paradigm Shifts

Non-Animal Methodologies

In vitro methods, including two-dimensional and three-dimensional cell cultures derived from human primary cells or induced pluripotent stem cells (iPSCs), enable the assessment of cellular responses to drugs and toxins without animal involvement. These approaches replicate specific tissue environments to predict absorption, distribution, metabolism, and excretion () properties, with studies demonstrating their utility in identifying earlier than traditional models. For instance, in human cultures has correlated with clinical outcomes in over 80% of cases for certain drug-induced liver injuries. Organ-on-a-chip (OoC) systems integrate , human cells, and biomechanical cues to mimic organ-level , such as , liver, or multi-organ interactions. Developed since the early 2010s, these devices have advanced drug screening by simulating and fluid flow, improving predictions of ; a 2022 review highlighted their success in modeling COVID-19-induced using patient-derived cells, reducing reliance on animal studies. Limitations include challenges in achieving physiological oxygen gradients and long-term cell viability, though integrations with sensors address scalability for high-throughput testing. Computational or modeling employs , quantitative structure-activity relationship (QSAR) algorithms, and physiologically based pharmacokinetic (PBPK) simulations to forecast drug efficacy and safety from chemical structures and human data. Peer-reviewed applications have accelerated hit identification, with AI-driven predicting binding affinities for targets like kinases, achieving hit rates comparable to wet-lab assays in SARS-CoV-2 inhibitor discovery. Regulatory adoption is growing, as evidenced by the U.S. Food and Drug Administration's (FDA) 2025 roadmap to incorporate such models for preclinical safety, potentially replacing animal data for monoclonal antibodies by integrating . Validation against human remains essential, given risks of to limited datasets. Human-based approaches, such as and patient-derived organoids, further complement these methods by leveraging volunteer data or biopsy tissues for personalized predictions. Organoids from iPSC lines have recapitulated pathophysiology, enabling mutation-specific drug responses that align with Phase II trial results. The FDA Modernization Act 2.0, enacted in 2023, endorses these non-animal strategies to expedite approvals while prioritizing human relevance over species differences inherent in animal models. Empirical evaluations indicate NAMs reduce false positives in by up to 30% in some cohorts, though integration with analytics is needed for systemic insights.

Emerging and Diversified Organismal Models

Advancements in and gene-editing technologies, such as /, have facilitated the adoption of non-traditional species as model organisms, enabling researchers to exploit species-specific traits absent in established models like mice or fruit flies. These emerging models address limitations in studying complex processes like aging, cancer resistance, and interactions, where traditional organisms often fail to recapitulate human-relevant phenotypes due to evolutionary divergences. Diversification promotes comparative biology across phylogeny, revealing conserved mechanisms and novel adaptations through - . The African turquoise killifish (Nothobranchius furzeri) has gained prominence as a model for aging research, owing to its exceptionally short lifespan of 3–9 months, which accelerates observation of age-related decline, including cardiac and behavioral changes. This species exhibits hallmarks of mammalian aging, such as and reduced regenerative capacity, allowing high-throughput lifespan studies that would span decades in . Genetic tools, including transgenics and mutants, have been developed to dissect pathways like insulin signaling, with recent work linking housing conditions to accelerated early growth but impaired . Naked mole-rats (Heterocephalus glaber) serve as a model for exceptional and disease resistance, living up to 30 years with , cancer immunity, and robust gastrointestinal barriers against irritants. Genomic analyses have identified adaptations like high-molecular-mass hyaluronan for tumor suppression and modified cGAS pathways for control, with transfers extending lifespan by 4.4%. Their eusocial structure also informs studies on immunity and hypoxia tolerance, contrasting with short-lived . Deer mice ( spp.), particularly P. maniculatus, represent diversified models for natural , pathogen susceptibility, and behavioral traits, diverging from house mice by ~25 million years. Recent research utilizes them for leptospirosis infection dynamics, compulsive-like rigidity, and olfaction genetics, leveraging wild-derived strains for epigenetic and studies. The Genetic Stock Center supports their tractability, enabling insights into ecologically relevant phenotypes like hantavirus transmission. Other emerging models include bats for extended lifespan mechanisms and eusocial insects for evolution, selected via evolutionary conservation profiles to model gene orthologs in disease contexts. This diversification enhances causal understanding of biological resilience but requires validation of translational through multi-model comparisons.

Ethical and Regulatory Dimensions

Welfare Standards and Oversight

Welfare standards for model organisms primarily apply to vertebrate animals capable of experiencing pain and distress, such as mice, rats, , and frogs, while microbial, unicellular, and most invertebrate models like and are exempt due to lacking central nervous systems associated with . The foundational framework is the 3Rs—replacement of with non-animal alternatives, reduction in the number of animals used, and refinement of procedures to minimize suffering—introduced by William Russell and Rex Burch in 1959 and adopted globally in regulatory policies. These principles guide harm-benefit analyses in research protocols, balancing scientific necessity against potential animal suffering. In the United States, the Animal Welfare Act of 1966, amended subsequently, regulates the care and use of most warm-blooded vertebrates in , excluding birds, rats, and mice bred for research from USDA inspections but requiring compliance via the Service Policy for federally funded projects. Institutional Animal Care and Use Committees (IACUCs) oversee compliance, reviewing protocols for 3Rs adherence, approving procedures only if alternatives are justified, and conducting semiannual facility inspections. Voluntary accreditation by AAALAC International assesses programs against standards from the Guide for the Care and Use of Laboratory Animals, emphasizing , veterinary care, and humane endpoints. European Union regulations under Directive 2010/63/ mandate project authorizations, severity classifications (non-recovery to severe), and retrospective assessments, with national competent authorities enforcing housing, transport, and killing standards tailored to species like mice and . For , welfare terms standardize husbandry to ensure consistency, including and stocking densities, though early larvae (up to 5 days post-fertilization) often evade full protections. models like fruit flies face minimal oversight, as empirical evidence indicates they lack pain perception akin to vertebrates, prioritizing cost-effective maintenance over welfare mandates. Oversight effectiveness relies on institutional self-reporting and audits, with IACUCs empowered to suspend non-compliant activities, though critiques highlight variability in enforcement and potential under-detection of subtle welfare issues due to reliance on researcher self-assessments. Empirical studies underscore the need for standardized welfare indicators across models to enhance and ethical rigor, as inconsistent application can undermine both animal and scientific validity.

Empirical Weighing of Benefits Versus Harms

Empirical evaluations of model organism use in research reveal substantial benefits in generating foundational biological knowledge, such as elucidating genetic mechanisms via Drosophila melanogaster that informed human chromosomal inheritance patterns, and developing targeted therapies like monoclonal antibodies from mouse models. However, direct translational success to human therapeutics remains limited, with animal model predictions of human drug efficacy correlating at only 37-60% and cancer drug translation rates as low as 8%. A review of 76 preclinical animal studies found that just 37% were replicated in humans, while 20% were contradicted, highlighting frequent discordance in toxicity and efficacy outcomes. These gaps suggest that while models accelerate hypothesis testing, they often overestimate benefits by failing to predict human-specific responses, leading to downstream clinical failures. Harms to animals are quantifiable in scale and severity: in the United States, approximately 110 million animals, primarily as model organisms, are used annually in experiments, many involving procedures classified as moderate to severe under welfare scoring systems. Globally, estimates exceed 192 million animals in 2015, with vertebrates comprising a significant portion subjected to pain, distress, or death despite adherence to the 3Rs principles of replacement, reduction, and refinement. In the , mice and fish dominate usage at over 95% of procedures, often in genetically modified models inducing chronic conditions mimicking human diseases, which impose prolonged welfare compromises. Economic harms compound this, with U.S. biomedical animal research costing billions yearly, much attributed to non-translating models that divert resources from alternatives. Weighing benefits against harms through harm-benefit analyses (HBAs) prospectively required by regulations like the U.S. Animal Welfare Act and Directive 2010/63/ often relies on subjective predictions, with retrospective assessments revealing frequent overestimation of benefits; for instance, a study of pre-clinical projects found that anticipated health impacts rarely materialized proportionally to animal harms incurred. Quantitative frameworks, such as those evaluating quality harms (e.g., poor study design inflating animal numbers without advancing knowledge) against generative productivity, indicate net societal benefits in select cases like vaccine development but question overall paradigm efficiency given high failure rates. Critics, drawing from empirical data on translational gaps, argue that invertebrate models like Caenorhabditis elegans or minimize harms while yielding comparable mechanistic insights, suggesting a reweighting toward non-sentient organisms could preserve benefits with reduced ethical costs. No consensus exists on a universal net positive ratio, as quality-adjusted life years (QALYs) gained are hard to attribute solely to models amid factors like advances.

Broader Impacts

Breakthroughs Enabled by Model Organisms

![Fruit fly Drosophila melanogaster]float-right Model organisms have facilitated foundational discoveries in genetics, beginning with Drosophila melanogaster. In 1910, Thomas Hunt Morgan identified the white-eyed mutation in fruit flies, demonstrating that genes are located on chromosomes and establishing the chromosomal theory of inheritance, which earned him the Nobel Prize in Physiology or Medicine in 1933. This work laid the groundwork for modern genetics by revealing principles of sex-linked inheritance and gene mapping. In , enabled key insights into gene regulation. François Jacob and discovered the in 1961, elucidating how bacteria control enzyme production in response to environmental , a mechanism that informed broader understanding of and earned the 1965 . E. coli also served as the host for the first recombinant DNA experiments in 1973 by Stanley Cohen and , pioneering genetic engineering techniques that revolutionized . Saccharomyces cerevisiae has driven advances in . Leland Hartwell's studies in the 1970s identified using mutants, revealing mechanisms that prevent genomic instability and contributing to the 2001 in or Medicine. research further uncovered pathways, with Yoshinori Ohsumi's 1990s discoveries explaining cellular degradation processes, earning the 2016 and informing treatments for diseases like cancer. Mice (Mus musculus) have underpinned immunological breakthroughs. In 1975, Georges Köhler and developed using mouse B cells to produce monoclonal antibodies, enabling targeted therapies and securing the 1984 . Knockout mouse models, refined since the 1980s, have clarified gene functions in mammalian physiology, accelerating for conditions such as and . These contributions demonstrate how model organisms provide causal insights into biological mechanisms otherwise intractable in humans.

Future Directions in Truth-Seeking Research

Emerging trends emphasize diversifying beyond traditional model organisms to include evolutionarily informed selections that better align with specific biological questions, such as identifying novel species for studying unique traits like adaptations or complex behaviors not recapitulated in classics like or mice. This approach leverages phylogenetic comparisons to prioritize models with conserved causal pathways relevant to human physiology, reducing extrapolation errors inherent in distantly related species. Policy shifts by major funding bodies signal a pivot toward integrating model organism findings with human-specific data, as evidenced by the U.S. (NIH) announcement in July 2025 to cease developing new funding opportunities exclusively for animal models of human disease, instead mandating incorporation of advanced non-animal methodologies like organoids and computational simulations to enhance translational fidelity. Similarly, the Food and Drug Administration (FDA) is advancing human-specific research paradigms, projecting a phase-down of in favor of bioengineered systems that more directly probe human causal mechanisms, thereby minimizing biases from interspecies physiological mismatches. These changes aim to empirically weigh model predictions against human outcomes, fostering research pipelines where model-derived hypotheses are rigorously tested in human cell lines or clinical cohorts to confirm generalizability. Technological integrations, including multi-omics profiling and , are poised to refine model organism utility by enabling precise recapitulation of human genetic variants and environmental interactions. For instance, CRISPR-based engineering in models like or C. elegans allows targeted introduction of patient-specific mutations, facilitating causal dissection of disease mechanisms that can be cross-validated with human (iPSC)-derived tissues. Concurrently, machine learning-driven analyses of aggregated model organism datasets promise to predict translational success rates, identifying subsets of findings with high human concordance based on conserved molecular signatures rather than assuming broad applicability. Long-term, truth-seeking paradigms will likely hybridize model organisms with in silico and -based alternatives, prioritizing empirical metrics of predictive accuracy—such as replication rates in trials—over historical precedent. This entails systematic meta-analyses to quantify model-specific failure modes, like incomplete modeling in , and reallocating resources to diversified platforms that capture -unique complexities, including microbiome-host interactions or aging trajectories mismatched across species. Such evolutions, accelerated by 2024-2025 regulatory inflections, underscore a commitment to causal realism by subordinating model reliance to direct evidence where feasible, ultimately elevating research toward mechanisms verifiable in the target species.

References

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