. How Important Is The Choice Of The Particular Animal For Each Particular Story?
Mo Med. 2013 May-Jun; 110(3): 207–211.
The Mighty Mouse: The Impact of Rodents on Advances in Biomedical Enquiry
Abstract
Mice and rats have long served as the preferred species for biomedical research animate being models due to their anatomical, physiological, and genetic similarity to humans. Advantages of rodents include their pocket-size size, ease of maintenance, brusk life cycle, and arable genetic resources. The Rat Resources and Inquiry Centre (RRRC) and the MU Mutant Mouse Regional Resource Centre (MMRRC) serve as centralized repositories for the preservation and distribution of the ever increasing number of rodent models.
Perceptions of Mice and Rats: An Introduction
Mention mice and rats to nigh people and images of unsanitary conditions and urban decay come up to mind. Rats accept been vilified as the carriers of the infected fleas that led to the dreaded Black Plague that decimated Europe, N Africa and Primal Asia in the fourteenth century. It has been suggested recently that an apology is in guild and that other influences, not rodents, were to blame.1 More recently, infected mice take resulted in Hantavirus outbreaks including the recent scare in Yosemite National Park where many campers contracted the deadly virus from mice living in the cabins.2
For many people, exposure to rodents consists of seeing them used every bit food for snakes or birds of prey at the zoo, or having to deal with unwanted rodents invading their dwellings. A kinder epitome of rats and mice sometimes appears in literature – think of the rodents in Due east.B. White's beloved books: the adventurous mouse Stuart in Stuart Little or the epicurean rat, Templeton, of Charlotte's Web fame. Think the heroic drawing character Mighty Mouse who always "saved the twenty-four hours" and of course, the best known mouse of all, Disney'southward Mickey Mouse.
What is not always appreciated is the extraordinary bear on that laboratory mice and rats have on biomedical research. They are often the preferred animal model for studies of human disease and the standard species of choice for pre-clinical trials.
Comparative Medicine Research
Comparative medicine is congenital on the power to use information from one species to empathise the same processes in other species. Basic biomedical research involves the characterization of genes/proteins, the study of anatomical and physiological functions and the characterization of normal and pathological states in a variety of animal species. This knowledge is then practical to agreement these same processes in humans. Likewise, information gained in the field of human medicine can be mined to advance veterinarian medicine because of the commonalities among species that course the ground of comparative medicine.
Laboratory rats and mice provide ideal animal models for biomedical inquiry and comparative medicine studies because they have many similarities to humans in terms of anatomy and physiology. Likewise, rats, mice, and humans each have approximately xxx,000 genes of which approximately 95% are shared by all three species.3 – half dozen The utilise of rodents for research purposes has economical advantages: mice and rats are relatively pocket-sized and require picayune space or resources to maintain, have short gestation times just relatively large numbers of offspring, and have adequately rapid evolution to adulthood and relatively short life spans. For example, mice have a gestation period of approximately 19–21 days; tin can exist weaned at three to iv weeks of age, and reach sexual maturity by five to six weeks of age, allowing large numbers of mice to be generated for studies adequately quickly.
The use of rodents also provides advantages related to the wealth of genetic information bachelor to scientists. The man genome was sequenced in 2001,4 , five with those of the mouse and rat following in 2002 and 2004 respectively.3 , vi The availability of the complete nucleotide sequences for all 3 species has enabled genome-wide comparisons across species which have been disquisitional for the identification and characterization of genes. The ability to use sophisticated molecular genetic techniques to manipulate the genes in mice and more recently rats, allows genes to exist "knocked out" (no expression) or expressed at designated times of development or in select tissues in society to ameliorate empathize their normal role and/or part in disease.
Mice as Models to Study Human Illness: Hereditary Deafness
The identification of genes responsible for hereditary deafness provides an excellent example of the utility of mice for studying man disorders. In humans, hearing loss is the nigh common sensory deficit, with congenital deafness occurring in one per every ane,200 to 2,000 live births. 7 Over a hundred different genes are involved in non-syndromic hearing loss.8 The mouse has been instrumental in identifying and characterizing a big number of these genes.
Traditionally, it has been difficult to study the genetics of hearing loss and deafness in humans due in office to the lack of big families or large numbers of affected individuals for studies, the issue of genetic heterogeneity (the phenomenon in which a single genetic disorder, in this case deafness, tin be due to mutations or defects in a number of different genes), and the general disability to perform detailed anatomical analysis on man ears, especially inner ears. Particularly problematic is the difficulty in ascertaining what damage is due to inherited factors versus environmental factors such as exposure to loud dissonance or infections.
The mouse allows investigators to circumvent all of these bug. Genetically identical inbred strains of mice carrying a single mutated gene are particularly valuable in identifying gene part. Many mice carrying mutations related to hearing loss accept been identified over the years because of the often obvious phenotype (physical characteristics) of a deaf mouse: failure to respond to noise as indicated by the lack of Preyer'south reflex (ear flick), unusual head tossing and circling (literally running around in a circle) behavior. This latter feature is the manifestation of the vestibular defects that are common in mouse deafness mutants. Dissimilar with humans, mice can be purposely bred to specific mates in order to generate many offspring with the desired genetic make-up (genotype). Because the mice are raised in controlled, pathogen-costless environments, the effect of environmental factors can be highly controlled. Thus, we can attribute whatsoever hearing deficits completely to the genetic mutation. Because of the identical anatomical structures, findings in the mouse can be directly correlated to the expected pathology in humans. Lastly, using comparative genomic techniques, identification of a cistron responsible for deafness in the mouse allows the equivalent (orthologous) gene to exist identified in people. Beyond these studies to identify genes important in auditory development and part, the mouse strain can serve as a model to further explore the biological function of the gene and improve understand its role in the auditory organisation. To date, over 55 non-syndromic human deafness genes accept been identified9 and in every case, a respective mouse mutant serves as a model for that particular form of deafness (http://hearingimpairment.jax.org/models).
Advantages of Rats in Biomedical Research
Since mice are minor in size and generally cost less to maintain, and because the tools to genetically manipulate their genomes have been available since the 1980s, mice are oftentimes the first choice equally a rodent model. Yet, in that location are many areas of investigation where rats are preferred, including cardiovascular research, behavioral studies and toxicology.10
Cardiovascular affliction is the leading cause of death and morbidity in developed countries (http://www.who.int/cardiovascular_diseases) and information technology is typically multifactorial (caused by combinations of genetic and ecology factors).eleven Rats are often the preferred rodent model for cardiovascular research where their larger size is an advantage, especially for facilitating surgical procedures and other types of testing. Many unique strains of rats have been generated that model the circuitous nature of homo obesity, diabetes, and cardiovascular disease and therefore in this case, rats provide excellent animal models for the study of these diseases.12 , 13
Rats are normally used for behavioral studies because they are much more social than mice and their behavior amend mimics beliefs seen in humans. For example, expansion of a three-base of operations pair sequence in the FMR1 gene is responsible for Fragile Ten syndrome, the most mutual cause of inherited intellectual disability in humans.14 This expansion leads to methylation of the FMR1 gene, substantially shutting it down such that the gene is not expressed.xv Defects in this gene are a known genetic crusade of autism.16 When the FMR1 gene is knocked out in mice, they exhibit elevated social interactions.17 However when the same cistron is knocked out in rats, they get less engaged in social play and emit fewer vocalizations during play sessions. These social impairments more than closely parallel social beliefs symptoms seen in humans with FMR1 mutations. Affected rats besides brandish compulsive chewing behavior. Compulsive and repetitive behaviors are core symptoms in autism spectrum disorders (http://www.sageresearchmodels.com). Thus, in this case, the rat is the more advisable rodent model.
Choosing the Best Species
In the by, the use of the mouse frequently eclipsed that of the rat considering of the availability of better molecular techniques to manipulate the mouse genome. Contempo advances in genetic tools to create knockout rat models promise to eliminate these barriers and may lead to an increase in the use of rats for a wider diversity of biomedical research. Ultimately, the choice of rodent model depends on which species more closely recapitulates the symptoms and disease procedure seen in humans. It is clear that rats are non simply huge mice and that each species has advantages and disadvantages that oftentimes depend on the particular procedure or cistron being studied. From a translational medicine standpoint, it is particularly critical to choose the appropriate model because a tremendous amount of money is spent testing drugs and therapies that ultimately fail at various stages of pre-clinical and clinical trials. One reason for this is that results obtained in fauna trials do not e'er accurately reflect outcomes in humans.
It has been estimated that new drugs accept an average of 15 years to go from discovery to market at an average cost of $900 million.xviii Based on a study from the Tufts Eye in 2001, it is estimated that of 5,000–x,000 compounds that enter the development pipeline, 250 volition arrive to preclinical trials and of those, only v volition move into homo clinical trials. Of those five, on average, only one volition really arrive to market place. The investment losses of money and time associated with the 4 failed drugs is huge. Interestingly, a retrospective study of several best selling drugs found that the mouse knock out phenotypes of the targets of these drugs correlated well with known drug efficacy. The therapeutic outcome observed in the knock out model was oftentimes a good indicator of success in the clinic.nineteen This supports the notion that establishing a more specific and sensitive preclinical trial prototype based on the best animal models will reduce drug evolution costs and more importantly, reduce the risk to human subjects in clinical trials.
Rodent Resource Centers
The use of rodents in biomedical research continues to rise and the number of unique strains and models is increasing tremendously every bit individual investigators and large federally funded multi-grouping projects generate increasing numbers of genetically engineered mice and rats.
The University of Missouri has the unique distinction of being the home of three National Establish of Health (NIH)-funded creature resource centers: The Rat Resources and Inquiry Centre (RRRC), the MU Mutant Mouse Regional Resource Eye (MMRRC) and the National Swine Resource and Research Heart (NSRRC). The RRRC and NSRRC are the simply Centers of their kind in the United States. The MMRRC is part of a consortium of 4 regional centers located throughout the U.South. The purpose of the two rodent-centric Resources Centers is to serve equally repositories for rat and mouse strains/stocks that are important for use in biomedical research. The Centers 1) import these important animal models, two) cryopreserve embryos and/or sperm equally a means to store and banking concern the models, and 3) serve every bit distribution centers to send the animals or cryopreserved materials to investigators worldwide who employ these models in their research.
These repositories came into existence as a means to centralize the storage and distribution of important rodent fauna models. The time and money used to create genetically modified fauna models and characterize them is quite large; it is therefore important for them to exist readily available to the scientific community for farther research. The Resource Centers have the burden from the individual investigators of preserving the strains and shipping the animals to other researchers. Importantly, the Resource Centers use strict quality control measures to ensure that the genetics and clean wellness status of these models are monitored and maintained at the highest standards.
Currently, the nearly highly requested rats that are distributed past the RRRC are strains that contain a genetic modification consisting of the addition of a fluorescent reporter gene (enhanced green fluorescent protein or EGFP) within their genome. The effect of this genetic addition is that every prison cell in these rats expresses the dark-green fluorescent protein, assuasive them to exist readily observed by fluorescence microscopy (see Figure ane). These strains are particularly useful for transplantation and immunological research. Regenerative medicine, adoptive cell transfer and identification of genetically modified cells later on gene therapy in vivo crave the power to rail donor cells in host tissues and the EGFP rat strains facilitate these types of studies. In 2012, the RRRC received requests for EGFP rat strains from 24 bookish institutions, inquiry institutes, and for profit companies located not only in the United States but worldwide.
Example of fluorescence seen in EGFP rat strains. Pictures of organs from SDTg(GFP)2BalRrrc (RRRC:0065) animals (images on right of each panel) and wild type controls (images on left of each panel). Upper images for each console are under bright lite, bottom images for each panel are under fluorescent light. Panel A: kidney; Console B: eye; Console C: lung; Panel D: eye.
Future of Rodent Models in Biomedical Research
Rats and mice will continue to play a central office in biomedical enquiry. Increasingly sophisticated manipulations of rodent models, including the creation of then called "humanized" rodents that carry man genes, cells, tissues, or organs may atomic number 82 to improved and refined models for developing therapeutics for homo disease. The ability of comparative medicine and the use of mice and rats will continue to provide a powerful tool for advancing the understanding of both normal and disease processes across species and facilitate the transition of research from "bench to bedside" to meliorate homo health.
Biography
•
Elizabeth C. Bryda, PhD, is with the Rat Resource and Inquiry Center, Department of Veterinary Pathobiology, Academy of Missouri.
Contact: ude.iruossim@eadyrb
Footnotes
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987984/
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