The model you choose can greatly impact your research results.
Animal models are an essential component to all areas of biomedical research. These models provide results that help us to extrapolate knowledge to study a particular disease state in humans. To ensure full utilization, a model needs to reliably mimic the normal anatomy and physiology of human organs and tissues of interest, as well as accurately reflect the morphological and biochemical aspects of disease pathogenesis. During the past 20 years, rodents have emerged as a reliable research species primarily due to their small size, abbreviated life span, reproductive affluence, known genetic background, and relative ease of procurement, handling, and housing.1 Along with this shift to predominately using rodents in research has come the advent of genetic manipulations. These manipulations have allowed the modern-day researcher to purchase a rat or mouse genetically suited specifically to the human disease model they are studying.
Selecting an appropriate rodent model for research is challenging. This is made more difficult by recent advances in genetic manipulations producing hundreds of different strains of mice and rats, which can make the selection process intimidating. Rodent model selection must be based on scientific rationale while considering humane and ethical endpoints and continuing to abide by the three Rs: refinement, reduction, and replacement. The American National Research Council Committee on Animal Models for Research and Aging defines an animal model as “… one in which normative biology or behavior can be studied, or in which a spontaneous or induced pathological process can be investigated, and in which the phenomenon in one or more respects resembles the same phenomenon in humans or other species of animals.”2 There are three types of animal models: homologous, isomorphic, and predictive. Animal models can be further subdivided into five groups: spontaneous, experimentally induced, genetically modified, negative, and orphan models. This article discusses the general factors that should be considered when choosing a rodent model.
The Different Classifications
Selecting an animal model requires an understanding of the types of models already established. Animal models are commonly categorized into one of five different classifications: induced, spontaneous, gene-modified, negative, and orphan.
Induced animal models are created in the laboratory, where seemingly healthy animals are manipulated in some way to induce the human condition or disease state. Common examples of induced animal models include streptozootozan induced diabetes and the surgically induced models of stroke.
Spontaneous animal models arise as a result of a naturally occurring mutation. Hundreds of these types of rodent models have been identified and characterized and are now available for commercial purchase. Common examples of spontaneous animal models include hypertension, arthritis, and diabetes.
The third category of animal model includes the genetically modified disease models. These models have arisen from the past 20 years of manipulation of the DNA in rodents creating both transgenic (rodents carrying inserted foreign DNA) and knockout models (rodents with specific genes removed from their genetic code), therefore better mimicking the condition the researcher wants to study. These models can help researchers study the genetic basis of disease, susceptibility, and resistance.
Another disease model that has been identified is the negative model: a useful research tool in which the disease state reliably does not develop in the animal model. Some rodents are resistant to a particular condition or disease. Examining why this is the case may provide answers to questions about disease resistance and its physiological basis.
The orphan model represents the final animal model to be classified. In these models the disease state occurs naturally in an animal model but has not been adequately described in the human counterpart.
Once the classification of animal models has been understood, the researcher can make an appropriate choice of animal model for his/her research.
Consider the Alternatives
Before the researcher can actually work with the animal model he/she has selected, they must also consider alternatives to the use of live animals in their research. The Guide for the Care and Use of Laboratory Animals3 endorses the U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (IRAC 1985)4 including the consideration for alternatives to replace or reduce the use of live animals in research. As such, each IACUC protocol should include an item that requests confirmation that the principal investigator has considered all non-animal alternatives before making the decision to use a specific animal model in his/her research. The advent of Web–based alternative searching tools, such as alt- Web,5,6 makes this step in the animal model selection much easier.
After the current literature has been reviewed and the researcher is satisfied that there are no useful alternatives present, then the selection of species/model becomes paramount. The Committee on Rodents, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council (1996) provides a robust list of criteria that should be followed in selecting experimental animals.7 Subsequent model development should be a multi-stage process beginning with the selection of the appropriate animal species. Today there are several hundreds of rodent models available, including new spontaneous mutations and genetically modified animals which are continually being developed. The researcher must consider all factors when selecting the best model for his/her work, and a thorough literature search should always be conducted to determine what models are available. Specialized searching databases are available to accelerate the research process by providing a Web–based resource for comprehensive information on most animal models and subsequent human diseases.8
Here are the steps that you should follow when selecting a rodent model:
- Review the common classification of animal models
- Define the purpose of the model to be studied
- Select rodent species and specific model
- Search literature to confirm no alternatives already exist
- Scientifically evaluate the model
- Validation/Repeatability of the model
Mouse and rat species accurately represent hundreds of animal models in current-day research. The selection of a rodent animal model for research remains a multi-disciplined approach in which Web–based databases have emerged to assist in the selection process.
- Handbook of Laboratory Animal Science Volume II, CRC Press, 200
- National Research Council Committee on Animal Models for Research and Aging
- The Guide for the Care and Use of Laboratory Animals, National Academies Press, 2011
- U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training
- www.altweb.jhsph.edu. The global Clearinghouse for alternatives to animal testing.
- NC3Rs. www.nc3rs.org.uk.
- Committee on Rodents, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Academies Press, 1996
- www.lamhdi.org National Institute of Heath, National Center for Research Resource
Jennifer Smith, DVM, DACLAM is the Associate Director of Veterinary Sciences, Taconic Farms Inc., Oxnard, CA; Jennifer.Smith@taconic.com.
Szczepan Baran, VMD, MS is the President for the Veterinary Bioscience Institute. Piedmont Triad Research Park, 200 East 1st Street, Winston-Salem, NC 27101. Dr. Baran also serves as an Adjunct Assistant Professor in the Department of Pathology at Wake Forest School of Medicine. He can be reached at firstname.lastname@example.org; www.vetbiotech.com.