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Genetically - Engineered Animals
A genetically-engineered animal is an animal which has had a random or targeted change in its nuclear or mitochondrial DNA (addition, deletion or substitution of some part on the animal’s genetic material) achieved through a deliberate human technological intervention.
Genetically-Engineered (GE) animal models may contribute positively to refinement and reduction in an experiment, for instance when the model more closely resembles the human disease of interest. However, the production of GE animals presents distinct challenges to the application of reduction and refinement. One key concern is the large number of surplus animals that must be generated to achieve a small number with the desired genome (challenging reduction). A second key concern is the unpredictability of phenotype expression. This can adversely affect individual animal welfare by causing pain, distress, and/or difficulties related to the husbandry and maintenance of breeding colonies (challenging refinement).
Genetic engineering may adversely affect the welfare of individual animals used to produce the genetically-engineered strain (i.e. egg donors, surrogate mothers and stud males) because invasive techniques are required.
Genetic engineering may also adversely affect the welfare of the resultant genetically-engineered offspring because:
- disruption is caused to animals’ physiological processes;
- poor fit between the new strain of animal and the environment may occur;
- unanticipated changes to genotype or phenotype may occur; and
- invasive techniques are needed to determine genotype (e.g., tissue samples).
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Three Rs Strategies in the Production of GE Animals
When the use of genetically-engineered animals is contemplated, investigators should consider using:
- genetically-engineered embryos in vitro rather than implanting them in recipient animals (reduction);
- tests on the effects of genetic-engineering on cell and tissue differentiation in embryonic stem cells in vitro, including using genomics and proteomics and other emerging technologies (reduction and replacement);
- pilot studies to demonstrate that the proposed genetically-engineered animals are fit for the scientific purpose (reduction);
- homozygous breeding pairs in order to reduce the number of animals born that do not have the desired mutation or are infertile (reduction);
- heterozygote breeders in situations where homozygote animals experience unacceptable morbidity, mortality or chronic disease (refinement);
- improved techniques in the collection of tissues, determination of genotype, and individual animal identification (refinement);
- inducible knock-out or knock-in systems so that the expression of phenotype can be controlled and only induced for a specific study period (reduction and refinement);
- strategies which maximize the use of surplus animals (reduction and refinement); and
- complementary approaches such as informatics, microarrays, cell, tissue and organ cultures, population studies, lower organisms and embryos (replacement, reduction, refinement).
(This section has been adapted from the National Health and Medical Research Council (Australian) Guidelines for the generation, breeding, care and use of genetically modified and cloned animals for scientific purposes)
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Welfare Assessment of GE Animals
Formal assessments of animal welfare should be part of phenotype characterization of GE animals. A GE animal welfare assessment protocol will:
- reveal special needs or problems with the strain;
- determine needs for handling, housing and breeding;
- contribute to refinement of the model by recommending relevant humane endpoints; and
- prevent duplication of models already developed.
(This section has been adapted from Jegstrup et al., 2003.)
For more information on genetically-engineered animals the following resources may be useful:
CCAC resources:
On-line resources:
- Bhogal N. & Combes R. (2006) The relevance of genetically altered mouse models of human disease. ATLA 34: 429–454.
- Dennis M. (2002) Welfare issues of genetically modified animals. ILAR Journal 43:100-109.
- ILAR Journal. (2006) Vol 47(2) Phenotyping of Genetically Engineered Mice. 172pp.
- National Health and Medical Research Council (Australia) (2007) Guidelines for the generation, breeding, care and use of genetically modified and cloned animals for scientific purposes. 44pp. Canberra: Australian Government.
- This guideline is published by the Australian government and contains a list of references on animal welfare and genetic modifications and example templates of monitoring record sheets for newly created GE animals.
- Robinson V., Morton D.B., Anderson D., Carver J.F.A., Francis R.J., Hubrecht R., Jenkins E., Mathers K.E., Raymond R., Rosewell I., Wallace J., & Wells D.J. (2003). Refinement and reduction in production of genetically modified mice. Sixth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. Laboratory Animals 37 (Suppl1): S1-S50.
- Wells D., Playle L., Enser B., Flecknell P., Gardiner M., Holland J., Howard B., Hubrecht R., Humphreys K., Jackson I., Lane N., Maconochie M., Mason G., Morton D., Raymond R., Robinson V., Smith J., & Watt N. (2006) Assessing the welfare of genetically altered mice. Laboratory Animals 40: 111-114.
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Other publications:
- Berg A. & Bohlooly Y. (2006) The program for phenotyping of genetically modified animals at AstraZeneca. Experimental and Toxicologic Pathology 57:383–384.
- Buehr M., Hjorth J., Hansen A. & Sandoe P. (2003) Genetically modified laboratory animals – what welfare problems do they face? Journal of Applied Animal Welfare Science 6:319-338.
- Crawley J. (1999). What’s Wrong with My Mouse? 329pp. New York: Wiley-Liss.
- Jegstrup I., Thon R., Hansen A.K. & Ritskes Hoitinga M. (2003) Characterization of transgenic mice—a comparison of protocols for welfare evaluation and phenotype characterization of mice with a suggestion on a future certificate of instruction. Laboratory Animals 37:1-9.
- Papaioannou V.E. & Behringer R.R. (2004) Mouse Phenotypes: A Handbook of Mutation Analysis. 235pp. Cold Spring Harbor NY: Cold Spring Harbor Laboratory Press.
- Ward J.M., Mahler J., Maronpot R.R., Sundberg J.P., Frederickson R. (eds.) (2000) Pathology of Genetically Engineered Mice. Iowa State University Press (Blackwell Publishing).
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