Comment: Every Silver Lining has a Cloud

Robert D. Combes and Michael Balls

The Scientific and Animal Welfare Issues Surrounding a New Approach to the Production of Transgenic Animals

The scientific basis and advantages of using recently developed CRISPR/Cas-9 technology for transgenesis have been assessed with respect to other production methods, laboratory animal welfare, and the scientific relevance of transgenic models of human diseases in general. As the new technology is straightforward, causes targeted DNA double strand breaks and can result in homozygous changes in a single step, it is more accurate and more efficient  than other production methods and speeds up transgenesis. CRISPR/Cas-9 also obviates the use of embryonic stem cells, and is being used to generate transgenic non-human primates (NHPs). While the use of this method reduces the level of animal wastage resulting from the production of each new strain, any long-term contribution to reduction will be offset by the overall increase in the numbers of transgenic animals likely to result from its widespread usage. Likewise, the contribution to refinement of using a more-precise technique, thereby minimising the occurrence  of unwanted genetic effects, will be countered by a probable substantial increase in the production of transgenic strains of increasingly sentient species. For ethical and welfare reasons, we believe that the generation of transgenic NHPs should be allowed only in extremely exceptional circumstances. In addition, we present information, which, on both welfare and scientific grounds, leads us to question the current policy of generating ever-more new transgenic models in light of the general failure of many of them, after over two decades of ubiquitous use, to result in significant advances in the understanding and treatment of many key human diseases. Because this unsatisfactory situation is likely to be due to inherent, as well as possibly avoidable, limitations in the transgenic approach to studying disease, which are briefly reviewed, it is  concluded that a thorough reappraisal of the rationale for using genetically-altered animals in fundamental research and by the pharmaceutical industry, and for its support by funding bodies, should be undertaken. In the meantime, the use of CRISPR/Cas-9 to generate new transgenic cells in culture is to be guardedly encouraged.

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Welfare Assessment of Transgenic Animals: Behavioural Responses and Morphological Development of Newborn Mice

Miriam van der Meer, Patrizia Costa, Vera Baumans, Berend Olivier and Bert van Zutphen

Four groups of mice of the same inbred strain, but with different transgenic backgrounds (no treatment; integration of a functional corticotrophin-releasing factor [CRF] gene construct; integration of a non-functional CRF gene construct; transgenic technique without integration of a DNA construct) were compared, in order to identify and quantify indicators of discomfort in transgenic animals. This approach enables us to differentiate between the effects of the technique of transgenesis and the effects caused by the expression of the transgene. This paper emphasises the search for differences in the early post-natal development of the animals. To this end, newborn mice have been subjected to various behavioural tests; moreover, their growth and morphological characteristics were measured from birth up to the age of 3 weeks.
The results indicate that the presence of the microinjected DNA-construct influences the survival rate during the first 2–3 days after birth. The average loss of pups was about 10%, in contrast to the groups without the DNA construct, in which none of the pups died. The increase in the relative body weight of pups with a functional CRF construct was significantly lower than in the other groups, but only during the first 11 days. No significant differences in morphological characteristics or behavioural development were observed between the four groups. This approach was found to be adequate for detecting a broad variety of behavioural and morphological characteristics. Before general conclusions about the extent to which the technique of transgenesis affects animal welfare can be drawn, more transgenic lines should be studied in this way.
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