Every Silver Lining has a Cloud: The Scientific and Animal Welfare Issues Surrounding a New Approach to the Production of Transgenic Animals

Abstract

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.

The ethics of genome editing in non-human animals: a systematic review of reasons reported in the academic literature

“…Second, various authors noted that genome editing in animals could enhance research in animal systems by creating better animal models of human disease [3,4,7,11,19,26,34 -52,92 -95,108,128,129,133,138 -140], which could ultimately benefit human health, for example, by leading to the creation of new medicines and therapies [26,126,133,140]. At the same time, it was argued that there is a lack of reproducibility of animal findings in humans [53,54,110], which could put human research participants at risk at a later stage of the research [110].…”

“…Second, it was argued that genome editing could be used to decrease the suffering of research animals, for example, by decreasing the occurrence of unwanted genetic effects [53] and reducing the number of animals [110] used to create animal model systems compared to traditional methods [110]. On the other hand, it was argued that, if genome editing were to be widely used, this decrease in suffering per experiment would be offset by the overall increase in the numbers of transgenic animals used in research [36,53]; in this way, genome editing could contribute to animal suffering by perpetuating their continued use in research [9,36,53,108]. Moreover, it was mentioned that genome editing could bring routine genome editing of non-human primates within reach, which could substantially diminish these organisms' welfare and quality of life [110].…”

“…re simplifying and speeding up the production of new transgenic animal models of human disease: most of such models fail to directly benefit humans; this lack of reproducibility may put human research participants at risk at a later stage 3 [53,54,110] CRISPR re bringing routine genome engineering of non-human primates within reach, which could help identify genetic underpinnings of disease or develop therapies: the moral permissibility of this approach is questionable given available alternatives 2 [110,126] [20,143] gene drives could be used to re-create species that may become a vector or reservoir for viruses that can be harmful for human beings 1 [81] genetic engineering re use to create a chicken strain with low allergenicity: there may not be a compelling need for doing so because allergy usually only occurs in children, and alternatives and egg substitutes are available 1 [80] various (ZFN, TALEN, CRISPR) re use to produce better quality food: little is known about the effects these modified organisms would have on humans when consumed 1 [35] CRISPR could increase productivity of the livestock sector: this is an undesirable outcome given the negative impact of meat consumption on human health 1 [104] various (ZFN, TALEN, CRISPR) efficiency for (n ¼…”

The ‘Genomic Revolution’ and its Impact on Medical Research

“…The majority of the animals produced in these steps will not contain the correct genotype, are therefore considered surplus to requirements and are usually killed. 13 Data from The Netherlands indicate that the number of animals that are bred but not used is almost equal to the number of animals used in experiments. 14 This number of surplus animals continues to increase, due to the ongoing rise in the use of genetically-altered animals.…”

Genetic Modification of Animals: Scientific and Ethical Issues

“…Clearly, off-target mutations remain a major issue, with persistent targeting of unintended genomic loci (Bisaria, Jarmoskaite and Herschlag, 2017, p. 21; see also Tsai and Joung, 2016), even as steps are taken to mitigate their occurrence and effects, such as using engineered/modified crispr components (see e.g. Bayat et al, 2017;Chandrasekaran, Song and Ramakrishna, 2017;Combes and Balls, 2014;Ding et al, 2016;Guha, Wai and Hausner, 2017). It is widely believed that the factors controlling crispr's precision and accuracy "are still not fully understood," and obstacles remain on the path to any clinical application (Jiang and Doudna, 2017, p. 524).…”