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      Ethical issues related to research on genome editing in human embryos

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          Abstract

          Although the potential advantages of clinical germline genome editing (GGE) over currently available methods are limited, the implementation of GGE in the clinic has been proposed and discussed. Ethical issues related to such an application have been extensively debated, meanwhile, seemingly less attention has been paid to ethical implications of studies which would have to be conducted in order to evaluate potential clinical uses of GGE.

          In this article, we first provide an overview of the debate on potential clinical uses of GGE. Then, we discuss questions and ethical issues related to the studies relevant to evaluation of potential clinical uses of GGE. In particular, we describe the problems related to the acceptable safety threshold, current technical hurdles in human GGE, the destruction of human embryos used in the experiments, involvement of egg donors, and genomic sequencing performed on the samples of the research participants.

          The technical and ethical problems related to studies on GGE should be acknowledged and carefully considered in the process of deciding to apply technology in such a way that will provide benefits and minimize harms.

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          Most cited references38

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          Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

          Cytosine and adenine base editors (CBEs and ABEs) are promising new tools for achieving the precise genetic changes required for disease treatment and trait improvement. However, genome-wide and unbiased analyses of their off-target effects in vivo are still lacking. Our whole genome sequencing (WGS) analysis of rice plants treated with BE3, high-fidelity BE3 (HF1-BE3), or ABE revealed that BE3 and HF1-BE3, but not ABE, induce substantial genome-wide off-target mutations, which are mostly the C->T type of single nucleotide variants (SNVs) and appear to be enriched in genic regions. Notably, treatment of rice with BE3 or HF1-BE3 in the absence of single-guide RNA also results in the rise of genome-wide SNVs. Thus, the base editing unit of BE3 or HF1-BE3 needs to be optimized in order to attain high fidelity.
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            Genome editing reveals a role for OCT4 in human embryogenesis

            Summary Despite their fundamental biological and clinical importance, the molecular mechanisms that regulate the first cell fate decisions in the human embryo are not well understood. Here we use CRISPR–Cas9-mediated genome editing to investigate the function of the pluripotency transcription factor OCT4 during human embryogenesis. We identified an efficient OCT4-targeting guide RNA using an inducible human embryonic stem cell-based system and microinjection of mouse zygotes. Using these refined methods, we efficiently and specifically targeted the gene encoding OCT4 (POU5F1) in diploid human zygotes and found that blastocyst development was compromised. Transcriptomics analysis revealed that, in POU5F1-null cells, gene expression was downregulated not only for extra-embryonic trophectoderm genes, such as CDX2, but also for regulators of the pluripotent epiblast, including NANOG. By contrast, Pou5f1-null mouse embryos maintained the expression of orthologous genes, and blastocyst development was established, but maintenance was compromised. We conclude that CRISPR–Cas9-mediated genome editing is a powerful method for investigating gene function in the context of human development.
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              Don't edit the human germ line.

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                Author and article information

                Contributors
                Journal
                Comput Struct Biotechnol J
                Comput Struct Biotechnol J
                Computational and Structural Biotechnology Journal
                Research Network of Computational and Structural Biotechnology
                2001-0370
                21 March 2020
                2020
                21 March 2020
                : 18
                : 887-896
                Affiliations
                Centre for Research Ethics and Bioethics, Uppsala University, Box 564, 751 22 Uppsala, Sweden
                Author notes
                [* ]Corresponding author. Emilia.niemiec@ 123456crb.uu.se
                Article
                S2001-0370(19)30517-3
                10.1016/j.csbj.2020.03.014
                7163211
                464b8d7c-e1f9-4a53-b032-b96fe04e5090
                © 2020 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 November 2019
                : 13 March 2020
                : 14 March 2020
                Categories
                Review Article

                genome editing,crispr-cas9,oocyte donation,egg donation,whole genome sequencing,research ethics

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