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      Human germline editing in the era of CRISPR-Cas: risk and uncertainty, inter-generational responsibility, therapeutic legitimacy

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          Abstract

          Background

          Clustered Regularly Interspaced Short Palindromic Repeats-associated (CRISPR-Cas) technology may allow for efficient and highly targeted gene editing in single-cell embryos. This possibility brings human germline editing into the focus of ethical and legal debates again.

          Main body

          Against this background, we explore essential ethical and legal questions of interventions into the human germline by means of CRISPR-Cas: How should issues of risk and uncertainty be handled? What responsibilities arise regarding future generations? Under which conditions can germline editing measures be therapeutically legitimized? For this purpose, we refer to a scenario anticipating potential further development in CRISPR-Cas technology implying improved accuracy and exclusion of germline transmission to future generations. We show that, if certain concepts regarding germline editing are clarified, under such conditions a categorical prohibition of one-generation germline editing of single-cell embryos appears not to be ethically or legally justifiable.

          Conclusion

          These findings are important prerequisites for the international debate on the ethical and legal justification of germline interventions in the human embryo as well as for the harmonization of international legal standards.

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          Most cited references30

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          Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs.

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            Cornerstones of CRISPR–Cas in drug discovery and therapy

            The use of CRISPR–Cas technology for gene editing has rapidly become widespread. Here, Corn and colleagues discuss the applications of this revolutionary tool in drug discovery and development, describing how it could make substantial contributions to target identification and validation, animal models and cell-based therapies.
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              Structure of Cre recombinase complexed with DNA in a site-specific recombination synapse.

              During site-specific DNA recombination, which brings about genetic rearrangement in processes such as viral integration and excision and chromosomal segregation, recombinase enzymes recognize specific DNA sequences and catalyse the reciprocal exchange of DNA strands between these sites. The bacteriophage recombinase Cre catalyses site-specific recombination between two 34-base-pair loxP sites. The crystal structure at 2.4 A resolution of Cre bound to a loxP substrate reveals an intermediate in the recombination reaction, in which a Cre molecule has cleaved the substrate to form a covalent 3'-phosphotyrosine linkage with the DNA. Four recombinases and two loxP sites form a synapsed structure in which the DNA resembles models of four-way Holliday-Junction intermediates. The Cre-loxP complex challenges models of site-specific recombination that require large changes in quaternary structure. Subtle allosteric changes at the carboxy termini of the Cre subunits may instead coordinate the cleavage and strand-exchange reactions.
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                Author and article information

                Contributors
                sebastian.schleidgen@fernuni-hagen.de
                hans-georg.dederer@uni-passau.de
                susan.sgodda@t-online.de
                stefan.cravcisin@uni-passau.de
                l.lueneburg@gmail.com
                cantz.tobias@mh-hannover.de
                theinemann@pthv.de
                Journal
                BMC Med Ethics
                BMC Med Ethics
                BMC Medical Ethics
                BioMed Central (London )
                1472-6939
                11 September 2020
                11 September 2020
                2020
                : 21
                : 87
                Affiliations
                [1 ]GRID grid.31730.36, ISNI 0000 0001 1534 0348, Faculty of Humanities and Social Sciences, Institute of Philosophy, , FernUniversität in Hagen, ; Universitätsstraße 33, 58097 Hagen, Germany
                [2 ]GRID grid.11046.32, ISNI 0000 0001 0656 5756, Faculty of Law, , University of Passau, ; Innstraße 39, 94032 Passau, Germany
                [3 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Translational Hepatology and Stem Cell Biology, REBIRTH Center for Translational Regenerative Medicine, Department of Gastroenterology, Hepatology, and Endocrinology, , Hannover Medical School, ; Carl-Neuberg-Str. 1, 30625 Hanover, Germany
                [4 ]Faculty of Nursing Science, University of Philosophy and Theology Vallendar, Pallottistraße 3, 56179 Vallendar, Germany
                Author information
                https://orcid.org/0000-0002-7564-8675
                https://orcid.org/0000-0002-1382-9577
                https://orcid.org/0000-0002-8316-7054
                Article
                487
                10.1186/s12910-020-00487-1
                7488432
                32912206
                9418bdd1-0664-4c7f-8178-98ac48df3100
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 13 February 2020
                : 27 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: 01GP1616A-C
                Categories
                Debate
                Custom metadata
                © The Author(s) 2020

                Medicine
                germline therapy,human embryos,therapeutic legitimization,responsibility for future generations,risks

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