Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE

De Wert G, Heindryckx B, Pennings G, Clarke A, Eichenlaub-Ritter U, Van El CG, Forzano F, Goddijn M, Howard HC, Radojkovic D, Rial-Sebbag E, et al. (2018)

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
De Wert, Guido; Heindryckx, Bjorn; Pennings, Guido; Clarke, Angus; Eichenlaub-Ritter, UrsulaUniBi; Van El, Carla G.; Forzano, Francesca; Goddijn, Mariette; Howard, Heidi C.; Radojkovic, Dragica; Rial-Sebbag, Emmanuelle; Dondorp, Wybo
Abstract / Bemerkung
Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns.
Page URI


De Wert G, Heindryckx B, Pennings G, et al. Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE. EUROPEAN JOURNAL OF HUMAN GENETICS. 2018;26(4):450-470.
De Wert, G., Heindryckx, B., Pennings, G., Clarke, A., Eichenlaub-Ritter, U., Van El, C. G., Forzano, F., et al. (2018). Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE. EUROPEAN JOURNAL OF HUMAN GENETICS, 26(4), 450-470. doi:10.1038/s41431-017-0077-z
De Wert, G., Heindryckx, B., Pennings, G., Clarke, A., Eichenlaub-Ritter, U., Van El, C. G., Forzano, F., Goddijn, M., Howard, H. C., Radojkovic, D., et al. (2018). Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE. EUROPEAN JOURNAL OF HUMAN GENETICS 26, 450-470.
De Wert, G., et al., 2018. Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE. EUROPEAN JOURNAL OF HUMAN GENETICS, 26(4), p 450-470.
G. De Wert, et al., “Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE”, EUROPEAN JOURNAL OF HUMAN GENETICS, vol. 26, 2018, pp. 450-470.
De Wert, G., Heindryckx, B., Pennings, G., Clarke, A., Eichenlaub-Ritter, U., Van El, C.G., Forzano, F., Goddijn, M., Howard, H.C., Radojkovic, D., Rial-Sebbag, E., Dondorp, W., Tarlatzis, B.C., Cornel, M.C.: Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE. EUROPEAN JOURNAL OF HUMAN GENETICS. 26, 450-470 (2018).
De Wert, Guido, Heindryckx, Bjorn, Pennings, Guido, Clarke, Angus, Eichenlaub-Ritter, Ursula, Van El, Carla G., Forzano, Francesca, Goddijn, Mariette, Howard, Heidi C., Radojkovic, Dragica, Rial-Sebbag, Emmanuelle, Dondorp, Wybo, Tarlatzis, Basil C., and Cornel, Martina C. “Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE”. EUROPEAN JOURNAL OF HUMAN GENETICS 26.4 (2018): 450-470.

2 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Genetic overlap between birthweight and adult cardiometabolic diseases has implications for genomic medicine.
Tekola-Ayele F, Lee A, Workalemahu T, Zhang W, Shrestha D, Amare AT, Ouidir M., Sci Rep 9(1), 2019
PMID: 30858448

112 References

Daten bereitgestellt von Europe PubMed Central.

CRISPR: gene editing is just the beginning.
Ledford H., Nature 531(7593), 2016
PMID: 26961639
Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.
Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, Butler K, Rivat C, Wright G, Somana K, Ghorashian S, Pinner D, Ahsan G, Gilmour K, Lucchini G, Inglott S, Mifsud W, Chiesa R, Peggs KS, Chan L, Farzeneh F, Thrasher AJ, Vora A, Pule M, Veys P., Sci Transl Med 9(374), 2017
PMID: 28123068
CRISPR gene-editing tested in a person for the first time.
Cyranoski D., Nature 539(7630), 2016
PMID: 27882996


GENETIC TECHNOLOGY REGULATION. Editing policy to fit the genome?
Isasi R, Kleiderman E, Knoppers BM., Science 351(6271), 2016
PMID: 26797999






Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells.
Vassena R, Heindryckx B, Peco R, Pennings G, Raya A, Sermon K, Veiga A., Hum. Reprod. Update 22(4), 2016
PMID: 26932460
Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer.
Zhou X, Xin J, Fan N, Zou Q, Huang J, Ouyang Z, Zhao Y, Zhao B, Liu Z, Lai S, Yi X, Guo L, Esteban MA, Zeng Y, Yang H, Lai L., Cell. Mol. Life Sci. 72(6), 2014
PMID: 25274063
CRISPR/Cas9 nuclease-mediated gene knock-in in bovine-induced pluripotent cells.
Heo YT, Quan X, Xu YN, Baek S, Choi H, Kim NH, Kim J., Stem Cells Dev. 24(3), 2014
PMID: 25209165
One-step generation of myostatin gene knockout sheep via the CRISPR/Cas9 system
Han H, Ma Y, Wang T., 2014
CRISPR/Cas9-mediated Dax1 knockout in the monkey recapitulates human AHC-HH.
Kang Y, Zheng B, Shen B, Chen Y, Wang L, Wang J, Niu Y, Cui Y, Zhou J, Wang H, Guo X, Hu B, Zhou Q, Sha J, Ji W, Huang X., Hum. Mol. Genet. 24(25), 2015
PMID: 26464492
Correction of a genetic disease in mouse via use of CRISPR-Cas9.
Wu Y, Liang D, Wang Y, Bai M, Tang W, Bao S, Yan Z, Li D, Li J., Cell Stem Cell 13(6), 2013
PMID: 24315440
Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA.
Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN., Science 345(6201), 2014
PMID: 25123483
Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos.
Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, Kang Y, Zhao X, Si W, Li W, Xiang AP, Zhou J, Guo X, Bi Y, Si C, Hu B, Dong G, Wang H, Zhou Z, Li T, Tan T, Pu X, Wang F, Ji S, Zhou Q, Huang X, Ji W, Sha J., Cell 156(4), 2014
PMID: 24486104
TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys.
Liu H, Chen Y, Niu Y, Zhang K, Kang Y, Ge W, Liu X, Zhao E, Wang C, Lin S, Jing B, Si C, Lin Q, Chen X, Lin H, Pu X, Wang Y, Qin B, Wang F, Wang H, Si W, Zhou J, Tan T, Li T, Ji S, Xue Z, Luo Y, Cheng L, Zhou Q, Li S, Sun YE, Ji W., Cell Stem Cell 14(3), 2014
PMID: 24529597
Generation of a monkey with MECP2 mutations by TALEN-based gene targeting.
Liu Z, Zhou X, Zhu Y, Chen ZF, Yu B, Wang Y, Zhang CC, Nie YH, Sang X, Cai YJ, Zhang YF, Zhang C, Zhou WH, Sun Q, Qiu Z., Neurosci Bull 30(3), 2014
PMID: 24838303
Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity.
Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, Zhang F., Cell 154(6), 2013
PMID: 23992846
CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.
Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C, Huang J., Protein Cell 6(5), 2015
PMID: 25894090
Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing.
Kang X, He W, Huang Y, Yu Q, Chen Y, Gao X, Sun X, Fan Y., J. Assist. Reprod. Genet. 33(5), 2016
PMID: 27052831
Generation of gene-modified mice via Cas9/RNA-mediated gene targeting.
Shen B, Zhang J, Wu H, Wang J, Ma K, Li Z, Zhang X, Zhang P, Huang X., Cell Res. 23(5), 2013
PMID: 23545779
One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering.
Yang H, Wang H, Shivalila CS, Cheng AW, Shi L, Jaenisch R., Cell 154(6), 2013
PMID: 23992847
Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes.
Yen ST, Zhang M, Deng JM, Usman SJ, Smith CN, Parker-Thornburg J, Swinton PG, Martin JF, Behringer RR., Dev. Biol. 393(1), 2014
PMID: 24984260
Highly efficient mouse genome editing by CRISPR ribonucleoprotein electroporation of zygotes
Chen S, Lee B, Lee AY, Modzelewski AJ, He L., 2016

BATCH-GE: Batch analysis of Next-Generation Sequencing data for genome editing assessment.
Boel A, Steyaert W, De Rocker N, Menten B, Callewaert B, De Paepe A, Coucke P, Willaert A., Sci Rep 6(), 2016
PMID: 27461955
Spermatogonial stem cell preservation and transplantation: from research to clinic.
Goossens E, Van Saen D, Tournaye H., Hum. Reprod. 28(4), 2013
PMID: 23427228
Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs.
Hanna J, Cheng AW, Saha K, Kim J, Lengner CJ, Soldner F, Cassady JP, Muffat J, Carey BW, Jaenisch R., Proc. Natl. Acad. Sci. U.S.A. 107(20), 2010
PMID: 20442331
Alternative Routes to Induce Naive Pluripotency in Human Embryonic Stem Cells.
Duggal G, Warrier S, Ghimire S, Broekaert D, Van der Jeught M, Lierman S, Deroo T, Peelman L, Van Soom A, Cornelissen R, Menten B, Mestdagh P, Vandesompele J, Roost M, Slieker RC, Heijmans BT, Deforce D, De Sutter P, De Sousa Lopes SC, Heindryckx B., Stem Cells 33(9), 2015
PMID: 26108678
The post-inner cell mass intermediate: implications for stem cell biology and assisted reproductive technology.
Van der Jeught M, O'Leary T, Duggal G, De Sutter P, Chuva de Sousa Lopes S, Heindryckx B., Hum. Reprod. Update 21(5), 2015
PMID: 26089403
Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells.
Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M., Cell 146(4), 2011
PMID: 21820164
Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice.
Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, Saitou M., Science 338(6109), 2012
PMID: 23042295
Complete Meiosis from Embryonic Stem Cell-Derived Germ Cells In Vitro.
Zhou Q, Wang M, Yuan Y, Wang X, Fu R, Wan H, Xie M, Liu M, Guo X, Zheng Y, Feng G, Shi Q, Zhao XY, Sha J, Zhou Q., Cell Stem Cell 18(3), 2016
PMID: 26923202
Reconstitution in vitro of the entire cycle of the mouse female germ line.
Hikabe O, Hamazaki N, Nagamatsu G, Obata Y, Hirao Y, Hamada N, Shimamoto S, Imamura T, Nakashima K, Saitou M, Hayashi K., Nature 539(7628), 2016
PMID: 27750280
Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.
Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NM, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, O'Keefe H, Takeda Y, Arizzi L, Alfarawati S, Tuppen HA, Irving L, Kalleas D, Choudhary M, Wells D, Murdoch AP, Turnbull DM, Niakan KK, Herbert M., Nature 534(7607), 2016
PMID: 27281217
Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs.
Bacman SR, Williams SL, Pinto M, Peralta S, Moraes CT., Nat. Med. 19(9), 2013
PMID: 23913125
Efficient Mitochondrial Genome Editing by CRISPR/Cas9.
Jo A, Ham S, Lee GH, Lee YI, Kim S, Lee YS, Shin JH, Lee Y., Biomed Res Int 2015(), 2015
PMID: 26448933
Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children.
Diot A, Dombi E, Lodge T, Liao C, Morten K, Carver J, Wells D, Child T, Johnston IG, Williams S, Poulton J., Biochem. Soc. Trans. 44(4), 2016
PMID: 27528757
Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.
Yamada M, Emmanuele V, Sanchez-Quintero MJ, Sun B, Lallos G, Paull D, Zimmer M, Pagett S, Prosser RW, Sauer MV, Hirano M, Egli D., Cell Stem Cell 18(6), 2016
PMID: 27212703
Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.
Zhang J, Liu H, Luo S, Lu Z, Chavez-Badiola A, Liu Z, Yang M, Merhi Z, Silber SJ, Munne S, Konstantinidis M, Wells D, Tang JJ, Huang T., Reprod. Biomed. Online 34(4), 2017
PMID: 28385334
Selective elimination of mitochondrial mutations in the germline by genome editing.
Reddy P, Ocampo A, Suzuki K, Luo J, Bacman SR, Williams SL, Sugawara A, Okamura D, Tsunekawa Y, Wu J, Lam D, Xiong X, Montserrat N, Esteban CR, Liu GH, Sancho-Martinez I, Manau D, Civico S, Cardellach F, Del Mar O'Callaghan M, Campistol J, Zhao H, Campistol JM, Moraes CT, Izpisua Belmonte JC., Cell 161(3), 2015
PMID: 25910206
SOX17 is a critical specifier of human primordial germ cell fate.
Irie N, Weinberger L, Tang WW, Kobayashi T, Viukov S, Manor YS, Dietmann S, Hanna JH, Surani MA., Cell 160(1-2), 2014
PMID: 25543152

Oocyte activation, phospholipase C zeta and human infertility.
Kashir J, Heindryckx B, Jones C, De Sutter P, Parrington J, Coward K., Hum. Reprod. Update 16(6), 2010
PMID: 20573804
Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos.
McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, Rabinowitz M, Fraser HB, Petrov DA., Science 348(6231), 2015
PMID: 25859044



Mitochondrial replacement therapy in reproductive medicine.
Wolf DP, Mitalipov N, Mitalipov S., Trends Mol Med 21(2), 2014
PMID: 25573721




The human embryo research debates
Green RM., 2001
Human embryonic stem cells: research, ethics and policy.
de Wert G, Mummery C., Hum. Reprod. 18(4), 2003
PMID: 12660256

Dondorp W, De G., 2005
I. The moral status of the pre-implantation embryo.
Shenfield F, Pennings G, Sureau C, Cohen J, Devroey P, Tarlatzis B; European Society of Human Reproduction and Embryology Task Force on Ethics and Law., Hum. Reprod. 16(5), 2001
PMID: 11464802
What if stem cells turn into embryos in a dish?
Pera MF, de Wert G, Dondorp W, Lovell-Badge R, Mummery CL, Munsie M, Tam PP., Nat. Methods 12(10), 2015
PMID: 26418764
Embryology policy: Revisit the 14-day rule.
Hyun I, Wilkerson A, Johnston J., Nature 533(7602), 2016
PMID: 27172031
ESHRE Task Force on Ethics and Law 12: oocyte donation for non-reproductive purposes.
ESHRE Task Forse on Ethics and Law, Pennings G, de Wert G, Shenfield F, Cohen J, Tarlatzis B, Devroey P., Hum. Reprod. 22(5), 2007
PMID: 17347168
Towards a European consensus for reporting incidental findings during clinical NGS testing.
Hehir-Kwa JY, Claustres M, Hastings RJ, van Ravenswaaij-Arts C, Christenhusz G, Genuardi M, Melegh B, Cambon-Thomsen A, Patsalis P, Vermeesch J, Cornel MC, Searle B, Palotie A, Capoluongo E, Peterlin B, Estivill X, Robinson PN., Eur. J. Hum. Genet. 23(12), 2015
PMID: 26036857

ESHRE Task Force on Ethics and Law 13: the welfare of the child in medically assisted reproduction.
ESHRE Task Force on Ethics and Law including, Pennings G, de Wert G, Shenfield F, Cohen J, Tarlatzis B, Devroey P., Hum. Reprod. 22(10), 2007
PMID: 17728354
IVF: regulation or prohibition?
McLaren A., Nature 342(6249), 1989
PMID: 2586619
The moral imperative to continue gene editing research on human embryos.
Savulescu J, Pugh J, Douglas T, Gyngell C., Protein Cell 6(7), 2015
PMID: 26113289
Ethics and germline gene editing.
Sugarman J., EMBO Rep. 16(8), 2015
PMID: 26138102

Buchanan A, Brock DW, Daniels N, Wikler D., 2000


“Alter-ing” the human species? Misplaced essentialism in science policy
Juengst ET., 2006

The child’s right to an open future
Feinberg J., 1980

Habermas J., 2003



Preimplantation genetic testing: normative reflections
De G., 2009
Comprehensive pre-implantation genetic screening: ethical reflection urgently needed.
Hens K, Dondorp W, Geraedts J, de Wert G., Nat. Rev. Genet. 13(10), 2012
PMID: 22945395
What was wrong with Eugenics? Conflicting narratives and disputed interpretations
Paul DB., 2014


Shakespeare T., 2014
Genetic dilemmas
Davis DS., 2010

De G, De G., 1990
Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.
Dondorp W, de Wert G, Bombard Y, Bianchi DW, Bergmann C, Borry P, Chitty LS, Fellmann F, Forzano F, Hall A, Henneman L, Howard HC, Lucassen A, Ormond K, Peterlin B, Radojkovic D, Rogowski W, Soller M, Tibben A, Tranebjærg L, van El CG, Cornel MC; European Society of Human Genetics; American Society of Human Genetics., Eur. J. Hum. Genet. 23(11), 2015
PMID: 25782669
Intrafamilial medically assisted reproduction.
ESHRE Task Force on Ethics and Law, de Wert G, Dondorp W, Pennings G, Shenfield F, Devroey P, Tarlatzis B, Barri P, Diedrich K., Hum. Reprod. 26(3), 2011
PMID: 21247920


Comfort N., 2012

Meta-analysis of the heritability of human traits based on fifty years of twin studies.
Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, Posthuma D., Nat. Genet. 47(7), 2015
PMID: 25985137
Human gene therapy: why draw a line?
Anderson WF., J Med Philos 14(6), 1989
PMID: 2614286

Harris J., 2010

Sandel M., 2007

Glover J., 2006
Being human: the ethics, law, and scientific progress in genome editing
Newson A, Wrigley A., 2016

Von W., 1985


Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®


PMID: 29326429
PubMed | Europe PMC

Suchen in

Google Scholar