Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Human germline genome editing

An Author Correction to this article was published on 10 December 2019

This article has been updated


With the advent of efficient, easy-to-use genome editing by CRISPR–Cas9, editing human embryos is now possible, providing tremendous opportunities to study gene function and cell fate in early human development. The technique can also be used to modify the human germline. Unresolved questions about pre-implantation human development could be addressed by basic research using CRISPR–Cas9. In this Perspective, we discuss advances in human genome editing and consider ethical questions and potential clinical implications of this technology.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Techniques for introducing and utilising genome editing of human embryos.
Fig. 2: A proposed workflow for preclinical evaluation of human embryo genome-editing experiments.

Change history

  • 10 December 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  1. 1.

    Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Jinek, M. et al. RNA-programmed genome editing in human cells. eLife 2, e00471 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Adli, M. The CRISPR tool kit for genome editing and beyond. Nat. Commun. 9, 1911 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Carroll, D. Genome engineering with zinc-finger nucleases. Genetics 188, 773–782 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Joung, J. K. & Sander, J. D. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2013).

    CAS  PubMed  Google Scholar 

  7. 7.

    Silva, G. et al. Meganucleases and other tools for targeted genome engineering: perspectives and challenges for gene therapy. Curr. Gene Ther. 11, 11–27 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Gasiunas, G., Barrangou, R., Horvath, P. & Siksnys, V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc. Natl Acad. Sci. USA 109, E2579–E2586 (2012).

    CAS  PubMed  Google Scholar 

  9. 9.

    Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Liang, P. et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6, 363–372 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kang, X. et al. Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing. J. Assist. Reprod. Genet. 33, 581–588 (2016).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Tang, L. et al. CRISPR/Cas9-mediated gene editing in human zygotes using Cas9 protein. Mol. Genet. Genomics 292, 525–533 (2017).

    CAS  PubMed  Google Scholar 

  13. 13.

    Joergensen, M. W. et al. Altered cleavage patterns in human tripronuclear embryos and their association to fertilization method: a time-lapse study. J. Assist. Reprod. Genet. 31, 435–442 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lammers, J., Splingart, C., Barrière, P. & Fréour, T. Morphokinetic parameters of ICSI tripronucleated embryos observed using time lapse. Reprod. Biomed. Online 28, 658–660 (2014).

    PubMed  Google Scholar 

  15. 15.

    Yao, G. et al. Developmental potential of clinically discarded human embryos and associated chromosomal analysis. Sci. Rep. 6, 23995 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Ma, H. et al. Correction of a pathogenic gene mutation in human embryos. Nature 548, 413–419 (2017).

    CAS  PubMed  Google Scholar 

  17. 17.

    Safari, F., Farajnia, S., Ghasemi, Y. & Zarghami, N. New developments in CRISPR technology: improvements in specificity and efficiency. Curr. Pharm. Biotechnol. 18, 1038–1054 (2017).

    CAS  PubMed  Google Scholar 

  18. 18.

    Fogarty, N. M. E. et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550, 67–73 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Frum, T. et al. Oct4 cell-autonomously promotes primitive endoderm development in the mouse blastocyst. Dev. Cell 25, 610–622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    CAS  PubMed  Google Scholar 

  21. 21.

    Daigneault, B. W., Rajput, S., Smith, G. W. & Ross, P. J. Embryonic POU5F1 is required for expanded bovine blastocyst formation. Sci. Rep. 8, 7753 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 29, 1046–1051 (2011).

    CAS  PubMed  Google Scholar 

  23. 23.

    De Souza, A. T. et al. Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice. Nucleic Acids Res. 34, 4486–4494 (2006).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Blij, S., Frum, T., Akyol, A., Fearon, E. & Ralston, A. Maternal Cdx2 is dispensable for mouse development. Development 139, 3969–3972 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kok, F. O. et al. Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish. Dev. Cell 32, 97–108 (2015).

    CAS  PubMed  Google Scholar 

  26. 26.

    Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21, 635–637 (2003).

    CAS  PubMed  Google Scholar 

  27. 27.

    Jackson, A. L. & Linsley, P. S. Noise amidst the silence: off-target effects of siRNAs? Trends Genet. 20, 521–524 (2004).

    CAS  PubMed  Google Scholar 

  28. 28.

    Scacheri, P. C. et al. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc. Natl Acad. Sci. USA 101, 1892–1897 (2004).

    CAS  PubMed  Google Scholar 

  29. 29.

    Robu, M. E. et al. p53 activation by knockdown technologies. PLoS Genet. 3, e78 (2007).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Rossi, A. et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524, 230–233 (2015).

    CAS  PubMed  Google Scholar 

  31. 31.

    Clift, D., So, C., McEwan, W. A., James, L. C. & Schuh, M. Acute and rapid degradation of endogenous proteins by Trim-Away. Nat. Protoc. 13, 2149–2175 (2018).

    CAS  PubMed  Google Scholar 

  32. 32.

    Hardy, K., Handyside, A. H. & Winston, R. M. The human blastocyst: cell number, death and allocation during late preimplantation development in vitro. Development 107, 597–604 (1989).

    CAS  PubMed  Google Scholar 

  33. 33.

    Boomsma, C. M. et al. Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF. Hum. Reprod. 24, 1427–1435 (2009).

    CAS  PubMed  Google Scholar 

  34. 34.

    Braude, P., Bolton, V. & Moore, S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 332, 459–461 (1988).

    CAS  PubMed  Google Scholar 

  35. 35.

    Vassena, R. et al. Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development. Development 138, 3699–3709 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Artley, J. K., Braude, P. R. & Johnson, M. H. Gene activity and cleavage arrest in human pre-embryos. Hum. Reprod. 7, 1014–1021 (1992).

    CAS  PubMed  Google Scholar 

  37. 37.

    Jarvis, G. E. Early embryo mortality in natural human reproduction: What the data say. F1000Res. 5, 2765 (2016).

    PubMed  Google Scholar 

  38. 38.

    Koot, Y. E., Teklenburg, G., Salker, M. S., Brosens, J. J. & Macklon, N. S. Molecular aspects of implantation failure. Biochim. Biophys. Acta 1822, 1943–1950 (2012).

    CAS  PubMed  Google Scholar 

  39. 39.

    Hertig, A. T., Rock, J., Adams, E. C. & Menkin, M. C. Thirty-four fertilized human ova, good, bad and indifferent, recovered from 210 women of known fertility; a study of biologic wastage in early human pregnancy. Pediatrics 23, 202–211 (1959).

    CAS  PubMed  Google Scholar 

  40. 40.

    Lee, A. & Kiessling, A. A. Early human embryos are naturally aneuploid-can that be corrected? J. Assist. Reprod. Genet. 34, 15–21 (2017).

    PubMed  Google Scholar 

  41. 41.

    Scott, R. T. Jr. et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil. Steril. 100, 697–703 (2013).

    PubMed  Google Scholar 

  42. 42.

    Mantikou, E., Wong, K. M., Repping, S. & Mastenbroek, S. Molecular origin of mitotic aneuploidies in preimplantation embryos. Biochim. Biophys. Acta 1822, 1921–1930 (2012).

    CAS  PubMed  Google Scholar 

  43. 43.

    Delhanty, J. D. & Handyside, A. H. The origin of genetic defects in the human and their detection in the preimplantation embryo. Hum. Reprod. Update 1, 201–215 (1995).

    CAS  PubMed  Google Scholar 

  44. 44.

    Maurer, M. et al. Chromosomal aneuploidies and early embryonic developmental arrest. Int. J. Fertil. Steril. 9, 346–353 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Vanneste, E. et al. Chromosome instability is common in human cleavage-stage embryos. Nat. Med. 15, 577–583 (2009).

    CAS  PubMed  Google Scholar 

  46. 46.

    Hassold, T. et al. A cytogenetic study of 1000 spontaneous abortions. Ann. Hum. Genet. 44, 151–178 (1980).

    CAS  PubMed  Google Scholar 

  47. 47.

    Bazrgar, M. et al. DNA repair signalling pathway genes are overexpressed in poor-quality pre-implantation human embryos with complex aneuploidy. Eur. J. Obstet. Gynecol. Reprod. Biol. 175, 152–156 (2014).

    CAS  PubMed  Google Scholar 

  48. 48.

    Kiessling, A. A. et al. Evidence that human blastomere cleavage is under unique cell cycle control. J. Assist. Reprod. Genet. 26, 187–195 (2009).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kiessling, A. A. et al. Genome-wide microarray evidence that 8-cell human blastomeres over-express cell cycle drivers and under-express checkpoints. J. Assist. Reprod. Genet. 27, 265–276 (2010).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Martinez, F. et al. Caspase activity in preimplantation human embryos is not associated with apoptosis. Hum. Reprod. 17, 1584–1590 (2002).

    CAS  PubMed  Google Scholar 

  51. 51.

    Kermi, C., Aze, A. & Maiorano, D. Preserving genome integrity during the early embryonic DNA replication cycles. Genes (Basel) 10, (E398 (2019).

    Google Scholar 

  52. 52.

    Hardy, K. Apoptosis in the human embryo. Rev. Reprod. 4, 125–134 (1999).

    CAS  PubMed  Google Scholar 

  53. 53.

    Cubbon, A., Ivancic-Bace, I. & Bolt, E. L. CRISPR-Cas immunity, DNA repair and genome stability. Biosci. Rep. 38, BSR20180457 (2018).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Canny, M. D. et al. Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nat. Biotechnol. 36, 95–102 (2018).

    CAS  PubMed  Google Scholar 

  55. 55.

    Takayama, K. et al. Highly efficient biallelic genome editing of human ES/iPS cells using a CRISPR/Cas9 or TALEN system. Nucleic Acids Res. 45, 5198–5207 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Wilde, J.J. et al. Efficient zygotic genome editing via RAD51-enhanced interhomolog repair. Preprint at bioRxiv (2018).

  57. 57.

    Balakier, H., MacLusky, N. J. & Casper, R. F. Characterization of the first cell cycle in human zygotes: implications for cryopreservation. Fertil. Steril. 59, 359–365 (1993).

    CAS  PubMed  Google Scholar 

  58. 58.

    Capmany, G., Taylor, A., Braude, P. R. & Bolton, V. N. The timing of pronuclear formation, DNA synthesis and cleavage in the human 1-cell embryo. Mol. Hum. Reprod. 2, 299–306 (1996).

    CAS  PubMed  Google Scholar 

  59. 59.

    Kim, S., Kim, D., Cho, S. W., Kim, J. & Kim, J. S. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res. 24, 1012–1019 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Horlbeck, M. A. et al. Nucleosomes impede Cas9 access to DNA in vivo and in vitro. eLife 5, e12677 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Isaac, R. S. et al. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function. eLife 5, e13450 (2016).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Gutschner, T., Haemmerle, M., Genovese, G., Draetta, G. F. & Chin, L. Post-translational regulation of Cas9 during G1 enhances homology-directed repair. Cell Rep. 14, 1555–1566 (2016).

    CAS  PubMed  Google Scholar 

  63. 63.

    Gu, B., Posfai, E. & Rossant, J. Efficient generation of targeted large insertions by microinjection into two-cell-stage mouse embryos. Nat. Biotechnol. 36, 632–637 (2018).

    CAS  PubMed  Google Scholar 

  64. 64.

    Sakaue-Sawano, A. et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487–498 (2008).

    CAS  PubMed  Google Scholar 

  65. 65.

    Sakaue-Sawano, A., Kobayashi, T., Ohtawa, K. & Miyawaki, A. Drug-induced cell cycle modulation leading to cell-cycle arrest, nuclear mis-segregation, or endoreplication. BMC Cell Biol. 12, 2 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Zhou, Y. et al. Painting a specific chromosome with CRISPR/Cas9 for live-cell imaging. Cell Res. 27, 298–301 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Reichmann, J., Eguren, M., Lin, Y., Schneider, I. & Ellenberg, J. Live imaging of cell division in preimplantation mouse embryos using inverted light-sheet microscopy. Methods Cell Biol. 145, 279–292 (2018).

    PubMed  Google Scholar 

  68. 68.

    Abe, T. et al. Visualization of cell cycle in mouse embryos with Fucci2 reporter directed by Rosa26 promoter. Development 140, 237–246 (2013).

    CAS  PubMed  Google Scholar 

  69. 69.

    Suzuki, T., Asami, M. & Perry, A. C. Asymmetric parental genome engineering by Cas9 during mouse meiotic exit. Sci. Rep. 4, 7621 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Egli, D. et al. Inter-homologue repair in fertilized human eggs? Nature 560, E5–E7 (2018).

    CAS  PubMed  Google Scholar 

  71. 71.

    Adikusuma, F. et al. Large deletions induced by Cas9 cleavage. Nature 560, E8–E9 (2018).

    CAS  PubMed  Google Scholar 

  72. 72.

    Reichmann, J. et al. Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. Science 361, 189–193 (2018).

    CAS  PubMed  Google Scholar 

  73. 73.

    Ma, H. et al. Ma et al. reply. Nature 560, E10–E23 (2018).

    CAS  PubMed  Google Scholar 

  74. 74.

    Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 36, 765–771 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Rees, H. A. & Liu, D. R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet. 19, 770–788 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Li, G. et al. Highly efficient and precise base editing in discarded human tripronuclear embryos. Protein Cell 8, 776–779 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Liang, P. et al. Correction of β-thalassemia mutant by base editor in human embryos. Protein Cell 8, 811–822 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Zhou, C. et al. Highly efficient base editing in human tripronuclear zygotes. Protein Cell 8, 772–775 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Zeng, Y. et al. Correction of the Marfan syndrome pathogenic FBN1 mutation by base editing in human cells and heterozygous embryos. Mol. Ther. 26, 2631–2637 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Jin, S. et al. Cytosine, but not adenine, baseeditors induce genome-wide off-target mutations in rice. Science 364, 292–295 (2019).

    CAS  Google Scholar 

  82. 82.

    Zuo, E. et al. Cytosine baseeditor generates substantial off-target single-nucleotide variants in mouse embryos. Science 364, (289–292 (2019).

    Google Scholar 

  83. 83.

    Yang, G. et al. Base-editing-mediated R17H substitution in histone H3 reveals methylation-dependent regulation of Yap signaling and early mouse embryo development. Cell Rep. 26, 302–312.e4 (2019).

    CAS  PubMed  Google Scholar 

  84. 84.

    Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature (2019).

    CAS  PubMed  Google Scholar 

  85. 85.

    McArthur, S. J. et al. Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. Prenat. Diagn. 28, 434–442 (2008).

    CAS  PubMed  Google Scholar 

  86. 86.

    Adler, A. et al. Blastocyst culture selects for euploid embryos: comparison of blastomere and trophectoderm biopsies. Reprod. Biomed. Online 28, 485–491 (2014).

    PubMed  Google Scholar 

  87. 87.

    Vilarino, M. et al. Mosaicism diminishes the value of pre-implantation embryo biopsies for detecting CRISPR/Cas9 induced mutations in sheep. Transgenic Res. 27, 525–537 (2018).

    CAS  PubMed  Google Scholar 

  88. 88.

    Thornhill, A. R. & Snow, K. Molecular diagnostics in preimplantation genetic diagnosis. J. Mol. Diagn. 4, 11–29 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Blais, J. et al. Risk of misdiagnosis due to allele dropout and false-positive PCR artifacts in molecular diagnostics: analysis of 30,769 genotypes. J. Mol. Diagn. 17, 505–514 (2015).

    CAS  PubMed  Google Scholar 

  90. 90.

    Chakrabarti, A. M. et al. Target-specific precision of CRISPR-mediated genome editing. Mol. Cell 73, 699–713.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Allen, F. et al. Predicting the mutations generated by repair of Cas9-induced double-strand breaks. Nat. Biotechnol. 37, 64–72 (2018).

    Google Scholar 

  92. 92.

    Shen, M. W. et al. Predictable and precise template-free CRISPR editing of pathogenic variants. Nature 563, 646–651 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Kim, D. et al. Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells. Nat. Methods 12, 237–243 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Tsai, S. Q. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat. Biotechnol. 33, 187–197 (2015).

    CAS  PubMed  Google Scholar 

  95. 95.

    Tsai, S. Q. et al. CIRCLE-seq: a highly sensitive in vitro screen for genome-wide CRISPR-Cas9 nuclease off-targets. Nat. Methods 14, 607–614 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Cameron, P. et al. Mapping the genomic landscape of CRISPR-Cas9 cleavage. Nat. Methods 14, 600–606 (2017).

    CAS  PubMed  Google Scholar 

  97. 97.

    Yan, W. X. et al. BLISS is a versatile and quantitative method for genome-wide profiling of DNA double-strand breaks. Nat. Commun. 8, 15058 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wienert, B. et al. Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq. Science 364, 286–289 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kim, D. & Kim, J. S. DIG-seq: a genome-wide CRISPR off-target profiling method using chromatin DNA. Genome Res. 28, 1894–1900 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Smith, C. et al. Whole-genome sequencing analysis reveals high specificity of CRISPR/Cas9 and TALEN-based genome editing in human iPSCs. Cell Stem Cell 15, 12–13 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Veres, A. et al. Low incidence of off-target mutations in individual CRISPR-Cas9 and TALEN targeted human stem cell clones detected by whole-genome sequencing. Cell Stem Cell 15, 27–30 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Baltimore, D. et al. Biotechnology. A prudent path forward for genomic engineering and germline gene modification. Science 348, 36–38 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Lanphier, E., Urnov, F., Haecker, S. E., Werner, M. & Smolenski, J. Don’t edit the human germ line. Nature 519, 410–411 (2015).

    CAS  PubMed  Google Scholar 

  104. 104.

    Savulescu, J., Pugh, J., Douglas, T. & Gyngell, C. The moral imperative to continue gene editing research on human embryos. Protein Cell 6, 476–479 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    National Academies of Sciences Engineering and Medicine. Human Genome Editing: Science, Ethics, and Governance. (The National Academies Press, Washington, DC, 2017).

    Google Scholar 

  106. 106.

    Nuffield Council on Bioethics. Genome Editing and Human Reproduction: social and ethical issues. (Nuffield Council on Bioethics, London, 2018).

    Google Scholar 

  107. 107.

    De Rycke, M. et al. ESHRE PGD Consortium data collection XIV-XV: cycles from January 2011 to December 2012 with pregnancy follow-up to October 2013. Hum. Reprod. 32, 1974–1994 (2017).

    PubMed  Google Scholar 

  108. 108.

    Jacobs, H. S. & Agrawal, R. Complications of ovarian stimulation. Baillieres Clin. Obstet. Gynaecol. 12, 565–579 (1998).

    CAS  PubMed  Google Scholar 

  109. 109.

    Baron, K. T., Babagbemi, K. T., Arleo, E. K., Asrani, A. V. & Troiano, R. N. Emergent complications of assisted reproduction: expecting the unexpected. Radiographics 33, 229–244 (2013).

    PubMed  Google Scholar 

  110. 110.

    Steffann, J., Jouannet, P., Bonnefont, J. P., Chneiweiss, H. & Frydman, N. Could failure in preimplantation genetic diagnosis justify editing the human embryo genome? Cell Stem Cell 22, 481–482 (2018).

    CAS  PubMed  Google Scholar 

  111. 111.

    Natsume, T., Kiyomitsu, T., Saga, Y. & Kanemaki, M. T. Rapid protein depletion in human cells by auxin-inducible degron tagging with short homology donors. Cell Rep. 15, 210–218 (2016).

    CAS  PubMed  Google Scholar 

  112. 112.

    Sternberg, N. & Hamilton, D. Bacteriophage P1 site-specific recombination. I. Recombination between loxP sites. J. Mol. Biol. 150, 467–486 (1981).

    CAS  PubMed  Google Scholar 

  113. 113.

    Sauer, B. & Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc. Natl Acad. Sci. USA 85, 5166–5170 (1988).

    CAS  PubMed  Google Scholar 

  114. 114.

    Lander, E. S. et al. Adopt a moratorium on heritable genome editing. Nature 567, 165–168 (2019).

    CAS  PubMed  Google Scholar 

  115. 115.

    Cyranoski, D. Russian biologist plans more CRISPR-edited babies. Nature 570, 145–146 (2019).

    CAS  PubMed  Google Scholar 

  116. 116.

    Cyranoski, D. China set to introduce gene-editing regulation following CRISPR-baby furore. Nature (2019).

  117. 117.

    Normile, D. China tightens rules on gene editing. Science 363, 1023 (2019).

    CAS  PubMed  Google Scholar 

  118. 118.

    Cyranoski, D. Japan set to allow gene editing in human embryos. Nature (2018).

  119. 119.

    Chiba, N. Japanese government considering legally restricting genome editing technology. (2019).

  120. 120.

    Reardon, S. World Health Organization panel weighs in on CRISPR-babies debate. Nature 567, 444–445 (2019).

    CAS  PubMed  Google Scholar 

  121. 121.

    Dzau, V. J., McNutt, M. & Ramakrishnan, V. Academies’ action plan for germline editing. Nature 567, 175 (2019).

    CAS  PubMed  Google Scholar 

  122. 122.

    Ledford, H. CRISPR babies: when will the world be ready? Nature 570, 293–296 (2019).

    CAS  PubMed  Google Scholar 

  123. 123.

    Cree, L. & Loi, P. Mitochondrial replacement: from basic research to assisted reproductive technology portfolio tool-technicalities and possible risks. Mol. Hum. Reprod. 21, 3–10 (2015).

    CAS  PubMed  Google Scholar 

  124. 124.

    Claiborne, A. B., English, R. A., Kahn, J. P. & ETHICS, O. F. NEW TECHNOLOGIES. Finding an ethical path forward for mitochondrial replacement. Science 351, 668–670 (2016).

    CAS  PubMed  Google Scholar 

  125. 125.

    Human Fertilisation and Embryology Authority. Scientific Review of the Safety and Efficacy of Methods to Avoid Mitochondrial Disease Through Assisted Conception: 2016 update. (Human Fertilisation and Embryology Authority, London, 2016).

    Google Scholar 

  126. 126.

    Hyslop, L. A. et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 534, 383–386 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Committee on the Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases; Board on Health Sciences Policy; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine (eds Claiborne, A., English, R. & Kahn, J.) Mitochondrial replacement techniques: Ethical, social, and policy considerations. (National Academies Press, Washington DC, 2016).

  128. 128.

    Deglincerti, A. et al. Self-organization of the in vitro attached human embryo. Nature 533, 251–254 (2016).

    CAS  PubMed  Google Scholar 

  129. 129.

    Shahbazi, M. N. et al. Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol. 18, 700–708 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Macaulay, I. C. et al. G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. Nat. Methods 12, 519–522 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    de Silva, E. & Stumpf, M. P. HIV and the CCR5-Delta32 resistance allele. FEMS Microbiol. Lett. 241, 1–12 (2004).

    PubMed  Google Scholar 

  132. 132.

    Luzzatto, L. Sickle cell anaemia and malaria. Mediterr. J. Hematol. Infect. Dis. 4, e2012065 (2012).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Dzau, V. J., McNutt, M. & Bai, C. Wake-up call from Hong Kong. Science 362, 1215 (2018).

    CAS  PubMed  Google Scholar 

Download references


We thank members of the Niakan, J. Turner and R. Lovell-Badge laboratories for helpful discussions and comments on the Perspective. We are grateful to J. Brock in the Scientific Illustrations team for generating figures. Work in the Niakan laboratory is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001120), the UK Medical Research Council (FC001120), and the Wellcome Trust (FC001120).

Author information



Corresponding author

Correspondence to Kathy K. Niakan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

A. Lea, R., K. Niakan, K. Human germline genome editing. Nat Cell Biol 21, 1479–1489 (2019).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing