June 26, 2023

expert reaction to conference presentation suggesting that early human embryos are often unable to repair damage to their DNA following genome editing

A conference presentation (not a published paper) presented at the European Society for Human Reproduction and Embryology (ESHRE) urges caution in gene editing of early human embryos.

Dr Darius Widera, Associate Professor in Stem Cell Biology and Regenerative Medicine, University of Reading, said:

“The experimental research presented by Dr Nada Kubikova at ESHRE indicates that early human embryos might have a less efficient genetic information repair system than adult human cells. The authors also suggest that this makes human embryos more prone to errors resulting from gene editing using methods such as CRISPR-Cas9.

“This important research raises additional safety concerns regarding gene editing in human embryos and highlights that any attempt to use this promising technology clinically is premature.

“However, the research is not yet peer-reviewed, and therefore, some important questions cannot be fully answered at this stage. There are various methods available for gene editing, each with different risks of introducing errors into the genetic material. At this stage, it is unclear what specific variant of CRISPR-Cas9 method has been used. Thus, more definitive conclusions can only be drawn once the research is published in a peer-reviewed journal article.”

Dr Helen O’Neill, Lecturer in Reproductive and Molecular Genetics, UCL, said:

“The use of genome editing in human embryos represents a huge opportunity in terms of better understanding early developmental processes and potential clinical uses. However, many studies have already highlighted the shortcomings of older genome editing mechanisms, in particular using Cas9, which causes double-stranded DNA breaks and can introduce unwanted mutations in human embryos. Genome editing techniques have evolved to open up the CRISPR toolbox to more refined editing tools such as base editing and prime editing, which do not require the DNA to be cut. We can be confident that these will pave the way for more efficient editing in human embryos.” 

Sarah Norcross, Director of PET, said:

“Many different approaches to genome editing have been developed over the years, including different ways to use CRISPR for genome editing. Each approach has its own limitations, and refinements are constantly being made.

 “All knowledge that can be acquired through research, of problems that can arise when editing the genomes of human embryos, is helpful.

 “Such knowledge adds to our understanding of basic biology, and also adds to the many considerations that would be involved, if it were ever proposed to edit the genomes of human embryos in a treatment situation.

“Besides considering scientific questions of safety and efficacy, there is also a need for thoroughgoing public debate and discussion, before we can consider using genome editing in reproductive contexts.

 “We need to maintain scientific rigour and ethical rigour, both of which were conspicuously absent when He Jiankui infamously established pregnancies using genome-edited human embryos.”

Prof Tony Perry, Head, Laboratory of Mammalian Molecular Embryology, University of Bath, said:

“As ever it’s hard to comment on a press release without access to the data. Any meaningful comment (with or without caveats) would need experimental details, such as the version of Cas9 they used: the finding that some Cas9 instigates DNA rearrangements is several years old.

“But there has also been a view for several years that making double-stranded DNA breaks in human embryos is at best clinically problematic. Efforts are being directed towards base and prime editing, which are later embodiments of Cas9 that don’t make double-stranded DNA breaks.”

Dr Asif Nakhuda, Head of the Gene Targeting Facility, Babraham Institute, said:

“The research findings on DNA errors being introduced via CRISPR gene targeting in human embryos, reported by Dr Nada Kubikova at the ESHRE annual meeting, assessed similar methods to those used to create genetically modified mice. From the extensive gene editing work performed on mice embryos for research purposes, it is known that there is significant drop-off from embryo manipulation to the number of actual mice born. It is also known that these “founder mice” require additional breeding to remove unwanted genetic changes. Most genome engineering facilities would agree that using CRISPR-Cas9 is unsuitable for editing human embryos that would undergo gestation, however more elegant methods are being worked on such as base editing and prime editing that don’t cause double-stand breaks and avoids using homology directed repair templates that could integrate randomly. In conclusion, modified versions of CRISPR-Cas9 still have significant potential in human embryo editing to cure non-idiopathic diseases and this study highlights the importance of technique refinement and rigorous testing to prevent unintended consequences.”

Dr Pete Mills, Director, PHG Foundation, said:

“These findings underline the need for further research to understand DNA repair in cells of the early embryo and confirm the obvious conclusion that it would be reckless to attempt this kind of genome editing in a treatment context.  Genome editing is, however, making important contributions to our understanding of early human development.  Further refinements to the techniques, including approaches that (unlike the one used here) do not involve making double-strand breaks in DNA, continue to emerge.

“In time, we may find ourselves with technically feasible strategies to intervene during embryogenesis.  It is therefore important that we keep in view the ethical questions about whether or in what circumstances they may one day find a use, and the legal and regulatory measures that would be required to control them, while accepting that it would be unthinkable to proceed in this direction without a prior, broad and inclusive societal debate.

“Preimplantation genome editing attracts a high level of attention owing to the complexity of the ethical issues it raises.  But this should not become a distraction from the development of gene and cell-based therapies for the treatment of existing people affected by serious health conditions, and from efforts to make such therapies available to those who could benefit from them.”

Abstract title: ‘Deficiency of DNA double-strand break repair in human preimplantation embryos revealed by CRISPR-Cas9’ was presented by Dr Nada Kubikova et al at the European Society of Human Reproduction and Embryology (ESHRE) conference on Monday 26 June 2023.

This work is not peer-reviewed and there is no paper.

Declared interests

Dr Darius Widera: “I have no conflicts of interest to disclose.”

Dr Helen O’Neill: CEO and Founder of Hertility.

Sarah Norcross: PET is a charity which improves choices for people affected by infertility and genetic conditions.

Dr Asif Nakhuda: “no conflicts of interest to declare.”

Dr Pete Mills: “No conflicts of interest to declare.”

For all other experts, no reply to our request for DOIs was received.