Crick researchers get OK for gene editing on human embryos

LONDON – The U.K. regulator has given researchers at the Crick Institute in London permission to use CRISPR/Cas9 gene editing on human embryos, with the aim of understanding which genes are involved in successful early development.

The work will look at the first seven days during which a fertilized egg goes from a single cell to a blastocyst of around 250 cells. The embryos will be donated by people undergoing in vitro fertilization treatment who have given informed consent to the use of the embryos in research.

Using CRISPR/Cas9 to make specific modifications to the genome will increase understanding of the genes human embryos need to develop successfully. While the work will not have a direct clinical application, the results could lead to improved success rates in in vitro fertilization (IVF) and better treatments for infertility.

The permission from the Human Fertilisation & Embryology Authority (HFEA) follows a review of the research proposal, which was submitted by embryologist Kathy Niakan in September. (See BioWorld Today, Sept. 21, 2015.)

Current U.K. law permits research on embryos up to 14 days post-fertilization. Each research project requires a license from the HFEA. However, granting permission to use CRISPR/Cas9 to modify the human genome is a new and controversial departure.

A high-level summit of scientists concerned about the possible misuse of gene editing in humans, held in Washington in December, recommended the formation of an international forum to ensure the technology is used only for appropriate ends.

However, the summit did not call for a complete moratorium on human germline editing, saying that with appropriate oversight, basic research involving gene editing of human embryos, eggs and sperm that is intended to increase understanding of their biology, should be allowed to proceed. However, any modified cells should not be used to establish a pregnancy. (See BioWorld Today, Dec. 8, 2015.)

The central question the Crick researchers want to address is what are the molecular mechanisms that regulate embryonic stem cell pluripotency and how these mechanisms are disengaged during cellular differentiation.

Niakan intends to start her research by accessing the role of the Oct4 gene (Octamer-binding transcription factor), which is thought to play a key role in the transition from a fertilized egg to a blastocyst that is ready for implantation.

The evidence from mouse models is that Oct4 is responsible for embryonic stem cells maintaining stemness. When Oct4 is knocked out, stem cells in mouse embryos differentiate in an uncontrolled manner.

Other genes it is intended to study include CDX2 and SOX17. Although the role of these genes has been elucidated in mouse models, this is seen as having limited relevance to human embryogenesis.

IVF treatment records show that only half of fertilized eggs form blastocysts. Of these only half implant and only half again develop beyond 12 weeks. In mice meanwhile, almost all fertilized eggs develop successfully.

Robin Lovell-Badge, also of the Crick Institute, said the assumption had been that what is true for the mouse will also be true for humans. “We now know through the work carried out by [Niakan] and others over the last few years that this is unlikely to be true; indeed there seem to be many differences.”

“The approval of her licence gives the exciting prospect that we will at last begin to understand how the different cell types are specified at these pre-implantation stages in the human embryo,” Lovell-Badge said.

This fundamental knowledge may help to improve success rates for IVF in ways that will not depend on genome-editing methods. “We will also learn about the use of the techniques in human embryos, how efficient and accurate they are, which will help inform the debate about whether germline treatments to make heritable changes would be practical and safe,” Lovell-Badge noted.

‘A TRIUMPH FOR COMMON SENSE’

Other scientists in the UK reacted positively to the HFEA approval. “The ruling by the HFEA is a triumph for common sense,” said Darren Griffin, professor of genetics at Kent University. While the prospect of gene editing in human embryos raised a series of ethical issues and challenges, the problem has been dealt with in a balanced manner. “It is clear that the potential benefits of the work proposed far outweigh the foreseen risks,” Griffin said

Rob Buckle, director of Science Programmes at the UK Medical Research Council agreed saying, “As genome-editing techniques develop, it’s vital that this work continues within a robust and adaptable regulatory framework so that its full potential can be realised in a scientifically, ethical and legally rigorous way.”

The decision also received support from patients’ groups. Alistair Kent, director of Genetic Alliance UK said the 180 patient organizations represented by the Alliance strongly support the research. “It may lead to progress in research into genetic conditions, and may eventually lead to the alleviation of the significant unmet needs that our members face,” Kent said

“We’d like to underline that the spare embryos that will be used in this work will have been donated for research purposes. Many of the women who make this donation have experienced being unable to have a child without artificial reproductive technology and make their donation altruistically with the hope of allowing others to benefit from improvements in knowledge and treatments,” Kent said.

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