September 20, 2017

expert reaction to first UK results of genome editing in human embryos

A team of scientists from the Francis Crick Institute has just published the first UK results of research using genome editing techniques on human embryos. The proof of principle study uses the CRISPR/CaS9 genome editing technique to study the role of the Oct4 gene in early human embryo development.

Dr Helen Claire O’Neill, Programme Director, Reproductive Science and Women’s Health, University College London, said:

“This proof of principle paper uses CRISPR genome editing to show that although genetic expression in the early mouse embryo may be similar to a human embryo, there are critical differences in the levels and resulting developmental capacity of these embryos when essential genes are mutated. This paper therefore elegantly highlights the need for further research using human embryos. The important findings by Fogarty et al reiterate that reliance on mouse models, or indeed human embryonic stem cell lines for understanding the fundamentals of early human embryo development, are useful, but only to a point. Indeed, most of the current practices used for IVF and assisted reproduction rely heavily on the inference that a mouse preimplantation embryo develops in the same way as a human embryo does. This includes the preclinical research in culture media, in which human embryos are grown clinically. This is a well designed and thorough investigation into the mechanisms of CRISPR mediated mutation in human embryos. The naturally high incidence, however, of aneuploidy (incorrect number of chromosomes) in the embryos used (which were donated from IVF cycles) also highlights a need for creation of human embryos for future research.”

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:

“One in every four couples has been affected by infertility and to address the issue, we have to understand the biology of the earliest stages of human development. To do that, we cannot rely only on animal, mostly mouse, models. In this proof-of-concept study, using genome editing CRISPR/Cas9 technology, the scientists have demonstrated that a gene POUF51 (OCT4) plays somewhat different roles in human than in mouse preimplantation embryos. This is in a way unexpected, because of the dogma that the earliest stages of development are common for all mammalian and even some non-mammalian species. The study is another proof that the findings from experimental animal models cannot be always extrapolated to humans.”

Prof. Magdalena Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology, University of Cambridge, said:

“I think this is very important proof of principle that CRISPR/Cas9-mediated gene elimination in human zygotes works.  The authors have used this technology to eliminate Oct4, a gene that regulates the balance between the pluripotency and differentiation in the first cell fate specification.

“It is known from the mouse embryo work that Oct4 functions in the first cell fate specification but elimination of Oct4 in the human embryo appears to affect embryogenesis a bit earlier than in the mouse.  This shows that although mouse and human embryos are so similar, they have their important differences and so both should be studied.

Dr Rob Buckle, Chief Science Officer at the Medical Research Council, said:

“This ground-breaking research cements the UK’s position as a global leader for scientifically and ethically rigorous laboratory studies using genome editing to understand early human development. Genome editing technologies – particularly CRISPR-Cas9 used in this study – are having a game-changing effect on our ability to understand the function of critical human genes. While the science is at a relatively early stage, these findings pave the way for uncovering the function of genes critical to human development and health, and importantly can tease-out critical differences to knowledge gained through working with animal models. As genome editing techniques develop it’s vital that this work continues within a robust yet adaptable regulatory framework so that its full potential can be realised in a scientific, ethical and legally rigorous way.”

Dr Andrew Chisholm, Head of Cellular and Developmental Science at Wellcome, said:

“This landmark study confirms CRISPR’s status as a transformative tool for research. The technique enabled the researchers to ‘knock out’ a gene called Oct4 to understand its effect on developing human embryos. Importantly, they show that the critical role of this gene in human embryos is distinct from its known roles in mice. Although studying human embryos is more challenging than similar experiments in mice, this work underscores why such studies are key to understanding our own biology.”

Prof. Robin Lovell-Badge, Group Leader, The Francis Crick Institute, said:

“This started out as a proof-of-principle experiment, but it went beyond this, revealing something novel about the role of a regulatory factor, OCT4, in early human embryo development. Sometimes evolution has the luxury of having a new gene to work with, other times it makes use of the pre-existing palette of genes. This very well done study shows that a critical regulator of the inner, pluripotent cells of the early embryo, acts earlier in human compared to mouse embryos and that it has been co-opted for additional essential roles, such as in the development of the outer cells that would normally go on to form the placenta. Although a surprise, perhaps it should not be – the placenta is a rapidly evolving and somewhat greedy organ, which has the job of extracting from the mother the best for its associated embryo. If an extra colour needs to be applied to its background to bring out a particular feature, then natural selection will take whatever it needs to paint the picture.

“There are many more questions posed by this first demonstration that genome editing can be added to the toolbox of methods that can be used to understand the biology of the early human embryo. Applying these methods will hopefully eventually lead to knowledge that can be applied to improve the success of IVF treatments, perhaps to reduce rates of implantation failure and miscarriage. More understanding of the embryo itself will also lead to better ways to derive and use stem cells corresponding the various cell types that are present in the embryo shortly before implantation. Knowing which genes and the pathways they control will be key to all of this.”

 * ‘Genome editing reveals a role for OCT4 in human embryogenesis’ by Norah M. E. Fogarty et al. published in Nature on Wednesday 20th September.

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/genome-editing/

Declared interests

Dr Helen Claire O’Neil: No declarations of interest.

Dr Dusko Ilic: No declarations of interest.

Prof. Magdalena Zernicka-Goetz: “I am funded by the University of Cambridge and the Wellcome Trust.”

Dr Rob Buckle: The research was chiefly funded by the UK Medical Research Council, Wellcome and Cancer Research UK.

Dr Andrew Chisholm: Wellcome co-funded the study.

Prof. Robin Lovell-Badge: Robin Lovell-Badge is both a colleague of Kathy Niakan, as well as members of her lab, and her official mentor at the Francis Crick Institute. He has not been a collaborator on any of her projects to date. He has either recently been or is still a member of several relevant organisations, which notably include: a member of the Scientific and Clinical Advances Advisory Committee (SCAAC) of the HFEA; a member of the Science Media Centre’s Advisory Board; a member of the National Academies of Sciences and Medicine study committee that authored a report on Human Genome Editing, published 14 February, 2017; chair of the Royal Society’s Genetic Technologies Programme. He has no financial interests to declare.