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New Scientist reported that biologist Denis Rebrikov intends to use CRISPR gene editing technology on the embryos of deaf couples who want hearing children.
Dr Norah Fogarty, Postdoctoral Fellow, The Francis Crick Institute, said:
“CRISPR/Cas9-mediated genome editing is a very powerful molecular tool that potentially could be used to make precise edits to faulty genes. However the safety of using this tool on human embryos has not been confirmed yet. More basic research in human stem cells and human embryos in vitro is required to understand how the embryo repairs DNA in response to CRISPR, whether we might have unwanted on-target mutations, and how can we overcome the problem of mosaicism, where not every cell in the embryo has been edited. Indeed, Nuffield Council of Bioethics report has concluded that while there is a medical need for genome editing, more basic research is required to establish the standards for clinical application.
“The scientific community hold the view that more preclinical research is required especially in light of recent work. In the study by the Mitalopov team (Ma et al. 2017) claiming that embryos were corrected for a mutation that causes hypertrophic cardiomyopathy, there is insufficient evidence that embryos were successfully fixed and it is unclear by which repair pathway. Moreover the reports in late 2018 that twin girls had been born in China after being edited as embryos at a gene CCR5 to make them resistant to HIV infection were alarming and have been universally condemned by scientists. The babies are mosaic for the edits (not all their cells have been corrected). The effect of this mosaicism on them as they grow up is not known.
“Indeed there are cases where it may be appropriate to use genome editing, for instance, where both parents are homozygous for a recessive disease-causing mutation, as is the case for deafness caused by GJB2 (the gene Rebrikov intends to correct). Indeed GJB2 mutations are the largest known contributor to inherited deafness, and Preimplantation Genetic Diagnosis (PGD) is approved in the UK by the HFEA for mutations in the gene GJB2. However it is currently not legal in the UK to use CRISPR/Cas9 in the clinic and to implant embryos that have undergone genome editing into a woman to establish a pregnancy.
“Ultimately it will be up to society to decide if genome editing is appropriate to be used to prevent the inheritance of disease conditions.”
Dr Lydia Teboul, Head of Molecular and Cellular Biology, MRC Harwell Institute, said:
“Our collective experience with laboratory animals clearly says that the outcome of genome editing in embryos is unpredictable and error prone. This means that current genome editing tools are not ready to be applied to human embryos.
“Also, mutations in the gene chosen as a target, GJB2, are linked to other diseases that affect eyes and skin and are associated with a higher risk of cancer. Any sort of modification of the action of this gene could potentially be risky to human health.”
Prof Shirley Hodgson, Professor of Cancer Genetics, St George’s, University of London, said:
“We are certainly not ready to do CRISPR on embryos, regardless of what condition or disease is trying to be cured. In the UK we have excellent regulations from the HFEA for what is appropriate for genes to be considered for Prenatal diagnosis, and it is essential that such regulations are in place for all types of genetic manipulations that involve human embryos.
“This would NOT be possible in the UK currently.
“I do not know whether scientists are permitted to do this in Russia but International regulations regarding CRISPR technology in humans are not yet in place.
“I think it is highly concerning that CRISPR should be proposed for preventing hereditary deafness because it is not life threatening. This is precisely the sort of discussions that should take place in the regulatory bodies. Many genetic conditions can be tested for by prenatal diagnosis which would not require CRISPR techniques; the problem with CRISPR techniques is that they are imperfect, can produce off-site mutations, and crucially are heritable i.e. can be passed down to the offspring of treated children.”
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:
“Several months ago, He Jiankui opened a Pandora’s box with the first gene-edited embryos using CRISPR. To me this suggestion looks like another scientist jumping the gun and wanting to be first, ignoring basic safety measures and using desperate people as guinea pigs.”
Prof Robin Lovell-Badge FRS, Group Leader, The Francis Crick Institute, said:
“It is not important to be the first to carry out germline genome editing, that dubious honour already goes to He Jiankui, it is important to do it well and to proceed only when it is clear that it is likely to be safe, giving the desired alteration in the target gene and no others, in a situation that meets a pressing medical need for which no better alternative exists, and, because of the societal concerns, only after there is sufficient support from an informed public. Moreover, it has to be done with good oversight, preferably under strict regulatory control, and with long term follow up – as would happen for any other new form of clinical intervention. Denis Rebrikov may think he can satisfy all of these criteria in his latest reported announcement of his intention to correct a faulty version of a gene that leads to deafness back and thus allow deaf couples to have children with normal hearing, but he cannot. This is not something that any individual can decide – the situation is just too complex. There are technical problems to be overcome. No one has yet achieved correction of a faulty gene in all cells of a human embryo using ‘homology directed repair’ – indeed attempts so far have either been very inefficient, or mysterious, where the repair happened by an unusual mechanism that did not make use of a DNA template, which would be necessary in the cases outlined by Rebrikov. Where is the evidence that he knows how to do this?
“Rebrikov should give the Commission established by the US National Academies of Sciences and of Medicine and the UK Royal Society a chance to propose a possible ‘translational pathway’ for germline genome editing, which should indicate many of the hurdles to be overcome. Moreover, the WHO Committee looking into mechanisms of governance in this area should also be given a chance to suggest how any clinical attempts should be regulated, in a way that would give the public some confidence that proper processes were being followed. Moreover, it still needs public support and this will be true for different types of application. Rubrikov needs to hear the concerns of scientists, clinicians, ethicists and regulators before he falsely gives hope to patients seeking solutions.”
Sarah Norcross, Director of the Progress Educational Trust, said:
“It is to the credit of Denis Rebrikov that he is at least discussing openly his plans to use germline genome editing, to attempt to avoid hereditary deafness in children. This is far preferable to the secretive manner in which He Jiankui acted last year, when he was responsible for the birth of the world’s first genome-edited babies.
“Nonetheless, Dr Rebrikov is proposing to do this in the face of a strong scientific consensus that such germline genome editing is not yet ready for use in the clinic, because questions of safety and efficacy – not to mention ethics – have yet to be resolved satisfactorily.
“It is not evident that Dr Rebrikov and his patients have a sufficiently compelling case to justify using this technology in this way at this time.”
Prof Darren Griffin, Professor of Genetics, University of Kent, said:
“Slow down, slow down. Before diving into clinical application, there is a lot to do before this can go mainstream. The main, and over-riding issue is safety. We really need to establish, using embryos donated for research, that there are no off-target effects of this sort of treatment. The technology is there to achieve this.
“Second, this is clearly an improvement on the reports from China at attempts to introduce HIV resistance, but there are still ethical concerns. Specifically, is there a compelling medical need and are there reasonable alternatives? Realistically, worldwide, these are standards that need to be introduced as a general rule of thumb.
“Finally, how will the deaf and hard of hearing community react to this? A public debate is essential and the deaf need to be heard. The condition is not life threatening, however, these (arguable noble) attempts to correct the situation have a significant chance of making matters worse.”
Declared interests
Dr Norah Fogarty: “No conflicts of interest.”
Dr Lydia Teboul: “No conflict of interest.”
Prof Shirley Hodgson: “I have no conflicts of interest.”
Prof Robin Lovell-Badge: “Robin Lovell-Badge is a member of the WHO expert advisory committee on Developing global standards for governance and oversight of Human Genome Editing. He has no financial or other conflicts of interest.”
Sarah Norcross: “The Progress Educational Trust is an independent registered charity whose purpose is to improve choices for people affected by genetic conditions and infertility, and to promote the responsible application of science.”
Prof Darren Griffin: “No COI.”