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It has been reported that a research group in China has used the CRISPR genome editing technique to modify human embryos with a specific genetic default. Reports suggest that the scientists used non-viable fertilised embryos with only limited success in achieving the attempted modification.
Prof. Robin Lovell Badge, The Francis Crick Institute
On the science:
“The experiments reported by Junjiu Huang and colleagues (Liang et al) in the journal Protein Cell on gene editing in abnormally fertilised human embryos are, I expect, the first of several that we will see this year. There has been much excitement among scientists about the power of these new gene editing methods, and particularly about the CRISPR/Cas9 system, which is relatively simple to use and generally very efficient. The possibility of using such methods to genetically modify human embryos, and therefore humans, has been on the cards since these methods were first described, and recently these prospects have been brought to the attention of the public through several commentaries made by senior scientists and commentators, some of whom have called for a moratorium to halt any attempts.
I disagree with a moratorium, which is in any case unlikely to work well, indeed I am fully supportive of research being carried out on early human embryos in vitro [in culture/in the lab], especially on embryos that are not required for reproduction and would otherwise be discarded. If the techniques work, there are many interesting questions that could be asked about the role of specific genes in early human embryo development, especially as there is accumulating evidence that equivalent stages of embryos from other mammals, notably the mouse from which most of our understanding has come, may rely on the activity of different genes.
The paper from this Chinese group is the first to ask if the methods work, and the answer provided is very equivocal. Yes, they do, but inefficiently and with several problems. The most critical of the latter are “off target” effects, where genes distinct from that being targeted (which in this case is the gene encoding betaglobin, a red blood cell protein), have ended up being mutated. This has occurred at a much higher frequency than has been found in other cases where the techniques have been applied to human cells in culture or to mouse embryos. Moreover, even within the betaglobin gene, there was a high frequency of incorrect editing (as if an autocorrect spell check function had been turned off), resulting in yet more errors in the DNA sequence. This leads the authors to suggest that a lot more work will be required to alter the techniques for use in human embryos. However, there are a few issues with the design of the experiments. First, specific DNA repair mechanisms are required for precise (homology driven) gene editing, whereas others lead to the sorts of errors reported in the paper. The authors used abnormally fertilised embryos, presumably because they did not want to be accused of using embryos that could undergo development to term if implanted. However, it is possible that the DNA repair mechanisms that are more likely to lead to errors have been activated in such abnormal embryos, as these struggle to cope with an abnormal genetic complement (they are triploid rather than diploid), and are destined to block early in development. Secondly, it would have made sense to test out the techniques and reagents (notably the “guide RNA”) using human embryonic stem cells, which would be more similar to human embryos than the somatic cell line they used. They also chose a gene target that might itself be problematic, given that it is part of a closely linked family of globin genes with highly related sequences, making it hard to target one without affecting the others.
The Nature commentary on this research suggests that previous attempts by the authors to publish their work had failed at least in part due to ethical issues. I do not know what these are. However, it is clear that if the work had been done in the UK, with the excellent regulatory system we have provided by the HFEA, any ethical concerns would have had to have been solved before the work could have been started, as it would require a licence from the HFEA. Indeed, with a licence, research of this sort could be conducted in the UK, and, with justification, it would be possible to use normally fertilised embryos. Of course, it would be illegal to implant any such manipulated embryo into a woman for further development. Indeed, a lot of the fuss about the possibility of germline gene editing is misplaced, because there are very few instances where it would be necessary to correct a gene defect (which was the ultimate aim of the work reported here), because alternative techniques, notably pre-implantation genetic diagnosis (PGD), can be used to choose embryos for implantation that would not develop diseases such as beta-thalassaemia.”
On the legal issues:
“It is legal to do this for research purposes on early human embryos in the UK with a licence from the HFEA, but the 14 day limit applies and it would be illegal to implant the embryos into a woman for further development.
In the USA, it is not possible to do such research with Federal funding (e.g. NIH), and although some States have rules that would forbid it irrespective of funding source, it would be legal with non-federal funds (charities, foundations, companies, private, etc). Indeed, in addition to research in vitro, it would in theory be possible in some States to implant the embryos in an attempt to obtain children. There is no equivalent to the HFE Act or HFE Authority in the USA and therefore no federal rules governing assisted conception (IVF, etc). Clinics are supposed to follow guidelines issued by professional organisations, such as the ASRM (American Society for Reproductive Medicine), but many do not, or they are selective about which part of the guidelines to follow. There may be local ethical review committees that clinics need to consult, but these are variable in quality and in the decisions they make.
As far as I understand it, China has guidelines issued by the central government, rather than laws governing both research and clinical applications using human embryos. These guidelines tend to be followed because it is not a good idea to fall on the wrong side of Government. But perhaps if a lab is a long way from Beijing, who knows …
It would be impossible to do these types of experiment in some European countries, notably Germany and Italy, but other countries have rather liberal laws, such as Spain and Sweden, and they may well permit research in vitro. In Germany and I believe Italy, it is only possible to carry out a procedure on an early human embryo that would not cause it harm. (I think that spare embryos left over from IVF have to be stored frozen, perhaps forever as they can’t be killed.) For example, PGD is illegal in Germany because embryos that are found to have a genetic defect have to be discarded and therefore “harmed”. It might be interesting to ask if the gene editing would be of benefit to the embryo, would it be legal to transfer it into a woman to obtain a child? I suspect the answer would come back “no” as this might constitute an affront to “human dignity” – but it has never been clear (at least to me) how “human dignity” can apply to a pre-implantation embryo, and if the gene editing had corrected a gene defect, in what way would it be harmed ?
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London Faculty of Life Sciences and Medicine
“Recent call for moratorium on genome editing research on human embryos, gametes and germ cells is just a call, not a law that can be imposed to any country. If the technology exists, scientists will continue doing such experiments and eventually one day repair of mutation causing genetic diseases can become a reality. Today, with a standard preimplantation genetic diagnosis (PGD) technology, we can pretty accurately determine for several hundred monogenetic inheritable diseases, which embryos carry the mutation and which do not, allowing us to select healthy ones and discard those with mutations. If and when one day genome editing in embryos becomes a successful and safe technology the couples who were so unlucky as to not have even a single healthy embryos will have an opportunity to have a healthy child.”
Dr Anna Smajdor, a medical ethics expert from the University of East Anglia’s Norwich Medical School, said:
“There is a whiff of hypocrisy about the moral outrage over reports that Chinese scientists have been modifying the DNA of embryos. Here in the UK we have given the go ahead to modifying the DNA of babies who will transmit these changes indefinitely to their offspring. The Chinese have tweaked DNA in embryos never destined to be born.”
Sarah Norcross, Director of the Progress Educational Trust, said:
“The UK has pioneered embryo research and while UK-based scientists need to keep a close watch on developments in China and elsewhere, public discussion of the ethics and implications for society of editing genes in human embryos needs to be stepped up so that policymakers can make informed decisions about whether the law should be changed in the UK to permit this type of research.”
Dr Ewan Birney, Associate Director, European Bioinformatics Institute, said:
“I am concerned by this paper. Using the gene editing technology (CRISPR/Cas9) in human embryos is unacceptable in the UK ethical framework, and I notice that in the Nature report, this paper was suggested to be rejected by journals potentially on ethical grounds. There is a striking contrast to the careful discussion and ultimate consensus approach on mitochondrial donation in the UK context.
“At a broader level, it is important to stress that scientists work under ethical rules, and the ethical rules are fundamentally societal, not scientific (though scientific advances often pose the question). This consensus position does change (for example, human transplants in the 1950s were viewed far less positively than now) but it is important this conversation happens in a consensus, societal way. In many ways, the UK framework is very responsible here.”
Dr Yalda Jamshidi, Senior Lecturer in Human Genetics, St George’s University Hospital Foundation Trust, said:
“Inherited genetic conditions often result because the function of a gene is disrupted. In theory replacing the defective gene with a healthy one would be the ideal solution. This type of treatment is what we call gene therapy and researchers have been working on developing techniques to accomplish this for many years.
Techniques to correct defective genes in ‘non-reproductive’ cells are already at various stages of clinical development and promise to be a powerful approach for many human diseases which don’t yet have an effective treatment. However, altering genes in human embryos can have unpredictable effects on future generations. Furthermore the study by Huang et al showed that the although the CRISPR/Cas9 technique they used can work in the embryo, it can miss the target in the gene and is too inefficient.
Future research on the technique may improve the accuracy and efficiency, however scientists still don’t fully understand the role of the DNA, and all of its genes. Therefore it is impossible to assess the risks from mis-targeted changes in the DNA sequence, which would affect both the treated embryo and any future generations.”
Prof. Shirley Hodgson, Professor of Cancer Genetics, St George’s University of London, said:
“I think that this is a significant departure from currently accepted research practice. This is because any manipulation of the germline of human embryos is potentially heritable. Can we be certain that the embryos that the researchers were working on were indeed non-viable? In the past all the gene therapy research that has been approved by regulatory bodies has been somatic, not germline, because of the potentially unpredictable and heritable effects of germline research. The fact that these researchers found that there were a number of “off target” mutations resulting from the technique they used is clearly a worry in this context. Any proposal to do germline genetic manipulation should be very carefully considered by international regulatory bodies before it should be considered as a serious research prospect. This is because of the obvious concerns about the heritability of the genetic alterations induced, and the way in which such research could spread from work on “non-viable” embryos, to work on viable ones once this type of research had been accepted in principle by international regulatory bodies.”
Prof. Darren Griffin, Professor of Genetics, University of Kent, said:
“Given the widespread use of the CRISPR/Cas9 system, such announcement was inevitable, sooner rather than later. We clearly have a lot of thinking to do. Germline manipulation is currently illegal in the UK but the question is bound to be asked whether this should change, especially if the safety concerns are allayed.
“If the technology is proved to be safe, then the question moves to whether it crosses a moral boundary to apply this technology in the clinic. Equally, some will ask if the procedure is safe, do we have a moral imperative to make sure that we do it.”
Mr Alastair Kent OBE, Director of Genetic Alliance UK, said:
“Families with a life-limiting genetic disease reading of this research will be interested to learn that it has been done, but will be only too aware of the scientific difficulties that will need to be overcome, and the ethical challenges that will need to be resolved, before it could be postulated as a potential therapeutic intervention for use in embryos destined for implantation in a woman through IVF. If there is to be further development of this work it will be essential that the experimental data is fully accessible so the methodology can be scrutinized carefully before further work that moves this closer to patients is contemplated. Failure to do this will render patients and families vulnerable, and risk bringing the wider field of gene transfer for serious diseases into disrepute.”
Prof. Bruce Whitelaw, Professor of Animal Biotechnology at the Roslin Institute, University of Edinburgh, said:
“The story reported in Nature News yesterday adds to the expanding uses of the genome editor technology while emphasising that for many applications technical improvements are needed. Genome editing is an exciting technical tool but it is still in the development phase. Those working with these tools need to strive to improve efficiency, investigate specificity and appropriately demonstrate the range of applications possible which must come through transparent research activity. For genome editing to deliver the many benefits it offers, we need multi-stakeholder governance of how we want to use it.”
Dr Philippa Brice, PHG Foundation, said:
“This story underlines the urgent necessity for international dialogue over the ethics of germline gene editing in human embryos, well in advance of any progression towards theoretical clinical application. Recent calls for a moratorium on any such research to allow time for expert and public consideration of what is and is not ethically, socially and indeed legally acceptable with respect to human germline genetic modification should definitely be heeded.”
Declared interests
Dr Ewan Birney: “I am not an expert in CRISPR/Cas9 but have a good understanding of its details and I work closely with people who are experts. Furthermore my knowledge in genomics means the information that is proposed to be edited is something I am an expert on.”
Mr Alastair Kent: I am employed by Genetic Alliance UK, the national charity working to improve the lives of patients and families affected by all types of genetic conditions. We are an alliance of over 160 patient organisations. Our aim is to ensure that high quality services, information and support are provided to all who need them. We actively support research and innovation across the field of genetic medicine.
Policy and practice in generating resources to support the work of Genetic Alliance UK (including that carried out as part of our projects SWAN UK and Rare Disease UK) is determined by the Trustee Board of the Charity, the members of which are nominated and elected by the patient organisations which comprise Genetic Alliance UK’s membership.
Having determined a strategy and a work plan Genetic Alliance UK then seeks resources to implement it from a wide range of potential funders including National Governments, the EU, the pharmaceutical and medical devices industry, the Medical Research Council, Wellcome Trust, The Big Lottery and others. Patient organisations also pay a subscription according to their size. Genetic Alliance UK does not accept unsolicited grants that are contingent on the organisation carrying out work on behalf of a third party that would be counter to the interests of patients and families with genetic disorders or which would hinder the effective delivery of the strategy endorsed by the Trustee Board.
Full details of our funding policy can be found here: http://www.geneticalliance.org.uk/ethicalcollaborationpolicy.htm
All our income is reported in our annual reports available here: http://www.geneticalliance.org.uk/annual-report.htm
I am invited to speak at a wide range of conferences and meetings on issues arising from my role as director of Genetic Alliance UK, the expenses for which are met directly or reimbursed to me by the organisers. These include public, private and voluntary sector bodies in the UK and internationally. I am also the Chair of the UK Rare Diseases Forum, the body set up by the four health ministers of the UK to monitor implementation of the UK Strategy for Rare Diseases and to report on progress every two years, and a member of NHS England’s Rare Disease Advisory Group.
No other interests declared.