中国の研究者らが世界ではじめてヒト胚をゲノム編集し、その成果をオンラインジャーナル Protein & Cellにおいて発表したことを受け、Natureは22日付けで編集記事を掲載しました。趣旨は「ゲノム編集をヒト胚に用いないとのルールを逸脱しており、倫理問題に発展しうる」とするものです。この件についての海外専門家コメントをお送りします。
Protein & Cellにおいて論文の著者らは、不妊治療クリニックから生存不可能な胚を入手し、CRISPR / Cas9とよばれる遺伝子改変技術を用いて、致死的な血液疾患関連遺伝子を操作したとしています。
Protein & Cell 論文原文リンク
(論文タイトル:CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes)
Mr Alastair Kent OBE
Director of Genetic Alliance UK
“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
“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
“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.”
Prof Shirley Hodgson
Professor of Cancer Genetics St George’s University of London
“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 Robin Lovell Badge
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.”
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