One year after the world learned of He Jiankui\u2019s editing of twins, gaps in rules remain.<\/p>\n
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Last November, a Chinese scientist provoked a global outcry when he announced that he had helped create the world\u2019s first genome-edited babies. Scientists swiftly and severely condemned Southern University of Science and Technology\u2019s He Jiankui for bypassing some safety and ethics checks. The revelation also prompted intense discussion about what should be done to block the next gene-editing rogue. Since then, various groups, including two major international organizations, have begun developing new regulatory frameworks to govern human genome editing. Meanwhile, debate has also swirled about whether there\u2019s an immediate need to prohibit gene editing in clinical research.<\/p>\n
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When He used the popular CRISPR-Cas9 tool to try and disable the molecular pathway that HIV uses to infect cells in twin girls when they were embryos, there was no existing international moratorium against creating CRISPR babies, or penalties in China for doing so.\u00a0Warnings<\/a>\u00a0had emerged from gene-editing conferences, but apparently they were not clear or emphatic enough. He, for instance, maintained that he\u2019d followed the\u00a0best practices<\/a>\u00a0set forth in 2017 by a panel of leading US scientists and ethicists, checking all the boxes related to safety and oversight. His work represented a significant leap in germline gene editing, which introduces heritable changes and therefore has the potential to stamp out rare, devastating genetic diseases such as\u00a0cystic fibrosis<\/a>\u00a0and\u00a0muscular dystrophy<\/a>. Yet serious concerns abound about off-target effects.<\/p>\n <\/p>\n<\/div>\n \u201cThe science is not ready; that is not even an issue,\u201d says Victor Dzau, director of the US National Academy of Medicine. Right now, he says, it would be irresponsible to move ahead with clinical germline editing. \u201cThe silver lining is that the world was awakened by the conduct of Dr. He, and we are all working very, very hard with all good intentions to make sure that this doesn\u2019t happen again\u2014not in the fashion that He did it. And that someday, if and when the technology is ready\u2014and I think all of us are very bullish about this technology\u2014that it will be helping humankind in the right way, knowing the risks and knowing the benefits.\u201d<\/p>\n <\/p>\n<\/div>\n To that end, the US National Academies of Medicine and Science and the UK\u2019s Royal Society have come together to assemble representatives from ten countries to develop a\u00a0framework<\/a>\u00a0that identifies scientific, medical and ethical requirements for the clinical use of human germline genome editing. \u201cWe\u2019re not going to tell the public whether they should use the technology,\u201d Dzau says, \u201cbut rather whether it\u2019s safe, the risks involved, and how it could be used.\u201d In August 2019, at the first of the committee\u2019s two planned meetings, members received reports on the current status of the science during a day-long public session. The final report will be published\u00a0next spring<\/a>.<\/p>\n <\/p>\n<\/div>\n An\u00a0advisory committee<\/a>\u00a0convened by the World Health Organization, meanwhile, is taking a broader view in its development of global standards for governance and oversight. Its 18-member panel of interdisciplinary scientists, bioethicists and experts in law, geopolitics and technology futurism is looking at all gene editing\u2014both germline changes, which are passed on to future generations, and somatic changes, which aren\u2019t. So far, the group has recommended that the WHO create an open registry of all studies of clinical applications of genome editing. A working group is fleshing out the details, including which research should be submitted\u2014preclinical as well as clinical, for instance\u2014and how to ensure that publishers and research funders require scientists\u2019 participation. Its final report, which will take the National Academies and Royal Society\u2019s findings into account, will come out after the final meeting next summer.<\/p>\n <\/p>\n<\/div>\n \u201cIt\u2019s been moving slowly,\u201d says Alta Charo, a panel member and a bioethicist at the University of Wisconsin\u2013Madison, of the groups\u2019 progress, chalking it up in part to bureaucracy at the WHO and the challenge of the academies creating a new kind of collaboration. \u201cI can only hope now these committees move more quickly.\u201d<\/p>\n <\/p>\n<\/div>\n When the WHO does make its recommendations on the criteria required for safe, ethical gene editing, individual nations will decide whether and how to adopt the regulatory framework and to enforce any laws created as a result of them. In countries with sophisticated regulatory systems, such as the United States and Japan, or impoverished nations without the resources to support such research, that likely won\u2019t be an issue, Charo says; the \u201cmillion-dollar question\u201d is whether mid-resource countries with traditionally lax enforcement will police gene editing. That wasn\u2019t the case, she points out, with unproven clinical stem cell research that took off in Mexico, Singapore, Ukraine and elsewhere. The WHO may be in a position, she says, to help spur more enthusiasm for enforcement in such places.<\/p>\n <\/p>\n<\/div>\n Although stricter enforcement could deter mavericks in years to come, the lack of clear rules in the interim won\u2019t stop the next scientist from using CRISPR to edit the germline in babies in the meanwhile. In\u00a0June<\/a>, Russian scientist Denis Rebrikov announced his intention to create more CRISPR babies, and it\u2019s widely thought that he\u2019s hardly likely to be the only one considering doing so.<\/p>\n <\/p>\n<\/div>\n Framing what\u2019s forbidden<\/strong><\/p>\n At the time He made his controversial claim, China had laws that\u00a0prohibited<\/a>\u00a0the creation of CRISPR babies, and the practice is either directly or indirectly outlawed in about 30 other countries. Several nations, including the UK, Japan, Canada and China, have express bans on gene editing in human embryos that will be used for reproduction. China tightened its\u00a0regulations<\/a>\u00a0in March, creating penalties for breaking the rules. Now scientists face up to $15,000 in fines and a five-year research ban; institutions that violate the regulations risk fines, blacklisting on grant applications and loss of their medical licenses.<\/p>\n The United States does not have an explicit ban, but federal regulations restrict germline editing. The US National Institutes of Health cannot fund any research in which an embryo\u2019s genome is edited, and the Food and Drug Administration (FDA), which regulates all gene therapies used in patients, can\u2019t consider clinical trial applications for any human germline genome editing. In some states, nonclinical research is legal, but it must be funded by non-federal sources.<\/p>\n The rules are murky in many countries. Russia, for instance, has a law that prohibits genetic engineering under most circumstances, but it\u2019s unclear how the rules would be enforced with regard to gene-edited embryos or babies. Rebrikov, a molecular biologist in Moscow who intends to seek approval from three government agencies for his experiments to create HIV-protected babies, told\u00a0Nature<\/i>\u00a0<\/a>in June that he was tempted to push ahead with the work while the government hashes out regulations but has since backtracked.<\/p>\n The following month, the WHO issued a\u00a0statement<\/a>\u00a0widely viewed as a rebuke. \u201cHuman germline genome editing poses unique and unprecedented ethical and technical challenges,\u201d said director-general Tedros Adhanom Ghebreyesus. \u201cRegulatory authorities in all countries should not allow any further work in this area until its implications have been properly considered.\u201d<\/p>\n The WHO gene-editing expert advisory committee made that interim recommendation, which stops stop short of calling for a moratorium\u2014something many scientists have advocated for. \u201cWhen you call for a moratorium, it immediately then raises another set of questions that are harder to answer: Who has the authority to put a moratorium in place? How do you enforce it? How do you determine when the moratorium is stopped?\u201d says Margaret Hamburg, the committee\u2019s co-chair and a former head of the FDA. \u201cIt has a certain appeal, because it conveys a strong message. But it also doesn\u2019t have a clear path in terms of what it means and how you implement it.\u201d<\/p>\n A moratorium is, by definition, a temporary prohibition of an activity. The approach has been used previously to take a time-when cutting-edge, powerful science has been at risk of outpacing ethical guidance, public acceptance or the law.<\/p>\n In some instances, a government imposes the freeze. In 1988, for instance, when researchers began transplanting fetal cells into the brains of adults with Parkinson\u2019s disease, the public balked and the Reagan administration declared a temporary moratorium on US federal funding for such experiments; it remained in place until 1993, when the Clinton administration lifted it. And in 2014, following mishaps at federal labs\u2014one handling anthrax and one handling avian flu\u2014the US government\u00a0halted<\/a>, for a then-undetermined amount of time, funding for gain-of-function experiments, in which viruses are genetically altered in ways that could make them more contagious, more deadly or both. Three years later, the moratorium was lifted when a formal process for evaluating whether the experiments should receive federal funding was put into place. No researchers are known to have broken these moratoriums, which had the significant force of the federal government behind them.<\/p>\n Other times, scientists themselves have pushed pause. In 2012, leading researchers from the Netherlands, UK, United States and other countries voluntarily halted certain types of experiments involving the H5N1 avian influenza virus so that scientists, government officials and the public could debate the need for the research and impose new safety measures. They initially expected a 60-day hiatus, but extended it indefinitely as discussions about how to proceed intensified. After a year, and following a two-day international meeting to discuss their progress, 40 researchers declared in a letter published in\u00a0Nature<\/i>\u00a0<\/a>and\u00a0Science<\/i>\u00a0<\/a>that the studies should restart in countries that had hammered out criteria for H5N1 virus transmission research.<\/p>\n The groundwork for the H5N1 research moratorium was laid out decades earlier, when rapid advances in recombinant DNA research sparked fears that a dangerous new pathogen might be created. More than 100 leading molecular biologists from around the globe voluntarily hit pause on many types of experiments using recombinant DNA technology for about a year beginning in July 1974. Then they, along with a few journalists and policymakers, gathered in Asilomar, California, to draft safety regulations governing genetic engineering. Those recommendations quickly became the basis for rules adopted across the globe, and \u201cAsilomar\u201d became shorthand for scientists acting in a socially responsible manner.<\/p>\n Asilomar has been invoked as a touchstone by numerous scientists who support a gene-editing moratorium. Yet there are concerns about researchers taking the lead. \u201cMaking a claim that the scientists and technologists who are leading development of these technologies also should be the ones to decide how they should or shouldn\u2019t be used, I think that that\u2019s highly problematic,\u201d says Benjamin Hurlbut, a biomedical historian at Arizona State University. \u201cTechnical expertise doesn\u2019t mean that you have expertise about what\u2019s good and bad for humanity.\u201d<\/p>\n It\u2019s already a complicated matter for an administration or group of scientists to decide when to lift a moratorium. Everyone interviewed for this article said it\u2019s important to get societal input on whether, when and how the research should be done. How exactly to do that, and to weigh whether public consensus would support ending a moratorium, is unclear.<\/p>\n <\/p>\n<\/div>\n<\/div>\n<\/section>\n Taking a break<\/strong><\/p>\n Although there is widespread support for a germline-editing moratorium, there is also broad disagreement about the specifics\u2014whether it should be voluntary or mandatory, for instance, and who should institute it. \u201cI believe that many of the people calling for a moratorium are doing it with different ideas in mind of what that is,\u201d Charo says.<\/p>\n The most detailed plan to date was published in a Commentary in\u00a0Nature<\/i>\u00a0<\/a>in March. Scientists and ethicists from seven nations called for a fixed period, perhaps five years, during which no clinical uses of germline would be allowed. The authors envision voluntary compliance by individual nations, which would retain sovereignty over scientific enterprises within their borders. \u201cAs well as allowing for discussions about the technical, scientific, medical, societal, ethical and moral issues that must be considered before germline editing is permitted, this period would provide time to establish an international framework,\u201d they wrote.<\/p>\n After that, countries would have to undertake more steps before starting any experiments, including a comment period of perhaps two years to discuss the pros and cons, and determining whether there\u2019s broad societal consensus in the particular nation. As for how that consensus might be reached, the authors point to the Global Genome Editing Observatory\u00a0proposed<\/a>\u00a0by Hurlbut and others. It would be an international network of scholars and organizations, similar to those established for climate change and human rights, that would facilitate diverse public conversations.<\/p>\n The\u00a0NIH<\/a>\u00a0supported the call. So did the European Society of Human Reproduction and Embryology and the European Society of Human Genetics, says Guido de Wert, professor of biomedical ethics at Maastricht University in the Netherlands and lead author of the two groups\u2019\u00a0joint position paper<\/a>\u00a0on germline genome editing. (They support basic and preclinical research in this area, and note that while clinical experiments might be an important intervention in the future, at present they would be \u201ctotally premature.\u201d) The WHO, the likely body to facilitate the proposed moratorium, thus far has instead called upon each country to keep its scientists in check.<\/p>\n In April, another group of scientists and industry representatives urged the US government to take the lead in instituting a binding global moratorium on germline genome editing. In a\u00a0letter<\/a>\u00a0to US Department of Health and Human Services secretary Alex Azar, orchestrated by the American Society of Gene & Cell Therapy (ASGCT), the 62 signees from five countries called for a ban on clinical research \u201cunless and until diverse stakeholders have the opportunity to broadly and deeply discuss and reach a societal consensus on these challenges.\u201d Azar has not responded.<\/p>\n The ASGCT, meanwhile, is forging ahead with efforts to help further such discussion. On 6 November, the group is hosting a public workshop at which attendees will discuss ethical, societal and policy issues in germline gene editing. Confirmed speakers include Hamburg and Francis Collins of the NIH. \u201cWhat should the boundaries be?\u201d is one of the big questions, says ASGCT executive director David Barrett. \u201cIt\u2019s something that should be inclusive of bioethicists, researchers, clinicians, but we also think it\u2019s necessary to include patients and their advocates in the discussion, and other individuals who can represent diverse views in society, to make sure that it is inclusive of a discussion as possible.\u201d<\/p>\n Such open conversation to understand varying viewpoints is essential, says Jennifer Doudna, a University of California, Berkeley, molecular biologist who pioneered the CRISPR-Cas9 genome-editing system. And that\u2019s why she doesn\u2019t support a moratorium. \u201cI think even the word \u2018moratorium\u2019 implies that you\u2019re not going to proceed to discuss the topic. And I think that would be a big mistake,\u201d she says. \u201cRather than squelching discussion of this topic, we should actively encourage it.\u201d<\/p>\n What\u2019s more, a global moratorium might not hold much sway in some countries. \u201cIn Russia, it would be unlikely that all scientists would listen to whatever US, or US-backed, scientists have to say,\u201d says biologist Konstantin Severinov, who works both at Moscow\u2019s Skolkovo Institute of Science and Technology and at Rutgers University in New Jersey. \u201cPeople will do it in spite of the international regulatory efforts.\u201d<\/p>\n As for Rebrikov, he told\u00a0Nature<\/i>\u00a0in October that he has pushed back his plan to implant gene-edited embryos until he gets approval from the Ministry of Health of the Russian Federation.<\/p>\n<\/div>\n<\/div>\n<\/section>\n <\/p>\n <\/p>\n <\/p>\n