#Science #CRISPR-Edited Babies Arrived, and Regulators Are Still Racing to Catch Up #BB

Last November, a Chinese scientist provoked a global outcry when he announced that he had helped create the world’s first genome-edited babies. Scientists swiftly and severely condemned Southern University of Science and Technology’s 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’s an immediate need to prohibit gene editing in clinical research.

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. Warnings had emerged from gene-editing conferences, but apparently they were not clear or emphatic enough. He, for instance, maintained that he’d followed the best practices set 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 cystic fibrosis and muscular dystrophy. Yet serious concerns abound about off-target effects.

“The science is not ready; that is not even an issue,” 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. “The 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’t happen again—not in the fashion that He did it. And that someday, if and when the technology is ready—and I think all of us are very bullish about this technology—that it will be helping humankind in the right way, knowing the risks and knowing the benefits.”

To that end, the US National Academies of Medicine and Science and the UK’s Royal Society have come together to assemble representatives from ten countries to develop a framework that identifies scientific, medical and ethical requirements for the clinical use of human germline genome editing. “We’re not going to tell the public whether they should use the technology,” Dzau says, “but rather whether it’s safe, the risks involved, and how it could be used.” In August 2019, at the first of the committee’s 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 next spring.

An advisory committee convened 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—both germline changes, which are passed on to future generations, and somatic changes, which aren’t. 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—preclinical as well as clinical, for instance—and how to ensure that publishers and research funders require scientists’ participation. Its final report, which will take the National Academies and Royal Society’s findings into account, will come out after the final meeting next summer.

“It’s been moving slowly,” says Alta Charo, a panel member and a bioethicist at the University of Wisconsin–Madison, of the groups’ progress, chalking it up in part to bureaucracy at the WHO and the challenge of the academies creating a new kind of collaboration. “I can only hope now these committees move more quickly.”

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’t be an issue, Charo says; the “million-dollar question” is whether mid-resource countries with traditionally lax enforcement will police gene editing. That wasn’t 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.

Although stricter enforcement could deter mavericks in years to come, the lack of clear rules in the interim won’t stop the next scientist from using CRISPR to edit the germline in babies in the meanwhile. In June, Russian scientist Denis Rebrikov announced his intention to create more CRISPR babies, and it’s widely thought that he’s hardly likely to be the only one considering doing so.

Framing what’s forbidden

At the time He made his controversial claim, China had laws that prohibited the 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 regulations in 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.

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’s genome is edited, and the Food and Drug Administration (FDA), which regulates all gene therapies used in patients, can’t 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.

The rules are murky in many countries. Russia, for instance, has a law that prohibits genetic engineering under most circumstances, but it’s 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 Nature in June that he was tempted to push ahead with the work while the government hashes out regulations but has since backtracked.

The following month, the WHO issued a statement widely viewed as a rebuke. “Human germline genome editing poses unique and unprecedented ethical and technical challenges,” said director-general Tedros Adhanom Ghebreyesus. “Regulatory authorities in all countries should not allow any further work in this area until its implications have been properly considered.”

The WHO gene-editing expert advisory committee made that interim recommendation, which stops stop short of calling for a moratorium—something many scientists have advocated for. “When 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?” says Margaret Hamburg, the committee’s co-chair and a former head of the FDA. “It has a certain appeal, because it conveys a strong message. But it also doesn’t have a clear path in terms of what it means and how you implement it.”

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.

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’s 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—one handling anthrax and one handling avian flu—the US government halted, 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.

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 Nature and Science that the studies should restart in countries that had hammered out criteria for H5N1 virus transmission research.

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 “Asilomar” became shorthand for scientists acting in a socially responsible manner.

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. “Making 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’t be used, I think that that’s highly problematic,” says Benjamin Hurlbut, a biomedical historian at Arizona State University. “Technical expertise doesn’t mean that you have expertise about what’s good and bad for humanity.”

It’s 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’s 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.

Taking a break

Although there is widespread support for a germline-editing moratorium, there is also broad disagreement about the specifics—whether it should be voluntary or mandatory, for instance, and who should institute it. “I believe that many of the people calling for a moratorium are doing it with different ideas in mind of what that is,” Charo says.

The most detailed plan to date was published in a Commentary in Nature 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. “As 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,” they wrote.

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’s broad societal consensus in the particular nation. As for how that consensus might be reached, the authors point to the Global Genome Editing Observatory proposed by 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.

The NIH supported 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’ joint position paper on 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 “totally premature.”) The WHO, the likely body to facilitate the proposed moratorium, thus far has instead called upon each country to keep its scientists in check.

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 letter to 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 “unless and until diverse stakeholders have the opportunity to broadly and deeply discuss and reach a societal consensus on these challenges.” Azar has not responded.

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. “What should the boundaries be?” is one of the big questions, says ASGCT executive director David Barrett. “It’s something that should be inclusive of bioethicists, researchers, clinicians, but we also think it’s 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.”

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’s why she doesn’t support a moratorium. “I think even the word ‘moratorium’ implies that you’re not going to proceed to discuss the topic. And I think that would be a big mistake,” she says. “Rather than squelching discussion of this topic, we should actively encourage it.”

What’s more, a global moratorium might not hold much sway in some countries. “In Russia, it would be unlikely that all scientists would listen to whatever US, or US-backed, scientists have to say,” says biologist Konstantin Severinov, who works both at Moscow’s Skolkovo Institute of Science and Technology and at Rutgers University in New Jersey. “People will do it in spite of the international regulatory efforts.”

As for Rebrikov, he told Nature in 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.

This article is reproduced with permission and was first published on October 24, 2019.