What's Next for Crispr Babies?

WHAT’S

n the three months since He Jiankui Some are concerned about how the public NEXT FOR announced the birth of twin girls with scrutiny will affect the future of the field, Iedited genomes, the questions facing the whether or not researchers aim to alter the scientific community have grown knottier. germ line. “The negative focus is, of course, not By engineering mutations into human good,” says Fredrik Lanner, a stem-cell scientist CRISPR embryos, which were then used to produce at the Karolinska University Hospital in Stock- babies, He leapt capriciously into an era in holm, who has been editing genes in human which science could rewrite the gene pool of embryos to study how cells regulate themselves. BABIES? future generations by altering the human germ But others predict that the He affair might line. He also flouted established norms for propel human gene editing forwards. Jonathan Following last year’s safety and human protections along the way. Kimmelman, a bioethicist specializing in There is still no definitive evidence that the human trials of gene therapies at McGill Univer- GETTY IMAGES: MIKE MCQUADE; BY ILLUSTRATION bombshell revelation, biophysicist actually succeeded in modify- sity in Montreal, Canada, argues that definitive investigations mount and ing the girls’ genes — or those of a third child action in the wake of the scandal could expe- expected to be born later this year. But the dite global cooperation on the science and its debates swirl about the experiments have attracted so much attention oversight. “That would stimulate, not hinder, future for gene-edited that the incident could alter research for years meaningful advance in this area,” he says. to come. Here, Nature explores four questions still humans. Chinese authorities are still investigating lingering around the births. He, and US universities are asking questions Here are the four most of some of the scientists he consulted. Mean- WHAT WILL HAPPEN TO HE — AND THE CHILDREN? while, calls for an international moratorium on He has been criticized, but not just because he pressing questions. related experiments, which could affect basic pursued germline editing. He also neglected to research, have motivated some scientists to do adequate safety testing and failed to follow BY DAVID CYRANOSKI bolster arguments in favour of genome editing. standard procedures in procuring participants.

FEATURE NEWS

He was subsequently censured by the health human research, and did not do so for this agrees that it was unclear how any of these ministry in Guangdong, where he worked, and project. They say that he did not attend recruit- individuals could have effectively blown the fired from his university. He did not respond ment or informed-consent meetings, did not whistle. Had the research been conducted in to Nature’s multiple attempts to contact him. authorize the use of his name as an author on the United States, a scientist could have con- At this point, further penalties seem to be any human-gene-editing paper and was not a tacted the Office for Human Research Protec- in the hands of the police. There are a range senior author on the paper. Rice University is tions or the Office of Research Integrity. But of criminal charges that He could face. While investigating Deem’s involvement. China has different values and opaque regula- recruiting participants, He and his team Other scientists have been chastised for tions. “If it is happening elsewhere, a scientist agreed to cover the costs of fertility treatment doing nothing to raise alarms about the work. may be wholly unfamiliar with the norms and and related expenses, up to 280,000 yuan He Jiankui told many US-based academics laws in that foreign country,” says Charo. (US$42,000). He also stipulated that participants would have to repay costs if they dropped THE LEGAL LANDSCAPE out. Liu Ye, a lawyer at the Shanghai Haishang A 2016 survey in Science examined existing laws (legislation) and documented policies (regulation) Law Firm, says that if such payments are found that explicitly govern gene editing or might be applied to such activities. The survey labelled countries to count as coercive measures, they could as restrictive, permissive or something in between. But specialists disagree over whether rules in 351 , 337–339 (2016). constitute a crime. Guangdong province also some nations might be intepreted to permit gene editing (see page 455). found that He used forged ethics-review docu- SCIENCE ments during recruitment of participants and Canada swapped blood samples to skirt laws against Belgium allowing people with HIV to use assisted United The Netherlands Kingdom China reproductive technologies. Germany France He claims to have disabled a gene called United

ET AL . SOURCE: R. ISASI ET CCR5, which encodes a protein that allows States Japan HIV to enter cells. He was aiming to mimic a South Korea mutation that exists in about 10% of Europeans, Mexico and helps to protect them from HIV infection. India But He might have inadvertently caused mutations in other parts of the genome, which could Restrictive Singapore have unpredictable health consequences. (He Intermediate Brazil claims to have found no such mutations.) Also, Permissive Australia CCR5 is thought to help people fight off the Legislation Regulation effects of various other infections, such as West Springer Nature is neutral about jurisdictional claims in maps. Nile virus. If the gene is disabled, the girls could be vulnerable. If they do suffer in a way that is about what he was doing, including three at She says this could change if the scien- linked to He’s procedure, and He is found to Stanford University in California, and Craig tific community follows through on plans have been practising medicine illegally, he could Mello, a Nobel-prizewinning molecular biolo- mapped out at a gene-editing summit held be sentenced to between three and ten years in gist at the University of Massachusetts Medical in Hong Kong in November — the only sci- prison, says Zhang Peng, a criminal-law scholar School in Worcester, who was an adviser for a entific forum at which He has presented his at Beijing Wuzi University. But identifying those company founded by He. Most of them say that work. The plans propose some kind of trans- health effects could take years. they advised He against proceeding. national advisory body and registry to identify He promised to follow up with the girls until Mello says He ambushed him during a break common norms and differences of opinions they were 18 years old, but it is unlikely that at an advisory board meeting to tell him of his between countries. Other organizations are the health ministry, which ordered He to stop plans and then notified him of the pregnan- also considering measures. Earlier this month, doing science, will allow him to be involved in cies by e-mail. “I immediately expressed my for example, the World Health Organization the evaluations. It is not known what, if any, concern and condemnation,” says Mello. announced the establishment of an inter- special measures are being taken to look out for But Natalie Kofler, a molecular biologist national committee to devise guidelines for the girls’ health or to track the other pregnancy. at Yale University in New Haven, Connecti- human gene editing. It will meet for the first cut, argues that researchers who knew about time in March (see ‘Human gene editing’). WHAT ABOUT THE OTHER SCIENTISTS IMPLICATED? this should have done more. The whole epi- Soon after He revealed his experiment, it sode, she says, is evidence of a growing divide HOW COULD HE’S ACTIONS AFFECT OTHER RESEARCH? became clear that he did not act alone or in between the values scientists proclaim, and Four years ago, a team of scientists from secrecy. The responsibility of other researchers those they actually uphold (see page 427). Guangzhou published a paper1 describing the who were in the know became hotly debated. Kimmelman shares those concerns, and says use of gene-editing techniques in a human The senior researcher with the most intimate that by remaining silent, scientists are in dan- embryo. The researchers used embryos with knowledge of the work seems to be Michael ger of creating a “latency period” in which a mutation that would prevent them from Deem, a biophysicist at Rice University in dangerous practices can emerge and evolve in growing into fetuses. It was, nevertheless, an Houston, Texas. Deem was once He’s adviser, a vacuum. “It often takes a debacle for people earthshaking study, and it triggered immediate and is a member of the scientific advisory board to realize that silence can often be a form of questions about germline editing. of a Shenzhen-based genome-sequencing complicity,” he says. Over the next two years, several groups — company that He founded. Deem was report- Stanford stem-cell biologist Matthew Porteus from China, the United States and the United edly also a senior author on a paper — which says he didn’t speak up for three reasons: he Kingdom — published results2–4 of similar remains unpublished — describing He’s experi- thought he had dissuaded He, he wanted to experiments. The studies went from using ments, and is said to have been present during respect He’s request for confidentiality and he non-viable embryos to using ones that could the recruitment of participants. What role he didn’t know where or how to report what he conceivably be implanted. Some tested new had is not clear. Deem’s lawyers acknowledge had heard. Others cite similar reasons. gene-editing techniques or combined gene that Deem sometimes comments on He’s Alta Charo, who specializes in law and bio- editing with cloning. Others verified gene edit- papers. But they insist that Deem does not do ethics at the University of Wisconsin–Madison, ing’s ability to correct mutations associated with

NEWS FEATURE genetic disease and analysed genes important oversight, says Leigh Turner, a bioethicist at in early embryo development, including some TIMELINE the University of Minnesota in Minneapolis. implicated in the failure of some pregnancies. In December, the education ministry called on The experiments triggered warnings. HUMAN GENE EDITING universities to investigate whether any of their Although the scientists involved touted their researchers were engaging in controversial work as careful basic research, many ethicists March 2015: Chinese researchers become gene-editing activity. And China’s annual leg- saw only one possible outcome: a clinical appli- the first to edit genes in a human embryo. islative meetings start on 3 March, so stricter cation not unlike what He has claimed to have June 2016: He Jiankui launches a project laws could be around the corner. done. Following the fiasco with He, will those to edit genes in human embryos, with the But there are many places with lax policies who are conducting embryo experiments face goal of a live birth. governing new biomedical technologies. Ishii a backlash? March 2017: He starts recruiting couples has surveyed countries with clinics that offer Some think that the outrage over He’s acts (each with an HIV-positive father) for the mitochondrial replacement therapy (MRT), will pass before that happens. “News cycles are experiments. a controversial procedure that has been used just so short these days,” says Kimmelman. “I’d Early November 2018: Gene-edited twin to correct genetic defects and boost success in be surprised if there are any major disruptions girls are reportedly born, and a second pregnancies. MRT is forbidden in many coun- to research as a result of this.” pregnancy with a third gene-edited tries because of uncertainties about its safety, But Shoukhrat Mitalipov, a reproductive biol- embryo is established. but Ishii has identified clinics offering the pro- ogist at the Oregon Health & Science University 25–26 November 2018: The MIT cedure in Russia, Ukraine, Spain, Albania and in Portland, fears the controversy could affect Technology Review reveals the existence of Israel. Most of these also have lax regulations factors such as funding and regulatory approv- the research programme; the Associated on gene editing, so the clinics could begin to als. Mitalipov is working on ways to repair Press quickly goes public with the story of offer untested services to curious parents at any mutated genes in human embryos, and hopes the girls’ birth. time. “There are so many candidates,” he says. that the approach can one day be used to edit 28 November 2018: He offers details Kimmelman suspects the next maverick will out heritable diseases. The US government pro- about his work at a gene-editing summit emerge from a large country: the more scien- hibits federal funding for such experiments, but in Hong Kong and is roundly criticized. tists there are, the more chances there are for Mitalipov and a handful of other US research- November–December 2018: China’s ‘anomalous’ behaviour. It would probably be a ers have managed to find other grant money for National Health Commission orders an nation that is not well established scientifically, the work. Right now, Mitalipov is cautious. “It investigation into He’s work. he says. “Incentives for a stunt like [He’s] are might be a bit early to evaluate a backlash,” he January 2019: He is censured by the probably diminished in a country where there says. “For sure, this case did not help.” Guangdong health ministry and fired are clearer and easier paths to scientific status.” Some scientists have called for a global mora- from his university. Or perhaps a researcher or physician from a torium on all research that would tinker with 18 March 2019: A World Health more developed and tightly regulated country the genes of human embryos, whether or not the Organization committee will meet to set will travel somewhere to produce a gene-edited embryos are subsequently implanted. The con- guidelines for human gene editing. baby. That happened with MRT, when a doctor cern is that any such research could lead to other August 2019: Third gene-edited baby from New York travelled to Mexico to help a premature attempts. “As we have clearly learnt expected. couple interested in using the technology. from China, nothing prevents someone from The investigations into He and others — going rogue,” says Fyodor Urnov, an Innova- and any punishments they might face — could tive Genomics Institute investigator at the Uni- Lovell-Badge, Julie Steffann and Charo all influence where researchers choose for their versity of California, Berkeley. He argues that voiced support for it as a necessary alternative next attempts, says Turner. If He’s collabora- such attempts could taint other safe and ethical to PGD when there are too few embryos to find tors outside China are subjected to sanctions, uses of gene editing, such as his efforts to cor- one suitable for implantation, and in rare cases that might help to limit researchers based in rect mutations in adult cells, which would not when both parents have two copies of a disease countries with strict laws from working outside alter the germ line. “I am strongly for a complete mutation. In some instances, gene editing might those jurisdictions. “What happens to Michael moratorium on all embryo editing,” he says. be the only way to ensure fertility treatments Deem — if in fact he was a meaningful partici- Momentum has grown for some sort of inter- are successful, says bioethicist Tetsuya Ishii of pant in the germline gene-editing study — will national moratorium, and powerful figures such Hokkaido University in Sapporo, Japan. also send a message,” says Turner. as Francis Collins, director of the US National But the wide range of laws leaves the Institutes of Health, have voiced support for one. WHERE WILL THE NEXT CRISPR BABIES BE BORN? door open to further attempts. “If different Some countries, including Canada, already have Although He’s plans to win support for his pro- jurisdictions adopt widely varying governance policies that ban the use of human-embryo gene ject backfired, no one doubts that there will be models for germline gene editing,” says Turner, editing even if there is no intention of implant- more mavericks like him. The technique is easy; “it seems plausible that at least some scientists ing the embryo (see ‘The legal landscape’). some of its applications are compelling; and will pursue opportunities to conduct clinical The future of embryo editing, especially the publicity can be enormous. But where and research.” ■ with the intention of producing babies, might under what circumstances another gene-edited depend on the debate over the need for it. Many baby could be conceived is anyone’s guess. David Cyranoski reports for Nature from sceptics point out that, although gene editing China would be an obvious choice, having Shanghai. can help to avoid passing on some disorders, produced the majority of gene-edited human 1. Liang, P. et al. Protein Cell 6, 363–372 (2015). many of these conditions can already be avoided embryos for research. The country also has an 2. Tang, L. et al. Mol. Genet. Genom. 292, 525–533 using a technique known as preimplantation ambiguous stance towards gene editing. (2017). genetic diagnosis (PGD) in which embryos cre- But He’s actions seem to have embarrassed 3. Ma, H. et al. Nature 548, 413–419 (2017). 4. Fogarty, N. M. E. et al. Nature 550, 67–73 (2017). ated through in vitro fertilization are screened China, judging by the removal of references to 5. Daley, G. Q., Lovell-Badge, R. & Steffann, J. for specific mutations. him from government websites and censorship N. Engl. J. Med. https://doi.org/10.1056/ But, in the wake of the He scandal, some on social-media platforms such as WeChat. (It NEJMp1900504 (2019). prominent scientists and bioethicists have was one of the top ten censored topics of 2018.) 6. Charo, R. A. N. Engl. J. Med. https://doi. 5-7 org/10.1056/NEJMms1817528 (2019). gone to bat for gene editing. In three articles He’s actions might prompt China to develop 7. Lovell-Badge, R. Development 146, dev175778 published earlier this year, George Daley, Robin new regulations and better institutional (2019).

CLARIFICATION The News Feature ‘What’s next for CRISPR babies’ (Nature 566, 440–442; 2019) now includes a comment from Michael Deem’s lawyer, in which he says that Deem was not a senior author on the human-gene-editing paper describing He’s experiments.