What’s next for human gene-editing

In the three months since He Jiankui announced the birth of twin girls with edited genomes, the questions facing the scientific community have grown

By engineering mutations into human embryos, which were then used to produce babies, He leapt capriciously into an era in which science could rewrite the gene pool of future generations by altering the human germ line. He also flouted established norms for safety and human protections along the way.

There is still no definitive evidence that the biophysicist actually succeeded in modifying the girls’ genes — or those of a third child expected to be born later this year. But the experiments have attracted so much attention that the incident could alter research for years to come.

Chinese authorities are still investigating He, and US universities are asking questions of some of the scientists he consulted. Meanwhile, calls for an international moratorium on related experiments, which could affect basic research, have motivated some scientists to bolster arguments in favour of genome editing.

Some are concerned about how the public scrutiny will affect the future of the field, whether or not researchers aim to alter the germ line. “The negative focus is, of course, not good,” says Fredrik Lanner, a stem-cell scientist at the Karolinska University Hospital in Stockholm, who has been editing genes in human embryos to study how cells regulate themselves.

But others predict that the He affair might propel human gene editing forwards. Jonathan Kimmelman, a bioethicist specializing in human trials of gene therapies at McGill University in Montreal, Canada, argues that definitive action in the wake of the scandal could expedite global cooperation on the science and its oversight. “That would stimulate, not hinder, meaningful advance in this area,” he says.

Here, Nature explores four questions still lingering around the births.

What will happen to He — and the children?

He has been criticized, but not just because he pursued germline editing. He also neglected to do adequate safety testing and failed to follow standard procedures in procuring participants. He was subsequently censured by the health ministry in Guangdong, where he worked, and fired from his university. He did not respond to Nature’s multiple attempts to contact him.

At this point, further penalties seem to be in the hands of the police. There are a range of criminal charges that He could face. While recruiting participants, He and his team agreed to cover the costs of fertility treatment and related expenses, up to 280,000 yuan (US$42,000). He also stipulated that participants would have to repay costs if they dropped out. Liu Ye, a lawyer at the Shanghai Haishang Law Firm, says that if such payments are found to count as coercive measures, they could constitute a crime. Guangdong province also found that He used forged ethics-review documents during recruitment of participants and swapped blood samples to skirt laws against allowing people with HIV to use assisted reproductive technologies.

He claims to have disabled a gene called CCR5, which encodes a protein that allows HIV to enter cells. He was aiming to mimic a mutation that exists in about 10% of Europeans, and helps to protect them from HIV infection. But He might have inadvertently caused mutations in other parts of the genome, which could have unpredictable health consequences. (He claims to have found no such mutations.) Also, CCR5 is thought to help people fight off the effects of various other infections, such as West Nile virus. If the gene is disabled, the girls could be vulnerable. If they do suffer in a way that is linked to He’s procedure, and He is found to have been practising medicine illegally, he could be sentenced to between three and ten years in prison, says Zhang Peng, a criminal-law scholar at Beijing Wuzi University. But identifying those health effects could take years.

He promised to follow up with the girls until they were 18 years old, but it is unlikely that the health ministry, which ordered He to stop doing science, will allow him to be involved in the evaluations. It is not known what, if any, special measures are being taken to look out for the girls’ health or to track the other pregnancy.

What about the other scientists implicated?

Soon after He revealed his experiment, it became clear that he did not act alone or in secrecy. The responsibility of other researchers who were in the know became hotly debated.

The senior researcher with the most intimate knowledge of the work seems to be Michael Deem, a biophysicist at Rice University in Houston, Texas. Deem was once He’s adviser, and is a member of the scientific advisory board of a Shenzhen-based genome-sequencing company that He founded. Deem was reportedly also a senior author on a paper — which remains unpublished — describing He’s experiments, and is said to have been present during the recruitment of participants. What role he had is not clear. Deem’s lawyers acknowledge that Deem sometimes comments on He’s papers. But they insist that Deem does not do human research, and did not do so for this project. They say that he did not attend recruitment or informed-consent meetings, and nor did he authorize the use of his name as an author on any human-gene-editing paper. Rice University is investigating Deem’s involvement.

Other scientists have been chastised for doing nothing to raise alarms about the work. He Jiankui told many US-based academics about what he was doing, including three at Stanford University in California, and Craig Mello, a Nobel-prizewinning molecular biologist at the University of Massachusetts Medical School in Worcester, who was an adviser for a company founded by He. Most of them say that they advised He against proceeding.

Mello says He ambushed him during a break at an advisory board meeting to tell him of his plans and then notified him of the pregnancies by e-mail. “I immediately expressed my concern and condemnation,” says Mello.

But Natalie Kofler, a molecular biologist at Yale University in New Haven, Connecticut, argues that researchers who knew about this should have done more. The whole episode, she says, is evidence of a growing divide between the values scientists proclaim, and those they actually uphold. Kimmelman shares those concerns, and says that by remaining silent, scientists are in danger of creating a “latency period” in which dangerous practices can emerge and evolve in a vacuum. “It often takes a debacle for people to realize that silence can often be a form of complicity,” he says.

Stanford stem-cell biologist Matthew Porteus says he didn’t speak up for three reasons: he thought he had dissuaded He, he wanted to respect He’s request for confidentiality and he didn’t know where or how to report what he had heard. Others cite similar reasons.

Alta Charo, who specializes in law and bioethics at the University of Wisconsin–Madison, agrees that it was unclear how any of these individuals could have effectively blown the whistle. Had the research been conducted in the United States, a scientist could have contacted the Office for Human Research Protections or the Office of Research Integrity. But China has different values and opaque regulations. “If it is happening elsewhere, a scientist may be wholly unfamiliar with the norms and laws in that foreign country,” says Charo.

She says this could change if the scientific community follows through on plans mapped out at a gene-editing summit held in Hong Kong in November — the only scientific forum at which He has presented his work. The plans propose some kind of transnational advisory body and registry to identify common norms and differences of opinions between countries. Other organizations are also considering measures. Earlier this month, for example, the World Health Organization announced the establishment of an international committee to devise guidelines for human gene editing. It will meet for the first time in March (see ‘Human gene editing’).

Source: The CRISPR-baby scandal: what’s next for human gene-editing

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