Henry T Greely on He Jiankui’s CRISPR babies

Stanford law professor Henry T Greely's new book CRISPR People: The Science and Ethics of Editing Humans explores the work of disgraced Chinese researcher He Jiankui, and how his controversial experiment will impact efforts to use gene-editing technology in humans.

28th May 2021

In late 2018 the scientific community was rocked by the news that the world’s first CRISPR-gene edited babies had been born in China. A pair of non-identical twins known as Nana and Lulu were born by emergency caesarean, their mother having been implanted with CRISPR-gene edited embryos – all without the knowledge, oversight or approval of the wider scientific community.

The scientist behind the births, He Jiankui, had recruited at least eight HIV-positive couples and used CRISPR to edit the CCR5 gene of their embryos in the hope that their babies would be resistant to HIV. Despite his claims of success, it seems that neither of the twins actually had the exact 32-base-pair deletion that might confer resistance to HIV, and it is likely that other CRISPR-edited babies were born as part of his study. He was eventually sentenced to three years in prison by Chinese authorities and has still not published full details or data on his controversial procedure.

In CRISPR People, the bioethicist and lawyer Henry Greeley explores what is known about the case, what remains unclear, as well as the impact of the case on genome editing research and its future.

In this exclusive extract, we join the story in late November 2019, just after reporters from MIT Technology Review and the Associated Press broke the news of the babies’ births to the world - and just days before Jiankui He was scheduled to talk at the Second International Summit on Human Genome Editing in Hong Kong.

Henry Greely, director of the Center for Law and the Biosciences at Stanford, and author of CRISPR People.

"The Summit was to begin on Tuesday morning, November 27; He was to talk on Wednesday, November 28. Robin Lovell-Badge, from the organizing committee, gives some background on the timing of and reason for He’s speaking role:

"A month or so before the Second International Summit on Human Genome Editing took place, several of us on the organizing committee heard rumours that He Jiankui.. . was using genome-editing techniques on human embryos for the purposes of trying to make children who would be resistant to infection by HIV. We knew that JK had presented relevant work, involving genome editing in mouse and monkey embryos, at meetings over the last couple of years, and that he had also started using the methods on human embryonic stem cells and human embryos in culture. However, there was concern that he felt he was in a position to try things for real: to make genome-edited human babies. We also heard rumors that JK had obtained local ethics committee approval to go ahead. Therefore, when we were deciding on additional speakers for the summit, JK’s name came up. Although we were aware that he had not published in this area, he had clearly been doing relevant research and we thought it might be useful for him to attend the summit where the science, safety, ethics and regulatory issues surrounding genome editing would be discussed. We sent him an invitation and he responded almost immediately to say that he would be very happy to present."

As the organizing committee gathered in Hong Kong on Monday morning, they arrived to the news about He’s experiment. For at least one of them, that news had come a little earlier.

Jennifer Doudna, also a member of the Summit’s organizing committee, said she first got word of He’s experiment in an email from him, which she received on Thanksgiving Day, November 22, three days before the news broke in the MIT Review. The email had the subject line “Babies Born.” Doudna was quoted saying, “I was just horrified; I felt kind of physically sick.” And again, saying, “Honestly, I thought, ‘This is fake, right? This is a joke,’” she recalls. “‘Babies born.’ Who puts that in a subject line of an email of that kind of import? It just seemed shocking, in a crazy, almost comedic, way.” Doudna says as a result she changed her travel plans and left a day earlier for Hong Kong.

Anne-Marie Mazza, then Senior Director of the National Academies of Sciences, Engineering, and Medicine (NASEM) Committee on Science, Technology, and Law, was the NASEM staffer in charge of the Summit. She had arrived in Hong Kong on the morning of Friday, November 23 (late Thursday night or early Friday morning for Doudna in California). She found an email from Doudna waiting for her, asking, urgently, if they could talk. Doudna told Mazza about He’s email over the phone; Doudna then telephoned David Baltimore, the organizing committee’s chair, who was in the U.S., and informed him. Over the next few days, Mazza, Doudna, Baltimore and bioethicist Alta Charo Baltimore talked about how to handle the He news, including how to inform the other members of the organizing committee.

Doudna arrived in Hong Kong Monday morning, about the same time He Jiankui had made the 90-minute drive from his lab in Shenzhen: “The nanosecond I landed at the airport, I had just a ton of emails from JK, desperate: I have to talk to you right now, things have really gotten out of control,” recalls Doudna... She went to Le Méridien hotel, where He was also staying, and checked in without immediately replying. “He actually had somebody come and pound on my hotel door.”

Sometime that morning Doudna and Lovell-Badge met briefly with He in the hotel lobby. (Remember, the Regalado article broke at about 8:15 a.m. in Hong Kong and the AP story no later than 10:48 a.m.) According to the same article in Science:

When Doudna finally sat down with He in the hotel lobby on the morning of 26 November, a few hours after the news of the babies broke, the Chinese biologist seemed surprised by the immediate, intense flood of attention and mounting criticism, she recalls. He even asked her whether he should discuss the gene-edited babies in his talk. “It was bizarre,” she says. “He seemed so naïve.”

STAT gives more of Doudna’s response:

Um, Doudna replied, you’ve dropped this shocking news on the world, right before our summit, and you’re not planning to mention it? He seemed surprised that she expected him to but agreed to have dinner with her and other members of the summit organizing committee that evening to talk it out.

At some time that morning, after the initial lobby meeting with He, Lovell-Badge and some other early arriving organizing committee members met to discuss how to handle the He bombshell. Should He present his work, how could they handle the He affair without letting it overwhelm the rest of the meeting, and whether and how to deal with the press about it before the meeting? They “collectively took the decision that, assuming JK was still willing to talk, he should be encouraged to present at the summit.”

Doudna, Lovell-Badge, Alta Charo, and Patrick Tam, an organizing committee member from Australia, met for dinner with He at the hotel on Monday night, November 26, to discuss his work. Shortly after the Summit Science reported:

On the eve of the International Summit on Human Genome Editing in Hong Kong, China, last week, He, a researcher at nearby Southern University of Science and Technology in Shenzhen, China, had dinner at the city’s Le Méridien Cyberport with a few of the meeting’s organizers. The news of He’s claim had just broken, and shock waves were starting to reverberate. But the reports were still so fresh that the diners sat in the restaurant without being disturbed.

“He arrived almost defiant,” says Jennifer Doudna, who did landmark CRISPR work at the University of California (UC), Berkeley. She and the other conference organizers politely asked He questions about the scientific details and rationale of his work, the permissions he had secured to conduct it, and how he recruited hopeful parents to participate and informed them about risks. He asked them whether his planned talk two days later should include data about the twin girls, who had a gene altered to make them resistant to HIV infection. “We were all like, ‘Uh, yes,’” Doudna says.

After more than an hour of questioning, He had had enough. “He just seemed surprised that people were reacting negatively about this,” Doudna says. “By the end of the dinner he was pretty upset and left quite abruptly.”

A later Science article says,

At a dinner with He later on 26 November, Doudna and other summit organizers lobbied for full disclosure. He agreed to describe his work in detail at his talk 2 days later, although he said he had received threatening text messages and had switched hotels for safety. Alta Charo, a bioethicist at the University of Wisconsin Law School in Madison, asked He whether he understood the importance of the principles spelled out in the two main documents that gave germline editing a yellow light of sorts: the 2017 NASEM report and a similar July 2018 report by the Nuffield Council on Bioethics in the United Kingdom.

“I absolutely feel like I complied with all the criteria,” He said. “That kind of rocked me back,” Charo says.

Ultimately, the organizing committee decided that He would give his scheduled talk on the second day of the Summit, Wednesday, November 28, as part of a panel called “Human Embryo Editing,” moderated by Robin Lovell-Badge and including presentations from Kathy Niakan, Paula Amato, Maria Jasin, and Xingxu Huang, but as a split session. The first four would speak, answer questions, and leave the stage. Then He would appear and would be the last to speak. The organizing committee released a statement at around 1:00 p.m. EST on Monday, November 26. In Hong Kong, that was about 2:00 a.m., Tuesday, November 26 (the starting day for the Summit), presumably after the dinner and just a few hours before the meeting’s start.

The statement read,

On the eve of the Second International Summit on Human Genome Editing, we were informed of the birth of twins in China whose embryonic genomes had been edited. The researcher who led the work, He Jiankui, is scheduled to speak at the summit on Wednesday.

The criteria under which heritable genome-editing clinical trials could be deemed permissible have been the subject of much debate and discussion by many research groups. . . . Whether the clinical protocols that resulted in the births in China conformed with the guidance in these studies remains to be determined. We hope that the dialogue at our summit further advances the world’s understanding of the issues surrounding human genome editing. Our goal is to help ensure that human genome editing research be pursued responsibly, for the benefit of all society.

One might ask about the fairness to the conference organizers of He’s cat-and-mouse game over “would he/wouldn’t he.” Of course, one might also ask whether, once they learned of He’s work, the conference organizers should have allowed such ethically questionable research to be presented at the Summit. Under the circumstances—where the world, and the organizing committee, knew very little about what had happened and He was already scheduled to talk—I think they made the right decision…but I could be wrong.

At the Summit

The Summit opened on Tuesday morning with the usual welcomes and charges from local dignitaries and organizers. Four panels—two on science, one on ethics, and one on law— followed that day until the meeting’s 6:00 p.m. adjournment. None of the panels focused on the He experiment.

The “Human Embryo Editing” panel was the third session on the following day, Wednesday, November 28. This panel was livestreamed, in China and around the world, and it is said that more than a million people watched. (I did, and, as it was recorded and is available online, you can, too [link]. The following discussion of the panel draws from my viewing of the livestream and of the recording.) Lovell-Badge moderated the panel. Drs. Niakan, Amato, Jasin, and Huang gave their presentations and took questions for the first hour and 15 minutes of the panel, which had been allocated a total of 90 minutes. At that point, these four speakers left the stage, and the moderator, Robin Lovell-Badge, implored the audience not to interrupt He—telling the audience that he, Lovell-Badge, had the right to cancel the session if there were too many interruptions, and reminding everyone of the Hong Kong University’s long tradition of free speech.

Dr. He presented his results for about 20 minutes, starting with mouse work and then moving to the babies. Afterward, He was questioned onstage by Lovell-Badge and Dr. Matthew Porteus, another scientist-member of the organizing committee, for about 15 minutes. David Baltimore, the chair of the organizing committee, spoke for a few minutes, stressing the need for societal consensus, arguing that further research would be irresponsible, and decrying that the experiment was neither transparent nor medically necessary. Baltimore called this “a failure of self-regulation by the scientific community, because of a lack of transparency.” For the remaining 25 minutes, He spoke with the moderators and then took questions from the audience.

Lovell-Badge questioned the selection of CCR5 given how little we know about it—particularly given some research that indicated it could make the babies more susceptible to influenza, and other research suggesting that editing CCR5 could enhance cognitive abilities. Dr. He responded that the gene had been “studied for decades,” and that he was against using editing for enhancement. Porteus asked how many women were part of He’s “pipeline” for his experiment, which is how we know (or think we know) that eight women were selected and one dropped out. Dr. He explained that eight couples were selected, one dropped out, and for the remaining seven couples, 31 embryos were injected, of which 70 percent were edited. He also explained that the clinical trial had ended given the “current situation.”

Porteus wanted to know how the trial and the consent process was designed. Dr. He referred to his Cold Spring presentation, where he apparently got feedback and criticism from some attendees; he also spoke with “top ethicists in the United States,” and had “a U.S. professor” and “a Chinese professor” review his consent, along with the four people on his team. According to He, he personally spent one hour and 10 minutes with each participant to explain the consent, after each participant had spent two hours with one of his team members. He was confident that the women were “very educated” and could understand the consents.

At this point, the moderators opened it up to questions from the general audience and from the media. David Liu from the Broad Institute questioned whether the experiment satisfied an “unmet medical need,” since sperm-washing technology can prevent prenatal paternal transmission of HIV. Liu also asked about the role of scientists in making decisions for patients. Dr. He said he felt proud about what he had done, to help the children survive, since HIV is such a horrible affliction. When pressed by another audience member on the ethics of his experiment, He said he was showing compassion by using available technology to help people with genetic disease.

Porteus interjected to ask if there were more pregnancies, and He told him that there was one. In a particularly difficult moment toward the end of the session, when Dr. Jasin from Sloan Kettering asked about the personal impact on Nana and Lulu and the family dynamics between them, given the disparate outcomes of the experiment, He explained that he wanted to give them “freedom of choice.” But He did not know how to answer when Dr. Jasin pressed him to consider how the families and the children, themselves, would deal personally with the fact that their genes had been edited.

At the end of the panel, He said he did not anticipate such a strong reaction from the international community.

I recommend that you watch the video of He’s presentation for yourselves. My own reaction shifted during it. At first, I was, in spite of myself, impressed with how straightforward and sincere He seemed. But, as his presentation went on, I began to notice more and more gaps in his analysis. And, as he struggled to respond to questions, I began to feel that he was well out of his depth—in much deeper waters than any reasonable person would have put himself.

After the audience questions, He left the stage and, shortly thereafter, left Hong Kong to return to mainland China. He cancelled his scheduled appearance at the Thursday panel. In the more than one year between then and when I wrote this chapter, he made no known substantive statements on the research.

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Henry T Greely is the Deane F. and Kate Edelman Johnson Professor of Law at Stanford Law School, director of the Stanford Center for Law and the Biosciences, chair of the Steering Committee of the Center for Biomedical Ethics at Stanford, and director of the Stanford Program in Neuroscience and Society.