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Amid uproar, Chinese scientist defends creating gene-edited babies – STAT

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HONG KONG — The scientist who single-handedly made #crisprbabies a trending topic on Twitter this week defended his experiment creating the world’s first gene-edited babies and the audacious way he announced it — through the press and a YouTube video — on Wednesday at the International Human Genome Editing Summit.

“For this particular case,” He Jiankui said of the twin girls born as the result of his work, “I feel proud.” And far from admitting to any second thoughts about what fellow scientists slammed as an “appalling act that threatens to set back the field of therapeutic genome editing,” He doubled down: he said he has started one more pregnancy, still in a very early stage, with genome-edited embryos.

He began more humbly in his first public remarks about his research, with a statement that drew quiet gasps from the audience: “I must apologize that these results leaked before peer review,” He said.

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In fact, his representatives had reached out to a reporter months ago and allowed extensive filming in his lab to tell the story of his work, as he acknowledged.

He meticulously orchestrated the announcement on Sunday — two days before the start of the summit — of his claim that the girls, created from genome-edited embryos, had been born a few weeks ago. He sat for interviews with and cooperated with extensive filming by the Associated Press, which was the first to report the news, and posted a series of videos online, in English, rather than publish his research in an academic journal. And when He submitted his slides to the summit organizers before the conference, they included nothing about the work having already led to the births.

He also admitted that his university was in the dark about what he was doing.

A number of prominent scientists were unpersuaded by He’s comments. “I don’t think this has been a transparent process,” said David Baltimore of the California Institute of Technology and chair of the summit organizing committee during a lengthy Q&A session following He’s 20-minute talk. “We only found out about it … after the children were born. I think there has been a failure of self-regulation by the scientific community because of the lack of transparency.”

Asked why he had kept his work hidden from the scientific community, He insisted he had not. He noted that he presented a talk at Cold Spring Harbor in the U.S. in 2017 and spoke with a scientist at the University of California, Berkeley, and ethicists in the U.S.  But only with the Berkeley scientist did he reveal his plan to create gene-edited babies.

He also disclosed that he has now submitted the study to a journal, but said he would not make the full results available for the scientific community to scrutinize until the paper is published.

The news of the births caused an uproar among scientists here and in the West because it crossed a line agreed upon by leading scientific organizations worldwide against editing the genomes of embryos for reproductive purposes. Such germline editing results in any changes to the DNA being inherited by future generations. Genome editing technology is also still relatively new and comes with technical and safety challenges, including the risk of DNA being inadvertently cut in the wrong place.

After his apology about the “leak,” He launched into a defense of his work with quiet assurance. People with HIV/AIDS experience crushing discrimination, He said, and significant numbers of children are infected. That led him to choose as his CRISPR target a gene called CCR5 which, when disabled, produces a cell receptor so crippled that HIV can’t use it as a portal into cells. People who have mutated CCR5 genes are therefore protected against HIV infection.

His answers weren’t always convincing, reminding some scientists of the evasiveness of politicians on Sunday morning talk shows. When David Liu of Harvard University, a leading developer of genome editing tools, criticized He for going forward with an experiment that did not address an “unmet medical need” (HIV is preventable and treatable), He said he feels the work was justified because the HIV-positive father of the twins felt that the technique allowed him to have children who would be forever immune to HIV. He also said he has “personal experience” with HIV, knowing of some villages with infection rates of 30 percent.

He Jiankui speaks during the International Human Genome Editing Summit in Hong Kong on Wednesday. Kin Cheung/AP

“It’s even more appalling and abhorrent now,” Liu, cofounder of the genome editing company Beam Therapeutics, told STAT. “His responses displayed a deeply disturbing naivete about the issues involved. I have a deep fear that this could set back the field [of therapeutic genome editing] so badly that patients won’t get the therapies they desperately need.”

Other experts in the audience were equally critical. “Having listened to Dr. He, I can only conclude that this was misguided, premature, unnecessary and largely useless,” said bioethicist Alta Charo of the University of Wisconsin, a member of the summit organizing committee.

The majority of He’s talk described the techniques he used and the discoveries he made in experiments with mice and monkeys, such as the finding that genome editing was most efficient when done close to fertilization; he therefore delivered the genome-editing molecule CRISPR-Cas9 via microinjection along with the sperm used to fertilize an egg. But “multiple” injections of CRISPR were required to raise the efficiency of editing enough to insure that most cells contained the DNA edit.

He is an expert in DNA sequencing, a technique he used to assess whether CRISPR caused unintended genetic changes. He found one off-target edit in an embryo before it was implanted, he said, but considered it unlikely to affect any biological function; when the parents deemed that an acceptable glitch, “the couple elected to implant this embryo to start a two-embryo pregnancy,” He said. He added that sequencing done after the births didn’t confirm the off-target edit.

Another glitch was that only some of the cells of the early-stage embryo were successfully edited; others retained their original CCR5 gene, meaning they might in fact not be protected against HIV. Again, He said the parents accepted that “mosaicism” and said they wanted the embryo implanted. Finally, one edit resulted in a CCR5 protein missing five amino acids. It’s not clear if that’s serious enough to disable the receptor and thus prevent HIV infection, Liu said.

That cavalier attitude also enraged his critics. Harvard’s Liu, who said he had to take an antacid tablet during the talk to keep from being sick, said it was “abhorrent” to expect parents, who presumably have little or no scientific training, to make a decision like that with apparently no outside help.

Much of the questioning focused on He’s process for gaining informed consent from the parents who volunteered for the trial. He admitted that he obtained consent from the couples himself, rather than having a trained, uninvolved professional do it.

“I explained to each family line by line and paragraph by paragraph” the meaning of the informed consent form, said He, who has been criticized for telling patients the experiment was about an “AIDS vaccine.” In addition, the form says the participants agree to protect “the project team’s trade secrets.”

“The patients were given a consent form that falsely stated this was an AIDS vaccine trial, and which conflated research with therapy by claiming they were ‘likely to benefit,’” Charo told STAT.

Eight couples enrolled for the study and one dropped out, He said. In each case, the father was HIV-positive and the mother was not. A total of 31 embryos were injected, He said, and 70 percent were edited.

The uproar over his work, He said in response to a question, has caused the clinical trial of using CRISPR to disable CCR5 in human embryos to be “paused due to the current situation.” But later he said that a second mother is pregnant at a very early stage.

He said the twins, named Lulu and Nana, are healthy and that “there is a plan to monitor the children for the next 18 years, with the hope that they will consent as adults for continued monitoring and support.”

The talk was eagerly anticipated, because He, 34, had provided no evidence to support the claims in the AP story. He would not reveal where the twins were born or where their family lives. He told AP that he sought ethics approval from a board at Harmonicare Women & Children’s Hospital in Shenzhen but that it was not one of the four that provided embryos for the research that led to the births. The hospital has since said the girls were not born there, either.

Attendees, several dozen scientists and reporters, had formed a line at the glass doors of the 500-person auditorium by 7:30 in the morning — three hours before the session was set to start — but the room had about 60 empty seats. Just before He’s session, however, three security guards with prominent earpieces took positions near the front of the room and a crush of photographers and other journalists swarmed in, filling aisles and scrambling for the last available seats (and looking terminally bored during the four talks before He’s).

“I’m quite aware that there is some interest in this session,” moderator Robin Lovell-Badge, a developmental biologist at London’s Francis Crick Institute, said with British understatement as he began the session, which nearly 5,000 people watched via webcast.

“He has to be given a chance to explain what he has done and why,” Lovell-Badge said, adding that “we will close the session immediately” if there is “unruly behavior” during He’s talk.

Unlike other speakers, who sat in the front rows and were called up to the stage when it was their turn to speak, He entered from a side door, walking briskly to the podium to polite applause.

Earlier this week, Harmonicare announced that it was investigating any ties it has to He’s research and condemned the use of genome editing in IVF embryos used to established a pregnancy. China’s National Health Commission has ordered officials in Guangdong province, where He’s laboratory in Shenzhen is located, to investigate his research, but it is not clear what laws or even guidelines He might have violated in China, where regulations on genome editing and human embryo research are looser than those in many other countries, particularly the U.S.

And Southern University University of Science and Technology of China, where He has his lab but has been on leave from teaching duties since early this year, issued a statement saying it knew nothing of He’s research, which it said “seriously violated academic ethics and standards.”

An editorial in China Daily said an experiment like He’s “could be disastrous were it conducted without rigorous safety guarantees,” saying such research is “considered a no-no.” It added, “There is no knowing why He did his experiment. It would be to his shame if he did it simply to gain fame. So a thorough investigation is more than necessary and urgent.”

He graduated from the University of Science and Technology in Hefei, in the eastern province of Anhui, then did graduate work in the U.S., earning a Ph.D. in biophysics from Rice University in Texas in 2010. He worked as a postdoctoral fellow in the Stanford University lab of Stephen Quake, returning to China in 2012 to join the then-year-old Southern University in the tech-heavy southern city of Shenzhen.

Even as criticism of He continued on the sidelines of the meeting as well as in some of the formal talks, there was a sense that human embryo editing was inevitable and could be done responsibly, as several recent bioethics reports have also concluded.

Speaking a few hours before He, Dr. George Daley, dean of Harvard Medical School, called for the establishment of “standards for assessing the competence of the practitioner” of CRISPR embryo editing. “Individuals given the right [to do this] have to be expert, have to be trained,” he said. But he expressed some polite impatience: “It is time to move forward from [debates about] ethical permissibility to outline the path to clinical translation … in order to bring this technology forward.”

Referring to He’s apparently unauthorized and largely unregulated research, Daley said, “The fact that the first instance of human germline editing came forward as a misstep should not let us stick our neck in the sand. … I don’t think a single practitioner who goes against the norms of the field represents a failure of scientific self-regulation.”

Just minutes later, however, biologist Kathy Niakan described experiments that raised a big red flag about the use of CRISPR-Cas9 in embryos. She uses the technique (in donated IVF embryos, with no intent to establish pregnancies) to disable certain genes and learn what role they play in early human development.

According to unpublished data she presented, the technique causes what she delicately called “on-target complexities.” That is, CRISPR-Cas9 hit the gene it was supposed to, but in addition to making the intended edit it caused large deletions of DNA and the loss or gain of segments on the chromosome (6, in this case) that contains the targeted gene.

“This is a significant new caution” for editing the genomes of embryos, Niakan said.

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