When the Chinese scientist He Jiankui, PhD, finally appeared at the International Summit on Human Genome Editing in Hong Kong, he wasn’t greeted by thunderous applause. Instead, he was confronted by the staccato clamor of a hundred press camera shutters. History was about to be made.
Wearing an open-neck shirt and carrying a tan leather briefcase, the 34-year-old He crossed the stage looking like a commuter hurrying to catch the Star ferry. There was some token applause as He reached the podium, the audience heeding the warning of moderator Robin Lovell-Badge, PhD: show some respect and restraint, or oblige the conference organizers to stop the session.
He shook hands with Lovell-Badge, pulled out his notes from his briefcase, and turned to face the audience. Over the internet, as many as 1.8 million people were watching the livestream.
This was not the setting He, of the Southern University of Science and Technology in Shenzhen, had imagined when he dreamed of editing the genome of a human embryo. Although prescheduled to appear at the summit, He had not divulged any clinical results with the conference organizers. His team had submitted a manuscript and was intent on keeping the work confidential until it was published in a leading medical journal. To orchestrate the maximum media coverage when the time came, He had granted exclusive interviews to a reporter from the Associated Press.
Everything changed two days before the start of the Hong Kong conference, when a reporter (Antonio Regalado of MIT Technology Review) broke the news that He’s team was recruiting volunteers for a genome editing trial. (This revelation was based on documents filed in a Chinese registry.)
Ordinarily, a genome editing trial wouldn’t be news. Several such trials are already underway in the United States, Europe, and Asia for rare genetic disorders and cancers, and in the next few years, a surge of clinical trials is expected as CRISPR (clustered regularly interspaced short palindromic repeats) reinforces its status as a powerful, accessible genome editing tool, and as the technology is aggressively commercialized
by biotech companies such as Editas Medicine, CRISPR Therapeutics, and Intellia Therapeutics.
But those companies (and others) are focusing on somatic gene surgery—using CRISPR-Cas9 as well as other editing technologies (zinc finger nucleases and transcription activator-like effector nucleases)—to treat individual patients for various diseases. By contrast, He was treating the DNA of human embryos, changing the genes not just of a particular tissue in a single patient but potentially every cell in the patient and for future generations. In so doing, He ignored the scientific consensus—voiced through conferences and literally dozens of official reports over the past few years—that the world was not yet ready for germline editing.
Shortly after the MIT Technology Review bombshell, the Associated Press elected to release its story reporting that He’s embryo editing had culminated in the birth of “safe and healthy” twin girls a few weeks earlier (November 2018). He’s choice of gene target was surprising: not a fatal hereditary disease like Huntington’s but a gene that encodes the CCR5 receptor that controls HIV infection.
Man of the hour
Opening the Genome Editing conference in Hong Kong was Nobel Laureate David Baltimore, PhD, a veteran of the legendary Asilomar conference on recombinant DNA in 1975. “Although [Aldous] Huxley could not have conceived of genome engineering,” Baltimore said, alluding to the author of Brave New World and the breaking news of He’s work, “we should take to heart the warning implicit in that book.”
The following day, He presented data for 20 minutes before answering questions for a further 40 minutes, during which he confirmed an additional pregnancy. He tried to explain and defend his work but left having raised more questions than he answered.1
In broken English, He described his rationale and preclinical studies in mice and monkeys. A small percentage of humans carry a 32-basepair deletion in the CCR5 gene that deprives HIV of its cellular foothold, rendering those people immune to infection (although there is evidence that the risk of West Nile disease is increased). He had initially recruited eight couples in which the man was HIV positive.
He did not show any pictures or reveal any details about the twins, only revealing their names, Lulu and Nana, leading some observers to question whether the entire episode might be a giant hoax. But for those willing to take He’s claims at face value, their implications are staggering. The response was fast and furious: gene editing experts and commentators used phrases like “disgusting” and “abhorrent” to describe a litany of concerns, including secrecy, informed consent, medical necessity, and much more.
Perhaps it should not be a complete surprise that the first attempt to conduct germline editing in human embryos should spring from China. The country has emerged over the past two decades as a major force in the life sciences. The first published report of gene editing in human embryos in 2015 came from a Chinese group. And a recent report in the Wall Street Journal warned that China was racing ahead in the clinical gene editing arena, especially for cancer patients.2
But who is He?
According to the South China Morning Post, He was born in Hunan province in southern China to a farming family. He shone academically in school: after graduating with a degree in physics in 2006, He joined a PhD program at Rice University. He later undertook a postdoc at Stanford University in the lab of renowned biophysicist Stephen Quake, PhD, co-founder of Fluidigm and Helicos. He published a paper in Science Translational Medicine in 2012 on immunotherapy. Returning to his homeland, He joined the faculty of a private university in Shenzhen, the Southern University of Science and Technology, receiving millions of dollars’ worth of government grants. He continued developing the single-molecule sequencing technology Quake had pioneered and helped launch two companies, Direct Genomics, which provides a single-molecule sequencing platform, and Vienomics, which develops liquid biopsy tests.
But about two years ago, He set his sights on germline editing. He submitted a hospital ethics statement in March 2017 citing a National Academies of Sciences report justifying germline editing for CCR5.3 He confided in a small group of American scientists—Mark DeWitt, PhD, a scientist at the Innovative Genomics Institute, and father-and-son bioethicists William Hurlbut, MD, and Ben Hurlbut, PhD, of Stanford and Arizona State, respectively—but conducted his work in great secrecy.
In August 2017, He presented preliminary data on gene editing accuracy at a major CRISPR conference at Cold Spring Harbor Laboratory. He showed data on the improving efficiency of gene editing by detecting off-target mutations using genome sequencing in more than 300 human embryos. Earlier this year, He confided in Stanford’s Matt Porteus, MD, PhD, who berated the Chinese scientist for modifying human embryos, and now says he wishes he’d alerted other experts.4
The most intense criticisms for He centered on his choice of HIV transmission as an “unmet medical need,” the strategy for editing the CCR5 gene, the informed consent process, and the intense secrecy throughout the project.
Although HIV is a common and serious public health threat in China, many experts say there are standard procedures to prevent HIV transmission that do not necessitate embryo gene editing.
David Liu, PhD, of the Howard Hughes Medical Institute and the Broad Institute, and the co-founder of Editas Medicine, challenged He on medical necessity grounds. “You already do sperm washing to generate uninfected embryos that could give rise to uninfected babies,” Liu said. “What was the unmet medical need?” He’s justification was to stress the public health menace of HIV affecting millions of patients rather than to focus on an individual family.
He’s gene editing also produced controversial results. Rather than engineer the 32-base CCR5 gene deletion that occurs naturally, He produced different mutations in the two twins, neither of which have been studied in animal models, let alone humans. “This is what really bothers me,” commented Sean Ryder, PhD, of the University of Massachusetts Medical School. “The children are test subjects for protein variants that haven’t been vetted in animals. Any of the variants could have unintended consequences.”
Yet more questions abound over the informed consent process, including whether the parents were adequately briefed. These are summarized superbly by Ed Yong in The Atlantic, who pulled together a list of 15 damning details of the He team’s work.5
David Baltimore led the criticisms just minutes after He’s talk: “I don’t think it’s been a transparent process. We found out about it only after it happened and the children were born. I personally don’t think it was medically necessary… I think there’s been a failure of self-regulation by the scientific community because of a lack of transparency.”
CRISPR pioneer Jennifer Doudna, PhD, from UC Berkeley conducted countless television interviews following He’s appearance. In an interview with CNN, she said, “I don’t think there’s any way to defend using a brand-new and experimental technology when there are established ways of avoiding HIV transmission.”
Respected chemist and In the Pipeline blogger Derek Lowe, PhD, went even further. He summed up He’s actions in one word: “Criminal.”6
Voices from China were also outraged. Qiu Renzong, PhD, is a leading bioethicist at the Chinese Academy of Social Sciences. Qiu asked, “How could Dr. He and [his] team change the gene pool of the human species without considering the need to consult other members of the human species?”
A few eminent scientists, however, argued that concerns raised by He’s work needn’t culminate in overreaction. “Just because the first steps [in germline editing] are missteps doesn’t mean we shouldn’t step back, restart, and think about plausible and responsible pathways for clinical translation,” said George Daley, MD, PhD, dean of Harvard Medical School.
Daley’s Harvard colleague, geneticist George Church, PhD, also called for balance. Speaking to Science, Church said, “It seems like a bullying situation to me. The most serious thing I’ve heard is that he didn’t do the paperwork right… As long as these are normal healthy kids, it’s going to be fine for the field and the family.”7
The day after He’s appearance, summit attendees in Hong Kong were still trying to process what had happened. Most of the reporters had left along with He, who returned to Shenzhen to begin cooperating with Chinese authorities.
The summit’s international organizing committee, a 14-member body that includes CRISPR and gene editing experts, gathered on stage as chairman David Baltimore read a closing statement that described He’s work as “deeply disturbing” and “irresponsible,” and that called for an independent assessment “to verify this claim and to ascertain whether the claimed DNA modifications have
The statement itemized numerous flaws in He’s study, including “an inadequate medical indication, a poorly designed study protocol, a failure to meet ethical standards for protecting the welfare of research subjects, and a lack of transparency in the development, review, and conduct of the clinical procedures.”
“The scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at this time,” the statement stressed.
NIH Director Francis Collins, MD, PhD, also accused He of trampling on ethical norms, while reiterating that the NIH does not support the use of gene editing technologies in human embryos. A statement issued by the NIH and signed by Collins read as follows: “The project was largely carried out in secret, the medical necessity for inactivation of CCR5 in these infants is utterly unconvincing, the informed consent process appears highly questionable, and the possibility of damaging off-target effects has not been satisfactorily explored.”9
In an interview, FDA commissioner Scott Gottlieb, MD, piled on: “Governments will now have to react” given that “the scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line.” Gottlieb called the response from the scientific community “far too tepid,” adding that “the credibility of the community to self-police has already been damaged.”10
Germline editing carries major risks: editing in early embryos may not carry through to every cell. Moreover, on- or off-target effects could produce unanticipated effects for not just the patient but for future generations.
But the committee clung to the possibility that germline editing could become acceptable in the future. There would need to be strict independent oversight, a compelling medical need, plans for long-term patient follow-up, and attention to societal effects.
The committee also insisted that a translational pathway for germline editing should be established that would require “standards for preclinical evidence and accuracy of gene modification, assessment of competency for practitioners of clinical trials, enforceable standards of professional behavior, and strong partnerships with patients and patient advocacy groups.”
What happens next?
He returned to Shenzhen after his appearance in Hong Kong, where he was expected to cooperate with an official investigation into his research. What might He and the Chinese authorities have planned to discuss? One possibility, suggested by Baltimore, was the issue of replication.
“In science, replicability is the way that we generally prove that something that someone else has said actually is true,” Baltimore said. Clearly, that is not feasible in this case. Baltimore wants to see the data from He’s twins but acknowledges that doing so will be difficult: “We don’t know where [the twins] are. We don’t know who they are. He’s trying to keep them confidential for reasons that make a lot of sense.”
The organizing committee called for an independent investigation but did not give specifics. Baltimore said, “It’s going to depend very much on what cooperation we get from him.”
Francis Collins also called for “a binding international consensus” on setting limits for germline editing research. Failure to do so promptly could result in additional ill-considered projects and risk “justifiable public outrage, fear, and disgust.”
As it is unclear if any reputable journal will be keen to publish He’s article, one option would be to disseminate his work by posting his manuscript in a preprint repository such as bioRxiv. He said he’d previously been advised not to, but Lovell-Badge urged him to reconsider.
An informal twitter poll after the Hong Kong summit found 71% in favor of bioRxiv posting a preprint on He’s work. Molecular geneticist Stephen Ekker, PhD, of the Mayo Clinic disagreed. “Sorry, preprint enthusiasts, but there needs to be an ethics check first. Stop giving [He] a megaphone, or others will do the same.”
He’s actions have cast a shadow over the gene editing field. But there was a glimmer of good news following the Hong Kong summit: Editas Medicine received an IND (Investigational New Drug) award from the FDA to launch a somatic gene therapy trial in a rare form of hereditary blindness. The CRISPR biotech industry hopes that the germline saga will not derail the promising therapies that are on the brink of entering the clinic.
The next International Summit on Human Genome Editing will be held in London, probably in 2021. Organizers will surely be hoping by then that the field has recovered from the Shenzhen shockwaves.
1. Scientist who claims to have made gene-edited babies speaks in Hong Kong. November 27, 2018.
2. Rana P et al. China, Unhampered by Rules, Races Ahead in Gene-Editing Trials. Wall Street Journal. January 21, 2018.
3. Regalado A. Rogue Chinese CRISPR scientist cited US report as his green light. MIT Technology Review. November 27, 2018.
4. Lash, A. “JK Told Me He Was Planning This”: A CRISPR Baby Q&A with Matt Porteus. Xconomy National. December 4, 2018.
5. Yong E. The CRISPR Baby Scandal Gets Worse by the Day. The Atlantic. December 3, 2018.
6. Lowe D. After Such Knowledge. In the Pipeline (a Science blog). November 28, 2018.
7. Cohen J. ‘I feel an obligation to be balanced.’ Noted biologist comes to defense of gene editing babies. Science. November 28, 2018.
8. Statement by the Organizing Committee of the Second International Summit on Human Genome Editing. November 29, 2018.
9. Collins FS. Statement on Claim of First Gene-Edited Babies by Chinese Researcher. November 28, 2018.
10. Usdin S. ‘Tepid’ Response to CRISPR Embryo Editing Could Lead to Regulations, Gottlieb Says. Biocentury. November 28, 2018.