Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

CHAPTER 17 A MACULATE CONCEPTION

On November 27, 2018, I walked from my hotel to the University of Hong Kong (HKU) campus for the opening of the Second International Summit on Human Genome Ethics. Campus is a bit of misnomer, as the university is squeezed into the precious real estate of Hong Kong Island. Entering the university, I hurried past the Pillar of Shame, an arresting statue that commemorates the Tiananmen Square protests.

As I entered the impressive Lee Shau Kee Lecture Centre, I spied the jovial face of Lap-Chee Tsui, the vice chancellor of the university and one of the summit organizers. Thirty years earlier, working at Toronto’s Hospital for Sick Children, Tsui led the discovery of the cystic fibrosis (CF) gene, teaming up with Francis Collins. It was a tour de force of genetic detective work, a lifeline for CF patients, and a magical moment for Tsui, who is originally from Taiwan. As a graduate student in Bob Williamson’s rival team in London hunting the CF gene, I’d enjoyed sharing a few beers with Tsui at various conferences. If anyone was going to scoop us, we thought, let it be him.

Tsui asked me what I thought of the magnificent venue as the audience began drifting in. He couldn’t resist telling me that he’d ordered the relocation of a reservoir serving more than 100,000 people in order to create space for this jewel of HKU’s centennial campus. Tsui’s success in literally the parting of the waters was impressive. But as Acts of God go, it was completely overshadowed by the revelations that were scheduled to take place on the stage in front of us.

The decision to hold the summit in Hong Kong was a compromise after the Chinese Academy of Sciences (CAS), the original hosts, pulled out. Feng Zhang suspected that the switch in venues signaled that the Chinese government probably knew about the CRISPR babies. “For some reason, [CAS] couldn’t find an auditorium to fit five hundred people in Beijing,” Zhang said sarcastically.¹ However, this particular conspiracy theory doesn’t hold water: Tsui had received an official invitation to host the summit in December 2017, following months of exploratory talks, well before the fateful pregnancy.²

Taking my seat in the section roped off for the media near the back of the hall, the only question on my mind was whether JK was going to show up. By now, everyone had heard the news of the CRISPR babies, foreshadowing a dark new chapter in the annals of medicine. But Doudna, Tsui, and the other conference organizers had two urgent concerns: Was JK telling the truth in those extraordinary YouTube videos or was this an implausibly elaborate hoax? And was he still going to appear to talk about the experiments leading to the twin births?

To answer those questions, Doudna, Alta Charo, Robin Lovell-Badge, and University of Sydney developmental biologist Patrick Tam arranged to meet JK for dinner on the eve of the conference at Le Méridien Cyberport hotel, where most of the speakers were staying. “He arrived almost defiant,” Doudna recalled.³ For the next hour or so, Doudna and colleagues peppered JK with questions: Why had he chosen HIV? How were the families recruited? What was the informed consent process? Why was there no public disclosure of any preclinical data? JK tried to answer and gave a preview of his presentation, dropping the news that a second woman was also newly pregnant with a gene-edited baby.

Around the table, JK’s inquisitors were dismayed by his offhand demeanor—what Doudna described as a combination of hubris and naïveté⁴—his stubborn self-belief and refusal to concede any mistakes or ethical lapses. “I got the strong impression that he saw Robert Edwards as a kind of hero, a paradigm breaker, a disrupter, and that he wanted to model himself after that,” Charo said.⁵ But JK’s dreams of emulating Edwards were fading fast. “JK was hoping to make a big splash with the news of the twin birth,” Tam told me.⁶ He asked whether he should present the results when he gave his scheduled talk on Wednesday morning? “We were all like, ‘uh, yes’,” said Doudna. Eventually JK’s patience during the dinner interrogation wore thin. He left some cash on the table and walked out of the restaurant before checking out of the hotel.

As I observed the ceremonial photographs and formal opening speeches by, among others, Carrie Lam, the chief executive of Hong Kong, I was confused. There was no acknowledgement of the elephant in the room: no mention of He Jiankui or the scandal that had broken. The only reference to the swirling drama was an oblique comment from organizing committee chairman David Baltimore, who said that gene-editing tools would be used in the clinic in the future. “We may even hear about an attempt to apply human genome editing to human embryos,” he said coyly. Then, as if on cue, he brought up Brave New World: “Although Huxley could not have conceived of genome engineering… we should take to heart the warning implicit in that book.”

Later that morning, we heard the first direct rebuke from the podium of JK’s actions. It came surprisingly from a fellow countryman: Qiu Renzong, the eighty-five-year-old senior statesman of China’s bioethics community and a member of the Chinese Academy of Social Sciences in Beijing. Qiu wasted no time in condemning his countryman. “There is a convenient and practical method to prevent HIV infection,” he said. To resort to germline editing was like “shooting a bird with a cannon.” Qiu accused JK of violating China’s Ministry of Health regulations on assisted reproduction and questioned whether he had obtained the correct IRB approval. His final salvo sent shivers down my spine:

“How could Dr. He and [his] team change the gene pool of the human species without considering the need to consult other parts of the human species?”⁷

It was a mild surprise then when George Daley, the Dean of Harvard Medical School, offered a more measured, even conciliatory, perspective. “Just because the first steps [in germline editing] are missteps doesn’t mean we shouldn’t step back, restart, and think about a plausible and responsible pathway for clinical translation,” Daley said. Also speaking that day were Feng Zhang and Doudna. Zhang was mobbed outside the hall by a scrum of reporters after his talk, a smaller huddle around Doudna. But for once, neither of the CRISPR pioneers were the star attraction. The main event was still to come.

Twenty-four hours later, the atmosphere in the packed auditorium was electric. Almost three hundred journalists, photographers, and film crews had by this time descended on Hong Kong to capture science history. The photographers and camera crews were herded into a media pen extending along one entire wall of the auditorium—far more than I remember attending the reasonably historic announcement of the Human Genome Project in June 2000. The organizers shuffled the program to devote sixty minutes exclusively to JK before lunch. Shortly before JK was scheduled to appear, I skipped down the aisle steps past the banks of photographers to the microphone in front of the stage to ask a question. It was just a ruse so I could slip into one of the few empty seats in the front row, where I sat next to Hong Kong’s most famous geneticist, Dennis Lo. I briefly wondered if security might come and have a word, but they had more pressing concerns.

As Robin Lovell-Badge from the Crick Institute prepared to introduce JK, I noticed the security guards stationed at both ends of the stage, a surreal indicator of the extraordinary event about to unfold. As a rookie editor at Nature, I had published Lovell-Badge’s career-making discovery—the identity of the male sex-determining gene on the Y chromosome—in 1991. Sounding like the headmaster of an English boarding school, Lovell-Badge warned the audience to be polite and even show JK some respect. HKU has a strong tradition of free speech, he said. Any outbursts from the audience would result in the session being cut short. As Lovell-Badge invited JK to come to the stage, there was an awkward pause that lasted thirty seconds as if, even at the last minute, JK had changed his mind.

When a side door opened, hundreds of people craned their necks to get a first glimpse of the man of the hour. As JK climbed the stairs stage right, there was a hush in the hall and almost no applause—just the clatter of high-speed camera shutters and the stroboscopic flashes from the legions of photographers camped on the opposite side of the hall. JK walked briskly across the stage, dressed casually in an open-neck shirt, carrying a tan leather briefcase. He looked more like a commuter hurrying to catch the Star Ferry in the Hong Kong humidity than a scientist at the center of a massive international storm. At the podium, he shook Lovell-Badge’s hand, and took in the scene. He’d imagined giving a lecture to a worldwide audience in front of Nobel laureates and scores of cameras, but not like this.

JK pulled his speech from his briefcase and for the next twenty minutes, delivered what was, on the surface, a fairly typical scientific lecture, accompanied by slides showing experimental data. The contents were anything but ordinary. He began with an apology—not for the manner in which he had conducted the study or obtained ethical approval or treated his patients, but that the story had become public. “First, I must apologize that this result leaked unexpectedly,” JK said. It was an acknowledgement that the carefully orchestrated plans to trumpet his success with a major science publication had collapsed. He also thanked his university, which he said was unaware of his gene-editing studies. He didn’t get much further before an irritated Lovell-Badge stood up and remonstrated with the photographers. The persistent clatter of camera shutters, coupled with the poor sound near the front of the stage, was making it difficult to hear. “Stop photographing!” Lovell-Badge ordered. “You must have a good photo by now!” The cameras went quiet.

After presenting results of preliminary gene-editing studies in mice and monkeys, JK went onto summarize his clinical work. The choice of gene target—CCR5—was perplexing. His goal had been to mimic the natural Δ32 deletion in CCR5 that renders many people immune to HIV infection. Without fanfare, JK presented the genetic sequences of Lulu and Nana that had been engineered at conception by human hand. The peaks and valleys of Lulu and Nana’s edited DNA sequence traces, like a multicolored polygraph, laid bare in graphic molecular detail the slipshod way the twins’ CCR5 genes had been modified. He did not show any photographs or reveal any further details about the twins or their health.

Had JK faithfully engineered the precise Δ32 deletion commonly seen in the human population, the public response might have been different, at least in some quarters. But while he had targeted the right spot in the CCR5 gene, he had no control over the edits, which consequently produced novel sequence variants with uncertain effects. Instead of precisely excising the 32 letters of genetic code, it was as if the editor had shut his eyes and slashed at the page with a red pen, hoping to erase the right words.

Following his prepared remarks, JK sat on stage between Lovell-Badge and Matthew Porteus to answer questions for a further forty minutes. He appeared slightly nervous but stoic and unapologetic. The biggest revelation was when JK confirmed there was an additional early (“chemical”) pregnancy. Baltimore led the criticisms. “I don’t think it’s been a transparent process,” Baltimore said. “We only found out about it after it’s happened and the children are 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.”

The first question from the audience was posed by Harvard’s David Liu, respectful but visibly angry. “What was the unmet medical need?” Liu wanted to know. JK’s protocol already included a sperm washing step that would essentially guarantee uninfected embryos. JK ducked the question, justifying his choice by stressing the public health menace of HIV affecting millions of patients in China. Indeed, many of his responses suggested that he still did not fathom the gravity of what he had done. For the final question, Lovell-Badge asked if JK would have performed the experiment on his own child? “If my baby might have the same situation, I would try it on them first,” JK replied. It was a calculated answer. I wasn’t sure I bought it, and nor did JK’s acquaintance, Chengzu Long. “He doesn’t give a shit about HIV. How dare he say that!”

A few moments later, to a smattering of applause, the Chinese scientist shook hands with his interrogators and exited through the same door he had entered sixty minutes earlier, evading any questions from the press. He was soon traveling back across the border to Shenzhen, where he would face an official university investigation while under house arrest. I wondered if we would ever see or hear from him again. In Hong Kong and around the world, the objurgation was just beginning.

The reaction to JK’s appearance was furious, as if a mass atrocity had occurred. “Disgusting” and “abhorrent” were some of the milder terms used to describe a laundry list of ethical and technical concerns—excessive secrecy, minimal informed consent, negligible medical necessity, amateurish molecular editing, and suggestions of fraud. And yet, the initial Chinese reaction had been positive, even euphoric. On November 26, the People’s Daily, the official mouthpiece of the Chinese Communist Party, had hailed JK’s breakthrough as a moment of national pride: “A milestone accomplishment achieved by China in the area of gene-editing technologies.”⁸ But the story was swiftly deleted as the condemnation reached a crescendo. It was replaced with a story indicating that an official investigation into JK’s actions was underway.⁹ Exhibit A in the global uproar, perhaps surprisingly, was an open letter signed by 120 Chinese scientists, which said: “This is a huge blow to the global reputation and development of Chinese science, especially in the field of biomedical research. It is extremely unfair to most scholars in China who are diligent in research and innovation and adhere to the bottom line of scientists.”¹⁰

Inside and outside the HKU auditorium, reporters and camera crews rushed to interview scientists for their reactions. Lovell-Badge was mobbed by a scrum of reporters and camera crews outside the auditorium. Not surprisingly, Doudna was in constant demand, giving a string of interviews in the harsh glare of the television lights, acting as the conscience of the scientific community. Unaccustomed to criticizing a fellow scientist, let alone on camera, she told Bloomberg she was “a bit horrified, honestly. And disgusted, really disappointed, that the international guidelines that many people worked so hard to establish were ignored.” JK wanted to be the first to achieve an historic milestone but “that’s an inappropriate reason to do something as momentous as this without appropriate oversight.”¹¹

Charpentier was not in Hong Kong but sent me a brief statement. “We are still at a very early stage of understanding the full implications of gene editing in human cells, and it would be irresponsible to apply the technology in the human germline,” she said, while insisting that basic research on human embryos was still justified.¹² But one thing was clear. JK had left an indelible mark on science in the 21st century. As Urnov told Al Jazeera: “We live in an age where there is such a thing called Microsoft Word for human DNA. That cat is out of the bag, the genie is out of the bottle.”¹³

Criticism rained down from all quarters. David Liu called the saga “an appalling example of what not to do with a new technology that has incredible potential to benefit society.” Feng Zhang called for a moratorium on clinical embryo editing “until we have come up with a thoughtful set of safety requirements.”¹⁴ Kathy Niakan, the only researcher in Europe to have conducted genome editing on human embryos, said “it is impossible to overstate how irresponsible, unethical, and dangerous this is at the moment.” She added, “There is a real danger that the actions of one rogue scientist could undermine public trust in science and set back responsible research.”¹⁵

NIH Director Francis Collins accused JK of trampling on ethical norms, while reiterating that NIH did not support the use of gene-editing technologies in human embryos. “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,” he charged.¹⁶ A letter to the Lancet signed by senior members of the Chinese Academy of Medical Sciences argued that JK had violated multiple government regulations on the ethics of human stem cell and sperm banks dating back to 2003.¹⁷

On social media and the blogosphere, reaction was even more intense. UCLA stem cell biologist Paul Knoepfler decried the use of the term “genome editing” to describe JK’s work. “He did not gene edit these babies… what He did really was to mutate those twin girls, particularly since he was changing a normal wild type gene to a mutant form. We should call it what it is.”¹⁸ British broadcaster and author Adam Rutherford called JK’s actions “morally poisonous.” Oxford University philosopher Julian Savulescu said the CRISPR babies were being used as “genetic guinea pigs. This is genetic Russian roulette.”¹⁹ You get the picture.

The former FDA Commissioner Scott Gottlieb warned of future government intervention. “The scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line.” And veteran chemistry blogger Derek Lowe called JK’s actions criminal. “This experiment should not have been done yet,” Lowe wrote. “We’re going to alter the human genome, of that I have no doubt. But there was no reason to alter it now, like this, under these conditions. He Jiankui has just made life more complicated for everyone working in the field, and for what?”²⁰

A few hours before JK’s public appearance, I received an email from Ryan Ferrell suggesting we meet after JK’s talk at a hotel on the south side of Hong Kong Island. Following JK’s exit, I suspected the afternoon sessions would be an enormous anticlimax, so told Ferrell I’d meet him that afternoon. It was a thirty-minute taxi to Ferrell’s hotel, which puzzled me when there were so many hotels near the university. I entered his small hotel room to find, sitting on the bed, the documentary team, Samira Kiani and Cody Sheehy, who had filmed JK’s speech and interview a few hours earlier. Cases of video equipment took up most of the floor space, so I sat on one. Ferrell apologized for the remote location but he was literally on the run. His visit to Hong Kong had turned into a scene from The Bourne Identity, as enterprising Japanese journalists had twice located Ferrell’s hotel and forced him to take evasive measures.

Ferrell was clearly exhausted and emotional, at times distraught. He blamed himself for the situation that JK found himself in. Ferrell had moved to Shenzhen on a mission. Part of his motivation was his sister, who suffers from a genetic disorder. Ferrell had wanted to help showcase the groundbreaking medical work of gene-editing trailblazers like JK. It was Ferrell who agreed to let Regalado sit in on JK’s meeting with the filmmakers a few weeks earlier. And he blamed himself for not being alert to the posting of JK’s CCR5 trial notice on the Chinese clinical trial registry website, which turned out to be Regalado’s smoking gun.

After an hour or so talking, we went to the hotel bar for a much-needed drink. Ferrell motioned to the Nature manuscript in his briefcase. Forty-eight hours earlier, he’d been confident that JK’s report would soon be published. But JK’s inability to provide any compelling rationale for his actions suggested that was unlikely. One option was for JK to post his manuscript on a preprint repository such as bioRxiv^I, a popular venue for scientists to post drafts of their manuscripts. But given the growing scandal, bioRxiv’s administrators were understandably reluctant about showcasing such a controversial article, especially given the ethical issues. Those concerns were summed up by the Mayo Clinic’s Stephen Ekker: “Sorry preprint enthusiasts,” Ekker tweeted, “but there needs to be an ethics check first. Stop giving [He] a megaphone, or others will do the same.”²¹

I disagreed. I didn’t see any point in sweeping JK’s actions under the carpet. It was far too late for that.

The morning after.

Day three of the summit felt like a heavy hangover after a raucous all-night party. The auditorium was less than half full and most of the media had dispersed in the wake of JK himself. One Asia-based reporter for ABC News stopped me to ask if I’d seen Michael Deem. She looked upset when I told her Deem hadn’t attended the conference and continued her search.

The one major item on the agenda was for the summit’s organizing committee, including Doudna, Porteus, Daley, and Lovell-Badge, to deliver a closing statement when almost everything that could be said had been already. With the full committee seated on stage, Baltimore read the statement, which had been hastily drafted the previous evening.²² The committee judged JK’s work to be “deeply disturbing” and “irresponsible,” while calling for an independent assessment “to verify this claim and to ascertain whether the claimed DNA modifications have occurred.” The glaring flaws in JK’s study included “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.”

Given the current state of the technology, Baltimore said the risks were “too great to permit clinical trials of germline editing at this time.” But not forever: germline editing could become acceptable in the future if there was strict independent oversight, a compelling medical need, long-term patient follow-up, and attention to societal effects. And echoing Daley’s earlier remarks, there should be a translational pathway setting standards for preclinical evidence and editing accuracy, the proficiency of the investigator, and robust partnerships with patients and advocacy groups.

But the committee’s call for an independent investigation rang hollow. Who would do the investigating? The committee lacked any jurisdiction to entice any cooperation from JK. When I asked Baltimore what actions he hoped to see from JK, he stressed the importance of examining the CRISPR babies, but that would be difficult given the absence of any public information about the twins’ identities and whereabouts.

We soon learned that JK was in no position to cooperate with any sort of external inquiry. In the weeks following his return to Shenzhen, although in email contact through his gmail account with reporters²³ and journal editors, his precise whereabouts were unknown. Several media outlets reported that JK had disappeared, based on his hasty departure from Hong Kong and the unceremonious removal of his university web page, where he had invited people to write to the world’s first gene-edited twins at a special email account: DearLuluandNana@gmail.com.

Speculation about JK’s whereabouts was understandable, although suggestions he had been executed seemed fanciful. In 2018, several prominent figures in Chinese society had “disappeared,” sometimes for months on end, including Meng Hongwei, the former president of Interpol. One of China’s most famous actresses, Fan Bingbing, vanished for nine months before returning to public view in April 2019, offering a groveling apology for tax evasion.

Four weeks after his Hong Kong bombshell, New York Times reporter Elsie Chen went searching for JK on the SUSTech campus. Acting on a hunch, she visited the main guest house, typically used to house faculty and visitors. That’s where she fortuitously spotted JK on the balcony of a fourth-floor apartment and was able to grab a couple of photographs.²⁴ He was guarded by a dozen unidentified men who barred reporters from getting too close. Inside the apartment was a woman, presumably his wife, and a young baby. The lobby was full of guests checking in for a conference, oblivious to the fact that China’s Most Wanted was under house arrest in their midst.

Around this time, JK told Lombardi he was being sequestered in academic housing for his own protection. Lombardi offered some final advice: stop looking for commercial funding, at least until you can present two healthy babies: “Put your head down and do your best, most ethical science for the next five years. And when you think you can put your head up again, keep it down another year.”²⁵

On January 21, 2019, the world learned JK’s fate. As reported by Xinhua, the Guangdong state news agency, the provincial investigation into JK’s actions concluded that, beginning in June 2016, JK had conducted prohibited reproductive experiments in secret while seeking “personal fame and fortune.” His behavior “seriously violates ethics and scientific research integrity, and seriously violates relevant state regulations, causing adverse effects at home and abroad,” the report stated. The head of the investigation said that JK, his colleagues, and relevant institutions would be “dealt with seriously according to the law.” SUSTech immediately jettisoned JK. The university posted a terse statement on its website: “Effective immediately, SUSTech will rescind the work contract with Dr. Jiankui He and terminate any of his teaching and research activities.”²⁶

I briefly wondered if JK could continue his work in industry. But six months later, in July 2019, Direct Genomics announced that JK had resigned and sold his stake in the company.²⁷ Another theory I heard from a member of the “circle of trust” was that JK’s disappearance might be part of a Faustian bargain: don’t incriminate any Chinese government officials in exchange for professional rehabilitation when the time is right.

Several months later at the World Science Festival in New York City, on a panel with Doudna, William Hurlbut indulged in some speculation about what might have happened had Regalado not sensationally revealed JK’s activities. What if JK had been able to publish and orchestrate coverage of his work as planned? JK expected some criticism from Europe and the United States, but not in his own country. If JK had not felt the wrath of scientific society, “the outcome might have been different.”²⁸ If the results had been published the way JK dreamed, accompanied by a syndicated AP exclusive, Hurlbut ruminated, “I think JK would not have been in so much trouble. And in China, maybe not any.”

Hurlbut offered a glimpse into JK’s emotions and contrition. In an email sent to Hurlbut shortly after his confinement in Shenzhen, JK belatedly showed some remorse for his actions rather than just the manner in which they had been made public. He felt badly and wished he had waited, acted more carefully, and selected a different gene target. But this hardly qualified as a public apology. More important is whether he will apologize to the twins, Lulu and Nana, and a third edited baby, believed to have been born around May 2019. We may never know.

Three months after losing his university job, and disappearing from public view, JK was named one of Time magazine’s 100 Most Influential People of the Year. It is a rare honor, although “influential” doesn’t necessarily mean laudable. The winners’ biographical sketches are usually written by previous honorees. JK’s entry was penned by none other than Doudna, who had received the honor in 2015. It was not pretty:

He Jiankui showed the world how human embryo editing is relatively easy to do but incredibly difficult to do well. Going against the consensus in the scientific community that CRISPR-Cas9 technology is still too experimental and dangerous to use in human embryos, he applied it to forever change the genomes of twin girls to give them immunity to HIV. His reckless experimentation on the girls in China not only shattered scientific, medical, and ethical norms, it was also medically unnecessary… He’s fateful decision to ignore the basic medical mantra of “do no harm” and risk the unintended consequences will likely be remembered as one of the most shocking misapplications of any scientific tool in our history.²⁹

Many of the Time 100 attended a black-tie gala at Lincoln Center in New York. What JK wouldn’t have given to walk on the red carpet with the Game of Thrones actress Emilia Clarke, or pose for photographs with Liverpool soccer legend Mohamed Salah, or dance to Taylor Swift, even discuss CRISPR with Rampage star Dwayne Johnson. It was not to be. There were no more celebrity selfies on WeChat. On that star-studded evening, the only JK in attendance was Jared Kushner.

I. BioRxiv is a preprint repository for biologists where they can post drafts of their manuscripts prior to peer review and publication in a journal. The site, launched by Cold Spring Harbor Laboratory in 2012, is modeled on arXiv, the popular physics preprint server. Posting a preprint allows authors to receive a timestamp of submission, solicit advice from other scientists, and disseminate results many months ahead of official journal publication. bioRxiv volunteers apply a quick screen before posting a preprint, checking for obscenity, nonsense, and any ethical red flags. The repository and its sister site, medRxiv, have come into their own during the COVID-19 pandemic, posting thousands of early results.