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

CHAPTER 14 #CRISPRBABIES

In April 2018, more than 15,000 scientists and physicians arrived in Chicago for the American Association of Cancer Research annual convention. In a hotel lobby, Marilynn Marchione, the chief medical correspondent for the Associated Press (AP), met an acquaintance, Ryan Ferrell. The year prior, Ferrell, working for a public relations company that represented Sangamo, had arranged for Marchione to have exclusive access to the launch of the first in vivo gene editing clinical trial in the United States.¹ Marchione’s story shadowed Brian Madeux, an Arizona man with Hunter syndrome, who became the first patient to receive the groundbreaking therapy.

Ferrell’s intention was obviously to orchestrate some headline news for Sangamo. But it was also a contingency plan: to build a relationship with a trusted medical reporter, making sure she knew the lead investigators in the event that there should be a serious adverse event in the trial. In Chicago, Ferrell asked Marchione if she was interested in working on another exclusive gene-editing story, this time nothing to do with Sangamo. This was a big one, he said, although he kept some cards close to his chest. In particular, he didn’t mention his dinner two months earlier with a Chinese scientist he’d worked with before, named He Jiankui, who was moving into clinical genome editing. Nor did he mention a bombshell email he’d just received from the same scientist, whom he called JK.^I That email revealed that JK had done something no-one else had dare attempt. And now a woman was pregnant, carrying a genetically edited fetus.

Ferrell had received an offer to shape the public revelation of a medical milestone that would put the Sangamo story in the shade: the first genome editing of a human embryo resulting in a pregnancy and twin births. Ferrell was already contemplating leaving his Chicago-based PR agency. In July, he handed in his notice and a few weeks later, flew to Shenzhen, having accepted a short-term contract from JK to advise his group.^II

Ferrell knew he could trust Marchione to tell the story of the CRISPR babies accurately and responsibly, even in the midst of what was sure to be an international media frenzy. In the second week of October, after a major Chinese national holiday, four China-based AP reporters visited JK’s lab at the Southern University of Science and Technology (SUSTech) in Shenzhen. While they interviewed JK, the photographer captured one of JK’s colleagues, embryologist Qin Jinzhou, injecting a human embryo with a CRISPR construct targeting a gene called PCSK9. JK told the reporters about the successful pregnancy, although the babies had not yet been born. On camera, he said defiantly: “The world has moved onto the stage for embryo genetic editing. There will be someone, somewhere who is doing this. If it’s not me, it will be someone else.”²

Marchione began drafting her exclusive story, keeping everything confidential, the timing of its release still to be determined. For her, the most profound aspect of JK’s experiment was “the enormity of the leap for humankind.” For the first time, a scientist had dared to rewrite the recipe of life, changing the script for this and future generations.³ Even after she got word of the twins’ birth, Marchione still needed confirmation of the births and evidence that JK had actually done what he was claiming. Although unlikely, scientists have been known to commit fraud. What if this was just one giant outrageous hoax?

JK planned to submit his research article detailing the editing and birth of the world’s first genetically edited babies to Nature. The first page of his manuscript listed ten coauthors, including JK’s American PhD mentor, Michael Deem, a professor at Rice University in Houston, Texas. JK was hoping that Nature would act with “Shenzhen speed” and rapidly review and publish the article. Shortly before the Hong Kong genome ethics summit in late November 2018, Ferrell sent Marchione a copy of JK’s draft manuscript. Lulu and Nana were test tube babies, conceived in a dish, their genetic makeup customized by a human hand using a fledgling gene-editing technology built around a billion-year-old bacterial enzyme. If true, she was holding literally the scoop of the century.

Marchione had no way of independently confirming the twin births—the identities of the children and their family, as well as their location, were a fiercely kept secret. But she had in mind to verify the results JK described in the manuscript. Both Marchione and her editors at AP insisted on doing things by the book. “We planned to publish only when—and if—we were satisfied that there was reasonable evidence that [JK’s] claim was legitimate, or if he made it public in some fashion,” she told me.⁴ With JK scheduled to speak at the summit, he would never have a better chance of commanding the world’s attention. How could JK resist the opportunity to pull the equivalent of a Steve Jobs mic drop: “And one more thing…”

Marchione sent extracts of the manuscript in confidence to a trio of medical and scientific experts—George Church, University of Pennsylvania cardiologist Kiran Musunuru, and Scripps Institute cardiologist Eric Topol. Musunuru said his heart sank as he opened the file. He called it “a soul-destroying moment.”⁵ This wasn’t a hoax. If anything, it was worse.

In the end, Marchione’s hand was forced. Shortly after touching down in Hong Kong, she got wind of a breaking story in MIT Technology Review. The reporter didn’t know about the births, but he knew that JK was on the verge of making history by overseeing a pregnancy using gene-edited embryos. By the time I arrived in Hong Kong on the eve of the summit, the world had changed. I spent the taxi ride to my hotel trying to keep calm as I saw a trending hashtag—#CRISPRbabies.

Antonio Regalado, a tenacious science reporter at MIT Technology Review, is tall and lean, with hollow cheeks and eyes befitting a journalist not averse to pulling an all-nighter in service of a scoop. With a physics degree from Yale, a degree from the New York University School of Journalism, and nine years at the Wall Street Journal, he has impeccable credentials. But he admits to drawing much of his inspiration from the supermarket tabloids. “This is my sensibility,” he says. “Are my stories worthy of Tech Review and Weekly World News?” Ideally, he wants his readers to come away from a story unsure if what they’ve just read is true. “But it is true! That’s the sweet spot for me.”⁶ Stanford’s Hank Greely quips: “He wants to be Woodward and Bernstein combined.”⁷

In pursuing a massive story such as editing human embryos, Regalado followed the advice Walter Gretzky once gave his precociously talented son, Wayne: “Skate to where the puck is going to be.” With eight of the first ten published reports of genome editing on human embryos emanating from labs in China, a country that seemingly lacked the legal restrictions or oversight of many countries in the West,⁸ Regalado was in no doubt where the first attempts to produce a gene-edited baby were going to take place. The opportunity to investigate his hunch came in October 2018, one month before the Hong Kong conference.

Regalado got the chance to tour China with a pair of documentary filmmakers, director Cody Sheehy and Samira Kiani, an Iranian expat physician-scientist at the University of Pittsburgh. Along with George Church and biohacker Josiah Zayner, Regalado was going to be a central character in their documentary, The Human Game.⁹ Providing ground support was Sheehy’s brother-in-law, Nicholas Shadid, a China-based consultant who spoke Mandarin. Shadid had scheduled interviews with scientists in Shanghai and Guangzhou, a city of 13 million people in southern China, including a visit to Sun Yat-sen University to interview one Huang Junjiu.¹⁰

In 2015, Huang published the first attempt to perform CRISPR genome editing on human embryos. He was motivated by the public health threat of thalassemia in his home city. His experiments were little more than a proof of principle: they had been conducted on malformed embryos rejected by an IVF clinic—“tripronuclear zygotes” in the trade—with no intention of implantation. The results were underwhelming. For all the supposed ease of use of CRISPR, Huang’s team reported only partial success in editing the target beta globin gene. Making matters worse, there was also evidence of random off-target edits in the genome.

Nevertheless, this was a world first so Huang could be forgiven for trying his luck by submitting his group’s report to Nature and Science. Both journals rejected the manuscript in quick succession. With rumors of the Chinese study spreading, Nature published an op-ed written by Ed Lanphier, CEO of Sangamo, and colleagues titled “Don’t Edit the Human Germline.” Lanphier, Fyodor Urnov, and colleagues called for a ban on editing human embryos, partly for moral and ethical reasons but also because of the negative impact it could have on the future of somatic gene editing.¹¹ Huang eventually published his report in a China-focused journal called Protein & Cell.¹² It is unclear how rigorous the peer review process was: the time from manuscript submission to acceptance was just forty-eight hours.

Huang had kept a low profile since his fifteen minutes of fame in 2015, so his willingness to be interviewed was a minor coup for Regalado. As the filmmakers settled into their Guangzhou Airbnb, Kiani received a surprise email from Ferrell. Earlier in the year, Kiani had asked Ferrell for access to film one of Sangamo’s gene therapy patients. In his email, Ferrell began by apologizing for not being able to help her film project, but all was not lost. He continued:

I’ve taken a post in a Chinese lab working on the safety of CRISPR gene editing at the time of embryo fertilization. My goal is to push the lab to engage the world more directly in science and ethics given the controversial nature of the work and the potential to disrupt others working on somatic therapies. Would you be open to reconnecting…?¹³

Kiani couldn’t believe her luck. Ferrell’s new Chinese lab was in Shenzhen, just a sixty-minute train ride from Guangzhou. “We are in China! Why don’t we meet?” she replied. Ferrell agreed to get together the next day, adding that he would be traveling with a Chinese colleague. Regalado did what any enterprising reporter would do: he googled the name of Ferrell’s companion, who had been copied on the email.

It was He Jiankui.

The meeting took place in the afternoon at the Westin Hotel, a short walk from the major train station in Guangzhou. Shadid led the group to a dimly lit corner of the lobby, telling the hotel staff that they were guests awaiting a very important Chinese scholar. Ferrell allowed Regalado to join, providing their conversation was off the record.

JK was initially reserved, wary of the intense American journalist scribbling notes. His English was passable, having spent four years in the United States. After a while, Regalado asked Shadid to switch to Mandarin. Shadid asked if JK was interested in taking part in the film, opening up his life “to show the world that he is a person first and a scientist second, with dreams and a moral point of view.” Shadid wanted to show a leading Chinese scientist as being similar to his Western counterpart, rather than the stereotypical boogeyman, “the personality-free Chinese lab rat with no individuality or moral agency.”

JK and Ferrell insisted they did not want to be portrayed as “evil scientists doing something immoral.” They wanted to change the perception of how China’s work in gene editing is perceived in the West and give it legitimacy. Kiani and Shadid suggested a return visit in the New Year, when they could film JK with his family. He seemed to like this idea. “He had a crazy twinkle in his eye,” Regalado recalled. He talked about a public opinion survey his team had conducted showing the Chinese public was largely in favor of gene editing. Ferrell then handed Kiani a sheet of paper. It was a list of five ethical principles that JK felt should shape the future of genome editing in human embryos. They hoped the guidelines would be published just before the Hong Kong summit. They were:

Empathy for patients—for some families, early gene surgery may be the only way to cure disease.

Only for serious disease, never for vanity.

No one can control a child’s life. A gene-edited child retains the same rights as a “normal” child.

Genes do not define us. DNA does not predispose us.

Everyone deserves freedom from genetic disease, regardless of wealth.

As the discussion turned to possible examples, JK said that editing the CCR5 gene to in effect immunize babies from getting HIV would fit his ethical criteria. HIV was a huge public health problem in China, particularly in western China. He opened some slides on his laptop, which showed preclinical gene-editing experiments on a few hundred human embryos. It was debatable, however, whether targeting CCR5 was tantamount to curing or merely preventing a disease. Privately, Regalado thought it was an extremely weak choice.

While JK believed editing this gene offered an important health benefit, the primary objective had to be safety. JK’s expertise was in genome sequencing, which lent him some credibility in screening for errant edits. The other nagging issue was mosaicism, a phenomenon that occurs when not every cell in the developing embryo carries a particular gene variant or edit. JK acknowledged the concern but he didn’t think it was a showstopper. He was more irked by one of Regalado’s magazine stories, which featured a full-page illustration of a baby reduced to a series of billiard balls or atoms. JK said the image, which looked like the baby was being blown apart, was disgusting.

“Is this being tested in humans?” Kiani asked him. “We have no human trials,” JK replied, while hinting that his plans would depend on the kind of response he received at the summit in a few weeks’ time. But later, JK conceded there was a gene-edited monkey fetus in a womb somewhere. So how close was he to producing a human baby? “Almost there,” he said. Regalado shivered. Almost there…

After JK and Ferrell left the hotel to return to Shenzhen, Sheehy turned on his camera while his friends exhaled and debriefed. “What just happened?” Kiani asked, her head spinning. “I think we just found out about this secret embryo editing project that we were looking for,” Regalado said incredulously. “It was a hell of a meeting.” Here, halfway around the world, he had stumbled upon the “promised land,” meeting the ambitious young scientist running one of the largest human embryo editing programs in China. Moreover, he had signaled his intentions to move from monkeys to humans. But when?

The Huang embryo editing report in 2015 triggered a serious worldwide reaction led by Doudna, culminating in a major international ethics summit in Washington, DC. “The unthinkable has become conceivable,” David Baltimore had cautioned opening the meeting. How would we as a society choose to use this capability—if at all? That put China back on its heels a bit. “They went from leading the science to being the caboose on the ethical conversation,” Regalado said. He picked up the sheet of paper listing JK’s five ethical guidelines for human germline editing. “This document is a list of moral principles after they did the experiment of editing embryos!” he said. “This is the necessary groundwork for producing a child with this technology.” JK was trying to prevent an ethical backlash by retrospectively framing his “principles” to stay one step ahead.

Regalado felt it was only a matter of time before we were talking about a genome edited fetus in a womb somewhere. “The monkey is the tryout for the real thing. We might be having that conversation in the near future.” Shadid agreed. Chinese government regulations meant there was only ad hoc enforcement, he said. “The Government can step in when they want and stop whatever’s going on or they could try the wait-and-see approach.”

Shadid said JK could be the human face of science and medicine in China, “the guy behind the first gene edited baby.” They could film JK in his own words, the man “behind editing the first baby while holding his baby daughter.” It was a tantalizing prospect. “I’ve never seen a more affable, expressive scientist in China,” said Shadid, not that the bar was particularly high. CCR5 offered a safe target and HIV a prevalent disease. To win the Chinese Central Committee’s approval, JK was going to need bioethicists, government officials, and hospital administrators to approve the clinical trial. “They need a reason why this is necessary. It all adds up.”

The next day, Regalado interviewed Huang as scheduled and duly wrote up a story for his magazine, but this wasn’t where the puck was going—he was desperate to find out what was going on in Shenzhen. Back in the United States, Regalado dug into JK’s story, hoping it would be the centerpiece in his article that would be the curtain-raiser before the Hong Kong summit. With one week to go, Regalado checked in with Kiani: Ferrell had told her that JK was planning on recruiting women in the New Year for trials targeting two genes—CCR5 and PCSK9.

On the Sunday morning of Thanksgiving weekend, November 25, two days before the Hong Kong conference started, Regalado finally hit the mother lode. Searching “He Jiankui” and “CCR5,” Google finally served up an entry in the Chinese Clinical Trial Registry—helpfully listed in Mandarin and English—that was backdated to November 8. The study leader was He Jiankui and the title said it all: “Evaluation of the safety and efficacy of gene editing with human embryo CCR5 gene.”

The trial inception date was listed as March 2017. The applicant was Qin Jinzhou, JK’s embryologist. The study rationale cited the Berlin patient as creating “a new medical model for HIV elimination.” JK would recruit HIV-positive patients with infertility, seek informed consent and ethical approval from the hospital. It went on: “Through the CCR5 gene editing of the human embryo in a comprehensive test system, we set to obtain healthy children to avoid HIV providing new insights for the future elimination of major genetic diseases in early human embryos.”¹⁴

And there was more. There were two documents linked to the registration. One was an ethics statement (in Mandarin) dated March 7, 2017, submitted to the Harmonicare Shenzhen Women and Children’s Hospital, entitled simply “CCR5 gene editing.” Seizing on the just-published National Academies of Sciences (NAS) report on genome editing, which “for the first time approved the ethics application for a major disease in an embryonic editing study,” JK outlined his plans to target CCR5 in embryos at risk of HIV. The use of CRISPR editing “will bring a new dawn for the treatment of untold numbers of serious genetic diseases.” And then:

We ardently expect that… [the project] will occupy the commanding elevation of the entire field of gene-editing technologies. Like the point of an awl sticking out through a bag, the project will stand out in the increasingly intense international competition of gene editing technologies. This innovative research will be more significant than the IVF technique which won the 2010 Nobel Prize and bring about the dawn of the cure for untold severe genetic diseases.¹⁵

But the real smoking gun, Regalado found, was in of all things an Excel spreadsheet. It was a table in Chinese but there was a familiar scientific term in the title: “cfDNA.” Now Regalado got goosebumps. cfDNA stands for circulating free DNA, the raw material for noninvasive prenatal testing (NIPT), the new standard procedure for performing genetic analysis on pregnant women. The table reported DNA analysis in maternal blood at three timepoints: 12, 19, and 24 weeks. NIPT was developed independently by Dennis Lo in Hong Kong and Stanford’s Stephen Quake—JK’s postdoc supervisor. JK’s expertise was in precisely this type of next-gen sequencing analysis that would be used to perform NIPT. Regalado concluded that JK was monitoring a pregnancy in a genome-editing trial. That could only mean one thing.

Regalado called Shadid in China, unconcerned it was the middle of the night in Shanghai. “Is this what I think it is?” he asked. Shadid said yes. Over the next few hours, Shadid worked on translating the ethics document. Next Regalado called JK and asked if any gene-edited babies had been born. JK declined to answer and referred him to Ferrell. Shadid alerted Kiani that Regalado was planning to publish his explosive story “as soon as people are awake in China.” Kiani called Ferrell, who had been asleep. Ferrell scanned his phone to find multiple messages from Regalado. When they finally spoke, Ferrell wouldn’t confirm anything but urged Regalado to delay his story while offering more access to JK.

But Regalado wasn’t interested. For about four hours, he’d been more or less the only person in the world who knew what JK had done and was ready to publish it. As he reviewed the story one last time, he thought: This is either the best story I’ve ever written, or it’s the last! But here it was—Weekly World News meets Tech Review.

China was waking up. Regalado clicked publish.

The term “exclusive” is hopelessly overused in the popular media, where every story and sound bite is tagged as breaking news. But in case anyone was in any doubt, Regalado prefaced his bombshell story with the word in all caps—and included it in the URL for good measure:

EXCLUSIVE: Chinese scientists are creating CRISPR babies¹⁶

At 7:15 P.M. (Eastern time) on Sunday, Regalado tweeted: “BREAKING: Chinese scientists making CRISPR babies.” The trial registration news was a bombshell, and while Regalado couldn’t say unequivocally that gene-edited babies had been born, there was an excellent chance that one or more had been conceived.

Regalado’s scoop left Marchione and the AP with an unforeseen dilemma. She had been stealthily preparing her own exclusive, waiting to release her story at the right time, either when JK presented on stage in Hong Kong, or when his Nature manuscript was finally published. After consulting her editors, she posted her own story, just a few hours after Regalado. The AP story contained two crucial exclusive details: the births of Lulu and Nana, genetically edited twins.¹⁷

Few people reading either story knew who JK was, but suddenly we could see and hear him in his own words. JK uploaded five short videos onto YouTube—a site ironically banned in China—in which he revealed the names of the twins and defended his decision to carry germline editing to term. Beaming like a proud parent, JK announced the birth of “two beautiful Chinese girls, Lulu and Nana.”¹⁸ The twins were safe and healthy, the gene surgery had worked with no off-target effects. “As a father of two girls, I can’t think of a gift more beautiful and wholesome for society than giving another couple the chance to start a family,” JK said.

Gene surgery should only be used to alleviate disease, JK insisted; any desire to deploy the technology cosmetically or to try to enhance a child’s IQ should be banned, as it is “not what a loving parent does.” He closed with the understatement of the year: “I understand my work will be controversial, but I believe families need this technology, and I’m willing to take the criticism for them.”

One of the few people who was not shocked by the sensational headlines was Doudna. Since 2015, she had galvanized the scientific community and led the ethical debate about CRISPR and its potential misuse on human embryos. She thought human germline editing was almost inevitable although she had resisted calls for a moratorium, fearing it could drive the research underground. In fact, she all but predicted the CRISPR baby saga. During an informal interview in 2017, she revisited her efforts to encourage ethical debate: “I didn’t want to see someone giving birth to a ‘CRISPR baby’ so that they could be famous and then having that lead to all kinds of health problems for that child that would then cause a backlash,” she said. “You could imagine this scenario.”¹⁹

Such a scenario could prompt fierce backlash from the public and legislators—not unlike the clampdown on federal stem cell funding in the wake of the birth of Dolly the sheep in 1998 and overblown fears of human cloning. Other commentators saw reason to be worried. In a TEDx talk in 2015, UCLA stem cell biologist Paul Knoepfler reacted to the first Chinese report of editing in human embryos. “I think someone is going to go that extra step and continue the GM human embryo work and maybe make designer babies,” he predicted.²⁰

Doudna’s biggest concern wasn’t so much the safety of CRISPR but the negative publicity that would accompany any rogue effort at germline editing, not to mention the government scrutiny that might shut down this new technology before it could help patients. In a discussion with NPR’s Joe Palca at Berkeley, Doudna discussed launching the debate around CRISPR and germline editing at a Napa retreat in January 2015. You can hold ethical debates, Palca said, but how are you going to stop somebody who is not here? “Apart from the lab police running around to stop them?” “I don’t even think we have the lab police,” Doudna replied to much laughter from the audience.²¹

But there was no laughing now. On the day after Thanksgiving—appropriately Black Friday—Doudna received a terse email from her acquaintance, He Jiankui, that left her feeling physically sick. The subject line read simply: “Babies Born.”²²

She headed to the airport, while confiding the news with a very close circle of colleagues including Barrangou, who was on a family vacation in London. She was preparing for a Hong Kong showdown.

I. He Jiankui is widely known as “JK,” so for convenience I have used this abbreviation (it is not intended as a term of familiarity). It is Chinese convention to write surname before given name.

II. Pulitzer Prizes have been won for this type of medical reporting. In 2011, a pair of reporters at the Milwaukee Journal Sentinel shared a Pulitzer for exclusive reporting on the life-saving genetic diagnosis of a boy named Nicholas Volker, who suffered a mystery autoimmune disease. By sequencing Volker’s genome, Howard Jacob and Liz Worthey identified a rare mutation. A bone marrow transplant almost certainly saved Volker’s life, mercifully ending a protracted diagnostic odyssey.