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

CHAPTER 19 GOING ROGUE

Today, Nature is part of a huge German publishing empire, Springer Nature. But in 1990, when I nervously began my first job as a science editor, Nature was a quintessentially British company, tucked away off famed Fleet Street in central London. I arrived bright and early on my first day wearing a sharp Italian double-breasted suit, expecting to walk into the sleek high-tech headquarters of the world’s most prestigious science journal. My heart sank as I entered a Dickensian newsroom resembling a primary school classroom with desks crammed together, books and newspapers spilling onto the floor. The only other pinstripe suit belonged to chief editor John Maddox, his presence evident from the plume of cigarette smoke wafting from his corner office.

This was before the invention of email or the World Wide Web. Manuscripts were mailed in quadruplicate hard copies. Maddox would smoke a pack of Marlboros and drink a bottle (or two) of wine while meeting his weekly editorial deadline. Geneticist Magdalena Skipper was appointed editor in May 2018, becoming Nature’s first woman chief editor. Assuming the position, she had many issues on her plate—open access publication, data reproducibility, women and diversity in science. But nobody anticipated the problem that landed on her desk six months later.

It was logical that JK would select Nature as the prize venue for his CRISPR babies report. The journal had published the double helix of course, but also the seminal IVF papers of JK’s idol Robert Edwards, as well as the first (and only) two human embryo editing studies conducted outside China. For many scientists, a Nature paper is the ultimate validation, the Oscar of scientific achievement. (Chinese scientists are also handsomely rewarded with a cash incentive for publishing in top-tier journals.)

JK uploaded his manuscript in November 2018, about a week before the Hong Kong summit. He emailed Craig Mello on November 22 to say that the paper had been sent out for peer review. Although Nature staunchly preserves the confidentiality of the review process, extracts of the manuscript were eventually published by MIT Technology Review and by Kiran Musunuru, one of the experts originally contacted by the AP to vet JK’s claims.¹ JK naïvely assumed his manuscript would be published expeditiously to worldwide acclaim. Months later, Fyodor Urnov trashed the manuscript as nothing more than “sets of pieces of paper.”²

Dissection of JK’s unpublished manuscript—“Birth of twins after genome editing for HIV resistance”—reveals a naïveté and arrogance on the part of the authors, as if assuming that the Nature editors would fall over themselves to publish this medical milestone. There were ten coauthors, JK positioned at the end of the list, signifying his senior status. The penultimate author was Michael Deem—indicating a major role in driving the work—although his lawyers later insisted that Deem had withdrawn his authorship name from the list of authors.

From the article’s opening summary, JK and his coauthors failed to accurately represent their work and reveal their true intentions. In reporting “the first birth from human gene editing,” JK wrote that his team had used CRISPR to “reproduce a prevalent genetic variant of the CCR5 gene,” when in fact the editing had failed categorically to reproduce the Δ32 deletion. JK asserted that his team had witnessed no off-target or cancer-causing mutations. And his revolutionary therapy would not only “control the HIV epidemic” but also “bring new hope to millions of families” desperate to avoid inheriting a genetic disease. Urnov could barely hide his disgust: “The profundity of the delusion and the hubris is overwhelming,” he said.³

JK reiterated his goal of trying to combat the spread of HIV worldwide, without addressing the overwhelming success of HIV antiviral drugs or the impracticality of addressing the epidemic via editing one embryo at a time. Nor did he dwell on the fact that during the IVF protocol, the father’s sperm were “washed thoroughly to remove infectious seminal fluid.” This was standard protocol, ensuring that any babies carried to term would not contract HIV.

From four healthy embryos, JK’s team analyzed the two that had been edited at the CCR5 gene. They reported just one off-target edit, unlikely to affect the activity of any genes. But brushed aside was the Catch-22 of embryo editing: the only cells tested from the blastocyst would, by definition, play no further role in the development of the embryo. The remaining cells of the embryo were not analyzed, making it impossible to measure what off-target effects might exist in those cells.

In the manuscript, JK said the babies were born in November 2018, even though reporting says the babies were born in late October. Perhaps this was a deliberate feint designed to throw off any amateur detectives trying to identify the CRISPR babies. JK wrote that the twins would undergo periodic medical testing at least until they were eighteen, including tests to ensure they were immune to HIV infection. Such experiments should have been conducted before Lulu and Nana became human guinea pigs. “This egregious violation of elementary norms of ethics and of research borders on the criminal,” Urnov fumed.

In his book The CRISPR Generation, Kiran Musunuru described the visceral emotion of being one of the first people outside JK’s group to read the manuscript, which he received from Marchione on the Monday after Thanksgiving. His dismay grew until he opened a figure that showed the DNA sequences of CCR5 obtained from the CRISPR-treated embryos. The first image (Lulu) should have shown two distinct traces—the normal sequence of CCR5 on one chromosome, a fifteen-base deletion on the other. This figure showed three. Musunuru knew that meant the embryo was mosaic, before emitting a guttural scream. It was a similar story with Nana’s embryo—three traces rather than the two edits JK had claimed.

The phrase that stuck in Musunuru’s mind was “hack job”—not an unusual occurrence among inexperienced researchers learning to use CRISPR, but unconscionable in a human embryo. Mosaicism happens naturally, the result of a random mutation occurring in one cell in the early embryo being passed down as that cell repeatedly divides. In principle, if applied early enough to a single-cell embryo, the CRISPR edits should be transmitted to all daughter cells. But Cas9 takes time to find the correct target sequence, so there is a possibility that the fertilized egg will have undergone cell division before the edits have taken place. If the CRISPR-Cas components are not shared evenly as the cell divides, genes will not be edited uniformly in the developing embryo.

Musunuru’s despair turned to anger as he saw signs of mosaicism at the off-target location in Lulu’s embryo, indicating that “both embryos were flawed.” The only silver lining: the mosaicism showed that Lulu and Nana were not a hoax. No scientist trying to invent such a sensational story would present such a mediocre editing job. He summed up: “The knowledge that somebody had gone ahead and made the first gene-edited babies—for better or for worse, a historic event for humankind—would have been distressing enough, even if it had been done perfectly. The fact that it had been done with flawed embryos, in such a careless fashion, made it a hundred times worse.”

Within a week, Nature closed the file as the scale of the scientific and ethical transgressions exploded around the world. Nature does not comment on the fate of specific articles but the guidelines were laid out by the editor of one of its sister journals:

Any manuscript reporting genetic modification of human embryos or gametes would need to follow strict scientific and ethical guidelines… On the basis of the available information, He’s research would not have met the editorial criteria adopted by Nature journals.⁴

JK decided to try again, resubmitting to the Journal of the American Medical Association (JAMA). In an extraordinary move, the JAMA editor sent the manuscript to eleven outside experts for review in early December, including George Church, before it too rejected the paper.

A year after being spotted on a guest house balcony, we finally learned JK’s fate. On December 30, 2019, the Nanshan District People’s Court of Shenzhen found JK and two colleagues guilty of “illegal medical practice.” (There is no law in China that expressly prohibits editing human embryos.) JK was sentenced to three years in prison, a fine of 3 million yuan (about $430,000), and a ban from further research in “assisted reproductive technologies.”^I Qin Jinzhou (the first author on JK’s manuscript) and Zhang Renli were handed fines and suspended sentences of eighteen and twenty-four months, respectively. “The three accused did not have the proper medical certification to practice medicine, and in craving fame and wealth, deliberately violated national regulations in scientific research and medical treatment,” the court stated. “They have crossed the bottom line of ethics in scientific research and medical ethics.”⁵

Reactions to JK’s incarceration ran the gamut. “What JK did was criminal: he broke laws of ethics and medicine, endangered lives, and stained an entire field for no reason other than hubris,” Urnov said. “What needs to be imprisoned, metaphorically speaking, is the entire enterprise of human embryo editing for reproductive purposes.”⁶ Doudna took a slightly more diplomatic tone. “As a scientist, one does not like to see scientists going to jail, but this was an unusual case,” she said.⁷ “Jail isn’t the right punishment [for JK], but just because we can do something with science doesn’t mean we should,” tweeted Scott Gottlieb, the ex–FDA commissioner. William Hurlbut expressed mixed feelings. “Sad story—everyone lost in this (JK, his family, his colleagues, and his country), but the one gain is that the world is awakened to the seriousness of our advancing genetic technologies,” he wrote.⁸

And then there was Josiah Zayner, the face of the biohacker community. Zayner sought to frame JK’s transgression as a minor speed bump on the road to human germline engineering, insisting the Chinese scientist would be remembered more than any scientist of his day. “As long as the children He Jiankui engineered haven’t been harmed by the experiment, he is just a scientist who forged some documents to convince medical doctors to implant gene-edited embryos. The four-minute mile of human genetic engineering has been broken. It will happen again.”⁹

So who is right? Zayner the biohacker, who believes that thousands of edited human embryos will be born during this century? Or Urnov, the creator of GMO humans, who insists that germline editing is a classic case of “a solution in search of a problem”?

From the instant his name hit the headlines, He Jiankui was branded a rogue scientist. Writing in the New York Times, Eric Topol said JK should be “castigated” and warned that there was no “foolproof way to rein in such rogue efforts.”¹⁰ In Hong Kong, Harvard Medical School dean George Daley said, “scientists who go rogue carry a deep cost to the scientific community.” JK’s university, hospital, and the Chinese authorities swiftly denied any knowledge of, or responsibility for, his actions. The picture of JK as a rogue agent—secretly seeking fame and fortune, lusting obsessively like a young Jim Watson for a Nobel Prize for himself and glory for his proud nation—spanned the globe.

It’s a convenient narrative, but is this the full story? I have my doubts.

First, JK was not some anonymous researcher emerging from some shadowy secret lair but a highly recruited talent lavished with state and national funding. His commercial success and hungry ambitions in genome sequencing were widely feted and highly publicized. He was featured on state television on a program called “Extraordinary Guangdong” in a segment entitled “The new top shot in the gene world.”¹¹ “Who gave him such very rare opportunity?” asked a group of Chinese bioethicists, suspecting the hidden support of influencers in the local or central government.¹² JK kept a running photo diary on his WeChat account of his meetings with high-profile science celebrities and Chinese dignitaries that was worthy of a Kardashian. Deem, Quake, Mello, and more were there for all to see. Lombardi considered JK to be clever but naïve. “I feel bad for the guy,” he told me. “He got thrown under the bus by somebody. He wasn’t doing this alone. There was some entity who knew exactly what he was doing.”¹³

Second, China is famed for its high-tech statewide surveillance. “It’s almost as good at surveillance as Russia is at hacking,” says George Church, only half-joking. “It’s hard to believe the most exceptionally successful surveillance state would not be paying attention to the most amazing story in the history of biology, right?” Church is convinced that somebody in the Chinese government hierarchy was privy to JK’s work.¹⁴ JK publicly acknowledged the Chinese Ministry of Science and Technology in his early embryo research. And we know that JK invited Yu Jun, a decorated scientist, BGI co-founder, and member of the Chinese Academy of Sciences, to sit in on at least one of his informed consent sessions with trial volunteers. In China, the needs of the state take precedence over those of the individual: Why should genomics and reproduction be any different? “Emperors have been ruling us for thousands of years,” BGI’s Wang Jian said. “I know the government is watching us at all times.”¹⁵ Would JK’s audacious activities be any exception?

Third, China has become a world leader in technology development. China’s massive investment in R&D—$300 billion in 2020—has made it a leader in 5G wireless communication, facial identification, artificial intelligence, high-speed rail, and many other areas of technology. In 2019, China successfully landed a lunar rover on the far side of the moon. “It is human nature to explore the unknown world,” said the head of China’s space program, as China spectacularly laid down another marker in the tightening race for technology supremacy.¹⁶

Genome editing technology is no exception. Chinese scientists did not develop CRISPR, but they have wasted no time pushing it into the clinic despite concerns of a “Wild East” approach to clinical gene editing.¹⁷ The first patients treated with CRISPR were at the No. 105 Hospital of the People’s Liberation Army in Hefei. By the end of 2017, almost one hundred patients in China had been treated with CRISPR genome editing for various cancers including liver, lung, prostate, and blood. There is less emphasis on the sort of fussy regulatory checks demanded by the FDA or its European counterpart. While patients have died, if their deaths are not attributed to CRISPR or the trial protocol, they are not considered adverse events and thus go unreported.¹⁸ By contrast, the first three American cancer patients administered CRISPR gene therapy were not reported until 2020.

Fourth, bioethics is a relatively young scientific discipline, but in China the field didn’t begin until the Ministry of Health issued its first national guidelines on medical ethics in 1998.¹⁹ Without enforcement mechanisms and riven with corruption, this did little to deter the harvesting of organs from executed prisoners or the profusion of shady stem cell clinics.

As noted earlier, Chinese researchers published eight of the first ten studies on human embryo editing. Scientists at the Chinese Academy of Sciences reported the first cloned primates²⁰—a pair of macaques patriotically named Zhong Zhong and Hua Hua—believing these could be useful animals in medical research. Yi Huso, research director at the Chinese University of Hong Kong Center for Bioethics, observed, “people are saying they can’t stop the train of mainland Chinese genetics because it’s going too fast.”²¹ Yi’s perspective was eerily prophetic: “We’re going to do it, then see what’s wrong, then fix it.”

In an article entitled “China will always be bad at bioethics,” Yangyang Cheng argued that one of the biggest cultural differences between East and West is the use of science to legitimize an authoritarian regime. While Jesse Gelsinger’s death set back the field of gene therapy by a decade, if it had occurred in China, “it would most likely have been either covered up or turned into propaganda depicting Gelsinger as a national martyr.”²²

Finally, another contributing factor is China’s infamous one-child policy of social engineering and population control, launched by Mao Zedong in 1979. Before it was abandoned in 2015, the policy showcased China’s draconian determination to curb population growth and a totalitarian control over women’s reproductive rights. This was compounded by the Eugenics and Health Protection Law in 1995, which showed that China’s leaders were willing to impose measures not only to reduce overall births but also “new births of inferior quality.”²³

Wang Jian, the billionaire cofounder of BGI, envisions a future society in which ubiquitous genetic testing will help eliminate a plethora of hereditary disorders. “If all the world’s children are able to receive genetic testing and prediction for [deafness], [blindness] and related diseases, all these genetic diseases will not exist anymore. How big an impact this will be to humankind!”²⁴ In her book, One Child, Mei Fong quotes the proprietor of an egg donor agency in California whose Chinese clients “almost always want taller, at least 5-foot-5. And they have questions about eyelids.” Fong concluded that “an openness to gene editing’s worst excesses may prove to be [China’s] one-child policy’s most unfortunate legacy.”²⁵

China is most likely to abide by international ethical standards “when its membership in the global political and scientific community depends on it—in other words, when it has no other choice,” Cheng writes.²⁶ For now, ethical debates and commissions dominated by Western scientists and ethicists won’t stop it. JK wasn’t inclined to wait patiently until every safety concern had been addressed and the world community deigned to give him the green light. As he said, “If it is not me, it will be somebody else.”

Benjamin Hurlbut, who corresponded extensively with JK for a spell after his house arrest, also disputes the popular “rogue” narrative. JK’s motivations were so familiar they were almost mundane. “Far from ‘going rogue’ and rejecting the norms and expectations of his professional community, He Jiankui was guided by them.” If anything, Hurlbut argues, the “rogue” label belongs not to JK but to “a scientific community that asserts that it alone has the authority to determine what it should and should not do, racing ahead of ethical concerns and public debate.²⁷

Hurlbut concludes that JK was following a familiar path that puts “a premium on provocative research, celebrity, national scientific competitiveness, and firsts.”²⁸ Hurlbut writes:

He was driven by the high-octane milieu of contemporary biotechnology, both in the United States and in China. He internalized ideas that led him to believe that his experiment would elevate his status in the international scientific community, advance his country in the race for scientific and technological dominance, and drive scientific progress forward against the headwinds of ethical conservatism and public fear…

JK, like many if not most scientists, had aspirations of fame and fortune. He jumped into an area of medical research that was cutting-edge and highly controversial, for which he had neither the technical skills nor maturity to handle. We may never know if he damaged the health of the CRISPR babies. His dreams of scientific immortality were reduced to infamy.

As the scientific community reacted to the CRISPR babies’ bombshell, there were ample concerns that someone else might attempt to follow in JK’s footsteps. “Who is to say that there won’t be one hundred other similar types of experiments that will take place, not only in China but in other medical tourism hotspots?” said Feng Zhang.²⁹ Around the world, there are hundreds of private, unregulated stem cell clinics luring patients with promises of “tomorrow’s treatments today” for everything from chronic back pain to Alzheimer’s disease. It would be no surprise if CRISPR clinics, as JK had planned, start to appear.

In testimony for the NAS commission, Sandy Macrae, CEO of Sangamo, said there were two good reasons that no legitimate biotech company would attempt germline editing. First, society wasn’t ready for it. Second, “there isn’t an obvious disease we want to go for, there isn’t a compelling rationale,” he said.³⁰ But Macrae did note that editing a single-cell embryo has one potentially big advantage over trying to edit millions of cells in an adult patient—a reduced chance for an error that could lead to cancer.

In the Spring of 2019, as Zhang and others had grimly anticipated, another scientist declared his intentions to perform germline editing. Like JK, Denis Rebrikov, head of the gene-editing laboratory at Russia’s largest fertility clinic, the Kulakov National Medical Research Center in Moscow, was little known outside his country. He made his first public proposal to edit human embryos a year before the CRISPR babies were born. Like JK, his initial idea was to target CCR5, specifically embryos from HIV-positive women who do not respond to anti-HIV drugs. “I’m crazy enough to do it,” he told Nature.³¹ His preliminary efforts using CRISPR in nonviable human embryos set off alarm bells. “Where is the evidence that he knows how to do this?” asked Lovell-Badge. “Rebrikov needs to hear the concerns of scientists, clinicians, ethicists, and regulators before he falsely gives hope to patients seeking solutions.”³²

But Rebrikov, a former champion in sambo, a Russian martial art, suplexed his critics. “We can’t stop progress with words on paper,” he said.³³ Russia might not be a free country politically, he said, but it was very free in science. Rebrikov quoted a Russian saying: “If you have success, you are right.” If Lulu and Nana were healthy, JK might yet salvage his reputation. And he wouldn’t rule out using genome editing for enhancement. “These people who are opposed [to enhancement] want to have all these things in their children but only by ‘divine providence,’ not by science. They are liars or stupid.”

Rebrikov changed tack to focus on an inherited form of deafness.³⁴ Mutations in the gene GJB2, which encodes a protein called connexin 26, cause hereditary hearing loss. The incidence is fairly high in Russia, where the mutation is thought to have spread from west to east over thousands of years. The most common GJB2 mutation is the deletion of a single letter in the sequence. About ten babies are born each year with hereditary deafness resulting from inheriting two dysfunctional copies of GJB2. Rebrikov identified several deaf couples in which both partners were homozygous for GJB2 mutations, meaning that PGT was not an option to produce a hearing-enabled child. If he could use CRISPR to repair one copy of the gene, the child should be able to hear. Rebrikov put the price of germline editing at about 1 million rubles, or $15,500. “I can see the billboard now: ‘You choose: a Hyundai Solaris or a Super-Child?’ ”³⁵

Six months after the Hong Kong summit, a small group of Russian medical experts and officials discussed Rebrikov’s plans in a closed-door meeting in Moscow with a very special guest—Maria Vorontsova, a pediatric endocrinologist and, more importantly, Vladimir Putin’s daughter. A few months later, Rebrikov defended his plans in a meeting at the Russian Academy of Sciences’ Institute of Philosophy.³⁶ One woman seriously considering Rebrikov’s trial, known as Yevgenievna, was devastated when her young daughter was declared deaf. Yevgenievna is aware of the risks of genome editing. “Which is better: to hear music or be suffering from cancer? That’s the question.”³⁷

Unlike JK, Rebrikov was fully transparent about his intentions—no secret circle of trust here. He gave interviews to a string of science journals, he had more relevant expertise, and the medical case had more merit than JK’s cause. But in July 2019, the WHO director-general, Tedros Ghebreyesus, stated that “regulatory authorities in all countries should not allow any further work in this area until its implications have been properly considered.” The Russian Ministry of Health evidently took note, responding that granting Rebrikov permission to undertake clinical germline editing would be premature and irresponsible.

Rebrikov steadfastly quotes a line from Lenin about the Bolsheviks’ seizure of power in 1917: “Yesterday was early, tomorrow will be late. Power must be taken today.”³⁸ Speaking of power, the Vorontsova connection raised the tantalizing idea that the Russian president could yet have a say. Putin has toured Rebrikov’s institute and publicly demonstrated his familiarity with CRISPR. During a televised town hall at the 19th World Festival of Youth and Students in Sochi, Putin, unscripted, said:

Mankind has become capable of interfering with the genetic code created by nature or, according to religious people, created by God. What are the practical consequences of that? One can almost imagine that people will be able to create human beings with specific characteristics. This person could be a mathematical genius or a brilliant musician, but also be a soldier—an individual capable of fighting without fear or compassion, without mercy or even pain. You see, humanity can enter, and most likely will enter, in the near future, a very difficult period of its development and existence, a period demanding great responsibility. And what I have just described may be more terrifying than a nuclear bomb. Whenever we do something, and whatever it is that we do, we should never forget about the ethical and moral foundations behind our actions. Whatever we do should benefit people. Make them stronger, not destroy them.³⁹

Putin is informed and apparently enamored by the possibility of conceiving a few more Tchaikovskys or Rachmaninovs in the next century, though the prospect of super soldiers would have more practical utility. And let’s face it, the bit about “ethical and moral foundations” was a nice touch.

Following JK’s disappearance and incarceration, the aftershocks continue to ripple through the scientific community. How should scientists respond? Should there be a worldwide ban or moratorium on germline editing research? And who would police the research community to ensure that no violations occurred? In March 2019, a group of eighteen leading scientists marshaled by Eric Lander called for a temporary global moratorium on germline editing research.⁴⁰ The signatories included Zhang and Liu, Emmanuelle Charpentier, Keith Joung, bioethicist Françoise Baylis, and Nobel laureate Paul Berg. For Lander, it was his first major pronouncement on genome editing since his notorious “Heroes of CRISPR” review three years earlier.⁴¹

While there were some disagreements among Lander’s coauthors on the merits of heritable editing, there was agreement on the need for a temporary moratorium rather than a permanent ban. Under the proposal, nations kept the right to make their own decisions, but committed to suspend any use of clinical germline editing unless certain conditions are met. During the moratorium—Lander thought five years sounded about right—“no clinical uses of germline editing whatsoever are allowed.” After that, countries could set their own policies so long as they provided public notice of any germline editing plans; allowed debate of all the medical, technical, and ethical issues during a consultation period; and ensured societal consensus supporting the application.

Future decisions about germline editing should be made by a broad group of stakeholders, “not by scientists, physicians, hospitals or companies, nor the scientific or medical community acting as a whole.” And importantly, the moratorium would not hamper clinical research in somatic gene therapy. Lander didn’t think an international treaty was plausible: there is no genome editing Thunderbirds task force that can physically stop a rogue actor or government. On the other hand, it would “place major speed bumps in front of the most adventurous plans to re-engineer the human species.” The risks of turning a blind eye, potentially hurting patients and eroding public trust, were much worse.

Lander’s call was immediately seconded by Francis Collins, who said the community needed a period of reflection and “a substantive debate about benefits and risks that provides opportunities for multiple segments of the world’s diverse population to take part.”⁴² A month later, some sixty researchers and ethicists made a similar plea in a letter to the director of the Department of Health and Human Services. Human genetic manipulation should be unacceptable, they wrote, calling for “a binding global moratorium” until serious scientific, societal, and ethical concerns are addressed.⁴³ The letter was cosigned by many gene therapy pioneers, including Jean Bennett, Jim Wilson, and Feng Zhang.

Conspicuously absent from joining the moratorium movement was Doudna, even though she’d been invited by Zhang to cosign Lander’s article. “This is effectively just rehashing what’s been going on for several years,” she said. “I don’t want to drive others underground with this [moratorium]. I would rather they feel that they can discuss it openly. Gene editing, it’s not gone, it’s not going away, it’s not going to end.”⁴⁴ George Daley felt that a moratorium raised too many questions, including how long should it last? How is it enforced? And who decides when to rescind it?⁴⁵ Church was less diplomatic. Without an enforcement mechanism, he said, “just calling for another moratorium is posturing.” Why not crank up the penalties for practicing medicine without FDA approval?⁴⁶

Doudna addressed the issue again on the one-year anniversary of the CRISPR babies. Writing in Science, she reiterated that moratoria were not sufficiently strong countermeasures. “The temptation to tinker with the human germ line is not going away,” she said. Violators should face loss of funding and publication privileges. “Ensuring responsible use of genome editing will enable CRISPR technology to improve the well-being of millions of people and fulfill its revolutionary potential.”⁴⁷

During remarks delivered at Harvard shortly after the commentary came out,⁴⁸ Lander assailed the critics with a mixture of disdain and bemusement. His call for a temporary moratorium was “flamingly obvious because in effect we have a moratorium” right now. The definition of a moratorium is “temporary prohibition,” yet some commentators were “squeamish about even using the dictionary word.” Lander thought this was fascinating, as if invoking the M word had some magical talismanic properties.

To critics who said a moratorium might be hard to lift? “It lifts!” Lander insisted. For those who said using the M word would discourage people from entering the field? Lander wanted to get people’s attention, “otherwise people wouldn’t have read any further.” And for those who claimed his proposal would not have prevented the actions of a rogue actor like JK? Lander pleaded no contest. “It wouldn’t—that wasn’t the point of it!” Lander insisted. Criminal acts occur: people murder each other despite laws prohibiting it. The proposal was not about preventing the actions of certain individuals but about “what countries should choose to do.” JK’s actions were China’s responsibility. In the United States, it’s the government’s responsibility.^II And to folks who might have reservations about the concept of international consultation such as “the Brits,” Lander exhaled: “Duh, that’s the point! If you don’t have the courage of your convictions after that consultation, then you shouldn’t be doing it.”

JK’s experiment was “utterly irresponsible,” a “complete screw up” that can happen when work is conducted in complete secrecy. And yet, members of the community knew his intentions and did nothing. “That’s not exactly what an upstander does, it’s a bystander.” Lander wished someone had called the press, but nobody did. “That’s really interesting and more disturbing maybe than that he did it.” Ultimately, Lander and colleagues felt a moratorium was the most prudent path forward. “I want our kids to be proud that we thought about this carefully,” he said.

The call for a moratorium capped a remarkable shift in policy statements. In 2015, the committee of the first ethics summit said germline editing would be “irresponsible” unless and until certain conditions were met. In 2017, the NASEM report concluded it “should be permitted” provided that conditions were met; and in 2018, the Hong Kong summit committee surmised that germline editing was acceptable in principle and needed a translational pathway. For Baylis, a Canadian bioethicist and author who joined Lander’s call for a moratorium, that progression was alarming. “There’s nothing that’s happened that warrants this kind of shift. What’s the hurry?”⁴⁹

With JK imprisoned, China has sent a resounding message warning off any other potential genome hotshots. The government required researchers to complete a survey to catalogue gene-editing programs in the country. China belatedly established an ethics commission to plug some of the jurisdictional gaps between the health and science ministries. What effect will these actions have? “It is also almost certain someone will attempt gene editing to make stronger, smarter, more attractive babies. Pandora’s box is wide open in China,” wrote Mei Fong.⁵⁰

In April 2019, Yang Hui, a young neuroscientist at the Shanghai Institute of Biological Sciences, and Wang Haoyi, a bioethicist at the Chinese Academy of Sciences, published a damning rebuke of JK’s work.⁵¹ The authors were “shocked” and “enraged” by JK’s “irresponsible conduct” that violated the medical ethics of China and the world. JK had no intention of trying to precisely introduce the Δ32 variant, they alleged, merely to break the CCR5 gene.

Despite his fierce criticism of JK, Yang Hui was advancing his own research on human embryos using base editing.⁵² He didn’t mention the JK controversy in the article—it was as if the CRISPR babies had never been born. But in a candid interview, Yang told a Chinese paper that gene editing, like weapons or drugs, could be used for either good or immoral purposes. If we’re allowing germline editing, then his goal was to leave no unedited embryo behind. “Even if there is just one embryo left unedited, it will create an ethical problem. An almost 100 percent efficiency is required before the technology can be used on humans,” he said.⁵³

That day might happen sooner than we think. And while Yang said the production of “superbabies” should be permanently banned, his zeal to follow in JK’s footsteps was apparent. Indeed, you could be forgiven for seeing shades of a new Cold War. “We are ahead of the competition in the United States,” he said. “We are working with the same spirit as building the first nuclear bomb!”

But if there are groups in China or anywhere else intent on pursuing germline editing, they have an uphill task. “Chromosomal mayhem” is not a phrase widely deployed in Nature headlines, but in June 2020 it was not an exaggeration.⁵⁴ A trio of bioRxiv preprints from the leading experts on genome editing in human embryos outside China—Niakan, Egli, and Mitalipov—independently reported worrisome “on target” DNA aberrations when using CRISPR to edit specific genes. Niakan’s group found that a fraction of embryos displayed unwanted deletions and rearrangements in the vicinity of the targeted gene, while Egli and Mitalipov also reported serious chromosomal damage or rearrangements in some embryos. It was a timely reminder that we still have much to learn about the raw mechanics of DNA repair processes at the earliest stages of embryogenesis before we can safely and responsibly consider genome editing in the human embryo.

I. “Illegal medical practice” has three grades in China: For an offense in which no one was harmed, the maximum sentence is three years (plus a fine). If a patient has been harmed, the maximum sentence is ten years, longer in cases with a loss of life. Whether the CRISPR babies were harmed in any way remains to be seen. JK’s sentence seems more than a slap on the wrist. Perhaps the Chinese government is sending a message of the dangers of money poisoning science.

II. Since 2016, the U.S. effectively has a ban on human germline editing. An amendment by Representative Robert Aderholt (Alabama) bars the FDA from funding clinical trial applications of gene editing of human embryos.