The other novel finding was the manner in which the mutant gene had been corrected. Mitalipov had expected that if gene editing occurred, the CRISPR machinery would cut the MYBPC3 gene and paste the guide sequence that was co-injected into the embryos. But instead, the repaired sequence appeared to emanate from the corresponding gene on the partner chromosome. This suggested a novel DNA repair mechanism—a gene replacement rather than an edit. Consequently, Mitalipov didn’t use the word “editing” in the title of his report but “correction.” “Everyone always talks about gene editing,” Mitalipov said. “I don’t like the word editing. We didn’t edit or modify anything. All we did was un-modify a mutant gene using the existing wild-type maternal gene.”23 Others weren’t so sure. Embryologist Tony Perry argued that the genomes of egg and sperm were too far apart for this mechanism to work. “The genomes are separated by what are, in cellular terms, intergalactic distances,” he said.24
But most observers judged the work to be an important step forward. “It feels a bit like a ‘one small step for (hu)mans, one giant leap for (hu)mankind’ moment,” said Doudna.25 And she predicted correctly that Mitalipov’s results would be “encouraging to those who hope to use human embryo editing for either research or eventual clinical purposes.”II Asked what was the biggest challenge in his research, Mitalipov said it was nothing technical but rather the regulatory approval required from three different committees vetting the research, which could be a forerunner to clinical trials in the future. He matter-of-factly said that dominantly inherited disorders would be prime targets. This would include cancer predisposition genes such as BRCA1 and BRCA2, which when mutated increase the odds of breast and/or ovarian cancer.
Mitalipov did not revel in the spotlight, appearing uncomfortable during a live interview on the Charlie Rose television show. But in his “giant leap for (hu)mankind,” Mitalipov felt his research offered hope for millions of people suffering from or carrying serious genetic diseases who worried about transmitting those genes to their children. “We now have a chance to prevent disease at the earliest possible stage of life,” he said.26 But given the backlash that had greeted the first human embryo tinkering in 2015, who would dare take the next step?
In Shenzhen, JK read the headlines and hype around Mitalipov’s study with incredulity bordering on disgust. Two years earlier, American scientists had rushed to condemn China’s initial exploration of human embryo editing, which had used nonviable embryos, but here they were basking in the media spotlight with an article in Nature, no less, using viable embryos, without anything like the same criticism. JK charged this was a double standard, nothing less than “scientific racism against the Chinese.”27 Feeling a sense of patriotic duty, JK was emboldened to push on.
In mid-2017, JK started talking to Lombardi about the idea of launching a gene-editing company. He wanted to hire a CEO for Direct Genomics so he could free up time to focus on the science of gene editing. He asked Lombardi for help to attract funding so that his “NewCo” would be an international company. “What do you want to do?” Lombardi asked. “We’re going to gene edit humans,” JK said. Lombardi was almost speechless. “You realize there’s a moratorium, right?”28
JK didn’t share Lombardi’s concern. The 2017 National Academies report on germline editing had surprised many observers in suggesting that germline editing could be permitted under certain conditions. JK sent Lombardi a rudimentary business plan, focusing on addressing the HIV health crisis in Southeast Asia. According to the plan, China was setting up a district that would do medical tourism around gene editing. “My stuff will be part of this,” JK told Lombardi. For the next twelve months, Lombardi scheduled exploratory meetings, with the intent of letting JK discuss his commercial aspirations with potential investors. Each time, JK canceled his trip at short notice.
One reason was that JK was starting to enroll couples in his clinical trial. Working with a Beijing-based organization that helps Chinese people with HIV, JK recruited eight couples where the father was HIV-positive. One couple subsequently dropped out. On a Saturday in June 2017, JK met two suitable couples interested in volunteering for his trial. For just under an hour, JK walked the couples through the informed consent process, presenting a document that described the risks of the procedures. The study was billed as an “AIDS vaccine development project.” JK was the project leader, while funding was provided by SUSTech. The project would knock out the CCR5 gene “to help these CCR5 gene-editing [sic] babies to obtain the genotype of the Northern European to naturally immunize against HIV-1 virus.” Each couple would receive about $40,000 for medical costs for the IVF procedure, genome editing, and hospital visits.29
While the document outlined the risks of genome editing, JK explained his team was not responsible for any off-target effects, which were “beyond the consequence of the existing medical science and technology.” And only JK’s team had the right to make any public announcement about the trial. Sitting at the end of the boardroom table watching JK invite these couples to make history were two notable observers.30 One was Michael Deem. The other, casually dressed in a blue T-shirt as if he’d just dropped in after a 5K run, was Yu Jun, a very prominent Chinese scientist, one of the four cofounders of BGI. Yu had sold his share of the organization, and was based in Beijing where he is on the faculty of the Chinese Academy of Sciences (CAS)—China’s equivalent of the NIH.31 Moreover, he is the chief editor of the official genomics journal of the Genetics Society of China. It was a glaring illustration of the high-profile friendships that JK had forged during his short time back in China.
Two months later, JK returned to the Cold Spring Harbor Laboratory, this time as an invited speaker. He stood at the podium where countless legends of molecular biology have presented, under the gaze of a large portrait of Jim Watson.III JK talked about the improving efficiency of gene editing, measuring off-target mutations by genome sequencing in monkey and human embryos. There was no indication that JK was about to rush into clinical germline editing, at least not until his penultimate slide—a New York Times magazine headline marking the death of Jesse Gelsinger. Human germline editing could occur “in the near future,” JK said, but “we should do this slow and with caution. A single case of failure may kill the entire field, just like this case—‘the biotech death of Jesse Gelsinger’ for gene therapy.”32
JK’s final slide—the traditional acknowledgements to collaborators and funding agencies—thanked Deem, DeWitt, and William Hurlbut. He answered a few technical questions from the audience, but no one packed into the auditorium seriously thought the young Chinese scientist was about to break from the international consensus on germline editing. Many (like me) were just hoping the evening session would wrap up on time so they could head down to the bar for a well-earned beer.
Three months later, during an advisory board meeting for Direct Genomics, JK welcomed his latest prize recruit, Nobel laureate Craig Mello, to Shenzhen. JK asked Mello about the possibility of using CRISPR to prevent HIV transmission in human embryos, but Mello didn’t think JK was really serious. Meanwhile, one of JK’s PhD students, Feifei Cheng, sent a series of emails to Penn cardiologist Kiran Musunuru, for advice about using CRISPR to target another gene, PCSK9: individuals with rare mutations in PCSK9 exhibit dramatically lower cholesterol levels. Musunuru replied to her first email but ignored the others. He forgot about the exchange completely until twelve months later, when Marchione emailed him JK’s draft paper.33