The Code Breaker, page 26
David Baltimore warned of a development that made this Napa meeting different from the Asilomar one forty years earlier. “The big difference today is the creation of the biotechnology industry,” he told the group. “In 1975, there were no big biotechnology companies. Today, the public is concerned about commercial development, because there’s less oversight.” If the participants wanted to prevent a popular backlash against gene editing, he said, they would have to convince people to trust not only white-coated scientists but also commercially driven corporations. That could be a tough sell. Alta Charo, a bioethicist at the University of Wisconsin Law School, pointed out that the close relationship between academic researchers and commercial companies could taint the credibility of the academics. “Financial interests undermine the ‘white coat’ image of scientists today,” she said.
One of the participants brought up the social justice argument. Gene editing would be expensive. Would only the wealthy have access? Baltimore agreed that was a problem, but he argued it was not a cause for banning the technology. “That argument doesn’t cut very deep,” he said. “That’s how everything is. Look at computers. Everything gets cheaper when it gets done wholesale. It’s not an argument against moving forward.”
During the conference, word began to circulate about some editing experiments on non-viable embryos that were already happening in China. The technology, unlike that of building nuclear weapons, could spread easily and be used not only by responsible researchers but also by rogue doctors and biohackers. “Can we really put the genie back in the bottle?” one participant asked.
The group agreed that the use of CRISPR tools for non-inheritable gene editing in somatic cells was a good thing. It could lead to beneficial drugs and treatments. So they decided that it would be useful to agree to some restraints on germline editing in order to prevent a backlash. “We need to create a political safe space by going slow on germline editing so that we can continue working on somatic cell edits,” one participant said.
In the end, they decided to call for a temporary halt on germline editing in humans, at least until the safety and social issues could be further understood. “We wanted the scientific community to hit the Pause button until the societal, ethical, and philosophical implications of germline editing could be properly and thoroughly discussed—ideally at a global level,” Doudna says.
Doudna drafted an initial version of the conference report, which she circulated to the other participants. After incorporating their suggestions, she submitted it in March to Science. It was titled “A Prudent Path Forward for Genomic Engineering and Germline Gene Modification.”6 Although she was the lead writer, the names of Baltimore and Berg were listed first. The happenstance of alphabetical order caused the two Asilomar pioneers to be at the fore.
The report clearly defined what was meant by “germline editing” and why crossing that threshold would be a major ethical as well as scientific step. “It is now possible to carry out genome modification in fertilized animal eggs or embryos, thereby altering the genetic makeup of every differentiated cell in an organism and so ensuring that the changes will be passed on to the organism’s progeny,” they wrote. “The possibility of human germline engineering has long been a source of excitement and unease among the general public, especially in light of concerns about initiating a ‘slippery slope’ from disease-curing applications toward uses with less compelling or even troubling implications.”
As Doudna hoped, the journal article got major national attention. The New York Times ran a story on page 1 by Nicholas Wade, with a picture of Doudna at her Berkeley desk and the headline “Scientists Seek Ban on Method of Editing the Human Genome.”7 But the headline was misleading. Indeed, in most of the publicity about the Napa report, a key point was missed. Unlike some other scientists at the time,8 the participants had purposely decided against calling for a ban or moratorium, which can over time become hard to lift. Their goal was to keep open the possibility of germline editing if it was safe and medically necessary. That was why, in the title of the piece, they called for “a prudent path forward,” which had become the watchword of many of the scientific conferences on human germline gene editing.
Chinese embryo work, April 2015
During the Napa conference, Doudna heard an unnerving rumor: a group of Chinese scientists had used CRISPR-Cas9 to edit, for the first time, the genes in an early-stage human embryo, which in theory could create inheritable changes. The mitigating factor was that the embryos were not viable. They would not be implanted in a mother’s uterus. Nevertheless, if true, the plans of well-intentioned policymakers would once again be disrupted by the zeal of eager researchers.9
The Chinese paper had not been published, but its existence had leaked. It had been rejected by the prestigious journals Science and Nature, and it was being shopped around. It was finally accepted by the somewhat obscure Chinese journal Protein & Cell, which published it online on April 18, 2015.
In the article, researchers at a university in Guangzhou described how they used CRISPR-Cas9 in eighty-six non-viable zygotes (precursors to an embryo) to cut out a mutated gene that causes beta thalassemia, a deadly blood disorder like sickle-cell anemia.10 Although the embryos were never intended to be grown into babies, a line had been toed, if not crossed. For the first time, CRISPR-Cas9 had been used to make potential edits in the human germline, ones that could be inherited by future generations.
After Doudna read the article in her Berkeley office, she stared out at San Francisco Bay feeling, she later recalled, “awestruck and a bit queasy.” Other scientists around the world were probably conducting similar experiments with the technology that she and Charpentier had created. That could lead, she realized, to some very unintended consequences. It could also provoke a public backlash. “The technology is not ready for clinical application in the human germline,” she replied when a reporter for NPR asked her about the Chinese experiments. “That application of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues.”11
* * *
The Napa conference and the Chinese embryo-editing experiments aroused the interest of Congress. Senator Elizabeth Warren hosted a congressional briefing, and Doudna went to Washington to testify with her friend and fellow CRISPR pioneer George Church. The event was so popular that it was standing-room only. More than 150 senators, congressmen, staffers, and agency personnel crammed into the room. Doudna recounted the history of CRISPR, emphasizing that it had begun as pure “curiosity-driven” research about how bacteria fight off viruses. Using it in humans, she explained, required finding ways to get it to the right cells in the body, a task that was easier when the edits were made in early-stage embryos. “But using gene editing in such a way,” she warned, “is also much more ethically controversial.”12
Doudna and Church wrote back-to-back pieces in Nature presenting their perspectives on making inheritable gene edits. Although their positions conflicted to some extent, they reinforced the case that scientists were dealing with the issues seriously and did not require new government regulations. “Opinion on the use of human-germline engineering varies widely,” Doudna wrote. “In my view, a complete ban might prevent research that could lead to future therapies, and it is also impractical given the widespread accessibility and ease of use of CRISPR-Cas9. Instead, solid agreement on an appropriate middle ground is desirable.”13 Church was more forceful in arguing that research, even in editing the human germline, should continue. “Rather than talk about the possibility of banning alteration of the human germline, we should instead be discussing how to stimulate ways to improve its safety and efficacy,” he wrote. “Banning human-germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism.”14
Church’s bio-enthusiasm was given a boost in the popular press by one of his Harvard colleagues, the well-known psychology professor Steven Pinker. “The primary moral goal for today’s bioethics can be summarized in a single sentence,” he wrote in an op-ed for the Boston Globe. “Get out of the way.” He took a brutal swipe at the entire profession of bioethicists. “A truly ethical bioethics should not bog down research in red tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as ‘dignity,’ ‘sacredness,’ or ‘social justice,’ ” he argued. “The last thing we need is a lobby of so-called ethicists.”15
The December 2015 International Summit
Following their Napa Valley meeting, Doudna and Baltimore urged the U.S. National Academy of Sciences and its sister organizations around the world to convene a globally representative group to discuss how to prudently regulate human germline editing. More than five hundred scientists, policymakers, and bioethicists—though very few patients or parents of afflicted children—gathered in Washington for three days at the beginning of December 2015 for the first International Summit on Human Gene Editing. In addition to Doudna and Baltimore, there were other CRISPR pioneers, including Feng Zhang, George Church, and Emmanuelle Charpentier. Cohosts included the Chinese Academy of Sciences and Britain’s Royal Society.16
“We are here as part of a historical process that dates from Darwin and Mendel’s work in the nineteenth century,” Baltimore said in his opening remarks. “We could be on the cusp of a new era in human history.”
A representative from Peking University assured the audience that China had in place safeguards to prevent germline gene editing: “The manipulation of the genes of human gametes, zygotes, or embryos for the purpose of reproduction is prohibited.”
Because there were so many participants and journalists, the meeting consisted mainly of canned presentations rather than real debate. Even the conclusions had been pre-cooked. The most important was almost identical to what had been decided at the small Napa meeting at the beginning of the year. Human germline editing should be strongly discouraged until stringent conditions were met, but the words “moratorium” and “ban” were avoided.
Among the conditions the group adopted was that germline editing should not proceed until “there is broad societal consensus about the appropriateness of the proposed application.” The need for a “broad societal consensus” was one that would be invoked often in discussions of the ethics of germline editing, as if a mantra. It was a laudable goal. But as the debate over abortion has shown, discussions do not always lead to broad societal consensuses. The organizers from the National Academy of Sciences realized that. Even as they called for public discussion of the issue, they created a twenty-two-person committee of experts to undertake a yearlong study on whether there should be a moratorium on germline DNA edits.
In their final report, issued in February 2017, the group did not call for a ban or a moratorium. Instead, it provided a list of criteria that should be met before germline editing should be allowed, among them: “absence of reasonable alternatives, restriction to preventing a serious disease or condition,” and a few others that were not insurmountable in the foreseeable future.17 Notably, it omitted one key restriction that was in the 2015 international summit report. There was no longer any mention of the need for a “broad societal consensus” before inheritable gene-editing would be permitted. Instead, the 2017 report called only for “broad ongoing participation and input by the public.”
Many bioethicists were dismayed, but most scientists, including Baltimore and Doudna, felt that the report had found a sensible middle ground. Those engaged in medical research saw it as providing a yellow light, allowing them to proceed with caution.18
In Britain, the Nuffield Council, the nation’s most prestigious independent bioethics organization, produced a report in July 2018 that was even more liberal. “Genome editing has the potential to give rise to transformative technologies in the field of human reproduction,” it concluded. “So long as heritable genome editing interventions are consistent with the welfare of the future person and with social justice and solidarity, they do not contravene any categorical moral prohibition.” The Council even went so far as to diminish the distinction between using gene editing to cure diseases and using it to provide genetic enhancements. “It is possible that genome editing could be used in the future for… enhancing senses or abilities,” the guide to the report read. The report was seen, correctly, as paving the way for human germline gene editing. The headline in the Guardian was “Genetically Modified Babies Given Go Ahead by UK Ethics Body.”19
Global regulations
Even though the U.S. National Academy of Sciences and Britain’s Nuffield Council espoused a liberal approach to germline editing, some restrictions were imposed in both countries. Congress passed a provision barring the Food and Drug Administration from reviewing any treatment “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” President Barack Obama’s science advisor, John Holdren, declared, “The Administration believes that altering the human germline for clinical purposes is a line that should not be crossed at this time,” and the director of the National Institutes of Health, Francis Collins, announced, “The NIH will not fund any use of gene-editing technologies in human embryos.”20 In Britain, likewise, the editing of human embryos was restricted by various regulations. But in neither Britain nor the U.S. was there an absolute and clear law against germline gene editing.
In Russia, there were no laws to prevent the use of gene editing in humans, and President Vladimir Putin in 2017 touted the potential of CRISPR. At a youth festival that year, he spoke of the benefits and dangers of creating genetically engineered humans, such as super-soldiers. “Man has the opportunity to get into the genetic code created by either nature, or as religious people would say, by God,” he said. “One may imagine that scientists could create a person with desired features. This may be a mathematical genius, an outstanding musician, but this can also be a soldier, a person who can fight without fear or compassion, mercy or pain.”21
In China, the policies were more restrictive, or at least so it seemed. Although there were no clear laws explicitly outlawing inheritable genetic editing of human embryos, there were multiple regulations and guidelines that prevented—or were believed to prevent—it. For example, in 2003 the Ministry of Health issued “Technical Norms on Human Assisted Reproduction” that specified, “Genetic manipulation of human gametes, zygotes and embryos for reproductive purposes is prohibited.”22
China has one of the world’s most controlled societies, and few things happen in clinics without the government’s knowledge. Duanqing Pei, a respected young stem-cell researcher who is the director general of Guangzhou Institutes of Biomedicine and Health, assured his fellow steering committee members at the international summit in Washington that germline gene editing of embryos would not happen in China.
That is why Pei and his like-minded friends from around the world were so shocked when they arrived in Hong Kong in November 2018 for the Second International Summit on Human Genome Editing and discovered that, despite all of their high-minded deliberations and carefully crafted reports, the human species had suddenly and unexpectedly been thrust into a new era.
PART SIX CRISPR Babies
A new species would bless me as its creator and source; many happy and excellent natures would owe their being to me.
—Mary Shelley, Frankenstein; or, The Modern Prometheus, 1818
He Jiankui taking a selfie with Doudna at Cold Spring Harbor Laboratory
Michael Deem
CHAPTER 37 He Jiankui
The eager entrepreneur
He Jiankui, the son of struggling rice farmers, was born in the Orwellian year 1984 and grew up in Xinhua, one of the poorest villages in a rural part of Hunan province in east-central China. The average family income there when he was a boy was $100 a year. His parents were so poor that they could not afford to buy him textbooks, so JiankuiI walked to a village bookstore to read them there. “I grew up in a small farming family,” he recalled. “I picked leeches from my legs every day in the summer. I will never forget my roots.”1
Jiankui’s childhood instilled in him a hunger for success and fame, so he heeded the exhortations on the posters and banners at his school that he should dedicate himself to pushing forward the frontier of science. He would indeed end up pushing that frontier, though less by great science than great eagerness.
Spurred by his belief that science was a patriotic pursuit, young Jiankui built a rudimentary physics laboratory at home, where he relentlessly conducted experiments. After doing well in school, he was tapped to go to the University of Science and Technology in Hefei, 575 miles to the east, where he majored in physics.
He applied to four graduate schools in the United States and was accepted by only one of them: Rice University in Houston. Studying under Professor Michael Deem, a genetic engineer who would later become the subject of an ethics investigation, Jiankui became a star at creating computer simulations of biological systems. “Jiankui is a very high-impact student,” Deem said. “He has done a fantastic job here at Rice, and I am sure he will be highly successful in his career.”
Jiankui and Deem devised a mathematical model for predicting what strains of flu would emerge each year and, in September 2010, coauthored an undistinguished paper on CRISPR that showed how the spacer sequences matching viral DNA are formed.2 Popular, gregarious, and an eager networker, Jiankui became president of Rice’s Chinese Students and Scholars Association and an avid soccer player. “Rice is a place where you can really enjoy graduate school,” he told the university magazine. “Outside of the lab, there’s a lot to do. Oh, my God, Rice has six soccer fields! That’s awesome.”3
