Just over a year ago, CRISPR pioneer Jennifer Doudna of UC Berkeley talked with me about the prospects that the gene-editing technology she had helped develop might be used in violation of ethical boundaries.
“I've mentally prepared myself for the day when I open my inbox or answer my phone,” she said, “and realize that somebody's going to be announcing the first CRISPR baby."
That moment undoubtedly came sooner than she expected—in late November, in fact, mere days days before the opening of a scientific summit on human genome editing that Doudna had helped to organize.
The news was that a researcher in China had altered a gene to endow an embryo with resistance to HIV, and that embryo had been carried to term, producing a live child purportedly with the heritable trait of HIV resistance. (A second child was born to the same anonymous couple, apparently without the altered gene.)
The news stunned the scientific community on the eve of the Hong Kong summit, not least because it breached the scientific consensus that editing the human germ line—that is, the genetic material that can be passed down to future generations—is unethical. Not only was the science of genetic alteration too uncertain to be applied to live human subjects, but the consequences of altering genetic traits posed the risk of permanent changes for the future of humanity itself.
As the claims made by Chinese scientist He Jiankui demonstrate, science has no real way of enforcing a consensus that something that can be done should not be done. But in the aftermath of He’s disclosure, the scientific establishment is pondering whether it took sufficiently firm actions to discourage germline editing. The answer plainly is no.
Several scientists at the forefront of the ethical debate have acknowledged this. Biologist David Baltimore, the president emeritus of Caltech, said so from the podium at the Hong Kong summit just minutes after He made a presentation on his project.
“There has been a failure of self-regulation by the scientific community because of a lack of transparency,” Baltimore said. His complaint was that He circumvented the only self-regulatory tool that science has, the public spotlight. He’s research had been conducted out of view of the scientific community—he said at the summit that not even his superiors at the Southern University of Science and Technology were fully aware of his project.
“An open process has not happened,” Baltimore said of the research. “We’ve only found out about it after it’s happened and after the children are born.”
Doudna also expressed frustration with He’s activities. “It is imperative that the scientists responsible for this work fully explain their break from the global consensus that application of CRISPR-Cas9 for human germline editing should not proceed at the present time,” she said in a statement distributed by UC Berkeley. “Public and transparent discussion of the many uses of genome editing technology must continue.”
Doudna was fully alive to how He had conducted his work out of the mainstream. Just after the work was disclosed, she and other organizers invited He to dinner in advance of his own appearance at the Hong Kong summit. “He arrived almost defiant,” she told Jon Cohen of Science magazine. “He just seemed surprised that people were reacting negatively about this. By the end of the dinner he was pretty upset and left quite abruptly.”
It shouldn’t surprise anyone that scientific self-regulation has failed in this case. Self-regulation almost never works in any context, because the self-regulators are hopelessly conflicted, whether they operate on Wall Street, the auto industry, or the consumer products field. Science has an especially discouraging history, drawn from the efforts of J. Robert Oppenheimer and other physicists to place limits on nuclear bomb technology. Many of them vociferously opposed development of the hydrogen bomb, but even physicists who opposed the research in principle found themselves drawn into helping with it under government auspices.
Scientists still hope to find a self-regulatory path because the alternative of government regulation and legislation has its own shortcomings. For one thing, that raises the likelihood of injecting politics into scientific research—would anyone want the climate change deniers haunting the hallways of Congress to have even more authority than they do today over climate science? And legislation can’t extend beyond national borders, leaving open the possibility, even the likelihood, that rogue scientists in rogue states will go ahead anyway.
He’s presentation at the Hong Kong meeting underscored for many researchers the drawbacks of conducting such research so far out of scrutiny. He’s research has not been published in any scientific journal, though He says it has been submitted to several peer-reviewed publications.
It’s unclear from his presentation whether he actually achieved what he set out to do, including whether the putative alteration of the CCR5 gene actually will confer immunity to HIV. It’s possible, experts say, that the alteration will make the subject more susceptible to other infections such as West Nile virus.
There also are questions about whether the parents involved in the experiment had adequate opportunity to give informed consent and why He ignored advice not to proceed with the work when he consulted experts in the field. There also are questions about why those experts, once He informed them of his plans, didn’t raise a public alarm. And many question whether He’s goal of endowing infants with HIV immunity really constituted an “unmet medical need” justifying a radical approach. Treatments of HIV are now common, and in any case the embryos He treated were not infected with HIV and unlikely to be, since the children’s father is HIV-positive is HIV-negative.
Both Doudna and Baltimore, as it happens, were part of a group that pondered in 2015 whether to propose an outright moratorium on germline editing. They chose not to, for several reasons. One, as Doudna told me last year, was that the term moratorium "implies some kind of enforcement, and how do you enforce something like that globally?"
But another is the natural reluctance of scientists to rule any research strictly out of bounds if it offers potential benefits, no matter how conjectural. Referring to the possibility that CRISPR might someday yield cures for conditions such as Huntington's and Duchenne muscular dystrophy, she wrote in her book “A Crack in Creation”: "The stakes are simply too high to exclude the possibility of eventually using germline editing."
The result of the discussions that Doudna, Baltimore, and 16 other biologists and bioethicists conducted in 2015 was a public statement that “open discourse” on the use of CRISPR technology to manipulate the human genome is “urgently needed.”
The statement recommended that steps be taken to “strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations.”
Other researchers say the scientific community missed a prime opportunity in 2015 to take a firmer stand—indeed, to implement a moratorium on gene editing experiments on humans. One is biologist Paul Knoepfler of UC Davis, who wrote this week on the medical site Stat that after the 2015 summit declined to call for a moratorium, “my feeling was that someone would report the creation of the first ‘CRISPR baby’ within the next few years. That might happen even with a moratorium, but the odds had just increased substantially.”
Knoepfler wrote that it was not too late to implement a moratorium now. He called for a “three-year moratorium on the implantation of gene-edited human embryos to make genetically modified babies.” Knoepfler acknowledged that “a moratorium won’t stop the most driven rogue, and one can reasonably ask how it would be enforced. But I believe it would send a strong message that going down this road in the near future won’t be tolerated.”
Stung by the news of He’s experimentation, the organizers of the Hong Kong summit released a statement with rather sterner language than the 2015 statement. They called He’s claim “deeply disturbing” and said “the procedure was irresponsible and failed to conform with international norms,” including “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.”
Knoepfler found much to be alarmed about in the scientific establishment’s approach to human germline editing, which he believes to be entirely too tolerant. At the Hong Kong summit, he noted, George Daley, dean of the Harvard Medical School and one of the conference organizers, cautioned against overreacting and using the He disclosure to discourage future research.
“Just because the first steps into a new technology are missteps,” Daley said, “it doesn’t mean that we shouldn’t step back, restart, and think about a plausible and responsible pathway for clinical translation.”
What would be a responsible pathway? To Knoepfler, we simply don’t know enough to map the route. “While the human genome is not some kind of pure, untouchable construct,” he wrote in his 2016 book “GMO Sapiens,” “it nonetheless requires respect as something that is both incredibly powerful and incompletely understood.”
The lack of understanding is not only biological, but social. “If optimistically it takes...100 tries to get a single, healthy GMO sapiens child,” Knoepfler wrote, “what happens to the 99 human embryos, fetuses, or even children that did not quite ‘work out’?”
So perhaps the only solution is a moratorium, strengthened by the “transparency” that Baltimore and others have called for. If the scientific establishment states with a single voice that human genome editing is outside ethical bounds, then ethical scientists will take care and comply; rogues will be rogues, but that’s a permanent human condition.