Nevertheless, within the next several years, Zhang would be among the elite group of scientists to stumble across the foundations of a new technology that would go far beyond the limits of gene therapy—and open a Pandora’s box of new ethical challenges. According to Michael Specter’s 2015 story on gene editing for The New Yorker, in the mid-2000s, an offhand comment from a colleague inspired Zhang to read up on CRISPR, a then obscure cluster of DNA found in some species of bacteria that produces an enzyme that dices up the DNA of invading viruses and reconfigures the pieces to form something like an immune system. He found a trickle of research indicating that it might be possible to tap CRISPR’s innate ability to navigate a genome and use it as a delivery vehicle and installation crew for genetic treatments.
In 2012, a team led by University of California Berkeley biochemist Jennifer Doudna became the first to show that CRISPR could be used to edit purified DNA. Zhang and his colleagues followed up a year later with a study showing more specifically that CRISPR could work in human cells. From there, it was off to the races.
Since Doudna’s and Zhang’s papers came out, the number of peer-reviewed articles published per year on the subject of CRISPR has grown more than 15-fold, according to an analysis by University of Washington biochemist Ian Haydon. The technology is being used to research a wide range of human diseases; to detect Zika virus at low cost; to improve production of rice, pork, mushrooms, bananas, and other foods; to produce malaria-resistant mosquitoes; and many other applications.
In September 2018, researchers from an American biotech company announced the preliminary results of the first-ever clinical trial to edit the genes of a living person inside their actual body, using a CRISPR-like technique called zinc-finger nucleases. The participants were a 45-year-old man from Phoenix, Arizona named Brian Madeux along with four other unnamed patients afflicted with Hunter syndrome, a rare genetic disorder that causes abnormalities in organ development and is often fatal by the time a carrier reaches their teens. The results of the trial were encouraging: A reduction by 50 percent, on average, of the urine sugars that are an indicator of the disease (although it’s too early to tell what exactly caused the reductions or whether they will translate to an alleviation of symptoms).
All of this insight into the potential benefits of CRISPR has also revealed some important risks, including a recent finding that cells with edited DNA could turn cancerous and evidence that between one and five percent of CRISPR edits happen in the wrong place on the genome, with as-yet-unknown consequences.
But in most of these experiments, the risk is not overwhelming. Take Brian Madeux: In the worst possible case, if the treatment somehow proved fatal, the fallout would be contained to him and his peers, who participated voluntarily, with full knowledge of the risks. “I’m old and having Hunter’s has done a lot of damage to my body,” Madeux told the Associated Press. “I’m actually pretty lucky I’ve lived this long.”
Which brings us back to Mitalipov’s embryo study in Oregon. The risks of edits to DNA in reproductive cells, what scientists call “germline” editing, differ fundamentally from “somatic” edits inside a living organism. If a person were allowed to be born from edited germline cells, the changes would be permanent and passed to all that person’s descendants. Germline editing presents a messy, entirely novel ethical problem without a clear solution. For now, and for the foreseeable future, a clinical procedure in the U.S. that sought to implant edited embryos in a woman to carry them through birth would require a human tissue-transfer authorization from the Food and Drug Administration, which is barred by law from even considering any clinical germline trials.
“No scientist has taken the next step, which is to implant [an embryo into a woman], and you wouldn’t find an ethics committee that would let them do so. There is still a line in the sand,” says I. Glenn Cohen, a bioethicist at Harvard Law School. “For some people, even the Mitalipov study crossed a red line.”
One of the first people to raise serious concerns about heritable DNA editing was none other than Jennifer Doudna. In her interview with Specter, Doudna recounted a harrowing nightmare in which a colleague invited her to explain her research to a powerful friend. The friend turned out to be Hitler, with a pig’s face, scribbling detailed notes.
“That dream has haunted me from that day,” she said. “Because suppose somebody like Hitler had access to this—we can only imagine the kind of horrible uses he could put it to.”
In early 2015, Doudna organized a small conference in Napa, CA with about a dozen of the country’s leading biochemists and bioethicists to discuss how human genetic engineering might be done ethically—a kind of updated Asilomar Conference for the CRISPR era that could grapple with familiar ethical questions in the context of new science.
“When things become technically feasible,” says University of Wisconsin’s Charo, who attended the conference, “you have to confront whether you’re willing to lose the benefit because of some principled objection. [CRISPR] raises a host of questions that have never been answered before, and the goal was to think about this now, before it becomes a major part of the social scene.”
The attendees were in agreement about the technology’s transformative potential in curing human disease and in other nonhuman applications. But, Charo says, “When it came to the germline stuff, it was clear that it wasn’t ready for primetime. There were too many uncertainties and the risks were way too high.”
The attendees produced an essay for the journal Science in April 2015 that “strongly discouraged…any attempts at germline genome modification for clinical application in humans.” That essay touched off a global ethical reckoning that is still unfolding today. As the science surges ahead, uncertainty and disagreements abound. Yet there’s wide agreement among ethicists that society needs to catch up to the science before the opportunity to press the brakes is lost.
“The time to address these moral questions is when they’re coming over the horizon,” Nuffield Council on Bioethics’s Mills says. “Not when they’re standing on the threshold and knocking on the door.”