Almost six months ago exactly, a group of scientists published an editorial in Nature entitled “Don’t edit the human germ line” in response to the rapid development and rising popularity of an accurate and easy-to-use gene-editing technique called CRISPR-Cas9. Their article was a strongly-worded entreaty for the scientific community to cease any and all gene-editing research in human reproductive cells, or the germline. The unknown risks of germline editing on future generations gravely outweigh the possible benefits, argued the authors.
Their words turned out to be like a gate in front of a growing surge of water — quickly the rising tide became too much to contain. Just a week after the Nature editorial was published, another group of scientists, including one of the inventors of CRISPR-Cas9, published a letter in Science calling for a “prudent path forward” instead of a moratorium. The authors of the Science article argued that germline engineering offered real promises — such as that of curing genetic diseases — that were worth exploring.
A month later, researchers in China announced that they had edited genes in non-viable human embryos leftover from in vitro fertilization (IVF) efforts at fertility clinics.
Now, an international group of stem cell experts called the Hinxton Group has endorsed moving forward with basic gene-editing research on human embryos and germ cells. Modifying the human germline provides a “vast scope for applications in human disease and health,” wrote the authors in a statement published to their website on Wednesday. They stopped short, however, of supporting gene-editing for clinical reproductive purposes, warning that the technology is not yet “sufficiently developed.”
Implied in the Hinxton Group’s statement, said Dana Carroll, a professor of biochemistry at the University of Utah who uses CRISPR in his research, is the belief that basic research on germline engineering is inevitable, and that trying to police it would be impractical. “Even though they didn’t say it explicitly, the authors clearly believe that people are going to go ahead and do it,” he said.
Ethical debates over technologies that tinker with human genes are not new, the Hinxton Group acknowledged in their statement. What is new, they believe, is the unprecedented precision, efficiency, and accessibility of CRISPR, as well as the cultural climate in which gene-editing research is taking place.
“Science has grown enormously in both size and geographic diversity, now encompassing many more people from many different cultures and regulatory environments,” they wrote. That, in combination with wider use of related techniques like IVF could mean that people will want to use gene-editing techniques for clinical reproductive interventions long before the science is ready for it, the authors fear.
That’s why, after making their case for basic research on germline editing, the Hinxton scientists spend the rest of their statement outlining ethical considerations for developing and governing gene-editing technologies for clinical purposes. They note, for instance, the need to prioritize medical interventions based on criteria like magnitude and frequency of need, feasibility and existing alternatives.
Carroll noted that it will also be important to consider the rights of the unborn individual whose genes are being edited. “If we’re talking about correcting a disease gene, then I think the individual who’s ultimately born with that correction is not going to have much to complain about,” he said. When it comes to modifications that are not life-saving, however, consent can get complicated.
“Just to give a ludicrous example, consider if parents decided they wanted a child that had six fingers on each hand,” proposed Carroll, “If hypothetically something like that could be done with genome editing, the child who’s born with extra digits could not have been consulted and might be upset at having that change made.” It might sound like an absurd scenario, said Carroll, but it gets at the grey area between genetic modifications that are clearly beneficial versus those that are more recreational.
In addition to moral considerations, improvements in specificity and efficiency have to be made before CRISPR would be close to ready for clinical application, said Carroll. “The thing most people are worried about is that, in fixing one genetic condition, you would generate another,” he said. “The horror scenarios are things like birth defects or cancer.”
However, those technical improvements are within reach, according to Carroll. He said he’d be surprised if it took more than five or ten years for CRISPR to be ready, technically-speaking, for clinical research. “Fifteen years ago, when all we had were zinc finger nucleases to do this sort of editing, if we tried to do germline gene correction we most certainly would have done more harm than good,” said Carroll. “Now we can see quite clearly what we need to do technically to make this an effective approach to therapy.”
Arthur Caplan, the director of medical ethics at New York University’s Langone Medical Center, however, does not think clinical applications of CRISPR will be happening so soon. “We’ve still got a lot of animal work to do,” he said. “Human embryo work is interesting, but to me it should be completely theoretical. We don’t know what we’re doing yet.”
Caplan said that similar processes, such as developing mitochondrial transplants, getting stem cell research to clinical trials, and figuring out gene-editing for non-reproductive cells, took a decade or longer. “I’m not optimistic that for some reason germline editing is going to be easier,” he said.
Furthermore, said Caplan, the general public is a long way from accepting research strategies like creating embryos specifically for gene-editing research, rather than relying on those left over from IVF — a step the Hinxton Group says will be necessary to answer certain research questions.
A low public opinion of germline editing, however, might not necessarily prevent clinical research from taking place, according to Carroll. “One of the things that I’ve learned by being involved in some of these discussions so far is that when it comes to their own health or the health of family members, people are often very willing to take more aggressive steps than you might suspect,” he said. “I wouldn’t be surprised if germline editing technology becomes quite widely accepted, even with some significant number of people still feeling very uncomfortable with it.”
Ultimately, if germline editing promises to save lives and alleviate human suffering, Carroll believes it may be difficult to fight. “I think that a lot of people may in the end say, ‘yeah, if it’s really safe and effective, let’s do it,'” he said.
Debra Mathews, a bioethicist at Johns Hopkins and a member of the Hinxton Group’s steering committee, agreed that it’s important to address basic research on germline editing as a present-day reality, and clinical research as a not-too-distant reality. “This research is already happening to some degree and to ignore that fact leads to poorly informed ethics, science, and governance,” she said. “My hope with this statement is that it will help shape and inform the ongoing and planned deliberations surrounding this set of technologies.”