No recent biomedical experiment has caused more consternation than He Jiankui’s creation of the first gene-edited babies, in 2018, which was widely seen as dangerous, unethical, and premature—and which led to his incarceration by China. Now, an international committee has concluded that gene-editing methods, despite substantial improvements, are still far from mature enough to safely introduce heritable DNA modifications into human embryos.
But they might be one day, in rare circumstances, adds the panel, calling for the formation of a global scientific body that would review proposals for what it calls “heritable human genome editing” (HHGE) and try to influence whether countries decide to allow its use. The group, which today released one of the most in-depth reports on the topic yet, spells out in great detail genetic situations that HHGE could address and the strict oversight that clinicians in the future must meet before again creating humans with modified DNA that they can pass on to offspring.
For more than 1 year, the International Commission on the Clinical Use of Human Germline Genome Editing reviewed the scientific literature on CRISPR and other ways to modify DNA, held public meetings and webinars, and consulted scientists, physicians, ethicists, and patient groups. The 18 members of the commission—who come from 10 countries and, as the report notes, include “experts in science, medicine, genetics, ethics, psychology, regulation, and law”—agreed with earlier groups that concluded no one should follow in He’s footsteps anytime soon. CRISPR—the genome editor He used, and refined versions of it—they concluded, still cannot “efficiently and reliably” make precise changes without causing “undesired changes in human embryos.”
The report stresses that it focuses on “initial clinical use” of HHGE, and says the field needs to be closely monitored and frequently reevaluated. “There are a lot of gaps in our knowledge and further research is needed,” Kay Davies, a geneticist at the University of Oxford who co-chaired the commission, said at a briefing today.
Organized by the U.K.’s Royal Society and the science and medicine branches of the U.S. National Academies of Sciences, Engineering, and Medicine, the commission aimed to describe a “responsible clinical translational pathway” that could move genome editing from the lab to assisted-reproduction interventions for human diseases. The report largely steers clear of the complex social and ethical implications of creating gene-edited babies. But it does delve into the governance of the issue, notably calling for creating an International Scientific Advisory Panel to assess proposed uses of HHGE, provide regular updates about related technologies, and review clinical outcomes if an edited embryo implanted into a mother is born. It also recommends the creation of an international mechanism by which a clinician or researcher could report plans for or uses of HHGE that they find concerning—in essence, a hotline for whistleblowers.
The commission’s foray into such issues has perturbed some. “The report strays beyond its scientific remit,” Sarah Norcross, director of the Progress Educational Trust, a charity focused on helping people with infertility or genetic conditions, said in a statement released by the U.K. Science Media Centre. “The World Health Organization (WHO) is still deliberating on the governance of genome editing, and should not feel constrained by this report's governance recommendations if it sees fit to deviate from them.”
The genome editing commission categorized potential uses of HHGE, creating a six-level hierarchy that ranges from the most to least compelling rationales to take the risk. The use of HHGE that is easiest to justify, they said, would be helping those rare couples who, even with in vitro fertilization (IVF) and screening of embryos, have little or no chance of having a baby that does not inherit a genetic condition—for example, Huntington disease, cystic fibrosis, beta thalassemia—that will cause “severe morbidity or premature death.” The report stresses that these situations are few and far between. People have two copies of most genes, one inherited from the mother and the other from the father. For a so-called recessive disorder such as cystic fibrosis, there are maybe one or two couples in the United States who both are “homozygous” for this mutation—meaning in their inherited pair of the gene—and would produce an affected child. In dominant disorders, like Huntington, a child needs to inherit only one mutated gene to develop the disease, so one homozygous parent, also a rarity, inevitably would pass on the disease to all embryos.
If HHGE is allowed, the panel said, any embryo edit should only “specifically change one DNA sequence into a specific desired sequence” that is common in “the relevant population.” This means the simplest, most frequently used form of CRISPR, which can cripple genes but does not fix them, should not ever be used in embryos; in He’s controversial experiment, for example, he attempted to knock out a gene and make the children’s cells resistant to HIV infection.
“I welcome the commission’s report, which continues to add depth to the ongoing global conversation about the science of germline editing,” says Alta Charo, a bioethicist at the University of Wisconsin, Madison, who is part of a committee organized by WHO that is examining how to best govern this controversial arena.
Harvard University chemist David Liu, who has pioneered improved genome editing technologies that borrow from CRISPR’s toolkit, describes the report as “thoughtful, balanced, and well-bounded.” But he still has misgivings about whether HHGE should ever be allowed. “I continue to struggle to imagine plausible situations in which clinical germline editing provides a path forward to address an unmet medical need that cannot be provided by other options,” Liu says. He and others stress that preimplantation genetic testing (PGT), which IVF clinics routinely use, could avoid the need for most human embryo editing. In all but the rarest circumstances, it would allow couples to select and then implant embryos that did not have the disease-causing mutations borne by parents.
There are some couples, however, who have a high likelihood of PGT failing to give them an unaffected child, and this is the one exception to the second-tiered category in the report. The third category of HHGE uses is for genetic diseases that have less serious effects and may also be corrected or treated, like deafness, for which there are now cochlear implants.
In the wake of He’s 2018 revelation, Denis Rebrikov, a DNA sequencing specialist at the Pirogov Russian National Research Medical University, has pursued a project to correct a deafness mutation in couples who each have the aberrant gene. Rebrikov, who is not yet satisfied he can safely edit a human embryo and so has not sought Russia’s approval to move forward, says the cases for which the commission would allow HHGE are so rare that the panel’s endorsement is meaningless. “In this formulation, it is a ban on editing the genome of the embryo in principle,” Rebrikov says.
Norcross echoes that criticism, calling the report’s criteria for human embryo editing “far too narrow.”
Diseases caused by several genes represent the fourth category of HHGE uses. The fifth, and most taboo in the eyes of the panel, would involve genetic enhancements of children, making make them resistant to HIV, better at sports, taller, smarter, or even able to withstand radiation exposures encountered during extended spaceflight.
A key danger of editing human embryos is that unintended “off-target” DNA changes will occur and not be detected before embryo implantation. The panel explores in detail a possible solution: editing the stem cells that produce human sperm or eggs before using those gametes for IVF. “This would have significant safety implications since the issues of on-target editing fidelity and avoidance of off-target events could be largely settled before any gamete is considered for use in the creation of an embryo,” the report notes.
Fyodor Urnov, a CRISPR researcher at the University of California, Berkley, says the report confirms the widespread consensus that, at best, there’s only a niche justification for editing human embryos. “The careful guidelines laid out in this report show that the list of problems that could be addressed by such editing is, in fact, quite small,” Urnov says. “It is an open secret in the gene-editing community that human reproductive editing is a solution in search of a problem.”