It was, perhaps, inevitable. Once we gained the ability to modify the DNA of an organism, it was only a matter of time before we turned that technology on ourselves and our offspring.
Now, Chinese scientists have edited the genome of a human embryo. Their work was quietly published late last week, on a Saturday, in the little-known, open-access journal Protein & Cell, an unusual way to introduce a first-of-its-kind study.
Typically, such results usually appear in the pages of a handful of respected journals like Science or Nature and are surrounded by a flurry of publicity. The lead researcher, Junjui Huang of Sun Yat-sen University in Guangzhou, attempted to publish in several journals but was turned down out of ethical concerns. David Cyranoski and Sara Reardon unearthed the paper and brought it to wider attention in an article they published late yesterday in Nature’s news section.
The journals may also have balked at the mediocrity of the science itself. “It came up with relatively non-break through results,” says George Church, a professor at Harvard University. It was “a fairly technical paper that didn’t provide any brand new insights.”
“Ethically, it is of huge significance,” says Arthur Caplan, a professor of bioethics at New York University. “The paper is much more interesting as an ethics paper than it is as a science paper. The science isn’t going to be impacted in any way by the appearance of this paper.”
Familiar Methods, Unfamiliar Sources
Much of the paper’s experimental method retraces well-trodden ground. The team used the CRISPR-Cas9 genome editing technique, a relatively new but powerful and widely-used method that allows scientists to modify genes more rapidly than before. Though the molecular machinery was first demonstrated as an editing technique in 2012, scientists have quickly become adept at wielding it, to the point where researchers at various levels—from undergraduates to tenured professors—are using it in labs around the world.
The Chinese team’s target was the gene responsible for β-thalassaemia, an inherited blood disorder that can lead to severe anemia. In that sense, they were on the right path. “I think there’s tremendous promise in genome editing for blood disorders, and other disorders, but particularly blood disorders,” says Dr. Daniel Bauer, a professor and blood disorder researcher at the Harvard Stem Cell Institute. But, he adds, this and other disorders could be corrected by altering a person’s blood stem cells. In that case, “one wouldn’t necessarily need to modify the germ line to have a benefit in this kind of blood disorder,” he says. Dr. Suneet Agarwal, an assistant professor at the Harvard Medical School who studies gene therapy and bone marrow disorders, agrees. “I don’t think it’s safe to try and achieve a clinical cure with this type of technology. We already know that it has a long way to go in terms of its development.”
Huang and his team said they collected embryos with the mutation from a nearby fertility clinic, according to Cyranoski and Reardon’s reporting, though little else is known about how they were created or obtained, Caplan points out. The researchers chose to modify tripronuclear zygotes, which are single-celled embryos that have an additional set of chromosomes. Humans, having two copies of each chromosome, are diploid. So while a triploid embryo may develop for several days or weeks, it ultimately has an extremely low chance of survival.
Using tripronuclear zygotes allowed the researchers to study whether their edits took hold and how they affected early development. Since the embryos were unable to develop into viable fetuses, it provided the team with a modicum of ethical cover. But it also prevented them from saying anything about the viability of the modified embryos.
Even then, the results weren’t promising. The researchers started out with 86 embryos, but just 71 made it to the end of the study. Of those, 54 were tested, and the team discovered that only 28 had successfully been modified. Worse, the CRISPR scissors missed their target often enough to be worrying. Two of the six embryos Huang’s team sequenced for off-target mutations were found to contain mistaken edits.
Despite the fact that the embryos weren’t viable, many scientists are concerned that Huang and his group plowed ahead before the rest of the community had arrived at a consensus on how to proceed. Back in the 1970s, when researchers first discovered how to splice new bits of DNA into a genome, a technology known as recombinant DNA, they held a conference at Asilomar in California in 1975 to hash out a number of guidelines. In January of this year, scientists met in Napa, California, to do the same for genome editing. They identified a number of guidelines, including calling for a moratorium on any modifications to the earliest phases of development, known as the germline.
“When you cross the germline bright line, you’re also opening the door to eugenic reasons—improvement, enhancement—not just disease,” Caplan says. The scientific community, he adds, hasn’t “even talked about that very much.”
Modifying the germline is ethically debatable, possibly perilous, but also potentially powerful. With current gene therapies, clinicians must modify every targeted cell in the body, which could number in the trillions. But in a zygote, the stage at which the Chinese group worked, they only have to modify one. As the embryo divides, every subsequent cell should retain the modifications. But if the editing technique fails to cut in the right place, as it did in several of the Chinese group’s modified embryos, every cell will also carry unintended edits, potentially introducing new, deleterious mutations. Furthermore, in the Chinese study, not every cell in the tested embryos contained the modifications. That kind of defeats the purpose of editing the germline.
Still, Church thinks this sort of experimentation should be happening, just at a more careful pace. “I’m one of the advocates of going forward cautiously,” he says. “This is one of the experiments I’m sure everybody would like to see.” Though there weren’t any breakthrough results—if the Chinese group had succeeded, Church points out, their work would certainly have been considered “more important”—he does see some value from their work. “It’s important for other safety and efficacy steps, and they even mention ways that you could improve the efficiency and specificity in the future.”
Kevin Esvelt, a technology development fellow at Harvard’s Wyss Institute, thinks this study could help put the brakes on any fast-movers in the field. “It’s a basic first step that provides a nice cautionary tale warning against clinical attempts any time soon.”
Despite many scientists’ reservations, this research isn’t likely to stop. Huang is hoping to refine his technique, Nature reports, either by tweaking his CRISPR-Cas9 system or using another gene editing technique like TALENs, which is more accurate and should lead to fewer off-target mutations. Furthermore, Huang’s group is not alone, Cyranoski and Reardon report. Four other groups in China are rumored to be working on editing human embryos.
To give the scientific community and the general public more time to consider the issue, Caplan thinks we should ask researchers to stop voluntarily. “I think we should have a moratorium,” he says. “Journals should not accept papers right now.”
“This experiment stirs attention to the fact that we need to have both national and international discussions about how to proceed, if at all,” Caplan adds. “But if we’re going to do it, we don’t do it by publishing a meaningless experiment in a third-tier journal. That’s not the way to begin.”