Chinese paper on embryo engineering splits scientific community

The announcement that a Chinese team had altered the genetics of a human embryo for the first time has ignited a firestorm of controversy around the world and renewed recent calls for a moratorium on any attempt to establish a pregnancy with such an engineered embryo. But it has also underscored that although scientists are united in their opposition to any clinical application of such embryo manipulation, they are split on the value of basic research that involves genetically modifying human embryos.

In China itself, where the precedent-setting research is big news and some in the public have expressed concern on the Internet about the embryo experiments, "most scientists are more positive," says Guo-Qiang Chen, a microbiologist at Tsinghua University in Beijing. "My personal opinion is that as long as they can control the consequences they should continue this work.”

That viewed is echoed by many outside of China as well. “I personally would defend the fundamental scientific value of research into gene editing” in human embryos, in part to explore the risks of any potential clinical use, George Daley, a stem cell biologist at Harvard Medical School in Boston, tells Science.

The paper at the heart of the debate, published online on 18 April in Protein & Cell, an obscure Chinese online journal published by an affiliate of China’s Ministry of Education, drew widespread attention only after Nature News reported it online on 22 April. Junjiu Huang and colleagues at Sun Yat-sen University in Guangzhou described how they attempted to use the CRISPR/Cas-9 system, a new technology that makes it easy to modify genes in cells, to edit the hemoglobin-B gene (HBB) in 86 human embryos donated for research by couples at an in vitro fertilization (IVF) clinic. In theory, this could be a way to prevent beta thalassemia, a blood disorder that results when that gene is mutated, but the embryos experimented on were selected because they were not viable; they had an extra set of chromosomes as a result of being fertilized by two sperm.

Two days after being injected with gene-editing molecules, only four of 54 surviving embryos that were tested carried the desired genetic changes; these embryos were mosaic, meaning only some cells had the intended changes. The edited embryos also had a large number of off-target effects, or mutations in genes other than HBB, that could be potentially harmful.

The performance of the technique proved so poor that the researchers emphasized that any clinical use of CRISPR/Cas9 for embryo editing is “premature at this stage." The project was reviewed by Huang’s university’s ethics board and complied with international and national ethical standards, according to the paper. The researchers used abnormal zygotes that would otherwise be discarded, “because ethical concerns preclude studies of gene editing in normal embryos,” they write.

Still, the paper drew anger from some quarters. The Center for Genetics and Society in Berkeley, California, called for a halt to such experiments. Huang told Nature News that the paper was rejected by Science and Nature in part because of ethical concerns. (In an e-mail, Huang initially welcomed an inquiry from Science and asked for a list of questions by e-mail, but then he did not reply.)

Rumors that such a paper was in the works sparked several published opinion pieces a month ago. In a commentary in Science, molecular biologist David Baltimore, president emeritus of California Institute of Technology in Pasadena, and 17 co-authors called for scientists and others to “strongly discourage … attempts at germline genome modification for clinical application in humans.”  (Many countries already ban germline gene modification.)

Several scientists led by Edward Lanphier, CEO of Sangamo BioSciences in Richmond, California, went further in a Nature commentary, calling for a voluntary moratorium on all experiments involving germline gene modification. Although the two groups were “90% in agreement,” they differed on this one point, Lanphier told Science: “We said let’s not perfect these technologies ahead of a conversation whether we should allow this technology.”

In contrast, two co-authors of the Science commentary say that they are comfortable with the Huang experiment. Daley points out that international guidelines developed by the stem cell researchers allow for experiments with human embryos as long as the cells are not allowed to grow for more than 14 days. “To further to inform any debate on whether this technology could be useful for eradicating disease, one has to understand the range of efficacy and off-target mutagenesis,” Daley says.

Harvard molecular geneticist George Church agrees that the consensus has long been that experiments on discarded IVF embryos are acceptable; the only new thing is that the Huang group “used CRISPR, which makes it noteworthy,” he says. Although he does not object to the the reported experiment, Church adds that the results “were fairly predictable.” He says one reason the researchers got so many off-target effects is because they did not use the latest version of the gene-editing technology.

But University of California, Berkeley, molecular biologist Jennifer Doudna, who organized a workshop that led to the Science commentary, says her personal opinion is that the Huang experiment was not necessary because scientists are still a long way from perfecting the CRISPR gene-editing method. “I don't see the value in working with human embryos right now. There’s a lot to be learned by working in other systems,” she says. In her view, the Huang paper provided little new scientific insight and seemed intended to “attract attention.” She is also troubled that, according to the dates noted in the paper, Protein & Cell apparently published the study 1 day after it was submitted. “I have to conclude this was not peer reviewed,” she says.

Neither Science nor Nature’s editorial staff would confirm that the journals reviewed the paper and rejected it in part because of of ethical concerns. In a statement, a Nature representative said the journal sometimes has papers reviewed by a bioethicist. Science issued a statement saying it supports recommendations in its earlier commentary and that while a consensus about germline genome editing is being developed, the journal “will carefully scrutinize all submissions for both technical and societal concerns and consult broadly.”

Chen, who uses CRISPR/Cas9 in his own research on microorganisms, and other scientists in China defend their country's ethical oversight of the new embryo research. Ethical review procedures in the United States and in China are very similar and based on the same principles, says Kehkooi Kee, a stem cell scientist also at Tsinghua, who earned his advanced degrees in the United States. Kee says that at Tsinghua a proposal for such work would have to be vetted by the university hospital's own institutional review board (IRB) as well as by the IRB of the collaborating hospital that supplies the donated embryos. At the national level, he says China's funding agencies do check on whether a grant applicant has the proper ethical approvals. Chen adds that in light of the current controversy, review boards "will probably be more strict," he says.

But he’s adamant the newly published research has value even if some consider its results a failure. Determining if these embryo engineering techniques can be useful in curing disease can be achieved "only by doing this kind of research; we might possibly see some positive outcome resulting from many failures," he says. Kee also defends the work. "The conclusion is valid, they are not hiding anything, and they are not saying this technique is ready for use in the clinic," he says.

The China work was funded by national grants and rumors continue to circulate that several other China teams have done similar embryo work. In the United States, such experiments could only take place with nonfederal funding because of a long-standing congressional prohibition on using federal funding for any research that destroys or puts at risk human embryos.

Regardless of where scientists stand on this new research, it has highlighted their shared desire to discuss whether, if ever, gene editing should be used in human embryos to prevent disease. Doudna is now helping to organize an international meeting later this year to come up with guidelines. “I think the goal of that meeting is to come together and identify a broader consensus about the appropriate way to proceed with these experiments,” she says. Now that the first human embryo gene-editing paper has been published, she adds, “we feel some urgency.”

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