Concerns surface on Chinese paper on genetic modification of human embryos

The paper that came out Wednesday from a research group in China reporting the first genetic modification of human embryos has sparked a lot of discussion. Some concerns about this paper have surfaced.

GM human embryo review

2-day review? The paper (HT to John Borghi) was in review only from March 30-April 1 — so at most 48 hours. Really? That certainly raises a red flag of inadequate or absent peer review. That kind of “review” in the past with high-profile papers has been associated with a high risk of errors being found later in such papers. I’m not saying that will happen here, but it wouldn’t shock me.

The journal? The paper was also published in the journal, Protein & Cell, which Buzzfeed reports is partially owned by the Chinese government. Could there be some kind of COI there? Also, why was the paper reportedly rejected at more rigorous journals? There have been suggestions that reviewers raised ethical issues, but this remains unclear.

Rushed as evidenced by striking typo. The paper’s abstract has a pretty bad typo in the abstract (emphasis mine) suggesting issues with preparation and peer review again:

Taken together, our work highlights the pressing need to further improve the fidelity and specificity of the CRISPR/Cas9 platform, a prerequisite for any clinical applications of CRSIPR/Cas9-mediated editing.

Of course anyone can make a typo and I certainly do on a regular basis in emails or draft blog posts, but in a published paper abstract?

Unnecessary and premature? Another question to ask here is whether doing these studies specifically in human embryos was at all necessary or provided novel insights specifically because it was done in human embryos (as opposed to limiting the work to say just 293 cells as they did in part of the paper). So far, I don’t see much if anything that has been gained from using human embryos here other than maybe a hint of unique DNA repair. Jennifer Doudna has raised that kind of concern with the paper:

“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.”

The bottom line seems to be a final question of whether publishing this paper now and including human embryos was prudent given all the circumstances. I’m on the fence.

What do you think?

Scientists in China create genetically modified human embryos: ‘A cautionary tale’

Update: apparently this paper (HT to @JohnBorghi) was only reviewed for 2 days (see image at bottom of post), raising major concerns about the depth of peer review.

Rumors have been flying for months that researchers in China and possibly elsewhere were shopping papers around at high-profile journals that reported gene editing and genetic modification of human embryos.

The rumors were right.

Today, one of the Chinese teams of researchers published their paper on genetically modified (GM) human embryos in the journal Protein & Cell.

The paper is open access so that’s good.

According to an excellent news piece in NatureNews by David Cyranoski and Sara Reardon, the paper had been submitted and rejected at top journals such as Nature and Science due at least in part to ethical issues. I had heard the same thing.

NatureNews quoted George Daley on this development:

“I believe this is the first report of CRISPR/Cas9 applied to human pre-implantation embryos and as such the study is a landmark, as well as a cautionary tale,” says George Daley, a stem-cell biologist at Harvard Medical School in Boston. “Their study should be a stern warning to any practitioner who thinks the technology is ready for testing to eradicate disease genes.”

The paper, entitled “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes” came from the lab of Junjiu Huang and is Liang, P. et al.

The authors apparently sought what they thought would be a relatively more ethically acceptable way to go by using the abnormal human 3PN embryos (that cannot develop normally because they have two sperm genomes) as a basis to create GM human embryos.

Liang, P. et al.

The team reported that the CRISPR gene editing in the human embryos didn’t go well (see Figure 2A above from the paper summarizing the basic numbers):

“We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic.”

Specific mutations in the HBB gene can cause beta thalassemia.

To make matters worse technically, there were high levels of off-target activity:

“These data demonstrate that CRISPR/Cas9 has notable off-target effects in human 3PN embryos.”

According to the NatureNews piece the issue was raised by some that the problems with the CRISPR-Cas9 targeting reported in this paper could have been due to the embryos being abnormal.

While formally possible, I think that is unlikely to be the whole explanation. I’m with George Daley on this being a cautionary tale.

It is worth noting that the current study had institutional ethical approval according to a statement in the paper:

“This study conformed to ethical standards of Helsinki Declaration and national legislation and was approved by the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. The patients donated their tripronuclear (3PN) zygotes for research and signed informed consent forms.”

Would an institutional review board in another country such as the US have given the green light to making GM human embryos? I don’t know.

This study reaffirms the reasons that a pause is needed on in vivo human gene editing studies.

Even though in principle I could support some kinds of in vitro work on gene targeting in human germ cells and even early embryos (see my ABCD plan), I have to admit that this kind of work and the outcomes reported here, where we now can see this in the real world as a paper and not just hypothetically, make me very uncomfortable from an ethical perspective.

I feel like I need to have more time to read this paper carefully and to learn more about how the work was done before coming to more concrete conclusions as to whether it is acceptable from an ethical perspective. In addition, it would be helpful to learn more specifically about why other journals rejected the manuscript and what ethical concerns were raised.

Several other groups in China (and perhaps elsewhere) are conducting similar research and rumor has it that at least one is using normal or near-normal human embryos that have only specific disease-associated mutations.

GM human embryo review