Paper on 1st use of CRISPR in normal human embryos: problems remain

The first report of the use of CRISPR gene editing in normal human embryos was published today as a short paper from a team in China. There have been rumors for over a year that more CRISPR human embryo papers were coming including some using normal embryos. Here’s one and we can now expect more even as there remain scientific and ethical discussions about this kind of work.

You can read the actual paper Tang, et al. here, published in the journal Molecular Genetics & Genomics. This work was published by Jianqiao Liu’s lab. They attempted editing in both abnormal (3PN)  and normal human embryos. Figure 1b from the paper of CRISPR’d nonviable embryos, is shown above.

Some proper gene editing was reportedly evident after injection of CRISPR in normal human zygotes. Further, the efficiency of the genetic modification of the CRISPR’d embryos was higher in the context of using healthy embryos than in previous reports that used nonviable embryos and in the nonviable embryos used in this same study.

But major problems remained such as incorrect editing (making of a disruptive Indel rather than a correction) and quite a bit of mosaicism. While they did not detect off-target effects at a handful of specific predicted possible off-target sites or by some WGS, such sites could still exist.

This is an interesting paper, but very short and with major tech hurdles evident as well as only 6 embryos analyzed, there’s much more to learn about this technology. I see it mainly as a tool for doing human developmental biology studies and even there it must be done in an ethical, transparent, institutionally approved, and cautious manner with bioethical training in advance.

I’m not convinced that enough discussion at a societal level has occurred yet even about this kind of research use. This is ethically tricky work. Here is the ethics statement from this paper:

“This study was approved by the ethics committee of the Third Affiliated Hospital of Guangzhou Medical University, numbered [2015] No. 068. The methods used in the present study closely followed the guidelines legislated and posted by the Ministry of Health of the People’s Republic of China. The patients involved in this study knew about and understood the usage of tripronuclear zygotes, immature oocytes and leftover sperm, and voluntarily donated them after providing informed consent.”

It would be wildly unethical to use this in humans now or any time soon and very unsafe. The authors themselves conclude:

“… the use of CRISPR/Cas9-mediated gene editing in reproductive clinics is not a current option due to both ethical and technical issues (safety, mosaicism, and other factors).”

I’m also still quite skeptical about the actual need, even hypothetically speaking, for this technology from a clinical perspective given established embryo screening methods like PGD/PGS. Yet still some people talk about stepping-stones toward using CRISPR in the germline in humans. What about future clinical use versus trait enhancement? Slippery slope here?

A practical conundrums here is that there’s a fairly simple switch to go from what was reported in this paper as research to instead have someone go rogue and implant the same kind of embryos in a surrogate to try to create a human being. What’s to stop that?

One thing seems certain: there are going to be many more research reports in the coming 1-2 years on the laboratory use of CRISPR in normal human embryos. Researchers in other countries have received approval to do such experiments even as it is not currently permitted in the U.S. So far there has not been much transparency from the researchers doing this kind of work prior to publication, which is unfortunate.

After I’ve had more time to read this paper, I plan to do a follow up post.