September 30, 2020

The Niche

Knoepfler lab stem cell blog

Researchers in China make genetically modified human embryos

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.

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.

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.Liang, P. et al., group in China gene editing human embryos

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.

 

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.”

GM human embryo reviewWould 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.

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