Journal Defends Its Publication Of Controversial Human Embryo Study

Illustration for article titled Journal Defends Its Publication Of Controversial Human Embryo Study

The science world was rocked last week by news that geneticists in China had modified the DNA of human embryos. In the face of mounting criticism, science journal Protein & Cell has issued a formal response explaining why it chose to publish the controversial study.

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As we reported last week, Junjiu Huang and colleagues at Sun Yat-sen University in Guangzhou made history by using the CRISPR-Cas9 gene-editing system to alter the DNA of non-viable human embryos. The researchers attempted to remove a mutation that causes beta thalassemia, a lethal blood disorder. Many of the resulting embryos were either unaffected or badly mutated. Science journal Protein & Cell, a monthly peer-reviewed journal published by Springer Science+Business Media, published the study despite these shortcomings, and despite some apparent ethical breaches that led Science and Nature to reject the study outright (though both journals have yet to make it precisely clear why they rejected the paper).

In response, Protein & Cell managing editor Xiaoxue Zhang has crafted an explanation defending the decision to publish the paper, saying it did so with “extraordinary care, consideration and deliberation,” adding that the unwanted mutations substantiated “the concerns that the therapeutic application of these new techniques could have unpredictable safety risks.” Zhang continues:

Because germline modification is permanent and heritable, it should be given the particular concerns...In this unusual situation, the editorial decision to publish this study should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw immediate attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos.

ScienceInsider’s Jocelyn Kaiser explains how the journal’s editor-in-chief, Zihe Rao, responded to allegations that the paper was accepted just two days after it was submitted, and thus insufficiently peer reviewed:

“Due to the scientific value and ethical dispute of this study, we not only conducted scientific peer-review, but also consulted related publishing and ethical experts,” wrote Rao, a structural biologist at Nankai University in Tianjin, in an e-mail to Science. “The authors also revised the manuscript based on our suggestions,” he added. He explains that the journal typically reviews submitted papers within 2 weeks, but for significant work they expedite the process. (A Springer representative tells Nature News that review went quickly in part because Huang and his colleagues also submitted the peer-review comments provided to them by Nature and Science and had revised the paper with them in mind.)

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Huang et al. were also accused of making some serious ethical breaches during the experiment. In response, Springer told Nature News that

the journal had checked the researchers’ institutional approval and the consent forms from the embryo donors. They also confirmed that the study was compliant with the Helsinki declaration on human-medical-research ethics and with Chinese law.

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It’s good that these discussions are happening. There’s still a lot of confusion over the study, and why it was conducted in the first place. But the claim that this research was published to “raise the alarm,” as though we didn’t know already that this science isn’t ready for producing babies, strikes me as suspicious.

Top image: Dr. Yorgos Nikas/SPL

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DISCUSSION

forestbrooklyn
Forest

I have trouble believing that any serious review was done of this paper. The Huang group did the work for this study (I’m not calling this an experiment) in triplonuclear (3PN) cells, which already have a lot of differences to normal cells.

They looked for evidence of off-target effects in 293T cells before trying out their CRISPR-Cas9 cassette in the 3PN cells. Why? Those cells come from totally different sources and can be expected to have totally different methylation patterns. Methylation makes DNA more or less open to being tampered with by other molecules. If a particular stretch of DNA is not open, then you wouldn’t expect to see an off-target effect acting on it. Are the methylation patterns equivalent between 293T and 3PN cells? I doubt it and they don’t address it.

They showed that they can edit a gene in these cells in a targeted manner. Great. So has every other researcher, who has published a CRISPR paper. Is what they did in any way novel? In a way, it is. They managed to publish a paper that contains no real controls or experimental rationale. That can’t be easy.

They state in the discussion section: “Our whole-exome sequencing result only covered a fraction of the genome and likely underestimated the off-target effects in human 3PN zygotes.” Considering that they are working with uncharacterized tumor cells, their sequencing probably also underestimated the differences between individual cells in the same bloody zygote.

The next two sentences in that same paragraph: “In fact, we found that even with an 8 bp mismatch between the G1 gRNA and C1QC gene (Fig. S6), the CRISPR/Cas9 system was still able to target the C1QC locus in human 3PN embryos (Figs. 3B and S5). Such off-target activities are similar to what was observed in human cancer cells.” Being cancer cells, one expects them to lack functioning DNA proofreading and repair enzymes. How are such enzymes expressed in these cells, relative to those of a normal zygote? The issue is not addressed. Would healthy cells be less prone to these off-target effects or not? That would be a pretty important piece of knowledge for anyone looking to move this technology towards a clinical setting. Of course, that comparison was not done. Obviously, doing so would involve a massive ethical violation, but the point is; if you can’t include controls in your experiment, then of what value is doing the experiment in the first place?

I’m risking tl;dr, so I’ll cut it off here. In the end, though, this paper is a scientific embarrassment and the attention that it brings to gene editing research can only do harm by reinforcing every baseless fear about mad scientists playing god with human embryos. There’s a lot of good science being done with CRISPR technology and a lot of the people doing it do so with ethical concerns firmly in mind. This group in shitting in everyone’s cheerios.