Nature Expresses Concern (and Creates Confusion) Over Hotly-Debated Paper

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Like science itself, scientific papers are not perfect. When a disagreement arises, there is a mechanism in place for disputes. When a mistake is found - and the debate gets loud enough - editors of the publishing journals issue what is called an "expression of concern" or EoC. EoCs are indexed by the publishing database Pubmed so that official complaints are evident. 

But, when a controversy recently erupted over one paper in the journal Nature, the editors handled it a different way. And some people are wondering why. 

The recent paper, Correction of a pathogenic gene mutation in human embryos, which was published in late August, created quite a splash. Why? An international team of researchers used the gene editing technique CRISPR–Cas9 in human embryos to correct a mutation in the gene MYBPC3. This mutation causes a thickening of the heart muscle that can lead to the condition hypertrophic cardiomyopathy - the leading cause of sudden death in young athletes. 

In particular, two key CRISPR-related issues - ones that are top topics of discussion in the gene editing world -were scrutinized. The first issue is off-target mutations - making a change to the genome that was not intended. The other matter in question is another important concern - the generation of mosaics. This happens when some cells, but not others, are genetically altered which results in a mixed population in the embryo. 

In the Nature paper, the authors claimed to have seen no evidence of off-target genetic changes and generated the formation of only a single mosaic, in an experiment involving 58 embryos. But are these legitimate claims? 

Since gene editing of human embryos is such a hot topic, findings like these are bound to be a big deal, since this is the type of paper that many journals would fall over themselves to publish. But other CRISPR experts were skeptical and raised concerns in a commentary entitled "Inter-homologue repair in fertilized human eggs?" only a week after the original paper. In the commentary, six genome editing experts raised red flags regarding the conclusion, the biggest of which is how the genomic changes were verified. Specifically, the original researchers provided evidence that the mutation was no longer in the cells, but the critics were not satisfied. Instead, they wanted to see direct evidence of the genetic correction. In other words, the absence of the mutation alone was insufficient to support the claims. 

The criticism took the wind out the sails of the Nature paper, and also made the editors at Nature think twice because this statement was recently added to the end of the paper:

"Readers are alerted that some of the conclusions of this paper are subject to critiques that are being considered by editors. Some of these critiques have been publicly deposited in preprint form. A further editorial response will follow the resolution of these issues." 

But, a wishy-washy note tacked onto the end of a paper is not the traditional path for questioning the validity of a paper and leaves scientists confused. The paper stood up to the test of peer-review but, did Nature push it through too quickly and without enough stringency? Science should elicit healthy debate - especially when the topic is human gene editing. But, if one (non-peer reviewed) commentary is enough to create the addition of an editorial comment - why are those concerns not enough to file a formal expression of concern? 

When the online site Retractionwatch asked Nature about their choice to only write a note, they responded - 

"We decided to issue an Editorial Note to indicate that we are aware of the discussions in the community, were looking into them and felt it was appropriate to flag them alongside the paper.  We did not feel we had enough information to issue a formal Expression of Concern, which could be added later, as could any other course of action, should they be deemed appropriate once we have better assessed the discussions." 

It is hard to know where this science stands and this could end up being a big deal. We're looking forward to Nature providing the next step in this story.  


1) Correction of a pathogenic gene mutation in human embryos