A Nature journal has posted a editor’s note to a recent letter on potential unintended consequences of CRISPR gene editing, after an executive at a company trying to commercialize the technology said the paper should be retracted.
The original article, published on May 30 as a correspondence in Nature Methods, suggested that using CRISPR in mice can lead to unexpected mutations. But last week, the journal added an “Editorial note” online. Nature Methods says the notice is not an expression of concern, which would be a stronger suggestion that the paper is problematic; it simply wants to alert readers to the fact that, as the note states:
…the conclusions of this paper are subject to criticisms that are being considered by editors. A further editorial response will follow the resolution of these issues.
As reported by Technology Review, the prospect of CRISPR causing widespread collateral genomic damage hurt the stock prices of Editas Medicine and Intellia Therapeutics, which are trying to develop CRISPR-based gene therapies. In response, researchers at both companies have written separate letters to the editor criticizing the methodology used in the paper. Editas’s scientists wrote first, joined by the firm’s co-founder and renowned geneticist George Church at Harvard University; Intellia followed less than a week later, posting the letter to its website.
This isn’t the first time we’ve seen corporations calling for the retraction of articles that aren’t good for their bottom line. The episode raises questions about how critics and authors alike should engage with ideas as they develop in the lab and in the literature.
Church told us that he began discussing the paper with other CRISPR researchers as soon as he found out about it, and that several of his Editas co-founders are planning their own replies to the journal.
Keith Joung, of Massachusetts General Hospital, told us he’s one of them; he has obtained data from the original researchers and is analyzing them in his lab.
Intellia CEO Nessan Bermingham has been the most forceful critic. Prior to the note addition, he told TechReview:
Given the issues around the design and interpretation I believe it is appropriate that the Nature Methods editorial board retract this paper.
Church told Retraction Watch he wasn’t sure if it deserved a retraction yet, “but it’s pretty darn close,” he said:
It’s not that the data are wrong, it’s that the experiment was not designed to support the question they were asking.
There should at least be an interpretation clarification.
A Nature spokesperson told us that the editorial note does not have its own DOI; it’s a response to “technical criticism raised in regard to this paper, and [the] editors are investigating this criticism.”
Nature wouldn’t say whether the corporate letters helped push them to issue the note, which was posted “following careful consideration of all communications sent to us:”
Our policy is to consider all criticism of work we publish very carefully and to publish relevant communications following appropriate technical review. However, for reasons of confidentiality we cannot comment on individual submissions to the journal.
Study co-author Alexander Bassuk of the University of Iowa told Retraction Watch that his team was not expecting this kind of response.
We were not thinking about industry at all. We simply made an unexpected observation using unbiased whole genome sequencing and wanted to share it with the research community.
He has been in contact with the journal editors about the editorial note, but they’ve not mentioned the possibility of an expression of concern, a correction, or a retraction, Bassuk said.
In their letters, the Editas and Intellia researchers suggest that the Iowa team chose improper controls, and should have performed sequencing of the parent mice to make sure the genetic variation they observed is due to CRISPR editing, and isn’t inherited. They also pointed to the small study size — two mice, one control — as a shortcoming.
Bassuk told Retraction Watch that they explain in the paper they used a so-called “colony control,” a similar mouse cohabiting with the subjects, rather than a mouse from the same litter:
Similar papers in Nature Methods and other journals have used the same [colony] control. Our study was designed the same way as previous in vivo studies – none of which sequenced parental controls.
But Church told Retraction Watch that if the authors had “contracted just about anybody who had worked on inbred strains or CRISPR in mice,” they would have learned that different mice from the same litter can have 1,000 genomic differences between them. “Two mice from the same colony are even less related,” Church said:
It’s enough to explain the result. If they haven’t ruled out that it’s due to the strain differences, it’s probably due to the strain differences, based on published strain characterizations.
As for how the journal is handling the situation, Church said of the editor’s note:
This seems like an adequate response for now, although to many, the correct explanation is already documented.
And it’s not just the study’s authors who missed this explanation, he told us, but the editors and reviewers as well:
I think everybody should have caught it.
Hat tip: Antonio Regalado
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“But Church told Retraction Watch that if the authors had “contracted just about anybody who had worked on inbred strains or CRISPR in mice,” they would have learned that different mice from the same litter can have 1,000 genomic differences between them. “Two mice from the same colony are even less related…”
I am sorry? Why then strain designation and vendor code is not mandatory in Science and Nature journals? I see only “C57BL6”. One reviewer tried to argue with me lately that FVB and FVB/NCrl are two different strains.
How can a respectable journal accept a paper base on a single experiment containing only 3 mice? What kind of science is that?
splashy…
Two mice and one control one is certainly somewhat too few, but in medical research it is not uncommon to publish a paper on NGS data from just one patient. A more interesting point is that none of the critiques notices that the data were also compared to genomes of the 36 strains in the Mouse Genome Project. This makes it somewhat more than 2 and 1. A similar story unfolded and was shut down in 2011 when it was shown that multiple CNVs were found in iPSCs.
Due to the experimental design, genetic drift would not account for the observed heterozygosity. The heterozygosity in F03 and F05 cannot be parentally inherited. Based on our standard practice for murine transgenesis, a standard procedure was followed by ordering 3-week old oocyte donors and 8-week old stud males from Jackson Labs. We did not breed these mice in-house. All the stud males and oocyte donors were ordered within a few weeks of one another. In fact, this is what JAX recommends to avoid genetic drift issues as part of their Genetic Stability Program. These freshly ordered mice were used exclusively for the purpose of rd1 repair and were not kept past 3-4 months of age. Based on the JAX order, it’s likely that parents that produced both the stud and oocyte donor were probably siblings, as it is common practice to use sibling matings to generate a colony of inbred mice. Thus, F03 and F05 could essentially be considered clones of one another and would be expected to have a high degree of homozygosity. Instead, we observed extensive heterozygosity. The number of observed SNVs is estimated to take over 3.5 years (even longer with normal backcrossing) and would still be expected to be homozygous. Such a timeline is incongruous with the generation of our mice. Genetic drift could not account for the amount of heterozygosity observed leading us to consider CRISPR therapy as the source.
Does anyone know if this report was peer reviewed?