“The data have spoken:” Controversial NgAgo gene editing study retracted

The author of a 2016 paper describing a potentially invaluable lab tool has retracted it, following heavy criticism from outside groups that could not reproduce the findings.

The paper had already been tagged with an Expression of Concern by the journal, Nature Biotechnology, which included data from multiple groups casting doubt on the original findings. Although the authors, led by Chunyu Han at Hebei University of Science and Technology in China, produced data to support their original findings, the journal has concluded — following “feedback from expert reviewers” — that the additional data “are insufficient to counter the substantial body of evidence that contradicts their initial findings,” according to an editorial released today:

We are now convinced that Han’s decision to retract the paper is the best course of action to support the integrity of the published record.

Here’s a link to the retraction notice, along with a thoughtful editorial explaining the journal’s decision-making.

The notice reads:

We are retracting our study because of the continued inability of the research community to replicate the key results in Figure 4, using the protocols provided in our paper. In this figure we report that the Natronobacterium gregoryi Argonaute can efficiently create double-strand breaks and edit the genome of human cells using 5ʹ phosphorylated single-stranded DNA as a guide. Despite the efforts of many laboratories (Protein Cell 7, 913–915, 2016; Nat. Biotechnol35, 17–18, 2017; Cell Res26, 1349–1352, 2016; PLOS One 12, e0177444, 2017), an independent replication of these results has not been reported. We are therefore retracting our initial report at this time to maintain the integrity of the scientific record. We nevertheless continue to investigate the reasons for this lack of reproducibility with the aim of providing an optimized protocol.

DNA-guided genome editing using the Natronobacterium gregoryi Argonaute” received much attention — and criticism — soon after it was published in May 2016. The paper described a gene-editing technique, known as NgAgo, which initial data suggested might work better than its widely used counterpart, CRISPR/Cas9. It’s already been cited 53 times, according to Clarivate Analytics’ Web of Science, and the findings received much media attention, as today’s editorial notes:

Coverage in the Chinese media was extensive, with headlines heralding the discovery of an entirely new gene editing system. NgAgo was easily the most widely covered paper in China last year; according to media monitor Meltwater, nearly 4000 Chinese news stories cited the Han paper in just the first two months after publication.

However, scientists quickly began to raise doubts about the conclusions. In August 2016, Nature reported:

Han says he receives dozens of harassing calls and texts each day, mocking him and telling him that his career is over — but he is convinced that the technique is sound….The stakes are high. Over the past few years, the CRISPR–Cas9 system has transformed biology. But it has also made scientists hungry for other methods to expand the gene-editing toolkit: NgAgo is one of several that have emerged. “A lot of us are really cheerleading and hoping that it works,” says geneticist George Church of Harvard Medical School in Boston, Massachusetts.

In November, 20 researchers published a letter in Protein & Cell saying they had been unable to replicate the findings. What’s more, they alleged Han’s lab turned them away when they tried to replicate the findings in mammalian cells. Later that month, Nature Biotechnology published an Expression of Concern, including correspondence with data from three groups that cast doubt on the findings.

Here’s what happened next, according to the editorial:

…last December, Han and colleagues and several additional independent groups who contacted the journal provided new data claiming to have reproduced NgAgo gene editing activity. At the time, these data were judged too preliminary by the editors and an external reviewer to warrant publication. We decided to give the original authors and new groups more time to gather additional experimental evidence to bolster their claims.

Now, more than a year after the publication of the original report, we have learned that the independent groups that reported initial success in reproducing the results have not been able to bolster their preliminary data to a publishable level. Similarly, after seeking feedback from expert reviewers, we have concluded that the latest data from Han and his colleagues are insufficient to counter the substantial body of evidence that contradicts their initial findings.

The editorial notes that there have been no signs of manipulation:

Our internal image integrity screening process found no obvious anomalies in the Han paper, a finding echoed by three external reviewers who re-examined the data.

The editorial concludes with an important reminder that this retraction does not represent a failure of the scientific process — in fact, the opposite is true:

Unraveling all the issues surrounding NgAgo didn’t happen in weeks or a few months for a reason. Even simple experiments take weeks to prepare, perform, analyze and troubleshoot. It does not help that the efforts of those carrying out replication studies often go unrewarded—it is unglamorous, unfunded and thankless work.

Little wonder then that to a 24/7 media and public that desire quick, definitive answers, the process of post-publication peer review can seem frustratingly slow. But when it comes to biology, answers are often not definitive. And when it comes to replication studies, the one thing we know is that it takes time. In the case of NgAgo, the time has now come and the data have spoken.

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