韩春雨召回“基因剪刀”，论文从自然子刊下架

  【博主按语】：

这次《自然·生物》没有单方面宣布撤销韩的文章，这是俺的一个猜测点（《自然·生物》不会撤销韩的文章）。

科学探索需要猜测，科学评论也需要猜测。

韩要求撤下文章，这一着对韩意义非凡。

因此，俺说：韩春雨召回“基因剪刀”。

韩召回了“基因剪刀”，客观上，文章被自然子刊下架。

韩春雨论文被自然子刊撤稿（凤凰网）

韩春雨NgAgo论文被自然子刊撤稿：系作者主动申请撤回（澎湃新闻网）

本期，韩春雨及同事撤回了发表于去年5月的一篇论文。该论文称，短5′磷酸化单链DNA可引导格氏嗜盐碱杆菌核酸内切酶（NgAgo）产生双链断裂，实现对人类基因组的编辑。论文一发表，便引起科研人员的极大兴趣和媒体的竞相报道。但是很快，在推特、博客和其它社交媒体的助燃之下，有关该研究可重复性的质疑开始迅速增多。去年11月，本刊发表了“编辑部关注”（Editorial Expression ofConcern），提醒科研界留意这些可重复性方面的担忧。为了最终解决这个争议，多个研究小组在数月里生成了更多的实验数据。如今尘埃落定，这也是世界各地的许多实验室为澄清NgAgo的功能而付出的大量时间、精力和资金的证明。

韩春雨的这篇论文自去年发表后所产生的影响力，再怎么夸张地说也不为过，尤其是在论文的来源地中国。中国媒体纷纷进行报道，以大标题宣告一项全新基因编辑系统的发现。这无疑是一篇中国去年被报道最多的论文；媒体监测公司融文（Meltwater）的数据显示，仅在论文发表后的最初两个月，就有将近4000篇相关的中文新闻报道。

NgAgo的轰动之处集中在它有可能补充，甚至取代CRISPR/Cas9基因编辑系统之一点上。NgAgo有望以一个目标序列进行基因编辑（Cas9不仅需要目标序列，还需要另外一个附近的识别（PAM）序列）。而且，初始数据还显示了它在其它方面的优势，如引物的稳定性更强（DNA相对于Cas9采用的RNA），增强特异性，减少基因组编辑脱靶，改善在基因组富含GC区域的活性，以及使所用的试剂更易于合成和处理。

如果说这一切都听上去太过美好而令人难以置信，那么去年夏天以来，随着越来越多的实验室无法重复该论文所报告的基因组编辑功能，质疑声便开始出现了。在各种基因组编辑会议上，在新闻讨论组和电子邮件中，这篇论文成为最热话题之一。这很快便引起媒体注意，有关该初始报告有效性的正反两方面的声音开始交锋。我们内部的图像完整性筛查没有发现韩春雨论文的明显异常，复查数据的三位外部评审人也持相同观点。

在此期间，《自然-生物技术》一直与科研界保持联络，关注各种为重复论文所做的持续努力。最终，在编辑们的协调下，三个独立小组的成果形成了一篇单独的反驳性论文，并通过了同行评议(Nat. Biotechnol.34, 768–773, 2016)。有了这些数据，我们就有充分的理由去提醒读者留意该论文可能存在问题，我们将正式的“编辑部关注”发表在该篇论文所在的网址上，此举得到包括韩春雨在内的两位论文作者的支持。

我们也询问了论文作者是否可以解答科研界为何难以重复他们的结果。于是，去年12月，韩春雨及同事，还有另外几个与本刊联系的独立研究小组，提供了新的数据，称已经重复了NgAgo基因编辑活性。当时，本刊编辑和一位外部评审人都判定这些数据太过初级，不满足发表标准。因此，我们决定给这些原始论文作者和新的研究小组更多时间来收集更多的能支持其论点的实验证据。

现在，距原论文发表已过去了一年多，我们了解到当初曾报告说初步成功重复出实验结果的独立研究小组，无法强化初始数据，使其达到可发表的水平。类似的，在征求专家评审人的反馈意见后，我们判定韩春雨及同事提供的最新数据不足以反驳大量与其初始发现相悖的证据。我们现在确信韩春雨的撤稿决定是维护已发表科研记录完整性的最好做法。

In this issue, Chunyu Han andcolleagues retract a paper published in May 2016 claiming that an Argonauteprotein (NgAgo) from the archaea Natronobacterium gregoryi can be guidedby short 5′ phosphorylated single-stranded DNAs to generate double-strandbreaks and edit the human genome (Nat.Biotechnol.34, 768–773, 2016). Although the paper was initiallygreeted with enthusiasm from researchers and intense media interest,speculation as to its reproducibility quickly grew, fueled by Twitter, blogsand other social media. Last November, this journal issued an Editorial Expressionof Concern to alert the community to these reproducibility questions. Finalresolution of the controversy necessitated the generation of additionalexperimental data from several groups over many months. That a retraction isnow issued is testament to the considerable time, effort and funds invested bymany laboratories around the globe that have sought to clarify NgAgo'sfunction.

It is hard to overstate the impactof the Han paper following its publication last year, especially in China, wherethe paper originated. Coverage in the Chinese media was extensive, withheadlines heralding the discovery of an entirely new gene editing system. TheNgAgo report was easily the most widely covered paper in China lastyear; according to media monitor Meltwater, nearly 4,000 Chinese newsstories cited the Han paper in just the first two months after publication.

The excitement generated by NgAgocentered on its potential to complement, or perhaps even supersede, theCRISPR–Cas9 gene editing system. NgAgo promised gene editing that required onlya single target sequence (Cas9 needs both the target sequence and an additionaladjacent recognition (PAM) sequence). What's more, initial data suggestedadvantages in terms of enhanced stability of the guide (DNA compared with RNAfor Cas9), improved specificity, reduced off-target editing of the genome andimproved activity in GC-rich regions of the genome; and the reagents used wereeasier to synthesize and handle.

If all this sounded too good to betrue, the failure last summer of an increasing number of laboratories toreproduce the genome editing activity reported in the Han paper started toraise doubts. The paper became a hotly discussed topic at genome editingconferences, news groups and e-mail lists. It didn't take long before the presstook notice. Claims and counterclaims regarding the validity of the initialreport were exchanged. Nature Biotechnology's internal image integrityscreening process found no obvious anomalies in the Han paper, a finding echoedby three external reviewers who reexamined the data.

Meanwhile, Nature Biotechnologykept in contact with the community about ongoing efforts to replicate thepaper. Ultimately, the editors were able to coordinate the work of threeindependent groups into a single peer-reviewed refutation paper (Nat. Biotechnol.35, 17–18, 2017). Withthese data in hand, we then had sufficient cause to alert our readers topotential problems with the paper by publishing the Editorial Expression ofConcern, which now appears alongside the original paper online—a step that wassupported by two of the authors, including Han.

We also asked the authors if theycould shed light on why the community was having difficulties reproducing theirresults. Accordingly, last December, Han and colleagues and several additionalindependent groups who contacted the journal provided new data claiming to havereproduced NgAgo gene editing activity. At the time, these data were judged toopreliminary by the editors and an external reviewer to warrant publication. Wedecided to give the original authors and new groups more time to gatheradditional experimental evidence to bolster their claims.

Now, more than a year after thepublication of the original report, we have learned that the independent groupsthat reported initial success in reproducing the results have not been able tobolster their preliminary data to a publishable level. Similarly, after seekingfeedback from expert reviewers, we have concluded that the latest data from Hanand his colleagues are insufficient to counter the substantial body of evidencethat contradicts their initial findings. We are now convinced that the decisionof Han and colleagues to retract the paper is the best course of action tosupport the integrity of the published record.

Publication of the NgAgo paper wasnot the end of the scientific process, it was the start. Like any other reportthat appears in the literature, it is the wider research community that testsmethods, identifies potential sources of error, validates reagents andoptimizes assays. In this case, it took dozens of dedicated individuals to workthrough the details of the published protocol and produce well-documented andcontrolled refutation studies (Protein Cell7,913–915, 2016;Nat. Biotechnol.35,17–18, 2017;Cell Res.26, 1349–1352, 2016;PLoS One12,e0177444, 2017).

The NgAgo controversy alsoillustrates the pros and cons of social media. Clearly, these platforms werevaluable for rapidly alerting the wider scientific community to problems withthe paper. But they also raised expectations that issues with this paper werestraightforward and could be solved quickly. Unraveling all the problems withthe NgAgo editing claim didn't happen in weeks or a few months for a reason.Even simple experiments take weeks to prepare, perform, analyze andtroubleshoot. It does not help that the efforts of those carrying outreplication studies often go unrewarded—it is unglamorous, unfunded andthankless work.

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