《自然-生物技术》编辑部对于发表“张辰宇研究”看法

原标题：再审“小RNA跨物种调控研究”，接受重复研究

原文链接：https://www.nature.com/articles/nbt.2748

当期自然-生物技术杂志封面

编者注：基因农业网曾在今年7月份发表文章《植物小RNA进入血液，惊世发现还是南柯一梦？》，介绍当前科学界对于南京大学张辰宇教授这项发现的评价，并在编者按中强调“即便这项研究结果真的成立，也不能证明食用转基因食品会在遗传学方面有某种特定的潜在危害”并做了解释，但此后反转人士及部分打着“科普”旗号的“专业人士”依然以此项研究作为转基因有着特殊危害的凭据。

目前看来，这项研究疑点越来越大。事实上，如果张的发现仅止于目前结果，则其研究与我们的现实世界有着巨大的矛盾冲突：假如其发现确凿的话，人类岂不是每天都在遭受跨物种小RNA的危害？人类进食植物果实已千万年，又是如何在跨物种小RNA冲击下维系繁衍至今的？特殊的主张需要特殊的证据，张辰宇的发现不仅仅需要更多的重复试验来验证，还需要更深入的理论解释来解决目前看到的矛盾。

（译者 孙滔）如同许多其它科学期刊一样，《自然—生物技术》在选择发表学术研究时特别看重其新颖性。鉴于此，旨在重复或核实先前研究的论文就较少发表。出于重要性及更广大读者需求的考虑，一项获得空白或阴性结果的研究在发表优先级方面一般会处于劣势。那我们为什么在这期第965页还是发表了一份重复其它期刊研究的论文呢？

因为这项研究澄清了2012年《细胞研究》（Cell Research）的一篇争议性论文。该研究由miRagen Therapeutics公司（美国一家专注于研发微小RNA疗法的科技企业）和孟山都联合完成。《细胞研究》发表的那篇论文出自中国南京大学张辰宇一项引发争议的研究，这项研究称在人体血浆中发现了植物小RNA，尤其是大米中的miRNA168a——它可以进入老鼠的血液中进行基因调控。

然而，我们发表的研究发现，没有证据显示老鼠在进食大米后其血液和肝脏中存在miRNA168a。酶联免疫吸附测定数据也与张辰宇用蛋白质印迹法得到的数据冲突，后者的数据显示水稻miRNA168a进入小鼠体内能抑制低密度脂蛋白受体衔接蛋白（LDLRAP1）表达水平。miRagen的研究则显示，饮食成分的差异有可能导致老鼠中低密度脂蛋白的变化，而非跨物种的miRNA作用使然。

为何这篇论文没有发表在《细胞研究》，而是发在了《自然—生物技术》呢？事实上，miRagen在向《细胞研究》提交其论文时被告知：该研究因为是阴性结果而难以发表。

我们不同意这种看法，并坚信该论文值得一丝不苟地印刷出版，因为这是一项将某个关键问题放在聚光灯下的阴性研究。

张辰宇最初关于小RNA跨物种调控的研究是一个非同寻常的结论。该结论与此前双链RNA不能进入人鼠体内进行RNA干扰的看法截然不同，它引发了植物小RNA对人体健康风险的担忧。《国际环境》期刊在3月份刊文提出需关注基于基因沉默机制的转基因作物对人体健康的影响，而此问题尚未在食品安全评价中考虑。这促使《澳大利亚和新西兰的食品标准法》的监管者对该问题进行了文献评估，并发表了一个对转基因作物监管的立场声明。

miRagen的研究引发高度关注，并让研究人员和监管者投入大量时间、精力和资源去评估其结论及其价值，这份报告在严格审查和重复研究后方授权发表。可惜，该论文没有发表在《细胞研究》上，它本来可以以双向链接形式指向张辰宇原先的论文。

发表重复研究是《自然—生物技术》和其它顶级期刊对其出版的论文自查自纠的一种手段。尤其是对于争议研究的证实，期刊还可以征求独立实验室的重复研究。

“重复首创研究”机构以另一种方式做重复研究。实验服务创业公司Science Exchange和开放存取期刊PLOS ONE合作提出了“可重复性首创”，研究可外包给中间独立机构进行可重复性测试。10月份，劳拉和约翰.阿诺德基金会提供了130万美元给过去两年内发表的50篇高水平癌症论文做重复鉴定。

重复学术研究的最大动力来自行业企业。企业拥有雄厚的资金实力，也先享其成。美国安进公司和拜耳公司是近期强烈关注该问题的机构。此外，在无法获得重复结果时，企业极少有动力去经受同行评议的考验，从这方面看，miRagen发布其阴性研究是值得赞扬的。

除了论文发表后的纠正机制，发表前的重复研究纠正工作也在进行中。比如研究自助者可以预留一部分经费给发表前的独立审核。如此，只有获重复研究证实的研究方能提交给期刊。

今年夏天，爱思唯尔旗下期刊《大脑皮层》（Cortex ）开始采取另一种手段以提高研究可重复性来减少偏差。该机制要求，研究者需在数据收集前提交实验设计来接受同行评议。如果其科学问题和方法被认为可行，那么作者即被告知，不论其结果如何先“原则上接受”。

重复研究是费劲不讨好的工作。迄今，期刊、资助者和研究者均对此不感冒。但只要读者关注，《自然—生物技术》将继续对其它阴性重复研究及苛求的努力保持开放态度。这是我们的态度，但建议研究者最好是将重复研究发表在原研究发表的期刊上，那样将使人们更加清晰掌握对原来研究的巩固或纠偏。

翻页查看自然杂志社编辑部英文原文：

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Do replication studies belong in top-tier journals?

Like many other scientific journals, Nature Biotechnology places a strong emphasis on novelty when selecting research for publication. As a result, studies describing replications or confirmations of previously published reports are less likely to be chosen. And studies detailing null or negative findings may not meet stringent editorial requirements for significance and relevance to our broad readership. Why then are we publishing on p. 965 a replication of a report published elsewhere in the literature?

One reason is that the new report, resulting from a collaboration between miRagen Therapeutics and Monsanto, clarifies what were controversial findings in a paper previously published in Cell Research (22, 107–126, 2012). The latter study, led by Chen-Yu Zhang of Nanjing University, China, required a corrigendum (Cell Res. 22, 273–274, 2012) and sparked vigorous debate because it reported the presence of plant microRNA (miRNA) in human blood plasma and suggested that one in particular, miRNA168a, from ingested rice could traverse into the circulation of mice resulting in the modulation of miRNA target genes in the animal.

In contrast to these findings, the report on p. 965 finds no evidence for uptake of plant miRNA168a in the plasma and liver of mice fed a rice diet. Enzyme-linked immunosorbent assay data from the current study also contradict western blots from the Zhang paper that suggested miR168a directly suppressed levels of low-density lipoprotein receptor adapter protein 1 (LDLRAP1) in mice. Finally, the miRagen study suggests differences in diet composition, rather than miRNA-mediated cross-kingdom gene regulation, likely account for alterations in low-density lipoprotein in mouse plasma.

But why put the paper in Nature Biotechnology rather than Cell Research, where the original report was published? In fact, the miRagen investigators did submit their paper to that journal but were told that “it is a bit hard to publish a paper of which the results are largely negative.”

We differ with this assessment and believe the paper is worthy of publication precisely because it is a negative result throwing light on a key research question.

The original finding from Zhang and colleagues that plant miRNAs are capable of cross-kingdom gene regulation was an extraordinary claim. It went against a large body of research in which the systemic administration of double-stranded RNAs was shown incapable of triggering the RNA interference pathway in humans (and mice). It also raised concerns that plant miRNAs could pose health risks to humans. Indeed, last March, an article published in Environment International (55, 43–55, 2013) went so far as to claim that gene modification of plants using gene silencing mechanisms raises concerns for human health and that these concerns are not adequately considered in food safety assessments. This prompted the regulator Food Standards Australia New Zealand to undertake an assessment of the scientific literature on the issue and to publish a position statement on the regulation of genetically modified crops developed using gene silencing.

When an initial report prompts this level of concern and involves a considerable investment of time, effort and resources from both researchers and regulators in evaluating its findings and understanding its implications, then a carefully controlled and executed replication study clearly warrants publication. It is unfortunate it was not published in Cell Research where it could have been bi-directionally linked to the original paper.

Providing space for publishing a replication study is one way in which Nature Biotechnology and other top-tier journals can facilitate the process of self-correction of the scientific literature. Journals could also actively solicit papers that seek to replicate research studies where corroboration by independent laboratories would be of particular interest (e.g., to corroborate a controversial finding).

The Reproducibility Initiative (Nat. Biotechnol. 30, 806, 2012) represents another way of replicating research. A collaboration between the Science Exchange and PLOS ONE, the initiative offers to broker independent validation of a researcher's work in return for a fee, with subsequent publication in the journal. In October, the Laura and John Arnold Foundation provided $1.3 million to the initiative to authenticate 50 high-profile cancer papers from the past two years (only ∼$20,000 per study).

But the faction with the greatest motivation to replicate academic findings must surely be industry. Companies have the deepest financial resources, and they have the most to gain. And it was groups at Amgen and Bayer that raised the recent chorus of concern about irreproducibility of the literature in the first place. Then again, corporations have few incentives to jump through all the hoops of peer review when they fail to reproduce results; in this respect, miRagen deserves praise for seeking to publish its negative findings.

Apart from the above post-publication correction mechanisms, efforts are also underway to improve reproducibility before findings become papers. For example, one idea being floated by certain funders is to set aside a portion of a research grant specifically for independent verification of the main study's results before publication; in this scheme, submission to a journal would proceed only after the results were corroborated.

This summer, the journal Cortex started offering yet another means of improving reproducibility and reducing bias. The mechanism, termed a “Registered Report,” involves peer review of an investigator's experimental design before data are collected. If the scientific question and methods are deemed sound, then authors are offered “in principle acceptance” of their article, irrespective of the study's outcome.

Replication is a difficult and thankless task. Until now, journals, funders and academics have shown little interest in it. Nature Biotechnology will remain open to publishing replication studies and rigorous efforts that fail to reproduce findings from other publications of high interest to our readers. It is our view, however, that the best practice is to publish such replication failures in the journal where the original findings were published. That way, the power of the scientific process to consolidate and modify our understanding of initial findings in a report is clearly visible to all.