《自然-生物技術》編輯部對於發表“張辰宇研究”看法_風聞

原標題：再審“小RNA跨物種調控研究”，接受重複研究

原文鏈接：https://www.nature.com/articles/nbt.2748

當期自然-生物技術雜誌封面

編者注：基因農業網曾在今年7月份發表文章《植物小RNA進入血液，驚世發現還是南柯一夢？》，介紹當前科學界對於南京大學張辰宇教授這項發現的評價，並在編者按中強調“即便這項研究結果真的成立，也不能證明食用轉基因食品會在遺傳學方面有某種特定的潛在危害”並做了解釋，但此後反轉人士及部分打着“科普”旗號的“專業人士”依然以此項研究作為轉基因有着特殊危害的憑據。

目前看來，這項研究疑點越來越大。事實上，如果張的發現僅止於目前結果，則其研究與我們的現實世界有着巨大的矛盾衝突：假如其發現確鑿的話，人類豈不是每天都在遭受跨物種小RNA的危害？人類進食植物果實已千萬年，又是如何在跨物種小RNA衝擊下維繫繁衍至今的？特殊的主張需要特殊的證據，張辰宇的發現不僅僅需要更多的重複試驗來驗證，還需要更深入的理論解釋來解決目前看到的矛盾。

（譯者 孫滔）如同許多其它科學期刊一樣，《自然—生物技術》在選擇發表學術研究時特別看重其新穎性。鑑於此，旨在重複或核實先前研究的論文就較少發表。出於重要性及更廣大讀者需求的考慮，一項獲得空白或陰性結果的研究在發表優先級方面一般會處於劣勢。那我們為什麼在這期第965頁還是發表了一份重複其它期刊研究的論文呢？

因為這項研究澄清了2012年《細胞研究》（Cell Research）的一篇爭議性論文。該研究由miRagen Therapeutics公司（美國一家專注於研發微小RNA療法的科技企業）和孟山都聯合完成。《細胞研究》發表的那篇論文出自中國南京大學張辰宇一項引發爭議的研究，這項研究稱在人體血漿中發現了植物小RNA，尤其是大米中的miRNA168a——它可以進入老鼠的血液中進行基因調控。

然而，**我們發表的研究發現，沒有證據顯示老鼠在進食大米後其血液和肝臟中存在miRNA168a。**酶聯免疫吸附測定數據也與張辰宇用蛋白質印跡法得到的數據衝突，後者的數據顯示水稻miRNA168a進入小鼠體內能抑制低密度脂蛋白受體銜接蛋白（LDLRAP1）表達水平。miRagen的研究則顯示，飲食成分的差異有可能導致老鼠中低密度脂蛋白的變化，而非跨物種的miRNA作用使然。

為何這篇論文沒有發表在《細胞研究》，而是發在了《自然—生物技術》呢？事實上，miRagen在向《細胞研究》提交其論文時被告知：該研究因為是陰性結果而難以發表。

我們不同意這種看法，並堅信該論文值得一絲不苟地印刷出版，因為這是一項將某個關鍵問題放在聚光燈下的陰性研究。

張辰宇最初關於小RNA跨物種調控的研究是一個非同尋常的結論。該結論與此前雙鏈RNA不能進入人鼠體內進行RNA干擾的看法截然不同，它引發了植物小RNA對人體健康風險的擔憂。《國際環境》期刊在3月份刊文提出需關注基於基因沉默機制的轉基因作物對人體健康的影響，而此問題尚未在食品安全評價中考慮。這促使《澳大利亞和新西蘭的食品標準法》的監管者對該問題進行了文獻評估，並發表了一個對轉基因作物監管的立場聲明。

miRagen的研究引發高度關注，並讓研究人員和監管者投入大量時間、精力和資源去評估其結論及其價值，這份報告在嚴格審查和重複研究後方授權發表。可惜，該論文沒有發表在《細胞研究》上，它本來可以以雙向鏈接形式指向張辰宇原先的論文。

發表重複研究是《自然—生物技術》和其它頂級期刊對其出版的論文自查自糾的一種手段。尤其是對於爭議研究的證實，期刊還可以徵求獨立實驗室的重複研究。

“重複首創研究”機構以另一種方式做重複研究。實驗服務創業公司Science Exchange和開放存取期刊PLOS ONE合作提出了“可重複性首創”，研究可外包給中間獨立機構進行可重複性測試。10月份，勞拉和約翰.阿諾德基金會提供了130萬美元給過去兩年內發表的50篇高水平癌症論文做重複鑑定。

**重複學術研究的最大動力來自行業企業。企業擁有雄厚的資金實力，也先享其成。**美國安進公司和拜耳公司是近期強烈關注該問題的機構。此外，在無法獲得重複結果時，企業極少有動力去經受同行評議的考驗，從這方面看，miRagen發佈其陰性研究是值得讚揚的。

**除了論文發表後的糾正機制，發表前的重複研究糾正工作也在進行中。**比如研究自助者可以預留一部分經費給發表前的獨立審核。如此，只有獲重複研究證實的研究方能提交給期刊。

今年夏天，愛思唯爾旗下期刊《大腦皮層》（Cortex ）開始採取另一種手段以提高研究可重複性來減少偏差。該機制要求，研究者需在數據收集前提交實驗設計來接受同行評議。如果其科學問題和方法被認為可行，那麼作者即被告知，不論其結果如何先“原則上接受”。

**重複研究是費勁不討好的工作。迄今，期刊、資助者和研究者均對此不感冒。**但只要讀者關注，《自然—生物技術》將繼續對其它陰性重複研究及苛求的努力保持開放態度。這是我們的態度，但建議研究者最好是將重複研究發表在原研究發表的期刊上，那樣將使人們更加清晰掌握對原來研究的鞏固或糾偏。

翻頁查看自然雜誌社編輯部英文原文：

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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.