In the latest Nature Reports Stem Cells Inside the Paper feature, senior Nature editor Natalie DeWitt discusses the paper by H. H. Chang et al. ‘Transcriptome-wide noise controls lineage choice in mammalian progenitor cells’, published in Nature 453, 544-547 (2008).

The Editor’s summary of this paper: Even in clonal populations of cells, there is significant phenotypic variation from cell to cell. This could reflect the ‘noise’ inherent in gene expression: or the various cell states could represent stable phenotypic variants. Chang et al. analysed the behaviour of an ‘outlier’ in clonal populations of mouse haematoipoietic stem cells that had very high expressions of the stem cell marker Sca-1 and found that outliers possessed distinct transcriptomes. Though the transcriptomes eventually reverted back to that of the median cells, while they differed they could drive the cells to express characteristics of distinct cell fates. Thus clonal heterogeneity of gene expression may not be due to noise in the expression of individual genes, but rather is a manifestation of metastable states of a slowly fluctuating transcriptome. These fluctuations may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.

The Nature Reports Stem Cells article provides the details of what the peer-reviewers thought of this paper when it was submitted, and how the authors responded. The initial view of the three peer-reviewers can be summarized as follows:

Reviewer 1 In summary, we believe that this paper reports a novel and important biological mechanism for differentiation: it gives evidence that slow stochastic variations in stem cell state last for a long time and result in different fates. It relates the recent finding of slow fluctuations in human protein levels to the biological outcome of cell fate, and finds long lasting differences in transcriptomes in different subpopulations. It is an excellent choice for Nature, provided that the comments are addressed.

Reviewer 2 Although the phenomenon described is immensely interesting and the idea of heterogeneity being retained within even clonal populations of cells is plausible, the authors merely describe this phenomenon and in some instances, do not provide conclusive data to support their interpretation. If a mechanism was determined this would definitely aid in its novelty and interest. In its current form, I believe this manuscript should not be accepted at Nature.

Reviewer 3 This is a very timely and interesting paper, that should be of interest to a broad range of researchers. However, I have some serious concerns over the modeling.

The details of the reviewers’ concerns, and the authors’ response, can be read at Nature Reports Stem Cells,

You can also read a set of question-and-answer sessions between editor Monya Baker and several of the peer-reviewers of the recent Nature Insight on Regenerative Medicine, here on The Niche, the blog of Nature Reports Stem Cells.

The newly launched journal Scholarly Research Exchange, published by Hindawi, is for original research articles in all areas of science, technology and medicine. The journal is operating a transparent peer-review system, in which authors and reviewers interact directly throughout the peer-review process. Authors submitting to Scholarly Research Exchange suggest potential reviewers, who are then approved by the journal’s editors. Reviewers are asked to provide an assessment of the quality of the manuscript, a written critique for the authors, and a written commentary for the journal’s readers. When the journal accepts its first articles for publication, the reviewers’ commentaries and their assessment of the manuscript’s quality will be published with them. In addition to these reviewers’ evaluations, members of the scientific community will be able to participate in a discussion around every manuscript.

A journal with a similar, but not identical, peer-review process is Biology Direct, published by BioMed Central, currently covering the areas of genomics, bioinformatics and systems biology, immunology, and mathematical biology. Biology Direct makes the author responsible for obtaining reviewers’ reports, via the journal’s editorial board, operates an open peer-review process, and publishes reviewers’ reports with the articles. It has been publishing articles since January 2006.

This month’s (March 2008) free-access Editorial in Nature Cell Biology (10, 247; 2008) addresses the journal’s peer-review process: specifically, what the journal does to ensure that its selection process is fair.

From the Editorial:

“A legitimate question for editors at Nature Cell Biology is whether we are considering alternatives to the status quo of anonymous peer review, in particular, why we do not use a ‘double blind’ process (which received significant endorsement in ”https://blogs.nature.com/peer-to-peer/2008/01/researchers_like_the_peerrevie.html">a recent survey of the Publishing Research Consortium). The existing process, based on a thorough pre-selection by five full-time editors and subsequent external peer review by carefully selected referees, works well — individual stories of woe notwithstanding."

The editorial goes on to outline how changes to the system, when being considered, must show a demonstrable improvement to the process. Several of the commonly proposed alternatives to the ‘single blind’ system are discussed in this light (see here for a recent popular debate on the topic at this blog). The Editorial concludes with a summary of the process as currently run by the Nature Cell Biology editors, together with the journal’s planned enhancments.

The editors welcome your views on the Editorial as comments to this post.

Further information about the Nature journals’ peer-review policies are available at the authors’ and reviewers’ website.

Connotea tags for peer-review.

This is the text of an editorial published in Nature in the 7 February issue (Nature 451; 605-606; 2008) . We, the journal editors, welcome your comments and suggestions.

Corrected 4 June 2008: Nature 453, 711 (2008).

Please see end of this post for text of correction correction to this editorial*

Should there be author anonymity in peer review?

Double-blind peer review, in which both authors and referees are anonymous, is apparently much revered, if not much practised. The Publishing Research Consortium (PRC) has assessed attitudes towards peer review among 3,000 academics in an international survey across the sciences and humanities. The results, released last month, strongly affirm the value of peer review [See earlier posting on Peer to Peer.]. They also highlight that 71% have confidence in double-blind peer review and that 56% prefer it to other forms of review. Support is highest with those who have experienced it (the humanities and social sciences) or where it is perceived to do the most good (among female authors). The least enthusiastic group is editors. So is it time for editors, and those at Nature in particular, to reconsider their position?

If referees know the authors’ identities, it may leave the latter vulnerable to biases about them or their previous work, their gender, their nationality or their being new to an area of research. But the PRC survey supports the contention of Nature and others that identifying authors stimulates referees to ask appropriate questions (for example, differentiating between a muddy technical explanation and poor experimental technique). Knowing author identities also makes it easier to compare the new manuscript with the authors’ previously published work, to ensure that a true advance is being reported. And knowing rather than guessing the identities of authors encourages reviewers to raise potential conflicts of interest to the editors.

Is there evidence that double-blind peer review presents a better alternative? It would do so if it generated more constructive comments in the minds of editors and authors, or if the identity of authors were truly protected, or if biases were reduced. So far, the jury is out. Although at least one study in the biomedical literature has suggested that double-blind peer review increases the quality of reviews, a larger study of seven medical journals (refs 2, 3) indicated that neither authors nor editors found significant difference in the quality of comments when both referees and authors were blinded. Referees could identify at least one of the authors on about 40% of the papers, undermining the raison d’être for double-blinding. The editors at the Public Library of Science abandoned double-blind peer review because too few requested it and authors were too readily identified.

The one bright light in favour of double-blind peer review is the measured reduction in bias against authors with female first names (shown in numerous studies, such as ref. 4 [previously discussed on Peer to Peer]). This suggests that authors submitting papers to traditionally minded journals should include the given names of authors only on the final, published version.

The double-blind approach is predicated on a culture in which manuscripts-in-progress are kept secret. This is true for the most part in the life sciences. But some physical sciences, such as high-energy physics, share preprints extensively through arXiv, an online repository. Thus, double-blind peer review is at odds with another ‘force for good’ in the academic world: the open sharing of information. The PRC survey found that highly competitive fields (such as neuroscience) or those with larger commercial or applied interests (such as materials science and chemical engineering) were the most enthusiastic about double-blinding, whereas fields with more of a tradition for openness (astronomy and mathematics) were decidedly less supportive.

Where does this leave journals? Editors have the responsibility to provide a neutral bridge between referees and authors and so may help to better shield authors from bias. Easily said! The evidence of the PRC survey suggests little faith in that impartiality, but editors — certainly at Nature and its related journals — take that responsibility seriously.

Nature’s policies over the years have generally moved towards greater transparency. Coupling that with the lack of evidence that double-anonymity is beneficial makes this journal resistant to adopting it as the default refereeing policy any time soon. But many of our readers are referees as well as authors. We welcome their views on author anonymity from both vantage points.

1. Publishing Research Consortium Peer Review in Scholarly Journals (Mark Ware Consulting, Bristol, 2008).

2. Justice, A. C. et al. J. Am. Med. Assoc. 280, 240–242 (1998).

3. Cho, M. K. et al. J. Am. Med. Assoc. 280, 243–245 (1998).

4. Budden, A. E. et al. Trends Ecol. Evol. 23, 4–6 (2008).

The Nature journals’ peer-review policies are described at our Author and Reviewers’ website, where you can also find links to our editorials on the topic, all free to access.

CORRECTION to the editorial:

The Editorial ‘Working double-blind’ (Nature 451, 605–606; 2008) referred to a study1 that found more female first-author papers were published using a double-blind, rather than a single-blind, peer-review system. The data reported in ref. 1 have now been re-examined2. The conclusion of ref. 1, that Behavioral Ecology published more papers with female first authors after switching to a double-blind peer-review system, is not in dispute. However, ref. 2 reports that other similar ecology journals that have single-blind peer-review systems also increased in female first-author papers over the same time period. After re-examining the analyses, Nature has concluded that ref. 1 can no longer be said to offer compelling evidence of a role for gender bias in single-blind peer review. In addition, upon closer examination of the papers listed in PubMed on gender bias and peer review, we cannot find other strong studies that support this claim. Thus, we no longer stand by the statement in the fourth paragraph of the Editorial, that double-blind peer review reduces bias against authors with female first names.

References

Budden, A. E. et al . Trends Ecol. Evol. 23, 4–6 (2008).

Webb, T. J. , O’Hara, B. & Freckleton, R. P. Trends Ecol. Evol. doi:10.1016/j.tree.2008.03.003 (2008).