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Proteins are some of the most fascinating and complex macromolecules in living systems that play extraordinarily diverse roles in sustaining life. These roles are mediated through the interactions that proteins make both with themselves and with other molecular constituents of the cell.
The focus of our laboratory is on investigating the principles that govern these interactions. We use molecular simulation and modeling techniques to study protein-protein protein-DNA and protein-ligand interactions at the atomic scale. We furthermore analyze the properties of known protein structures and sequences in order to gain insight into how evolution has shaped the functional specificity of proteins.
In parallel to these molecular level investigations we are actively engaged in developing quantitative and integrative computational approaches for analyzing physical and functional interactions between proteins, protein complexes and biochemical pathways at the cellular level. All our research activities closely combine the development of methods and software tools with their application to important biological problems with relevance to human health.
Recent Blog Posts
It hasn’t been a real good week for peer review. In the same week that the Lancet fully retract the original Wakefield MMR article (while keeping the retraction behind a login screen – way to go there on public understanding of science), the main stream media went to town on the report of 14 stem cell scientists writing an open letter making the claim that peer review in that area was being dominated by a small group of people blocking the publication of innovative work. I don’t have the information to actually comment on the substance of either issue but I do want to reflect on what this tells us about the state of peer review.
There remains much reverence of the traditional process of peer review. I may be over interpreting the tenor of Andrew Morrison’s editorial in BioEssays but it seems to me that he is saying, as many others have over the years “if we could just have the rigour of traditional peer review with the ease of publication of the web then all our problems would be solved”. Scientists worship at the altar of peer review, and I use that metaphor deliberately because it is rarely if ever questioned. Somehow the process of peer review is supposed to sprinkle some sort of magical dust over a text which makes it “scientific” or “worthy”, yet while we quibble over details of managing the process, or complain that we don’t get paid for it, rarely is the fundamental basis on which we decide whether science is formally published examined in detail.
There is a good reason for this. THE EMPEROR HAS NO CLOTHES! [sorry, had to get that off my chest]. The evidence that peer review as traditionally practiced is of any value at all is equivocal at best (Science 214, 881; 1981, J Clinical Epidemiology 50, 1189; 1998, Brain 123, 1954; 2000, Learned Publishing 22, 117; 2009). It’s not even really negative. That would at least be useful. There are a few studies that suggest peer review is somewhat better than throwing a dice and a bunch that say it is much the same. It is at its best at dealing with narrow technical questions, and at its worst at determining “importance” is perhaps the best we might say. Which for anyone who has tried to get published in a top journal or written a grant proposal ought to be deeply troubling. Professional editorial decisions may in fact be more reliable, something that Philip Campbell hints at in his response to questions about the open letter [BBC article]:
But there is perhaps an even more important procedural issue around peer review. Whatever value it might have we largely throw away. Few journals make referee’s reports available, virtually none track the changes made in response to referee’s comments enabling a reader to make their own judgement as to whether a paper was improved or made worse. Referees get no public credit for good work, and no public opprobrium for poor or even malicious work. And in most cases a paper rejected from one journal starts completely afresh when submitted to a new journal, the work of the previous referees simply thrown out of the window.
Much of the commentary around the open letter has suggested that the peer review process should be made public. But only for published papers. This goes nowhere near far enough. One of the key points where we lose value is in the transfer from one journal to another. The authors lose out because they’ve lost their priority date (in the worse case giving the malicious referees the chance to get their paper in first). The referees miss out because their work is rendered worthless. Even the journals are losing an opportunity to demonstrate the high standards they apply in terms of quality and rigor – and indeed the high expectations they have of their referees.
We never ask what the cost of not publishing a paper is or what the cost of delaying publication could be. Eric Weinstein provides the most sophisticated view of this that I have come across and I recommend watching his talk at Science in the 21st Century from a few years back. There is a direct cost to rejecting papers, both in the time of referees and the time of editors, as well as the time required for authors to reformat and resubmit. But the bigger problem is the opportunity cost – how much that might have been useful, or even important, is never published? And how much is research held back by delays in publication? How many follow up studies not done, how many leads not followed up, and perhaps most importantly how many projects not refunded, or only funded once the carefully built up expertise in the form of research workers is lost?
Rejecting a paper is like gambling in a game where you can only win. There are no real downside risks for either editors or referees in rejecting papers. There are downsides, as described above, and those carry real costs, but those are never borne by the people who make or contribute to the decision. Its as though it were a futures market where you can only lose if you go long, never if you go short on a stock. In Eric’s terminology those costs need to be carried, we need to require that referees and editors who “go short” on a paper or grant are required to unwind their position if they get it wrong. This is the only way we can price in the downside risks into the process. If we want open peer review, indeed if we want peer review in its traditional form, along with the caveats, costs and problems, then the most important advance would be to have it for unpublished papers.
Journals need to acknowledge the papers they’ve rejected, along with dates of submission. Ideally all referees reports should be made public, or at least re-usable by the authors. If full publication, of either the submitted form of the paper or the referees report is not acceptable then journals could publish a hash of the submitted document and reports against a local key enabling the authors to demonstrate submission date and the provenance of referees reports as they take them to another journal.
In my view referees need to be held accountable for the quality of their work. If we value this work we should also value and publicly laud good examples. And conversely poor work should be criticised. Any scientist has received reviews that are, if not malicious, then incompetent. And even if we struggle to admit it to others we can usually tell the difference between critical, but constructive (if sometimes brutal), and nonsense. Most of us would even admit that we don’t always do as good a job as we would like. After all, why should we work hard at it? No credit, no consequences, why would you bother? It might be argued that if you put poor work in you can’t expect good work back out when your own papers and grants get refereed. This again may be true, but only in the long run, and only if there are active and public pressures to raise quality. None of which I have seen.
Traditional peer review is hideously expensive. And currently there is little or no pressure on its contributors or managers to provide good value for money. It is also unsustainable at its current level. My solution to this is to radically cut the number of peer reviewed papers probably by 90-95% leaving the rest to be published as either pure data or pre-prints. But the whole industry is addicted to traditional peer reviewed publications, from the funders who can’t quite figure out how else to measure research outputs, to the researchers and their institutions who need them for promotion, to the publishers (both OA and toll access) and metrics providers who both feed the addiction and feed off it.
So that leaves those who hold the purse strings, the funders, with a responsibility to pursue a value for money agenda. A good place to start would be a serious critical analysis of the costs and benefits of peer review.
Addition after the fact: Pointed out in the comments that there are other posts/papers I should have referred to where people have raised similar ideas and issues. In particular Martin Fenner’s post at Nature Network. The comments are particularly good as an expert analysis of the usefulness of the kind of “value for money” critique I have made. Also a paper in the Arxiv from Stefano Allesina. Feel free to mention others and I will add them here.
There remains much reverence of the traditional process of peer review. I may be over interpreting the tenor of Andrew Morrison’s editorial in BioEssays but it seems to me that he is saying, as many others have over the years “if we could just have the rigour of traditional peer review with the ease of publication of the web then all our problems would be solved”. Scientists worship at the altar of peer review, and I use that metaphor deliberately because it is rarely if ever questioned. Somehow the process of peer review is supposed to sprinkle some sort of magical dust over a text which makes it “scientific” or “worthy”, yet while we quibble over details of managing the process, or complain that we don’t get paid for it, rarely is the fundamental basis on which we decide whether science is formally published examined in detail.
There is a good reason for this. THE EMPEROR HAS NO CLOTHES! [sorry, had to get that off my chest]. The evidence that peer review as traditionally practiced is of any value at all is equivocal at best (Science 214, 881; 1981, J Clinical Epidemiology 50, 1189; 1998, Brain 123, 1954; 2000, Learned Publishing 22, 117; 2009). It’s not even really negative. That would at least be useful. There are a few studies that suggest peer review is somewhat better than throwing a dice and a bunch that say it is much the same. It is at its best at dealing with narrow technical questions, and at its worst at determining “importance” is perhaps the best we might say. Which for anyone who has tried to get published in a top journal or written a grant proposal ought to be deeply troubling. Professional editorial decisions may in fact be more reliable, something that Philip Campbell hints at in his response to questions about the open letter [BBC article]:
Our editors [...] have always used their own judgement in what we publish. We have not infrequently overruled two or even three sceptical referees and published a paper.
But there is perhaps an even more important procedural issue around peer review. Whatever value it might have we largely throw away. Few journals make referee’s reports available, virtually none track the changes made in response to referee’s comments enabling a reader to make their own judgement as to whether a paper was improved or made worse. Referees get no public credit for good work, and no public opprobrium for poor or even malicious work. And in most cases a paper rejected from one journal starts completely afresh when submitted to a new journal, the work of the previous referees simply thrown out of the window.
Much of the commentary around the open letter has suggested that the peer review process should be made public. But only for published papers. This goes nowhere near far enough. One of the key points where we lose value is in the transfer from one journal to another. The authors lose out because they’ve lost their priority date (in the worse case giving the malicious referees the chance to get their paper in first). The referees miss out because their work is rendered worthless. Even the journals are losing an opportunity to demonstrate the high standards they apply in terms of quality and rigor – and indeed the high expectations they have of their referees.
We never ask what the cost of not publishing a paper is or what the cost of delaying publication could be. Eric Weinstein provides the most sophisticated view of this that I have come across and I recommend watching his talk at Science in the 21st Century from a few years back. There is a direct cost to rejecting papers, both in the time of referees and the time of editors, as well as the time required for authors to reformat and resubmit. But the bigger problem is the opportunity cost – how much that might have been useful, or even important, is never published? And how much is research held back by delays in publication? How many follow up studies not done, how many leads not followed up, and perhaps most importantly how many projects not refunded, or only funded once the carefully built up expertise in the form of research workers is lost?
Rejecting a paper is like gambling in a game where you can only win. There are no real downside risks for either editors or referees in rejecting papers. There are downsides, as described above, and those carry real costs, but those are never borne by the people who make or contribute to the decision. Its as though it were a futures market where you can only lose if you go long, never if you go short on a stock. In Eric’s terminology those costs need to be carried, we need to require that referees and editors who “go short” on a paper or grant are required to unwind their position if they get it wrong. This is the only way we can price in the downside risks into the process. If we want open peer review, indeed if we want peer review in its traditional form, along with the caveats, costs and problems, then the most important advance would be to have it for unpublished papers.
Journals need to acknowledge the papers they’ve rejected, along with dates of submission. Ideally all referees reports should be made public, or at least re-usable by the authors. If full publication, of either the submitted form of the paper or the referees report is not acceptable then journals could publish a hash of the submitted document and reports against a local key enabling the authors to demonstrate submission date and the provenance of referees reports as they take them to another journal.
In my view referees need to be held accountable for the quality of their work. If we value this work we should also value and publicly laud good examples. And conversely poor work should be criticised. Any scientist has received reviews that are, if not malicious, then incompetent. And even if we struggle to admit it to others we can usually tell the difference between critical, but constructive (if sometimes brutal), and nonsense. Most of us would even admit that we don’t always do as good a job as we would like. After all, why should we work hard at it? No credit, no consequences, why would you bother? It might be argued that if you put poor work in you can’t expect good work back out when your own papers and grants get refereed. This again may be true, but only in the long run, and only if there are active and public pressures to raise quality. None of which I have seen.
Traditional peer review is hideously expensive. And currently there is little or no pressure on its contributors or managers to provide good value for money. It is also unsustainable at its current level. My solution to this is to radically cut the number of peer reviewed papers probably by 90-95% leaving the rest to be published as either pure data or pre-prints. But the whole industry is addicted to traditional peer reviewed publications, from the funders who can’t quite figure out how else to measure research outputs, to the researchers and their institutions who need them for promotion, to the publishers (both OA and toll access) and metrics providers who both feed the addiction and feed off it.
So that leaves those who hold the purse strings, the funders, with a responsibility to pursue a value for money agenda. A good place to start would be a serious critical analysis of the costs and benefits of peer review.
Addition after the fact: Pointed out in the comments that there are other posts/papers I should have referred to where people have raised similar ideas and issues. In particular Martin Fenner’s post at Nature Network. The comments are particularly good as an expert analysis of the usefulness of the kind of “value for money” critique I have made. Also a paper in the Arxiv from Stefano Allesina. Feel free to mention others and I will add them here.
Posted by: starclosure
Analyzing a FriendFeed group with Ruby and R:
FriendFeed is a social media service, where groups of people can post interesting information from the Web, and "like" or comment posts from others. Statistical Bioinformatician Neil Saunders is a member of the "Life Scientists" group, and has posted an analysis of the group's activity in 2009 to his blog. He used Ruby and the FriendFeed API to extract the data (group members, posts, comments, and "like"s), and then used R to analyze and visualize the data. For example, here's a look at the daily traffic in posts, comments, and likes represented as a calendar heat map.
You can see all of the Ruby and R code used to implement this and other analyses (What makes a popular post? Is there a relationship between "like" and comment activity?) at the link below.
What You're Doing Is Rather Desperate: The Life Scientists at FriendFeed: 2009 summary
You can see all of the Ruby and R code used to implement this and other analyses (What makes a popular post? Is there a relationship between "like" and comment activity?) at the link below.
What You're Doing Is Rather Desperate: The Life Scientists at FriendFeed: 2009 summary
Posted by: starclosure
A sample from Biology and Medicine:
- A Paradigmatic Complex System: The Immune System: Irun Cohen of the Weizmann Institute of Science is a physician and researcher who is trying to understand the complex immune system.
- Bioinformatic, Structural Biology and Structure Based Ligand Design in drug discovery: Discover how drugs are researched and developed.
- Molecular Biology: Macromolecular Synthesis and Cellular Function: Qiang Zhou from Berkeley discusses new findings in DNA research.
- Evolution of the Human Species: The discussion about evolution is still active. This lecture considers evolution from genetic and fossil records.
- Ventricular fibrillation in the human heart. Why is it different from the dog and pig heart?: Kirsten ten Tusscher looks at the structure of the human heart in this talk.
- Craig Venter on DNA and the sea: Biodiversity and genomics scientist Craig Venter talks about starting to writing the genetic code instead of just reading it.
- How Bacteria Cause Disease: Warren Levinson explains how bacteria are transmitted.
Posted by: starclosure
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