My Favorite Papers of 2012

These are the papers that I thought were the most interesting in my world this year. It was a big year for hormonal messengers involved in obesity and diabetes.  These include Fgf21 (Kim et. al) and VEGF (Hagberg et. al).  From a biochemistry perspective there was a lot of great work on the role of SREBP1 (Moon et. al) and its regulation both from a dietary (Haas et al.) perspective and from a mechanistic perspective (Owen et al.).  Finally both Kim et al. and Kusminski et al. highlighted the importance of mitochondrial function in the systemic response to obesity.



Haas, J., Miao, J., Chanda, D., Wang, Y., Zhao, E., Haas, M., Hirschey, M., Vaitheesvaran, B., Farese, R., Kurland, I., Graham, M., Crooke, R., Foufelle, F., & Biddinger, S. (2012). Hepatic Insulin Signaling Is Required for Obesity-Dependent Expression of SREBP-1c mRNA but Not for Feeding-Dependent Expression Cell Metabolism, 15 (6), 873-884 DOI: 10.1016/j.cmet.2012.05.002

Hagberg, C., Mehlem, A., Falkevall, A., Muhl, L., Fam, B., Ortsäter, H., Scotney, P., Nyqvist, D., Samén, E., Lu, L., Stone-Elander, S., Proietto, J., Andrikopoulos, S., Sjöholm, A., Nash, A., & Eriksson, U. (2012). Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes Nature, 490 (7420), 426-430 DOI: 10.1038/nature11464

Kusminski, C., Holland, W., Sun, K., Park, J., Spurgin, S., Lin, Y., Askew, G., Simcox, J., McClain, D., Li, C., & Scherer, P. (2012). MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity Nature Medicine, 18 (10), 1539-1549 DOI: 10.1038/nm.2899

Moon, Y., Liang, G., Xie, X., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Brown, M., Goldstein, J., & Horton, J. (2012). The Scap/SREBP Pathway Is Essential for Developing Diabetic Fatty Liver and Carbohydrate-Induced Hypertriglyceridemia in Animals Cell Metabolism, 15 (2), 240-246 DOI: 10.1016/j.cmet.2011.12.017

Kim, K., Jeong, Y., Oh, H., Kim, S., Cho, J., Kim, Y., Kim, S., Kim, D., Hur, K., Kim, H., Ko, T., Han, J., Kim, H., Kim, J., Back, S., Komatsu, M., Chen, H., Chan, D., Konishi, M., Itoh, N., Choi, C., & Lee, M. (2012). Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine Nature Medicine DOI: 10.1038/nm.3014

Owen, J., Zhang, Y., Bae, S., Farooqi, M., Liang, G., Hammer, R., Goldstein, J., & Brown, M. (2012). From the Cover: Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase Proceedings of the National Academy of Sciences, 109 (40), 16184-16189 DOI: 10.1073/pnas.1213343109

My Favorite Papers of 2012 by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

How is PtdIns(5)P Made?

For most phosphatidylinositides, the routes of synthesis and degradation have been largely elucidated.  However, due to difficulty in detecting PtdIns(5)P, only recently have investigators been able to assess the synthesis and degradation of this phospholipid.  The major stumbling block has been the separation of PtdIns(5)P from PtdIns(4)P, which migrate quite closely on HPLC/TLC based separations.  The two major advances in the field have been improved separation of these monophosphorylated lipids (for example see Sarkes and Rameh 2010 and Zolov et al. 2012) and separation-independent identification of PtdIns(5)P by an enzyme based phosphorylation assay. (see Jones et al., 2012).  I am a co-author on the Zolov paper and work closely with that group.

Which enzymes are involved?

Potential Routes for PtdIns(5)P Synthesis.

The simplest mechanism is through phosphorylation of PI directly by a PtdIns-5-Kinase.  There are two known classes of Ptdins-5-Kinases in mammalian cells, Pikfyve and three isoforms in the PtdIns(4)P-5-Kinase family (Pip5k1a, Pip5k1b and Pip5k1c).  Classically, Pikfyve is thought to convert PtdIns(3)P into PtdIns(3,5)P₂ wheras the other classes phosphorylate PtdIns(4)P into PtdIns(4,5)P₂.  I think that the strongest evidence is that Pifkve is essential for PtdIns(5)P levels in the cell, either directly or indirectly.

Biochemically, there seems to be three potential ways by which PtdIns(5)P could be made, through direct phosphorylation of PtdIns, or through dephosphorylation of either PtdIns(3,5)P₂ or PtdIns(4,5)P₂.  Of course, it is possible that in different contexts, each of these pathways could be involved.

Route 1: Direct Phosphorylation of PtdIns

Although there is limited evidence that the PtdIns(4)P-5-Kinases can phosphorylate PI, there is substantial evidence that PI(5)P can be generated by Pikfyve, in vitro (Sbrissa et. al, 1999).  Inside cells, it is less clear whether this is the case.  There is rapid and tightly correlated turnover of both PtdIns(3,5)P₂ and PtdIns(5)P in most cells (Zolov et. al, 2012, Sbrissa et al., 2012) to the point that it is difficult to tell if changes in PtdIns(3,5)P₂ preceed changes in PtdIns(5)P or correlate with them independently.  

Route 2: De-Phosphorylation of PtdIns(3,5)P₂

Two main lines of evidence support the possibility that PtdIns(3,5)P₂ could be the source of some or all of the PtdIns(5)P in the cell:  

1. Myotubularins, which are 3-phoshphatses leads to increased PtdIns(5)P and their deletion may lead to reductions in PtdIns(5)P (Vaccari, et al., 2011, Oppelt et al., 2012).
2. The kinetics of acute PtdIns(5)P synthesis or degradation may lag slightly behind the synthesis or degradation of PtdIns(5)P.  In any case, the levels of PtdIns(5)P and PtdIns(3,5)P₂ are very tightly correlated (Zolov et al., 2012).

The killer experiment here would be to test whether ablation of PtdIns(3)P levels would have direct effects on PtdIns(5)P levels, but since it is not clear whether PI3K inhibitors such as Wortmannin would affect Pikfyve in vivo that experiment may not be interpretable without ruling out direct effects first.

Route 3: De-Phosphorylation of PtdIns(4,5)P₂

An alternate theory has suggested that some or all of PtdIns(5)P is derived by the activity of a 4-Phosphatase which convertes PtdIns(4,5)P₂ into PtdIns(5)P.  The exact identity of this 4-phosphatase is not yet known.  Jones et al. show that peroxide increases PtdIns(5)P levels, and propose a role for PtdIns(4,5)P₂ dephosphorylation in that process.  However, in contrast to our findings (Zolov et al., 2012), this paper finds no role for Pikfyve in the synthesis of PtdIns(5)P, using similar approaches but a different assay to measure PtdIns(5)P (see below).

What is the Best Way to Measure PtdIns(5)P?

Regarding the role of Pikfyve, there seems to be a controversy here.  I've summarized the assays and their results in the table below.

Assay	Inositol Labelling	Mass Assay
Summary	Cells are grown in inositol depleted media with radioactive inositol. Cells are lysed and lipid headgroups are separated by HPLC based on charge.	Cells are grown in any condition, lipids are extracted and phosphorylated with PIP4K and radioactive ATP. Only PtdIns(5)P can be phosphorylated by this enzyme, so all hot PIP2 (based on TLC and counting) is derived from PtdIns(5)P.
Normalization	Total phosphatidylinosotol	Total cellular phospholipids
Result	Pikfyve knockdown/inhibition nearly completely decreases PtdIns(5)P levels.	Pikfyve knockdown/inhibition does not affect PtdIns(5)P levels.

Setting aside the role of peroxide in PtdIns(5)P as potentially a special case, you could make arguments for both methods.  Hopefully this can be resolved quickly since knowing where this lipid comes from is the first step in figuring out what it does.

References

Jones, D., Foulger, R., Keune, W., Bultsma, Y., & Divecha, N. (2012). PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation The FASEB Journal DOI: 10.1096/fj.12-218842

Oppelt, A., Lobert, V. H., Haglund, K., Mackey, A. M., Rameh, L. E., Liestøl, K., Oliver Schink, K., et al. (2012). Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration. EMBO reports. doi:10.1038/embor.2012.183

Sarkes, D., & Rameh, L. E. (2010). A Novel HPLC-Based Approach Makes Possible the Spacial Characterization of Cellular PtdIns5P and Other Phosphoinositides.The Biochemical journal384, 375–384. doi:10.1042/BJ20100129

Sbrissa, D., Ikonomov, O. C., & Shisheva, A. (1999). PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin. J Biol Chem, 274(31), 21589–21597. pmid:10419465

Sbrissa, D., Ikonomov, O. C., Filios, C., Delvecchio, K., & Shisheva, A. (2012). Functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636. American journal of physiology. Cell physiology, (313). doi:10.1152/ajpcell.00105.2012

Vaccari, I., Dina, G., Tronchère, H., Kaufman, E., Chicanne, G., Cerri, F., Wrabetz, L., et al. (2011). Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS genetics, 7(10), e1002319. doi:10.1371/journal.pgen.1002319

Zolov, S. N., Bridges, D., Zhang, Y., Lee, W., Riehle, E., Verma, R., Lenk, G. M., et al. (2012). In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proceedings of the National Academy of Sciences of the United States of America, 109(43), 17472–7. doi:10.1073/pnas.1203106109


How is PtdIns(5)P Made? by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

How is SREBP Regulated by Insulin?

SREBP is a transcription factor which integrates anabolic signals and drives transcription of several important lipogenic genes such as Fatty Acid Synthase, Acetyl-CoA Carboxylase and the LDL Receptor.  In liver tissue ,this serves to enhance the uptake, synthesis and storage of lipid in the postprandial state.  The biochemical mechanisms by which this happens is unclear but a recent paper from the Brown and Goldstein laboratory has shed some light on this.

Figure: SREBP Processing and Translocation (from http://en.wikipedia.org/wiki/Srebp)

Previously it had been known that insulin causes both the cleavage and nuclear translocation of SREBP in hepatocytes (see Figure). Confusing the issue was the fact that SREBP was also increased transcriptionally. Owing to the presence of a SRE element in the promoter, I thought that the transcriptional effects were likely due to a positive feedback loop where insulin causes SREBP processing, which in turn causes more transcription of the mRNA.  Adding credence to this hypothesis was the fact that inhibitors of the PI3K->mTORC1 pathways (Wortmannin and Rapamycin) inhibited both transcription and processing of SREBP1.

In the Owen et al. paper, a transgenic rat is generated which puts SREBP1c under the control of a non-insulin responsive promoter, allowing for examination of the processing of SREBP1c independent of the SREBP1c promoter.  Consistent with previous findings, they show that both Wortmannin and Rapamycin block processing and mRNA synthesis, but that another inhibitor LYS6K2 which is specific for S6K (a target of mTORC1) blocks only processing and not mRNA levels.



This not only suggests that S6K is the proximal effector of the PI3K-mTORC1 pathway with respect to processing, but that S6K plays no role in the transcriptional regulation.  This also, for the most part, excludes a role for the SREBP -> SRE positive feedback loop, since under LYS6K conditions, SREBP cleavage is blocked but mRNA levels are unchanged.  Put another way, if the SREBP positive feedback loop was important, then this would suggest that mRNA of SREBP would be reduced under all conditions in which SREBP processing is blocked.

Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, Goldstein JL, & Brown MS (2012). Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proceedings of the National Academy of Sciences of the United States of America PMID: 22927400


How is SREBP Regulated by Insulin? by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

Rab5 Knockdown In Vivo

This paper from the Zerial Laboratory describes a study in which the three mammalian isoforms of Rab5 are reduced in whole livers or cultured hepatocytes by a lipid nanoparticle mediated knockdown treatment. They then analyse images from these cells and liver sections and determine that there are reduced early endosomes, late endosomes and lysosomes in cells depleted of Rab5.

They also identify two functional defects in these tissues; reduced LDL uptake and impaired apical polarity of the hepatocytes. They also generate a simplified model of Rab5/early endosomal dynamics and suggest a role for Rab5 in vesicle fission as well as fusion. Although this model fits the available data quite well, it ignores several other key components of endosomal formation and maturation.

The authors also present the curious finding that while Rab5 depletion reduces both LDL uptake and endosome numbers, dynamin depletion only affects LDL uptake but not the number of endosomes. One possible explanation for this defect is that they quantify the presence of endosomes in this assay largely by EEA1 puncta. Since EEA1 is a Rab5 effector, it is possible that in the Rab5 depleted cells there is still a population of early endosomes, but that these are not detected by EEA1 staining.

Together this study presents a convincing picture for the role of Rab5 in endosomal dynamics, and highlight the important role of Rab5 in both endocytic pathways and in the establishment of polarity in vivo.

Citation

Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, Epstein-Barash H, Kuchimanchi S, Peng CG, Ruda VM, Del Conte-Zerial P, Hengstler JG, Kalaidzidis Y, Koteliansky V, & Zerial M (2012). Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature, 485 (7399), 465-70 PMID: 22622570

Disclosure: I have received constructs and yeast strains from the Zerial laboratory in the past.



Rab5 Knockdown In Vivo by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

Why Isn't There Anonymous Post-Publication Peer Review

If pre-publication review is anonymous, and it almost always is why isnt there anonymous post-publication peer review? If there is a benefit to anonymous review, then isn't it odd that the Faculty of 1000 and most journals commenting/letter to editor mechanisms require the submitter to provide a real name and appointment. Would post-publication review of articles suck less if it were anonymous?

Why Blog

Based on the twitter meme #whydoiblog. This is a good question, seeing as I do this infrequently and without a ton of focus. I guess I'd say to get something off my chest that I think other people might want to hear. I aspire towards being able to talk about research in a more public and open way, but until I am independent that is unfair to people who might not want to operate that way. Until then I'll continue to use this as a sporadic forum for me to speak out to the ether.

Why Blog by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

What Should Be Done about Reproducibility

A recent Commentary and linked editorial in Nature regarding reproducible science (or rather the lack thereof in science) has been troubling me for a few days now. The article brings to light a huge problem in the current academic science enterprise.

What am I talking about?

In the comment, two former Amgen researchers describe some of the efforts of that company to reproduce "landmark studies" in cancer biology. Amgen had a team of about a hundred researchers called the reproducibility team and their job was to test new basic science findings prior to investing in following up these targets. Shockingly, according to the authors, only 6/53 of these landmark studies were actually reproduced. When things were not reproduced they contacted the authors to attempt to work through the potential problems. This is an incredibly dismal 11% reproducibility rate!

Could it really be that bad?

The first problem is what exactly is meant by reproducibility. In the commentary the authors acknowledge that they did attempt to use additional models in the validation process and that technical issues may have under-lied some of these differences. They also point out that their sample set is biased with respect to the findings. These were often novel and cutting edge type findings and typically more surprising than the general research finding. Also, their definition of reproducibility is unclear. If researcher says drug X has a 10 fold effect on something and the Amgen guys say it has a 3X effect on the process is that a reproducible finding. My initial reaction was that the 89% were thing where the papers said something like thing X does thing Y and there was no evidence supporting that. We don't know, and in a bit of an ironic twist, since no data is provided (either which papers were good and which were bad, or within those, which findings were good and bad) this commentary could be considered both unscientific and non-reproducible itself (also we are awfully close to April Fools Day).

So there is some bad papers out there, who cares?

Reproducibility is at the heart of everything we do as scientists. No one cares if you did something once and for reasons you cant really explain, were never able to do it again. If something is not replicable and reproducble for all intents and purposes it should be ignored. We need measures of these to be able to evaluate research claims, and we need context specificity to understand the breadth of claims. Ill toss out few reasons why this problem really matters both to those of us who do science, and to everyone else.

This is a massive waste of time and money

From the commentary:

Some non-reproducible preclinical papers had spawned an entire field, with hundreds of secondary publications that expanded on elements of the original observation, but did not actually seek to confirm or falsify its fundamental basis.

Wow, really? Whole fields have been built on these? In a way I don't feel bad for these fields at all. If you are going to work in a field, and are never going to bother even indirectly testing the axioms on which your field is built then you are really not so good at the science. If you are going to rely on everyone else being correct and never test it then your entire research enterprise might as well be made from tissue paper. More importantly, if you are on top of these things you are going to waste time and money figuring out not to follow this up. Hopefully this is the more common case. This really goes back to the difficulty in publishing negative data to let people know which conditions work and which don't.

The reward system for science is not in sync with the goals of the enterprise

Why are people publishing things that they know only happen one out of six times? Why are they over-extending their hypotheses and why are they reluctant to back away from their previous findings? All of these things are because we are judged for jobs and for tenure and for grants on our ability to do these things. The person who spends 3 years proving that a knockout mouse model does not actually extend lifespan walks away with nothing, the one who shows it (even if done incorrectly) gets a high impact paper and a job. Even if it didn't take an unreasonable amount time and effort to publish non-reproducible data, the risk of insulting another researcher or not contributing anything new might be enough to prevent this. Until the rewards of publishing negative or contravening data are on par with the effort, people just won't do it.

This reflects really poorly on science and scientists

Science is always and probably has always been under some type of "attack". Science as an entity and scientists as their representatives need to not shirk this off or ignore it. We have to deal with this problem head-on, whether it be at the review level or at the post-publication level. People who are distrustful of science are rightful to point at this and say, why are we giving tens of billions of dollars to the NIH when they are 89% wrong. Why not just give that money to Amgen, who seem to be the ones actually searching for the truth (not that they will share that data with anyone else).

Can anything be done?

The short answer is its really going to be difficult and its going to rely on a lot of moving parts. Reviewers should (and in my experience do) ask for explicit reprodicibility statements in the papers. This can go farther, if someone says this blot is representative of 5 experiments then there is no reason the other 4 couldnt be put in the supplement. If they looked at 100 cells and show just one, then why cant the rest be quantified in some way. Post-publication, there should be open (ie not just in lab meetings) discussion of papers and the problems and where they match or mismatch with the rest of the literature. Things like blogs and the Faculty of 1000 are great, but how often have you seen a negative F1000 review? Finally, eventually there ought to be some type of network of research findings. If I am reading a paper, and I would like to know what other results agree or disagree with this, it would be fantastic to get there in a reasonable way. This is probably the most complicated, as it requires not only publication of disagreeing findings, but also some network to link them together.



Begley, C., & Ellis, L. (2012). Drug development: Raise standards for preclinical cancer research Nature, 483 (7391), 531-533 DOI: 10.1038/483531a


What Should Be Done about Reproducibility by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.

Future Bridges Lab Rules version 0.1

Lab Rules

Version 0.1.3 on July 14, 2012 by Dave Bridges

Remember when you were growing up and you would say, well when I’m older I will (or won’t) do that.
I have been thinking of that, for my future when I run my own group.
It is fairly easy (and as a bit of a blowhard I do this all the time) to say I would do this, or I would do that.
I think posting this publicly will encourage me to stick to these rules.
Below are some roles and a bit of rationale and caveats.
This is the first version of this post but future versions will include links to the previous versions.
The version numbering is described in the Lab Policies README.
Check out the GitHub Repository for more granular changes.

Supervision of Trainees

Trainee-Advisor Contract

Both myself and trainees (either mine, or co-supervised trainees) will read, discuss and sign a contract describing our roles and responsibilities both as a trainee/employee and a mentor. This will include data dissemination/publishing rules, expectations of productivity, note keeping and time commitment, rules for dealing with other members both in my group and in collaborations, rules for sharing of reagents and data, rules for adjucating disagreements and grounds and procedures for termination. These rules will be in conformity with any institutional rules. Exceptions can be discussed and the agreement can be modified throughout the term of the relationship. I will post a generic version of this agreement in a publicly viewable location.

Online Presence

All trainees will appear on the laboratory website and write a blurb about their research interests and goals. Trainees will be strongly encouraged to blog, tweet and otherwise engage in social networking tools regarding their research and the work of others, but this is not required. Links to their publicly available social network profiles will be posted on the laboratory website.

Open Access Policy

Trainees will be made aware of the open publishing, dissemination, software and data/reagent sharing policies of the laboratory at the outset and will have to agree to these standards.

Reagents, Software and Tools

Software Usage

Wherever possible, free open source software will be used for data acquisition, analysis and dissemination. Exceptions will be made if necessary, but trainees will be encouraged to use/incorporate/development free tools.

Software Development

If software, scripts or the like are generated they will be released under a permissible open source license such as CC-BY and the license will be attached explicitly to the source code. Scripts and programs will be uploaded to a public revision control database such as GitHub or similar (my GitHub profile is here).

Publishing of Protocols and Scripts

When not present in the published article, detailed step by step protocols, data analysis scripts and other things which cannot fit into either methods and materials sections or supplementary materials will be posted online and linked to the publication’s online presence (post or as a comment on the paper’s website).

Protocol Sharing

Protocols will be made available online in a wiki format in a publicly available location, whether they have been published on or not. Editing will be restricted to laboratory members and collaborators.

Reagent and Tool Sharing

Reagents generated by my group will be shared upon request without condition (aside from potential restrictions placed by other collaborators, funding agencies and the institution). These reagents will be shipped with an explicit statement of free use/sharing/modification. Once a reagent sharing license is generated/identified it will be linked to in this document. This policy includes unpublished reagents and will never require attribution as a condition. If a reagent is obtained from another group and modified, we will offer the modified reagent back to the originator immediately.

Publishing and Data Dissemination

Open Access Journals

I believe that all work should be available to the public to read, evaluate and discuss. I am strongly against the mentality that data/knowledge should be restricted to experts and the like. I will therefore send all papers in which I am corresponding author and have supervised the majority of the work to journals (or their equivalent) which are publicly available. The two major caveats will be for work in which I am a minor (less than 50% effort) collaborator and the primary group leader wants to submit the work elsewhere. This will not exempt any potential major impact publications, no matter how awesome they may be. Delayed open access does not count in this respect.

Open Peer Review

Journals will be selected which publish non-anonymous reviewer comments alongside the articles whenever possible. If this is not done, and if permissible by the publisher and/or reviewers I will re-post the reviewer comments online without any modifications.

Public Forum for Article Discussion

Although I will encourage discussion of articles to occur at the point of publication (for example via the posting of comments directly at the website of the publisher), I will also provide a publicly available summary of every published finding from which I am an author (corresponding or not) and allow commenting at that point too. This discussion post will also link to or contain the reviewer and editor comments where possible. This summary might be a blog post, a facebook post or a google plus post or anything else that might come up in the future. If I am not the primary author or corresponding author I will encourage the first or corresponding author to write the post and link/quote that directly.

Presentations

All presentations of published data will be posted on an online repository such as Slideshare or something similar. My slideshare profile is here. If unpublished or preliminary data is presented privately and then is later published, then those slides will be presented upon publication. Similar to papers, an online blog post or the like will also accompany that upload. If audio or video of the presentation is available, that will be uploaded as well.

Data Sets

All datasets, once published will be made available in manipulable (preferably non-proprietary) formats for further analysis. Based on the scheme set out by the Linked Data Research Center Laboratory, all data will be provided at level 2 or above.

Chickens and Eggs

Yesterday two posts appeared in my feed both challenging the requirement of glamor mag (Nature, Science, Cell) level publications for career advancement.  Michael Eisen (@mbeisen) wrote a post in response to this idea suggesting that this is not a criteria for hiring in his experience (he is referring to job applications where he is, at UC Berkeley as well experiences with his  trainees).  Key point:

My own lab provides several examples that demonstrate this reality. My graduate students have gone on to great postdocs and many have landed prestigious fellowships “despite” having only published in open access journals. More curiously, I have had four postdoctoral fellows go out onto the academic job market, who  all got great jobs: at Wash U., Wisconsin, Idaho and Harvard Medical School. Not only did none of them have glamour mag publications from my lab. None of them had yet published the work on the basis of which they were hired! They got their interviews on the basis of my letters and their research statements, and got the jobs because they are great scientists who had done outstanding, as of yet unpublished, work. If anything demonstrates the fallacy of the glamour mag or bust mentality this is it.

In fact, as a co-founder of PLOS and a strong, vocal advocate of open science his group primarily publishes in PLOS journals.  He hasn't been the last author on a non-PLOS paper since a PNAs paper in 1998, so he is certainly putting his science where his mouth is. Earlier in the day, William Gunn (@mrgunn) made a similar argument:

I'm starting to think that the plodding careerists who always raise the "but I have to publish in X journal for my career" criticism just need to be routed around. You shouldn't be in science because you want a stable career, you should be here because you can't fathom doing anything else.

Now these are both admirable positions to take.  But as the title alludes to, this is a chicken and egg problem.  If a postdoc decides to only publish in open access journals then he hopes that prospective departments and grant committees agree with his stance.  If a faculty member takes this stance he hopes that grants and tenure/promotion committees agree.  If tenure and promotion committees agree, then they hope granting agencies agree.  If granting agencies agree then they hope that the public (or their foundations or government agencies agree).  If any link breaks, then its a risk.  As someone who agrees with this, I might find a department happy with this policy, but if my NIH study section isn't on board then I am in some trouble.

Taking this further, I thought why should this even only apply to open access and open review.  Lets say I do all my research totally in the open, self-publishing it online either on my own site or on a pre-print server like ArXiv or the newer Faculty of 1000 Research and engaging in discussion on these forums.  If I completely ignored journals entirely, would anyone accept this as being ok?  I posted it on twitter, and there were positive responses, but that is really hard to imagine.

Without anonymous peer-review how could I (or the reader) be assured that controls were done properly and the context of the work was appropriately stated.  If that is done via peer review posted with the article anonymously how could the reader be sure I didn't just delete the bad reviews or comments.  If I post some data on a blog or pre-print server and some other person finds it, expands on it and publishes it in Science then do I have any right to feel aggrieved?  Who should get the credit?

In an ideal world, things might work analogously to how Rosie Redfield (@rosieredfield) has addressed the arsenic life question.  After posting an initial rebuttal online, Dr. Redfield did some experiments, engaged with the community about the data and put it all together.  This was (to me at least) the first archetypical evidence of the open evaluation of a research claim.  It was done in the open, public suggestions were incorporated, the work was posted to a preprint archive and then in the end.... it was submitted to Science.

Now this is not entirely fair to Dr. Redfield, Science was chosen as that was where the first arsenic paper was published and where her (and other) critiques were published.  But if this, most open and public scientific re-evaluation, still needs glamour mag validation what hope does the rest of research have?

So who should mandate this?  Various policies of public access have helped make publicly funded research open access and a new generation of scientists has shown more proclivity towards goal but who needs to take the first steps.  Dr. Eisen suggests it has to be everyone.  For this change to happen, primary researchers, group leaders, departments, granting agencies and the public all need to take that step, and leave those who are betrothed to impact factor chasing looking like relics of the past.


Chickens and Eggs by Dave Bridges is licensed under a Creative Commons Attribution 3.0 Unported License.