OK I’ve been away a very long time.  Maybe that means I have a life….  But I needed a place to say this:

Douglas Kell (Chief Executive of the UK’s BBSRC) is interviewed in a recent issue of Nature (volume 458, page 1063).  He bangs the drum for systems biology, and says: “the reductionist strategy certainly hasn’t helped us to understand complex systems”.  …certainly hasn’t helped us to understand…  How absurd is that?

For those of us still interested in molecular biology a lovely irony follows.  Asked to identify the scientific achievement that gave him greatest satisfaction, Kell nominates the discovery of resuscitation promoting factor (Rpf) in Micrococcus luteus and related Gram-positive Bacteria.  Now I thought that the Rpf work was cool (see for example, The rpf gene of Micrococcus luteus encodes an essential secreted growth factor) but it is surely an illustration of how an elegant reductionst approach can help us to understand a complex system.

There, rant over.  You could say that I’ve been resuscitated from my dormancy, ha ha.  Expect to hear from me again in another year or so.  Or maybe sooner.

As is being reported in the New York Times, and elsewhere, the Texas Education Agency’s director of science Christine Comer has been forced to resign.  Her misdemeanor appears to have been nothing worse than forwarding details to a ‘local online community’ (whatever that means) of a lecture by a philosophy professor who testified as an expert witness in the 2005 Dover case.  Read more about the story at the National Center for Science Education.

So, I looked up the Texas Education Standards, which say (amongst other things):

Science concepts. The student knows the theory of biological evolution. The student is expected to:

(A)  identify evidence of change in species using fossils, DNA sequences, anatomical similarities, physiological similarities, and embryology; and

(B)  illustrate the results of natural selection in speciation, diversity, phylogeny, adaptation, behavior, and extinction.

Which is all well and good, except that the standards are up for 10 year review in 2008…

This cartoon accompanies a review in Nature of Steven Pinker’s new book, The stuff of thought, language as a window into human nature. I don’t think it’s a new cartoon, I have a recollection of seeing it before, in connection with Project Steve. Anyway, I like it, but then I would, wouldn’t I…

Go watch Doris Lessing’s delightful response to winning the Nobel Prize. The reporter seems to tell her that she has won the ‘Nobile’ Prize for literature (perhaps that accounts for her reaction). Look out for the artichoke being brandished by her son. I was very pleased to hear this news having read and enjoyed quite a number of her books (albeit more than 20 years ago).

I was amused to read that Ms Lessing thought that a film crew was in her street to record an episode of Morse. Now even I, as a non-TV-watching non-UK-resident, know that John Thaw (the actor who played Detective Morse) died several years ago, and that Morse has therefore not been recorded for an equally long period. Evidently, Ms Lessing does not watch TV very much, something else to applaud, I think.

The unexpected appearance of this blog in Bio::Blogs 15 (the bioinformatics blog journal) prompts me to ramble some more on the topic of bioinformatics, and specifically gene annotation and re-annotation, from the perspective of an ‘experimental’ micro/molecular biologist.

I moaned recently about a published study in which obviously incorrect conclusions about gene function were reached on the basis of naïve sequence comparisons. Pawel made some suggestions as to how (computationally) mistakes like this might be avoided. In the particular case I was bothered about, some common sense application of biological understanding should also have prevented the error. This was a case not of incorrect annotation during a genome sequencing project, but rather incorrect re-annotation by investigators looking at single genes on a case-by-case basis.

As Pawel mentioned, we should expect and tolerate annotation errors in large-scale sequencing projects. An interesting case is described in a recent paper in the Journal of Bacteriology from James Ferry’s lab. Here, a gene annotated as encoding a carboxymuconolactone decarboxylase is instead shown to encode a enzyme (MdrA) that has protein disulfide reductase activity and contains an [Fe-S] cluster. Correction of all annotation errors is not a realistic goal if it requires painstaking biochemistry of the type described in this paper. But doing some biochemistry will improve the accuracy of computational predictions; the two approaches are (obviously) synergistic. Interestingly enough, from the way that the paper is written it seems that Ferry’s study was stimulated by the annotation error. The presence of the gene in a cluster of others probably related to oxidative stress was one clue to the annotation error (physiology of the organism was another). So, if the gene had been elsewhere in the genome, and incorrectly annotated, then this work may never have been done!

There is some very interesting biochemistry in the paper as well. The authors show that the disulfide reductase activity and oligomeric state of MdrA are regulated by an iron-sulfur cluster. A Cys-X-X-Cys motif is required both for cluster formation and for disulfide reductase activity, but the [Fe-S] form of the protein is apparently catalytically inactive. The data lead the authors to hypothesize that MdrA trimers are crosslinked to form an enzymatically inactive hexamer by a single [2Fe-2S] cluster. In this model, loss of the cluster (perhaps in response to oxidative stress) leads to the formation of trimeric MdrA with disulfide reductase activity.

Lessner, D.J. & Ferry, J.G. (2007) The Archaeon Methanosarcina acetivorans contains a protein disulfide reductase with an iron-sulfur cluster. Journal of Bacteriology 189: 7475-7484

A recent paper reports some of the most naive sequence-based bioinformatics I have ever come across. I won’t (but could) deconstruct the analysis line-by-line, rather let this one quotation serve as an example:

Looking at the similar domain architecture in NorR of E. coli and DIP1512 of C. diphtheriae we can safely assume that they are functional homologues, inspite of the non-finding of GAF and HTH domain in DIP1512.

Now, NorR is a three domain transcriptional activator. It has a GAF domain required for signal sensing, a AAA+ domain that interacts with RNA polymerase and a HTH domain required for DNA binding. The above statement (ignoring its glaring internal contradiction) refers to the conclusion that a protein that lacks the GAF domain and the HTH domain is nevertheless a ‘functional homologue’ of NorR. Besides sharing only one of NorR’s three domains, the DIP1512 protein also lacks a conserved sequence motif that is absolutely required for the interaction with RNA polymerase.

Being active in a related area of research I find this all rather aggravating, but I’m not sure what to do about it, other than venting here (which feels somewhat like stepping outside my office and yelling into the Texas wind).

For an excellent bioinformatic treatment of NorR and other proteins that respond to nitric oxide, I thoroughly recommend the work of Dmitry Rodionov and colleagues, as reported here.

Gupta, S., Bansal, S., Deb, J.K. and Kundu, B. (2007) Interplay between DtxR and nitric oxide reductase activities: a functional genomics approach indicating involvement of homologous protein domains in bacterial pathogenesis. International Journal of Experimental Pathology 88: 377-385

Rodionov, D.A., Dubchak, I.L., Arkin, A.P., Alm, E.J. and Gelfand M.S. (2005) Dissimilatory metabolism of nitrogen oxides in bacteria: comparative reconstruction of transcriptional networks. PLOS Computational Biology 1: e55

Are you interested in using your blog to post serious reviews of published research?  “Bloggers for Peer-Reviewed Research Reporting” (BPR3) are conducting a poll to choose an icon to represent BPR3.  I’m not sure what I think of all this, but I like Kevin Z’s icon:

Science writer Georgina Ferry has a nice website.  I especially liked this:

It drives me mad that when people use the word ‘culture’ they invariably mean the arts. The sciences are as much an expression of human culture and civilisation as music, dance or painting.

I very much enjoyed reading Ferry’s biography of Dorothy Hodgkin a few years ago, and am looking forward to her new biography of Max Perutz, as soon as I can get hold of a copy.

A remarkable new paper in Science (subscription required for full text) shows that several Bacteria express a flavin-containing light-activated protein kinase. Amazingly, in Brucella abortus, the photoreceptor is apparently required for full virulence. An accompanying commentary speculates that when the pathogen is expelled from its host, virulence genes are up-regulated by light in order to prepare it for re-infection of a new host.

Swartz, T.E., Tseng, T-S., Frederickson, M.A., Paris, G., Comerci, D., Rajashekara, G., Kim, J-G., Mudgett, M.B., Splitter, G.A., Ugalde, R.A., Goldbaum, F.A., Briggs, W.R. and Bogomolni, R.A. (2007) Blue-light-activated histidine kinases: two-component sensors in Bacteria. Science 317: 1090-1093

I found this interesting post from FemaleScienceProfessor, who has (as a journal Editor) conducted some informal research into the time taken to review papers, in reviewers sorted into groups by seniority.  In general, early career and retired scientists are the fastest reviewers, with some outliers.  Individual reviewers tend to be consistent in the time taken to review:

I thought there would be more variation because the time frame might be affected by how busy someone is, as well as factors related to the manuscript length and quality: some manuscripts are easy to review and some require a huge amount of time. But no.. time-to-review seems to be a personality trait more than anything else.

From my own experience as an Editor soliciting reviews I would entirely agree with this.  And, as a reviewer, I almost always return reviews before the deadline, irrespective of how busy I am or how difficult the paper.