It’s all in the mind

Neuroscience is a fascinating subject, and not just because our friend Robert Sapolsky is a Faculty Member. Neuroscience (at least at F1000) covers a spectrum of subjects and disciplines, from the molecular basis of odour discrimination, through neural processing in the retina all the way up to anticipation of rewards and what chemical signals drive spontaneous learning and the pursuit of information.

In that vein, then, it’s rather fitting that

the last two decades of neuroscience and biological psychiatry research have revealed [that] there are no meaningful categorical differences in brain structure or function that map onto categorical clinical disorders

Ot to put it another way, it’s being on the ends of the spectrum, not having a discrete genotype, that makes you ’sick’. Ahmad Hariri of Duke University evaluated a paper from Robert Plomin (just down the road at King’s College) which synthesizes current thinking about mental illness into a conceptual framework summarized by the single statement

there are no categorical psychiatric disorders but rather a continuous range of behaviors which, at the extremes, may interfere with daily functioning.

The critical thing is that mental illness appears to be polygenic; that is there are multiple genes, each which have a small effect. Thus qualitative disorders, the ones that occupy pscychologists and psychiatrists, are simply the extremes of the bell curve of quantitative effects—there is a continuous range of brain structures and functions mapping onto a continuous range of behaviours. (‘Simply’, he says.) Now that’s all very well, but for the most part we don’t actually know what those quantitative traits, those individual genes, are. That shouldn’t be a major problem: Hariri recommends replacing categorical endpoints (exclusive) with quantitative biological and behavioural phenotypes (exclusive) in ongoing research. Extremes of the spectrum are important—medically and socially—and accepting this framework has enormous implications for the diagnosis, treatment and prevention of mental illness.

Which way is ‘up’?

I wrote a fluff piece for The Scientist ‘Hot Papers’ section last week (actually, I wrote three but only one is of concern now). It turns out that a long-held belief (there’s no other word) about segregation of different cell types in the developing embryo might well be wrong. The proposed mechanism is really intriguing but you’ll have to wait for me to tell you about it. In a almost-parallel development (pun not intended) another paper on F1000 looks at a similar problem in plants—in this case the generation of apical-basal patterning in Arabidopsis. This is important for establishment of root and shoot identities at opposite ends of the plant. Turns out that the previously-characterized PLETHORA genes and the CLASS III HOMEODOMAIN-LEUCIN ZIPPER transcription factor(don’t ask me why plant biologists have to shout so much) act antagonistically to define shoots versus roots.

While we’re talking about plants, Swiss researchers have found that the membrane at the Casparian strip is a diffusional barrier, and much like tight junctions in animal cells, generates polarity within cells. Two boron transporters (BOR1 and NIP5;1) are markers for polarization and allowed the researchers to trace polarity’s back to the embryo.

Changing your mind

Anyone who has spent any time at all looking at protein structures knows that NMR and x-ray crystallography tell you different things. Crystal structures give you the impression of something fixed in space, and NMR structures usually look like something constructed from over-cooked spaghetti. They’re both representations of course, but someone has finally pointed out that native structures of proteins should be described in terms of ensembles rather than some ‘average’ structure. I’m not convinced this counts as a ‘paradigm shift‘ but it’s good to see these thoughts in print. Oh, and I get to use my new ‘Hidden Jewel’ icon! Tell me what you think.

Another challenging paper was published in Cell last month, identifying the tumour suppressor NF2 as a partner of (yet another) E3 ubiquitin ligase. The protein of NF2 is called ‘Merlin’, for ‘Moesin-Ezrin-Radixin-related protein’, and has signficant similarity to one domain of the cytoskeletal protein I did my thesis on. So the surprise is that Merlin appears to be active in the nucleus, rather than (or in addition to?) at the plasma membrane.

This paper is going to alter the way we think about the tumor suppressor NF2 [...] These findings are surprising and will make us reassess how Merlin works.

says Jonathan Chernoff of the Fox Chase Cancer Center. This has shades of the whole ‘nuclear actin’ controversy.

Men of Harlech

Finally, all is not what it seems in the Welsh valleys. Mutant monster worms are using calcium binding and sensing pathways to deal with environmental lead, turning into mutant killing compost eaters of DOOM! Well, not quite, but it does appear that a population of the little wrigglers in the unpronounceable Cmystwhyth Valley diverged from the rest of the species 17 thousand years ago. One lineage is pretty normal, the other eats lead for breakfast. The authors of the paper recommend mandatory genotyping of all individuals prior to field-based ecotoxicological assays, particularly those using discriminating genomic technologies. I say we take off and nuke the site from orbit, etc.