Nature Chemistry | The Sceptical Chymist

Doing the worm…

Despite its small size (about one millimeter long), the nematode Caenorhabditis elegans has been used to study a wide range of “”http://www.nature.com/nrd/journal/v5/n5/full/nrd2031.html">biological processes including apoptosis, cell signalling, cell cycle, cell polarity, gene regulation, metabolism, ageing and sex determination." Which is pretty amazing, as it truly is a simple organism: the adult hermaphrodite has 959 somatic cells!

In the May issue of Nature Reviews Drug Discovery, Kaletta & Hengartner wrote:

The cellular complexity and the conservation of disease pathways between C. elegans and higher organisms, together with the simplicity and cost-effectiveness of cultivation, make for an effective in vivo model that is amenable to whole-organism high-throughput compound screens and large-scale target validation.

I was surprised to learn that complex diseases can be investigated using this worm – scientists are even using it to “”http://www.nature.com/nrd/journal/v5/n5/full/nrd2031.html">identify additional mode of actions of fluoxetine [an antidepressant] and to further elucidate the molecular mechanism of depression."

C. elegans is getting a lot of attention at NPG this week: in the May 4th issue of Nature, Kwok et al. screened 14,100 small-molecules in living worms and identified 308 compounds that induced a range of phenotypes, including slow growth, lethality, uncoordinated movement and morphological defects. One of these small-molecules (a 1,4-dihydropyridine that they named nemadipine-A) induced an Egl phenotype (egg-laying defects).

The authors then screened 180,000 “”http://www.nature.com/nature/journal/v441/n7089/full/nature04657.html">randomly mutated wild-type genomes" to look for dominant genetic suppressors of the nemadipine-A-induced phenotype, and they performed a number of follow-up experiments that indicated that the protein Egl-19 (the only L-type calcium channel alpha1-subunit in C. elegans) is a target of nemadipine-A.

This isn’t completely unsurprising, as other 1,4-dihydropyridines are known to “”http://www.nature.com/nature/journal/v441/n7089/full/nature04657.html">antagonize the alpha1-subunit of L-type calcium channels“), but it’s an important demonstration that C. elegans can be used to quickly identify the targets of biologically active small-molecules – to quote Professor ”http://www.mgh.harvard.edu/cvrc/crvc/peterson/index.html">Randall Peterson, “”http://pubs.acs.org/cen/news/84/i19/8419notw8.html">[t]arget identification has been one of the thorniest problems in small-molecule screening, so this is a welcome and encouraging advance." And it’s so simple, Professor Peter Roy (the lead author of the study) said “”http://pubs.acs.org/cen/news/84/i19/8419notw8.html">I could teach a first-year undergrad to do it"…

Joshua

Joshua Finkelstein (Associate Editor, Nature)

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