Friday, December 31, 2010

End of the year with chemogenomics

Taken from jurvetson at:
Around this time of the year it is customary to make an assessment of the year that is ending and to make a mental list of things we wish for in the year ahead. Here is my personal (but work related :) take on this tradition.

My academic year ended with the publication of two works related to chemogenomics. Chemogenomics or chemical genomics tries to study the genome-wide response to a compound. Usually, collections of knock-outs or over-expression of large number of genes are grown in the presence or absence of a small molecule to assess the fitness cost (or advantage) of that perturbation to the drug response. This is what was done in these two works.

In the first one, Laura Kapitzky (a former postdoc colleague in the lab) used a collection of KO strains both in S. cerevisiae and S. pombe to essay for the growth in the presence of different compounds. The objective was to study the evolution of the drug response in these distantly related fungi. In line with what was previously observed in the lab for genetic-interactions and kinase-substrate interactions we found that drug-gene functional interactions were poorly correlated across these two species. Perhaps one interesting highlight from this project was that we could combine data from both fungi to improve the prediction of the mode-of-action of the compounds.

The second project, in which I was only minimally involved in, was a similar chemogenomic screen but at a much larger scale. As the tittle implies "Phenotypic Landscape of a Bacterial Cell" (behind paywall), is a very comprehensive study of the response of the E.coli whole knock-out library against an array of compounds and conditions. Robert, Athanasios and other members of the Carol Gross lab did an amazing job of creating this resource and picking some of the first gems from it.

Something that I wanted to highlight here was not so much what was discovered but what I was left wanting. These sort of growth measurements tell us a lot about drug-gene relationships. We also have a growing knowledge of how genes genetically interact either by similar growth measurements in double-mutants or by predictions (as in STRING). These should allow us then to make prediction about how drugs interact. If two drugs can act in synergy to decrease the growth of a bug we should be able to rationalize that in terms of drug-gene and gene-gene interactions. I find this is a very interesting area of research. Naively these sort of data should allow us to predict drug combinations that target a specific species (i.e. pathogen) or diseased tissue but not the host or the healthy tissue. Here is a scientific wish for 2011, that these and other related datasets will give us a handle on this interesting problem.

As for the future, I am entering the final year of my current funding source (thank you HFSP) so my attention is turning into finding either some more funds or another job. I will continue working on the evolution of signalling systems, in particular trying to find the function of post-translational modifications (aka P1). Unfortunately the project failed as an open science initiative, something that I have mostly given up for now. I think the main reason it didn't work was because of lack of collaborators of similar (open) interests and non-overlapping skill sets as Greg and Neil were discussing in the Nodalpoint podcast a while ago.

See you all in 2011 !