The Seven Stones

SB 3.0 day 3

How to develop organisms with modified and extended genetic codes? Can bacteria be evolved to replace given metabolic pathways by “exotic” alternative ones or eliminate altogether given amino acids from the entire proteome? These were the topics of a few talks presented at the third Synthetic Biology conference, Zurich, Switzerland.

I already wrote in my first SB3.0 post on the technology being developed in George Church’ laboratory to enable automated editing of the bacterial genome, for example to eliminate or mutate a given codon. Yesterday, Jason Chin presented his work on the engineering of an “orthogonal” translation system that works independently of the endogenous translation machinery. As a first step, pairs of tRNA / aminoacyl tRNA synthetase (aaRS) with altered specificity were developed, by adopting a heterologous aaRS from Methanococcus jannaschii and evolving it to shift its activity towards loading of an unnatural amino acid (Chin et al, 2002). The second step was to develop orthogonal ribosome / mRNA pairs by selecting new 16SRNAs recognizing mutated mRNA header sequences (Rackham and Chin, 2005). Finally, to enable efficient translation of amber codon, the resulting orthogonal ribosomes were evolved to escape competition with release factor RF1. Put together, these components (unnatural amino acid/aminoacyl tRNA synthetase / mRNA / ribosome) reconstitute a complete orthogonal translation apparatus that works with high fidelity in parallel with endogenous translation. Such orthogonal systems enable “programmatic” incorporation of fluorescent groups, stabilizing groups or photo-crosslinking agents into proteins and may even be substrate for novel cellular logic (Rackham and Chin, 2005).

Volker Döring was arguing that reassignment of portions of the genetic code might even be a mean to increase safety of engineered organisms. I am not sure I fully followed this. Such organisms are probably resistant to lateral gene transfer and would, for the same reason, avoid “genetic pollution”. But as Sven Panke pointed out in a question, these bacteria would also loose some “enemies”, eg bacteriophages?, given that they are likely to be resistant to infection by virus, which expect a given genetic code. Not sure it really increases the safety of these organisms, but I may have missed something…

More fundamentally, Philippe Marliere who works on re-designing entire portions of the metabolism by evolving alternative pathways replacing the natural ones, suggests that applying sophisticated and imaginative selection pressure schemes can force organisms to evolve in regions of the metabolic/functional space they would otherwise never explore: “the task of synthetic biology (in metabolism) could be to widen the search performed by natural selection, to diversify the set of reactions and metabolites useful to the cell: we are their only chance”

Comments

Comments are closed.