Turned up to eleven: Fair and Balanced

Tuesday, August 13, 2002

Jay Manifold e-mailed me to ask my thoughts on the topic of Post-Transcriptional Gene Silencing. I was e-mailing him back, when I realized that this was a cheap way to get a blog entry for the day, so here it is...

PTSG is not a particularly new idea (in molecular biology terms). The notion of PTGS (also called anti-sense RNA) treatment has been kicking around for at least five or six years. I don't know how much interest the drug-development community has in this. Anti-sense RNA is RNA (ribonucleic acid, a molecule similar to DNA, which plays a very important role in moving information around in a cell) that matches up, or hybridizes with the DNA or RNA that encodes a gene. In the model that you describe, the matchup is between mRNA, which is being used to encode a protein gene product, and the anti-sense RNA, which is complementary to that sequence (DNA and RNA match up in the following way, ala Chargaff A-T, G-C; in RNA, substitute U for T). this interferes with the cell's mechanism for making proteins, which translates single stranded mRNA into a polypeptide chain, and makes a functional protein.

Since I don't work directly on this topic, nor in drug discovery, I can only point out some potential issues. One is basic science. We don't really understand the nature of this system. It is actually a system that is used by cells in their own regulation, so it is clearly a possible functional pathway for therapy, but that, as always, must be tested. There are a number of potential pitfalls to using this therapy as a drug;

1) oligonucleotide synthesis is not cheap In order for a profitable drug to be made, it pretty much has to be amenable to either (relatively) cheap chemical synthesis or fermentation methods (growing bacteria or yeast that make the drug). Neither of these seems good for oligonucleotides, although technological advances in oligonucleotide purification may make fermentation methods feasible.

2)RNA is very unstable This is the biggest problem. RNA is a biologically unstable molecule, which is prone to rapid degradation in and out of cells. It is devilishly hard to work with in the lab (most researchers try like hell to avoid it). Putting RNA into a stable suspension/solution for injection (I am pretty sure an oral delivery system would by unfeasible) might be a real stumbling block. In vivo, RNA molecules that need to hang around are tagged at the ends, so the cells know not to destroy them.

On the plus side, this technique has been shown to be effective in a number of in vitro cell culture systems, and now, it appears, in plants. I suspect it is a long way from the market, but it is very interesting.