The Futile Cycle

I have now seen molecular biology applied to Real Life.

I live in a graduate student dorm (for now), and just yesterday, the bathroom I share with other students on my floor was broken. Mainly, when water went down the sink, black, dirty water would bubble up from the shower floor drain. Gross. Luckily, flushing the toilet didn’t cause any similar problems. But by that serendipitous sewage problem, I learned that the drain of the sink fed directly into the same pipe system that the shower drain did, while the toilet drained into a separate pipe system (or it tied in further downstream of the drainage problem).

In summary, I found one way that the system broke (a mutation) that led to interesting behaviors (a phenotype), and by characterizing these behaviors, I gained a better understanding of how that system worked (a mechanism).

Molecular biology! In the real world!

Small interfering RNAs (siRNAs) have been going through an interesting revival period as of late. In the past two months, there have been at least six high profile papers in Nature and Science on siRNAs. True, we’ve already seen siRNAs long ago; in fact, the 2006 Nobel Prize in Medicine went to Andrew Fire and Craig Mello for their work in discovering siRNAs in animals. The thing is, after Fire and Mello’s initial work, many people thought that RNA interference (i.e. the process by which siRNAs inhibit genes) was an evolved anti-viral mechanism that just happened to have a very general, highly evolutionary conserved, and extraordinarily useful gene regulatory “side effect” that researchers could use for manipulating and studying biology. It sounds too good to be true.

It was.

Such a useful gene regulatory mechanism just couldn’t sit around as a “side effect” for very long. Evolution, by random mutations, is constantly exploring many different ways of regulating gene expression, so it stands to reason that animals might have evolved ways to regulate genes with siRNAs. The only problem is that no one has found any endogenous siRNAs — until recently, of course.

The five papers in Nature (Watanabe et al., Murchison et al., Czech et al., Okamura et al., and Kawamura et al.), and one paper in Science (Ghildiyal et al.) all describe how they separately discovered these native small RNAs that function to regulate gene expression. This is no anti-viral mechanism or some weird gonad-specific thing; this is genuine gene regulation! The papers span both fruit flies and mice.

It’s surprising, really, that these discoveries didn’t come about sooner, but I suppose the technical innovations here and there are what led to these discoveries. One of the biggest factors that probably contributed to the new wave of siRNA discoveries is the coming of next-generation sequencing technology, which allows for sequencing of lots and lots of really short pieces of DNA and RNA, perfect for looking at small RNAs.

The discovery two years ago of endogenous siRNAs in nematodes using this technology also helped spur this new wave. No one was sure whether these endogenous siRNAs were specific to worms, or whether other animals had these traits. Worms had one trait they shared with plants and fungi that other animals don’t: an RNA-dependent RNA-polymerase (RdRP), which amplifies siRNA signals. Worms, plants, and fungi had endogenous siRNAs, but because of the differences in the players, it was certainly possible that they had something that mammals and fruit flies didn’t. The next step, of course, was obvious enough that it led to this new flood of papers, all using pretty straightforward bioinformatics, biochemistry, and sequencing to scour fly and mouse genomes for siRNAs.

For a while, the hotness factor of RNA was starting to wear off in the field, but it seems like interest might come back in a new wave. I’m game for another revival.