The Futile Cycle

It seems someone in Apple’s iPhone division likes go:

Oh, the strange places that it shows up…

I just went and saw the new Indiana Jones movie. I guess I got what I expected, but still. Despite the signs in the earlier films of George Lucas’ insistent, steady drive to transform Indiana Jones from an engaging, hapless archaeologist and treasure hunter to a flat, boring superhero, a small part of me still had harbored a tiny flame of hope. What a bucket of cold water.

The movie is best seen while shouting at the screen, making fun of the camp dialogue, and generally taking it as a very good parody of the Indiana Jones series. Like any good parody, it comes complete with extraordinarily campy dialogue, over-the-top in-jokes, trite characters, mindless plot, and a John Williams score. It has to be on purpose. There’s no way that the movie would have been this much of a parody by accident.

Either that or it will be a movie that years down the line will be shown as a shining example of what happens when mediocre movie-makers get to make exactly the kinds of films they want, without the good taste that editorial oversight and budget constraints provide.

Well, at least I’ve seen it now. And I got popcorn.

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.

The internet allows people to produce some amazing things. Go see! Twitter as it was meant to be seen.

Every two weeks, I look forward to my copy of Cell (yes, I’m a big dork that way). This week, I found Cell had a really surreal cover: a drawing of a phoenix.

Curious, I turned to look at the cover description. It was, to say the least, quite cheesy:

Cover art…depicts CASK kinase as the Phoenix, presumed dead in the fires of evolution, resurrecting in an unanticipated active form.

A little purple much? It was apparently drawn by the second author of the corresponding paper. A good drawing…but “cheeserific” symbolism (to quote a friend of mine).

Another cheesy cover I saw a while ago was this Nature cover, hearkening back to pulp science fiction:

Awesome retro-nerd-ness!

Sorry for the lack of posts, but alas, science (especially biology) does not wait, and things die when neglected.

Meanwhile, I have around three weeks left in my final laboratory rotation before I have to choose my thesis lab, and I’m having a hard time deciding. Coincidentally, Nature Reviews Molecular Cell Biology just published a two-part article called “How to succeed in science: a concise guide for young biomedical scientists.”. There are some interesting tidbits in here, and it gives an interesting, biology-centric perspective on how to look on one’s career. Part I is focused on choosing a field and a lab for graduate school and post-doctoral work. Part II focuses mostly on how to generate ideas and make discoveries. I thought both were excellent reads.

I also recently found Dent Cartoons, which is the home of the famous Nine Types cartoon trilogy. Check it out; very amazingly true!

Ah, Ph.D. comics, how true it all is.

I remember my father once telling me about a time in his lab, in which the lab members were sitting around talking, disappointed that they didn’t have anything to submit to a conference. Suddenly, one of them had a great idea! He checked the time: 12 hours to go until the submissions deadline! All the lab members got together and cranked out some preliminary data. Someone rushed out, sat down, plugged out a poster abstract based on the preliminary data, and emailed it to the conference with 30 minutes left! And it was accepted!

Yet another article from Nature today on RNA therapeutics, this time on using RNAi to stop angiogenesis in the eye to prevent blindness. Some people have seen that the VEGFR receptor can be targeting for knockdown by RNA interference using short 21-nucleotide siRNAs. Apparently, no one bothered to do the control here.

The authors of this paper did the control, in which one uses a “scrambled” or off-target siRNA to show that the effect of the silencing is sequence-specific. Except, in this case, the effect wasn’t sequence-specific. In fact, any old RNA would work, as long as it was longer than 21 nucleotides.

This might ring some bells about innate immunity. One of the early problems with RNAi in humans was that long double-stranded RNAs, which can be chopped up in cells to form the siRNAs, cause human cells to become inflamed. Specifically, the RNAs activated some Toll-like receptors, leading to a mounting of the innate immune response. This immune response was originally evolved to combat RNA viruses, which often have double-stranded RNA genomes or go through a double-stranded RNA intermediate during infection. This problem was later solved by using pre-made short RNAs, which don’t really induce the immune system response.

In this paper, it seems the authors have found this effect at play again. Many of the RNAs they tried activate the immune response, which in turn causes the cell to suppress angiogenesis!

Yesterday in Nature was a really exciting paper on miRNA-targeting therapeutics: Locked-Nucleic Acid-based knockdown of miRNAs in vivo!

microRNAs (miRNAs) are really tiny regulatory RNAs (about 22 nucleotides long); efficient, specific hybridization would normally require something much longer. Recently, though, the use of “locked nucleic acids” has become more popular. These are RNA analogues that have an extra bridge in the ribose sugar, making oligos of them rigid. Entropically, this greatly enhances binding of the LNAs to the RNAs, which means that one can use them for things like in situ hybridization much more easily and specifically! Not only that, but the use of LNAs instead of normal RNAs means that the half-lives of the oligos become much longer, similar to what one would see with morpholinos.

The authors injected LNAs into monkeys in order to target miR-122, which regulates cholesterol metabolism (among other things). They managed to effectively silence the miR-122 and they showed a drop in cholesterol levels!

Very exciting stuff!