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.

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!

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!

Dr. Free-Ride over at Adventures in Ethics and Science has written a post on a topic near and dear to my own heart: the boundaries between science and belief. Her position is that there is no conflict in the mind of a scientist who believes in a supernatural deity. It’s a topic that I’ve been mulling over for the past 10 years or so.

In some ways, it is very easy to fall into the strict regime in which “if one believes that the scientific method leads to truth, that is the methodology to be applied in all beliefs of truth, public and private.” I think many scientific atheists hold to this sort of belief very often.

There is, of course, that very crucial “if” in that sentence that many philosophers will jump on. Does the scientific method lead to truth, exactly? Maybe not. No truly introspective scientist says that they know the entire truth; all we have are models that work well enough. Where does the photon “go” when it’s absorbed by an electron? Well, we don’t know; we don’t even really know what “absorbed” means, but as long as we do good bookkeeping on the energies and momenta of all the particles, it seems to work out pretty accurately, at least as far as we can tell.

In addition, can I know that my senses are the same as others’? What makes a schizophrenic’s reasonings about the truth of the world less “true” than mine? Does the fact that I have to wear glasses make a difference on my conclusions about how something looks? So truth is, perhaps, more a social construction, especially truth based on scientific observation. “Truth” needs to be verifiable to someone else, and based on some standard that others can replicate, not based on my unique, idiosyncratic senses.

But I feel something fundamentally wrong with simply saying that the scientific doesn’t lead to some sort of generation of knowledge. After all, the keyboard under my fingers feels real enough. I can hit it with other things, to ascertain its existence. Is the possibility that I’m some sort of “brain in a vat” really going to bar me from asserting the truth that my computer exists? Though Dr. Freeride might characterize my belief in the reality of the world I sense as a scientifically unjustifiable metaphysical commitment, can it really not be? Am I not justified in asserting that the world is real until I have reason to believe it’s not? (Being unplugged from the Matrix might do it.)

Is there, then, truth other than this sort of knowledge?

In the mix of the whole “Scienceblogs is white!!” non-event, Razib at Gene Expression had some questions to ask about the underrepresentation of Asians in blogging, even though Asians tend to be over-represented in science research. He speculates that maybe Asian American cultures tend not to cultivate literary talents as much.

I’m going to go out on a limb and speculate some more. I think Asian Americans tend to emphasize mathematical and technical fields because of social and migratory selection.

Namely, the over-representation of Asians in certain fields has to do with the immigrant language barrier. It’s hard to get a job if you don’t speak English well; part of being successful in the humanities is being able to communicate, as that’s largely what one does in those fields: communicate and analyze other people’s communications. On the other hand, technical fields, especially highly mathematical fields, tend to translate better across language barriers because mathematics is universal these days. Those immigrants who are able to obtain green cards or visas are those who have valuable skills that can translate immediately to results, and those skills tend to be technical.

You’d think that it would still be hard to survive any academic job without a good command of English, but immigrants can be amazingly resourceful, and academia can be surprisingly forgiving of bad speaking ability (let’s face it, professors are often not model speakers, even the native English speakers). I know that my dad had an insane amount of trouble learning english, but his mathematical ability was top-notch. He survived his thesis defense by writing down his entire presentation beforehand and memorizing it, word-for-word.

So what I’m saying is that the American barriers and limitations to immigration create an artificial, societal selection such that only those immigrants with technical abilities are able to pass through the immigration filter with any amount of ease.

This model, of course, makes some predictions. As English language teaching abroad increases, more immigrants and more minorities with backgrounds from those countries should start to appear in the humanities. In addition, this kind of filter effect should happen even with non-Asian ethnic groups, as long as there is some sort of language barrier. I’m curious as to how many British scholars, for example, populate the humanities compared to, say, German speakers (I’m trying to pick countries that have roughly the same overall economic status, and similar “white”-ness and cultural backgrounds). More Africans and Hispanics should populate the sciences compared to other disciplines, too.

The main problem with generalizing this model to other immigrant and minority groups is that there are fewer scholars that are, say, black, or Hispanic in academia, compared to Asians. There might be too much noise to definitively affirm or rule out this “filter effect” in such groups. There might be enough immigration, however, from Britain and Europe to do some sort of preliminary analysis.

A lot of news stories are once again talking about breakfast and its connections to weight and obesity. Consider this BBC article as one example. This Reuters article hypes breakfast as magically keeping teens skinny. The original Pediatrics journal article is here.

What’s wrong with all of this? The research doesn’t say whether eating breakfast makes someone lose weight. All it says is that skinnier teens eat breakfast more often than more obese teens, on average. That doesn’t mean that suddenly eating breakfast more will make you lose weight.

Consider, these details in the paper. People who eat breakfast more also: “more likely to be white, to come from a higher [socio-economic status], and to engage in higher levels of physical activity.” Hmmm, breakfast-eaters do more exercise, huh? I wonder if that has anything to do with the difference in weight…hey, will eating breakfast also make me white and wealthy? Awesome!

Sure, the authors try to correct for the physical activity differences in their regression, but no regression is perfect, and since all of the data is essentially self-reported, it’s hard to tell whether hours spent per week in “strenuous, moderate, and mild exercise” is really a good reflection of lifestyle choices. Maybe they take the stairs more often, or bike and walk more than those who don’t eat breakfast. Is running a mile moderate, strenuous, or mild exercise?

In addition, there are the classic correlation-versus-causation arguments: perhaps people who eat breakfast are just those who tend to have a higher metabolism naturally, and so they have the energy in the morning to get up early enough to eat breakfast. Or perhaps breakfast eaters are just more conscientious of their life choices, including sleeping, planning ahead, being less stressed, and so on, which might contribute to their lower BMI. Their eating breakfast in the morning could then be just one more symptom of their conscientiousness.

Though this article was published in the journal called Pediatrics, really this is just a sociological or economic study, not a medical study. Researchers and the news should stop hyping it as some sort of recommendation for preventing obesity. Breakfast isn’t a therapy just yet.

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Timlin, M.T., Pereira, M.A., Story, M., Neumark-Sztainer, D. (2008). Breakfast Eating and Weight Change in a 5-Year Prospective Analysis of Adolescents: Project EAT (Eating Among Teens). PEDIATRICS, 121(3), e638-e645. DOI: 10.1542/peds.2007-1035

All right, time to settle a vitally important issue in lab science.

I’ve heard people pronounce “autophagy” as both AW-tuh-fey-jee and uh-TAW-fuh-jee. Clearly, it should be pronounced as the former, like any normal person. The latter pronunciation makes the speaker sound pretentious and silly, whereas the former makes him or her sound practical and to the point, like a serious scientist.

Don’t come quoting to me from the dictionary, either. Do you say “HA-rass” for “harASS”, though that’s the way it is in the dictionary? No, of course not. Because you’d sound like a silly fop otherwise.

Besides, everyone pronounces “autophagosome” as AW-tuh-FA-go-some, and not uh-TAW-fuh-go-some. And no one says uh-TAW-mow-beel for “automobile.”

So there. Those who say “uh-TAW-fuh-jee” will be teased mercilessly.

This is really quite odd. In today’s Science
bacteria have been found to nucleate many ice particles in the atmosphere, including snowflakes. In other words, bacteria are raining and snowing from the sky!