The Futile Cycle

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?

From Uncertain Principles comes this gem of a sentence:

My opinion, in the end, is that a lot of what people find objectionable about fraternities and sororities is not an inherent property of the organizations, but rather an emergent property of large groups of 18-22 year old Americans.

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.

In between running around to experiments, attending classes and seminars, reading the literature, eating, and sleeping, I’ve manage to catch chapters of Intuition, by Allegra Goodman. I started the book because of a glowing review from Dr. Free-Ride. I finished it last week, and I’ve been mulling it over in my head.

This book is quite possibly one of the best novels I’ve read in the past year (though, it’s looking like it might be the only novel I’ll read this year…).

It is set in Cambridge, Massachusetts, at a biomedical research institute that’s right next to Harvard’s campus. If this sounds familiar, that’s because the author did some research for the book at the Whitehead Institute, a huge biomedical research institute geographically in between MIT and Harvard. Allegra Goodman did some wonderfully thorough research for the book, because it abounds in the small details of a real lab. Old machines, nude mice, foil-capped bottles of reagents and media.

And the people, the characters, the scientists: how wonderful! They are the classical archetypes that anyone who’s worked for a while in academia would recognize instantly: the hard-working, technically brilliant East Asian immigrant, the powerful lab techs, the rising star who suffers from “imposter syndrome”, the senior post-doc who resents the rising star for all the breaks he’s had going to prestigious schools, the lab head who’s too scientifically cautious to promote her lab well, the star oncologist with a flair for selling the research (”a poet of the NIH form”) but with less-than-stringent scientific skepticism.

Yet, none of the characters are stereotypes. None of them fit their archetypes. All of the characters are quite real, with real motivations, dreams, emotions, and agendas. That, in the end, is probably what ignites the central conflict of the entire book. I will not divulge much about the book’s plot, as I suggest to all of you that you go out and read it if you haven’t yet.

Still, a little thought as to what I see from the book, without spoiling the book (I hope). It seems like the book makes plain that truth — even in science — is hard to know, as it is always seen through the eyes of a person, through a glass darkly. Even the events of the story, told from so many points of view, are not clear. Agendas are confused. All because of people.

The conflict between the exacting requirements of science and the people who actually synthesize and propagate the knowledge seems to be almost the central conflict in the book. Science — true science — happens on the scale of years and decades: ideas are proposed, experiments are done, hypotheses are rejected or accepted, experiments are replicated. Science takes time, and truth only emerges with a grain of certainty years after the fact.

But for many of us in science, especially in the present day, we are forced to live on a faster time scale. Grants are due, demanding results. Jobs demand papers. Papers, of course, require experiments. One can get scooped, if one doesn’t move fast enough. Scientists don’t have the luxury to wait for science proper to catch up, and so sometimes, in the milieu of researchers running back and forth in their frantic-paced lives, some can trip and get crushed under the slow-moving glacier that is real, absolute truth, not for evil or malicious intents in their souls, but for the fact that they, too, have dreams.

But the book does hold out hope. Although science is harsh, people are resilient, and that is why science is able to happen at all. The book is almost a tribute to scientists, and an acknowledgment of the many sacrifices that people make to pursue a career that they love.

Go read it. It is delightful!

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!