The Futile Cycle

There are two interesting new papers out in the newest issue of Molecular Cell, and one from Science a week back that’s online early:
An Important Role for the Multienzyme aminoacyl-tRNA Synthetase Complex in Mammalian Translation and Cell Growth: Seems that the two different forms of Arginine tRNA synthetase have different roles in the cell, one to make tRNAs for synthesizing proteins, and to make tRNAs for degrading them via the ubiquitin pathway!

Human Alu RNA is a Modular Transacting Repressor of mRNA Transcription During Heat Shock:
Non-coding RNAs have been shown to have transcriptional regulatory properties, but this particular paper discusses one that looks a lot like a protein, in the sense that it seems to have modular “domains.” Pretty neat work!

Selective Blockade of MicroRNA Processing by Lin-28: The main discovery of the paper is, of course, nicely summarized in the title. The idea is that Lin-28 prevents the biogenesis of let-7, one very well-studied (though not well-understood) family of microRNAs, by binding to the RNA and preventing Drosha and Dicer from gaining access to it.

Day to day, I work a lot with clear, colorless drops of liquid, shuttling them back and forth between small plastic vials. I also work with cells, but they just look like cloudy suspensions in strange-smelling liquids.

But every time I look at cells under a microscope, I can’t help but gaze in wonderment. Cells! Under a microscope!

Even better are images and videos online from the American Society for Cell Biology, which I found via Bitesize Bio. Make sure to check out the videos, some of which are absolutely spectacular and inspiring. Some of my favorites include watching rat heart cells beating in a Petri dish, seeing fish cells zooming across slides (especially check out how fragments of cells without a nucleus can still move around! Movement is thus, at least in the short term, independent of transcription), the movement of mitochondria within a cell, seeing chromosomes divide in real time using just light microscopy, and watching Drosophila embryo syncytial division (where all of the nuclei divide simultaneously, without cytokinesis).

Biology is an absolute wonder, and I hope you find these videos as inspiring as I do.

I’ve found a bunch of tools recently that have made organizing my life a lot easier, especially with integrating labwork into the rest of my life.

First up is Remember the Milk, which is a free, online to-do list manager. It’s simple, but very useful. I can create multiple lists, tag each list item, and create smart lists based on searches. It’s all done very well, including lots of AJAX-y goodness and keyboard shortcuts to boot. For FireFox users, it has nice integration with Google Gears for offline access. It also integrates into Gmail and Google Calendar, though I’ve used those features less. The only caveat I have with RTM is that I wish its keyboard shortcuts mimicked those in Gmail. Gmail’s shortcuts seem much more intuitive than RTM’s, such as using “x” instead of “i” to select or deselect items.

Having an online tool is really handy, as sometimes I don’t have my computer with me, especially in lab. My To-Do list, however, is only an internet connection’s away.

Next is Gmail. Yes, many people use Gmail, but I especially like to use Gmail to shuttle little bits of data back and forth as attachments on drafts of letters to myself. Very handy! And Gmail’s recent introduction of IMAP has made it a lot easier to keep track of my email from both my home computer as well as a lab computer.

Another amazingly useful tool is Google Calendar. It’s very handy to be able to check my schedule from any computer, but the main problem is that I like the way iCal is integrated into the rest of my system! It picks up dates and times from email read in Apple Mail, it integrates with the Address Book, and alerts are simple to create, making it so much easier to manage my time at my home computer.

So I use BusySync. The 2.0 beta (as I write this) includes Google Calendar synchronization, which is an absolute godsend. The synchronization is seamless!

RTM combined with Google Calendar + BusySync + iCal is a killer combination for me; I can keep track of experiments, time points, appointments, meetings, seminars, classes, and even the rest of my life regardless of what computer I’m on! And now that I use an electronic lab notebook published online (though under a password), I can access data and procedures from home, too, so that I can plan out experiments or process data and record it wherever I am. It’s glorious!

Alas, the only thing I can’t do is pipette my reactions or maintain cell culture from home…Hey Honda, any chance you might come out with an ASIMO Laboratory Rat model?

Since when do universities write press releases for review articles? Is it really necessary?

Via Pharmalot, apparently Pfizer is going to court to try to force the NEJM to release its confidential reviews of articles on Celebrex and Bextra, two of Pfizer’s products that have been targeted for lawsuits on their side effects.

Now, I’m not saying either way whether Pfizer is guilty of misinformation and such on Celebrex and Bextra, but this subpoena is just wrong. The scientific peer-review process has traditionally depended on confidentially to ensure candid and honest statements about the quality of research without fear of repercussions or retribution. It’s not perfect, but it’s sure a hell of a lot better than going without a peer-review system, and trying to break the confidential review system is like trying to force journalists to open up their sources. It stops the flow of good journalism, and it stops the flow of proper science.

Pfizer isn’t doing itself or the rest of the drug industry any favors, either. For whatever reason, people hate drug companies even more than they hate other companies (except maybe Big Tobacco), perhaps because they think that drug companies are evil machines sucking money out of sick and desperate people. That’s not true, and there are many noble people, including doctors and scientists, working hard out there in the drug industry to find the latest drugs to help people, but these kinds of antics from the top are just awful. I don’t envy the researchers at Pfizer, as they don’t deserve society’s scorn for all of this.

Lately, genome-wide association studies are popping up everywhere. Just scanning through the latest Nature Genetics, almost half of the articles are such linkage studies. The studies represent one of the greatest convergences of population genetics, fundamental molecular biology, the human genome project, the HapMap project, disease biology, and microarray technology.

Leonid Kruglyak has a great review article out in Nature Reviews Genetics on the history and development of such genome-wide studies.

I think these kinds of studies will eventually have the potential to revolutionize medical diagnostics and drug therapy, since it’ll become easier and easier to figure out risk factors for disease and tailor drug therapies to the specific risk categories a patient falls into. I’m really excited to see how this field progresses, especially when newer technologies arise for rapid sequencing of genomes!

Pure Pedantry links to an awesome paper on visualizing the cell cycle in mice using fluorescent markers. They can even look at the cell cycle state of cells in histological sectionsof mice! Check out the blog post, because Jake Young highlights the coolest picture and the coolest video in the paper; the movie at Cell and ScienceDirect seem to be down, so you can see the video at Pure Pedantry or at Google Video.

One of my biggest fans got me a copy of The Eighth Day of Creation, which I’d been wanting to read for some time now. In the first chapter, check out this old-timey maxiprep (i.e. large-scale DNA isolation and purification) protocol, courtesy of Avery, MacLeod, and McCarty from their historic 1944 paper demonstrating that DNA was the carrier of genetic information in cells:

To get [DNA], they grew virulent Type III pneumococci at blood heat in twenty-gallon vats of broth made from beef hearts, spun out the bacilli in an iced centrifuge, suspended them in brine, and brought the “thick, creamy suspension of cells” quickly to a temperature hot enough to kill the cells and to inactivate “the intracellular enzyme known to destroy the transforming principle” [DNase]… They then washed the cooked pneumococci in three changes of brine to remove capsular sugar as well as whatever protein would come away, extracted the bacteria by shaking them for an hour in a solution of bile salt to break the cell walls (and then threw away the cell residue), and reprecipitated the extract with pure grain alcohol.

“The precipitate forms a fibrous mass which floats to the surface of the alcohol and can be removed directly by lifting it out with a spatula,” the paper said. This was now washed several times with chloroform to remove protein, and suspended yet again. A digestive enzyme was put in to eat away any remaining capsular sugar. Removal of protein was repeated, “until no further film of protein-chloroform gel is visible at the interface.” Pure grain alcohol was added again, “dropwise to the solution with constant stirring.” At a concentration where the alcohol nearly equalled the extract, “the active material separates out in the form of fibrous strands that wind themselves around the stirring rod. This precipitate is removed on the rod and washed….The yield of fibrous material obtained by this method varies from ten to twenty-five milligrams per seventy-five liters of culture.”

Wow, and I thought maxipreps take too much time now! Compare the above to a more modern DNA isolation protocol, courtesy of Black Knight.

Reading back over the posts that I made for Just Science week, it seems like I had a theme going (unintentionally), which is that biology is a lot more random than most people seem to think.

For one thing, molecules don’t act like robots. They don’t whir and click into perfectly aligned machines that do everything smoothly. Molecules jiggle, they backtrack, they pause, they drift away, they snap apart, they even do things wrong. A lot. A ton of our evolution has been oriented towards controlling (or harnessing) the randomness of the molecular world in which we live. Though we speak in the language of determinism, that is simply a metaphor for a much more random reality. I think biologists sometimes do the world a disservice by hiding behind these deterministic metaphors.

On a larger scale, not everything in biology need be from adaptation. Evolution is quite random; it is a tree of historical accidents that has been pruned and shaped by natural selection.

Sometimes random is just random. Our bones aren’t white for a good reason; it just so happens that white is the color of the molecules and minerals in our bones. In the same way, I’ve tried to argue that some phenomenon in cell biology and molecular biology may just be historical accidents with no adaptational or functional meaning. I think that that should be the default theory for any phenomenon that biologists discover.

After all, if the intelligent design community is pushing for a default theory of a purely functional world, in which everything was specifically made by a greater being for a purpose, then (since they’re wrong) the default theory for real science is the opposite: the history of any species is a series of historical accidents, a tree grown with its roots buried deep in the rich soil of randomness.

I was rereading a classic paper by Francis Crick, the one in which he describes how they discovered the triplet nature of the genetic code. [Crick et al. (1961) Nature 192, 1227-1232.] It’s an absolutely fantastic paper – extraordinarily well written, clear in logic, and with no lack of charm – but this time through, something else caught my eye (emphasis added):

¹¹Feynman, R. P.; Benzer, S.; Freese, E. (all personal communications).

This, of course, refers to the rather famous Richard P. Feynman, the bongo-playing, womanizing theoretical physicist of quantum electrodynamics fame.

Apparently, Feynman took a summer off and did work on phage T4 genetics, specifically on the rII region. During his work, he figured that he was isolating multiple mutations in the same gene - a mutation and its suppressor. It’s neat that he was so close to getting to the fundamental nature of frameshift mutations, but alas, he returned to theoretical physics soon afterwards. Thus, it was up to another physicist-turned-biologist (Francis Crick) to discover the real nature of reading frames and the triplet code.

But in any case, a really neat historical crossover between fields.