The Futile Cycle

I am now moved in to my new room in graduate school. Classes have yet to start, but the weather is nice, the rooms are spacious, and the campus is very beautiful. It’s a bit weird to settle into a new campus this fall instead of returning to the old undergraduate campus, but I’m very excited about what’s to come. I’m also nervous that I’ve gotten soft during the summer, so I’m currently reviewing a bit of genetics, but in the meantime, I stumbled upon this interesting article on treating HIV by raising its mutation rate.

This is an interesting idea, since one would normally think that raising mutation rates on an organism would just increase the opportunities for it to become more virulent, more resistant, etc. But HIV is a pretty high-mutation rate virus already (any specific one letter mutation will arise more than 20,000 times per day); by the estimate of Martin Nowak, it’s mutation rate is currently the highest possible rate that allows for efficient adaptation and natural selection, in that if the mutation rate were lower, the virus would not adapt as quickly to adverse conditions (e.g. drugs), and if the mutation rate were higher, the virus would mutate so much that it would find it difficult to maintain any beneficial mutations. It’s at the cusp, the so-called “error threshold” (which is roughly the reciprocal of the genome length). So, by raising the mutation rate of HIV even higher, one could tip HIV over the error threshold and make the HIV quasi-species unstable enough to hamper its spread.

I only wonder, however, what kind of cancerous havoc it might raise in the human body. The drug doesn’t look flat enough to incorporate into anything but the most error-prone of DNA polymerases (e.g. HIV reverse transcriptase), but still, clinical study might show high rates of skin cancer and congenital defects for fetuses. The lack of a double bond on the major groove side of the nucleoside should prevent too many cycloadducts from forming with UV light, but then again, I’m no expert in heterocycle photochemistry, seeing as almost all the heterocycle-forming reactions I’ve ever tried to do ended with awful black tar on the bottom of my tiny flask.

There’s nothing quite as nightmarish an experience as driving in downtown Boston at night with confusing directions and under a time limit.

The Perseids meteor showers are happening tonight, from around 10 PM (August 12) to dawn (August 13), concurrent with a new moon (which makes them easier to see). Unfortunately, I can’t get to a rural area, but my part of town is a little darker, so I hope to see something!

This brings back many memories of the good old Macintoshes. I found an excellent webpage that explained how to set up an emulation of Dark Castle, with all the appropriate links to files, and now I’m working my way through “Fireball 4. ” I remember playing this on my dad’s old Mac way back in the 1980s on a black-and-white System 6 machine. I don’t know what happened to that old Mac or the Dark Castle disks (probably relegated to archival floppy hell), but now I have my own working copy!

For those of you who want to play along, all you really need is to follow the instructions on that website, and download the appropriate Mini vMac emulator for your system (works for almost any system). The hardest part is getting Dark Castle onto a disk image, and that unfortunately requires borrowing a non-Intel mac for a few minutes. But to relive the past…it’s completely worth it!

If you want other great old-timey Macintosh games, try Macintosh Garden. (All these on Mac Garden require the Classic environment, which means no Intel Macs, sorry. Maybe you can get them to work under emulation, I don’t know.)

EDIT: I got Beyond Dark Castle working as well.

I borrowed my brother’s copy after he was done, and after a straight 5 hours or so of reading, I’m done with Harry Potter. It took me a bit of time to surface from the deluge, so I’m still pondering whether I really like the book or not.

First of all, it isn’t great. Not masterful, not horrifically tragic, not stupendously inspiring. My first thought was, “it’s finally just done.” I mean, it’s been at least 10 years that I’ve known about the phenomenon, so after all this time, the beginning feels simultaneously long ago (I barely remember even reading the first book) and yet very near. My second thought: “It was ok,” in a “that meal was filling and tasted fine” sense. Perhaps I’m a sentimentalist at heart, but I rather like (mostly) happy endings. My third set of thoughts was more complicated. They were very similar to this review in the Atlantic (there are spoilers after the first paragraph or so). “A children’s story after all.”

In the end, I think I settled somewhere between “I’m glad it’s over” and “I guess I enjoyed parts of it.”

My favorite part about Harry Potter was probably that the world J. K. Rowling constructed was so accessible. Tolkein’s works, though masterful, always had that academic, stuffy, history-tome feel that just made me sleep (I never did get through the Silmarillion). Not only that, but the magic never did have a sense of logic; it was foreign, completely enigmatic. I think that was the point, because then users of magic, like Gandalf, became mythic and inscrutable, a little like Merlin from the Arthurian legends. Phillip Pullman’s world in His Dark Materials was difficult to understand as well, and very creepy. There was just something wrong with it, I can’t really place my finger on it. I think that was intentional, too, in its construction, as the plot was pretty dark and creepy, and from the perspective of the young protagonists, confusing and foreign.

On the other hand, Potterworld was quite charming and friendly, with magic a part of everyday life. There was a degree of casualness that very few other settings had. Magic was common, in a sense, and that made for some very entertaining little details in the world. It wasn’t a rigorous, self-consistent world-system, but just a cartoon of what it would be like to live with magic all around. This friendliness was all, no doubt, designed because the first book or two were meant to make the magical world as inviting as possible to the young audience.

Unfortunately, very little of that was given in the last book, which was a bit disappointing. It was mostly action, with bits of plot-ish-ness in the in-betweens. And, of course, characters die off. It felt formulaic, at times; “oh, she’s offed another one.” Plotting is not J. K. Rowling’s greatest of abilities. But no matter. In the end, the story wrapped up, much in the ways I expected, and then that is that. The series is over. And I’m not unhappy with the way she ended it (even the epilogue, to cap off the whole book of misdeeds, isn’t really that bad).

Now all that has to happen before the second coming is that Robert Jordan actually finish his series. Which may never happen.

For those of you in the Cambridge, MA area, seriously, one of the best Italian restaurants I know of is Basta Pasta Trattoria. My friend introduced me to the restaurant in the very last week of college, but fortunately my family lives around Boston, so I’ve been able to return. Very great (I’d give it a 24 on the Zagat scale) but also insanely cheap. I mean, a huge bowl of delicious, heavenly risotto (try the white risotto with thyme, lemon, prosciutto, and goat cheese) for less than $9? It’s like a liter and a half of the stuff, too. What’s better for a poor student/post-doc? Also, the mini arancinis (fried rice balls and fontina cheese, with tomato sauce) are awesome.The only problem is that they’re a bit of a walk away from any T station (basically at the intersection of Putnam Ave and Western), and it’s in a residential neighborhood (i.e. little to no parking) but they do catering. I’m not sure if they do delivery. I go there by walking from Harvard Square, which is like 15 mins. The walk there is easy, the walk bad is hard because I’m usually stuffed full.

Part of the problem with looking at a field like computational biology or systems biology (which I have some interest in) is that it’s hard to figure out how to narrow the field into one project that I can do for graduate school.

In synthetic organic chemistry, this was a relatively easy proposition. Pick a molecule, not too big, not too small, with interesting complexity, and make it. Then you’re done with your Ph.D. (course, this is much easier said than done). In traditional biochemistry, molecular biology, or cell biology, you’d focus on one protein, one pathway, one set of activities, one phenotype, and then figure out what they do, how they interact, what affects them, etc. When you generate enough publications and have a good, detailed story to tell about the systems, you’re done.

But computational biology feels like a whole ‘nother thing. It’s probably because I’m still not quite as familiar with that field, but it seems very methodological, more than anything else, and so it’s hard to find a particular angle to break down the problem and get a story out of it for a thesis. There’s not just one specific model system to work on, or one biochemical system that one can mine. At some point, it feels a little arbitrary, that you choose a system hoping that your hammer will find a nail you can hit; it could be that you choose wrong and just get screwed (I couldn’t help myself with that pun).

I remember reading about Eugene Shakhnovich’s work on protein folding, and he always had a particular angle to hit the topic with: his lattice folded proteins. One of the professors that I talked to at my new university tends to focus on bacterial chemotaxis. I need a good focus point by which to approach the field. Large-scale topics for data-mining, such as the ENCODE project, just seem too big for me to do as part of my Ph.D. project, and it would probably make my Ph.D. drag on and on in a way that would both make me depressed and make my work harder.

Perhaps I can find a particular algorithm to work on, if I decide to do a “big biology” sort of project. A particular technique, perhaps? I feel like doing a particular methodology is the only manageable way to approach “looking at systems-level behavior.” Otherwise, you’re relying on luck (pick a system and hope you can use your hammer). Because systems biology isn’t really a field, right? It’s just a methodology.

Maybe that’s why people like the reductionist mode of research so much? At least it’s easy to find a story to tell. I guess it’s a little like history. Everyone wants a handle, some sort of focal point. So you get focal points, like Alexander the Great, or Napolean. Even when studying social trends and situations, such as poverty and crime, you get the Italian Mafia, Tammany Hall, Five Points. Focal points.

So here I am, trying to wade through the literature and find a good focus.

From now until around May, I’ll be on the hunt for a Ph.D. advisor. Amusingly, I came across this Nature article on what makes good mentors at the same time that PhD comics had this strip:

I’ve been filling out a bare-bones hourly log of what I’ve been doing all day, so that I can look back at the end of the day and see what I have and have not done. I got the idea from Getting What You Came For, which is an interesting book (a review of it sometime later).

It’s going to be an interesting experiment. So far, it has been making me focus on what I’m accomplishing (and also on what I’m very much not) and what I spend my time on all day. Not only that, I have a log at the end in case I forget a couple days later whether I accomplished anything this past week. It feels like a good way to lend some structure to an otherwise very structure-less summer, where I don’t have work days, or really any work other than what I want to do. On the other hand, it does bring too much highlight upon hours that I don’t spend doing something “productive.” Is it bad to enjoy part of my day reading blogs? I don’t think so, and yet the log makes me feel as though I need to eradicate anything that isn’t work. So, perhaps the log is a bit of a double-edged sword.

I will continue for the next few weeks or so, and see if I feel like it’s helping my productivity, or whether it is just an unnecessary distraction and a source of unneeded stress.

One of the things that is taking a while to get used to, moving to a new school, is the new (lower) level of online access to journals. My undergraduate university had pretty wide access to almost any biomedical or physical journal that I wanted access to. It might be because it had a medical school attached, or something. I was pretty spoiled.

My new university, though, doesn’t have a medical school, and (maybe as a consequence) it doesn’t have as much access to online journals. Now, I wouldn’t complain if some of the journals that I don’t have access to were really obscure, or if they were medical journals oriented purely towards clinical practice.

But the Nature subjournals?? I mean, they’re not that big, certainly not as big as their parent, but they have some very non-obscure things going on in there, and most are definitely not clinical journals. Not only that, but genetics is something that the new university is trying to push, at least in the past few years, and yet no Nature Genetics? No Nature Chemical Biology? Not even Nature Cell Biology?

Weird. Have I been spoiled too much by my previous university, or is it too unreasonable to ask for a few of the major second or third tier journals in their electronic form?

EDIT: Wow, I feel like a total goof. False alarm. For some reason, it worked this afternoon, though it wasn’t working no matter what I tried yesterday. I do have access to the Nature subjournals. Very strange, since other journals were working yesterday; it was only the Nature subjournals that weren’t…