Coffee: good for your brain

And now for some science in the news: Drinking 3-5 cups of coffee a day leads to a lower risk of dementia later in life! It decreases your risk of Alzheimer's and has also been associated with a lower risk of type 2 diabetes and Parkinson's.

I love reading articles extolling the benefits of my deep addiction.

Polyketides again

I've been thinking lately that I would like to go into polyketide chemistry, lately. I'm going to work in a lab this summer that works with bacterial polyketides, and as far as I can tell, the whole field pretty much brings my all my interests together. Even in light of what I said about combinatorial chemistry (and in this case, biology) which is an aspect of playing around with biosynthetic genes.

It's one area of chemical biology that has caught my interest this year (which is basically when I started browsing the chemical biology lit). It relies heavily on organic and bioorganic chemistry, but also genetics and even tracing evolutionary pathways (like this review that talks about how the classifications of polyketide synthases are a little rigid). There's a med chem/natural products discovery aspect to it, since a lot of these structures are really promising medicinally as antibiotics and chemotherapeutic agents (and like I posted yesterday, the genome-mining approach). There's a synthetic organic aspect because a lot of these structures are good targets for total syntheses due to their medicinal qualities. There's an enzymology aspect because a lot of these biosynthetic enzymes have really interesting proprieties. And then there's even some work on trying to harness enzymes that do mechanistically biosynthetic transformations hard to emulate with classical reagents for use in total synthesis, like this total chemoenzymatic synthesis. There's a structural biology aspect too--like this paper looking the structural basis for polyketide synthases docking and substrate specificity. I suspected there would be some biomimetic organic synthesis based on some of these bacterial polyketide biosynthetic pathways out there, and a quick google search told me that there's is, indeed, loads of work being done in that area.

I've started bookmarking webages of labs that publish in this area (and other areas that look interesting) because...well, I figure if I still want to go into this (kind of specialized) area by the time I decide to apply to grad school in a couple years, that's probably a decent approach. It just seems like such a promising area for me and for my desire to bring all these interests of mine together. And just to see where it goes generally. It's not a cutting-edge new field, but just a field that keeps getting cooler and cooler as our tools to do science get cooler and cooler.

Knowing vs. Finding Information

One thing I think my generation is very good at is finding information. Not necessarily knowing information off hand, but being able to sift through search engines and databases and find what we want. People of my parents' generation keep complaining that we can't do basic math, we can't spell, and our handwriting is atrocious. But my parents are amazed at the speed at which I can retrieve information off the Internet. (Part of it is that I waste an atrocious amount of time browsing--but I do discover a lot of new neat shortcut Internet applets and webpages this way).

Now in light of science education and science as a whole, I'm not sure where this puts us. I have a really hit or miss memory (I either know extremely detailed information or I totally blank out), and memorizing enough information to do well on exams is a chore. I mean, I'm glad I was asked to memorize the amino acids in biochemistry, enough basic organic reactions, and enough pKas to be able to guesstimate most pKas of organic materials because it does help with my fluidity in understanding papers and talks. It's not that I'm incapable of memorization--I'll do it. I'm supposedly "good" at things that people traditionally associate with being memorization heavy, which I contest are more problem solving. In fact, the way I studied organic chemistry was by stringing together the reactions in goofy synthesis problems of partial structures of psychedelics that I looked up on wikipedia or just some molecule I thought looked cool that I made up. I would make up practice problems for my friends--and this would give me a chance to think about the problems retrosynthetically and when I got to a problem on a test I was used to thinking about a variety of sequences that would be useful for making and breaking bonds and had several strategies for this laid out in my head. I talk to a lot of my classmates who also did well in that class and most of them tended to take a more conventional flash card and practice problem approach. I did some practice problems and flash cards, sure, but every now and then I needed to make it more of a game to maintain my interest. It probably has something to do with my ADHD--I try to turn studying into games because when I'm engaged I go into hyperfocus mode which is really conducive to studying, writing papers, or lab work (ADHD can be a curse, but also a blessing). This is a tangent, though.

My ability to retrieve information came especially in handy in my advanced synthetic organic course when all of our exams were open book and taken straight out of the lit. The problems, then, were extremely difficult, but that meant that I could focus on categorizing information and developing strategies in my head for how to put it together rather than storing it, which is much better for my learning style.

Given the great abundance of information available to us, I'm not even sure that knowing information off-hand is even all that useful--especially in very interdisciplinary fields. I think it's more important to be aware that information exists and then be able to retrieve it quickly or ask another person who is an expert. Learning how to critically think, to research, to evaluate, and to organize information is important when you have endless sources of it at your finger tips.

Honing these skills, obviously, is not always a practical approach for a lot of classes geared at giving you a basic background in the subject, though, and I'm not sure how to reconcile this. I also see how you should very detailed information about a project you are very close to, like a thesis. But in terms of a general knowledge base of scientific literacy? I still contest that it's more important to know how to find information in this day and age.

Incidentally, a friend of mine who is a classicist said similar issues came up in their field when the Perseus Project went up. It meant that they didn't necessarily need to memorize as many strict grammatical rules and vocabulary since it was hyperlinked in the text, and revolutionized the way students would go about reading ancient texts. So the question of "how much information is necessary to hold in your head compared to what has conventionally been deemed necessary" is not unique to science. I guess in some ways it's akin to the fact that people stopped memorizing whole epics to perform orally after the printing press allowed books to become widely available and people talked of the demise of the oral tradition. In reality it just led to a whole new set of opportunities in literature.

Genome Mining for Natural Products

I've discovered a lot of interesting science in ChemBioChem, a European chemical biology journal. We have more access to more of these journals than most of the Nature journals; it must be because there is some relatively cheap Wiley journal package that comes with Angewandte Chemie, since we basically get all of the European chemistry journals that are published by that group.

But in any case, one pet area that has been fascinating me lately is the convergence of genetics, microbiology, analytical chemistry, and synthetic chemistry to the discovery of new natural products, especially in examining modular biosynthetic polyketide genes. This review that came out a few days ago, Strategies for Discovering New Natural Products through Genome Mining, went through basically what is being done in the field.

The authors explain that natural products discovery has not been favored by pharmaceutical industries for a while as a way to discover new drugs. Most of the 20th century (after penicillin was discovered) is described as the golden age of antibiotics and natural product discovery. It has fallen out of favor because it is time intensive and often leads to discovery of natural products that are already known.

But now, in a post genomics era with so much bioinformatic data out there, we actually have new strategies to approach discovering natural products, especially in examining biosynthetic gene clusters. We can search for PKS (polyketide synthase) domains, we can knockdown genes, and (most exciting to me) you can reconstruct products in vitro to determine if that gene cluster is actually making what you think it is (and then confirm what you have with NMR and MS). Of course, with the reconstruction strategy there are certain problems, like finding the right promoter and so forth, but chemoenzymatic total synthesis to reconstruct biosynthetic pathways has been done in vitro before.

Polyketides are neat from a pharmacological standpoint, because the secondary metabolites tend to have a lot of medicinal properties. They are also neat in that a lot of the genes are modular, so there have been some papers where they re-arrange them essentially doing synthetic chemistry in a cell instead of in an RBF. And sometimes they have neat little genes beyond just PKS genes--I recently wrote a paper for school reviewing research on a gene that was responsible for doing a powerful oxidation to form a chiral THF ring. It seems like a way to both discover new natural products with pharmaceutical value and to generally get a better mechanistic grasp of biosynthesis.

Combinatorial Chem

I've been reading about combinatorial chemistry lately, especially its applications in drug discovery. Last semester Jordan Katz (a Reed alum who recently finished his PhD) gave a talk about using a combinatorial approach to find the right inorganic materials for solar cells--unrelated to drug discovery, but showing that it is a useful technique in a variety of applications. This paper and this paper aren't exactly new, but they were my first introduction to the idea of screening a modular library that utilized a combinatorial approach (papers read in my topics in biochemistry course this past fall).

I think I understand the utility of such an approach. Biological systems are complicated, and the idea of design feels really...strange in some ways. Nature works through selection, not design. I know that there are drugs that have been designed, but I can see how a combinatorial approach would be a useful angle since there are so many potential compounds that could be pharmacologically active (is "chemical space" the right term?).

But every time I read a paper that uses a combinatorial approach, all I can think is how boring it must be for the poor grad student or lab tech carrying it out, since it's a conceptual problem that takes a lot of hands going through tedium to sort through. I think at an abstract level, design is more appealing because it is just more satisfying conceptually to think through a rational structure. At least, as a reader, it's more satisfying to read about. I can't help but find combinatorial chemistry boring, however useful of a tool it may be.

This Upcoming Semester

I'm enjoying these last few days of basking in winter break (classes start up again on Monday); browsing the Internet endlessly and guilelessly, watching TV on my computer, and drinking with my friends. But I'm gearing up for the start of a new semester that will hopefully be good.

Between my theoretical organic chem class (advanced mechanistic organic chemistry) and my intro inorganic class, I'm hoping that MO theory might actually make some semblance of sense. A professor described it once as "chemistry's version of the stork story", so I'm aware of some level of fundamental bullshit going on in describing orbitals and chemical bonding, but I'd really like it to be a little more coherent in my head conceptually than it currently is. When I tutor organic chemistry sometimes I feel like a total faker, drawing meaningless balloons and calling them a HOMO and a LUMO. I understand it well enough to sort of describe what's going on in the Diels-Alder, but just barely. I've been introduced to some ideas that are useful mnemonics for stereochemistry and useful to know to generally understand what's going on in the lit in synthetic organic chemistry (concerted reactions, thermally allowed vs. photochemically allowed, chair like transition states, etc.). But apparently this class goes really into the Woodward-Hoffman rules, and I imagine that conrotatory and disrotatory will mean a whole lot more to me after the end of the semester than it does now. I'll also get a better grip on how to use Spartan, which will be good because computer modelling is useful and not something I am terribly comfortable with.

I'm hoping that i-chem will fill some gaps I currently have in my chemistry knowledge. I felt both in synth and in biochem that some things would have made more sense having more background in inorganic. In any case, the textbook looks pretty interesting and it's a chance to do some totally new chemistry. Along getting a better grip on MO theory, I'd also like to get a better grip on coordination chemistry and remember that d orbitals actually do exist. And to be reminded that there are chemists who don't view carbon as the center of everything and who regularly look beyond the first two rows of the periodic table.

Statistical thermodynamics, my physical chemistry course, looks pretty gross. I know I shouldn't be closed-minded, but I was flipping through my book and saw the return of angular momentum and it gave me chills flashing back to intro physics. I know I'll get through it and I know I'll appreciate it in retrospect, but...it'll be a slogging through it experience. It's going to be a lot of math--and I'm much more into the descriptive aspects of chemistry, or at least that part comes a lot more intuitively.

It's going to be a very chemistry-intensive semester; I'm only taking one biology course and it's a seminar on membrane-membrane interactions that meets twice weekly run more like a journal club than a class, not a full lecture-lab course. This is the first time I've taken so much chemistry at once and I hopefully won't OD on it. It's also pushing me out of my chemical comfort zone of pushing around arrows, but that's probably a good thing.

I'm also excited about my independent study. It's a not-on-the record, not-for-credit thing, which is good because it means I can do as much or as little on it as I have time for. I'm not sure exactly what my synthetic target is going to be, but I've worked in that lab before and the research done in there is ongoing, so I'm familiar with the overall project. I'm going to chat about it with Pat (the prof whose lab I'm working in) on Tuesday to work out some details. I'm not sure if I'm going to continue to TA organic lab this semester or not. I was asked for my availability, but I think it depends on how people's schedules work out. I'm also only taking one lab class--biochemical methods--which is the first time this has ever happened in college. In the past I've always taken two or three labs at once.

I have to take my quals this upcoming spring. Reed sort of mimics the PhD system and junior year you have to take junior qualifying exams in your major before you can register for your senior thesis. As an interdisciplinary major, I need to take both the biology exam and the chemistry exam, so that's going to be two intense weekends this spring.

And then...wow. Next year I'm going to be a senior. Next year I need to take analytical chemistry, one more liberal arts course to fill a group requirement, and my thesis and then I'm allowed to graduate. Crazy times.

Liberal Arts College vs. University

I am very much a proponent for a small liberal arts school science education. I have no idea how I will fare later in life, but I have no doubts that my education has been anything but excellent, and, on the whole, superior to my friends' educations that go to large institutions.

See, even here I had some large lecture-based classes that kind of sucked. Introductory chemistry was ~120 people. However, even with 120 people in the course it was a) taught by a professor b) all our exams were graded by him (even if he hired student graders for homework and lab reports) and c) he knew every one of our names. Even then he was down for p-set help and just dropping by his office to chat. And this particular professor is what drew me into the chemistry department in the first place. Later my courses got smaller and more specialized, and I suppose that is the case anywhere.

My friends at Berkeley, University of Illinois, and other large research-focused institutions describe to me gen chem and even organic chem classes as being ~500 people. My sophomore organic class was 70 people, and this was considered abnormally large (usually it's closer to 50), and definitely much larger than the average Reed class. They also describe this trend towards making it more interactive involving clickers that digitally record answers to multiple choice questions on the screen, which in reality is an easy way for the TA to take attendance (which I think is silly; we're all adults now, the only person you're hurting is yourself--unless you don't get anything from going to lecture anyway--and then what's the point?). Students get around this by getting their friends to go to class and press their respective clickers for them, and take turns who goes to class just to press the clicker enough to get participation points.

My friend Luke is in the aerospace engineering program at the University of Illinois--which is a great program, one of the best in the country--and he says the big advantage is that in a couple labs they got to go see real planes and play with the mechanics. You just don't have those sorts of facilities at a smaller institution. But he said he also did not know a professor well enough to ask for a recommendation when applying to summer programs and he has no clue what he is going to do when applying to graduate school. He said that he often feels that the access to larger facilities in the end doesn't outweigh the benefits of having mentors relationships with professors who know you personally considering how infrequent access to these facilities are.

I know I certainly complain enough about Reed not having subscriptions to Nature Chemical Biology or Nature Reviews Drug Discovery, and I would have access to that at someplace like, say, Berkeley. I also know that if you are an undergrad confident, savvy, and lucky enough to ask and land a research position then you get to do things that we can't do here. Our science is modest; sound in methodology, but far from cutting edge. Profs publish, some more than others, but not that often. I know that if you are bright and self-directed you can make use of the facilities and resources of being in a larger institution, but in all honesty, it seems like most undergrads get lost in the sea. It also seems like anyone who is extremely self-directed does a fair bit of teaching themselves things; and while I'm all for self-teaching, it makes me question what the point of having class is. If the syllabus is online, if you have libraries full of books and journals to read, and if you can check your answers against an answer key, no wonder people at larger schools skip class. I always found that self-directed learning is great, but complemented by really excellent teachers.

I am sure there are some students who are better equipped to deal with bigness than I am. But I feel like for most of us, we're still figuring our shit out and we need more interaction to keep us from just skating through. I feel like I am solidly accountable for my work, and no one is just shuffling me through the system, and like I am getting trained to think like a scientist. Yeah, Berkeley has some sweet facilities, but it's not like I would get a chance to use them as an undergrad in all likelihood anyway.