Eh, future

Posts like these make me scared--because being a "jack of all trades, master of none" is basically what I have been on track to be through all of my undergraduate education (this whole BMB business with extra chemistry classes). The PI who I sent my CV to who I will be working for this summer saw this as a good thing; he was impressed by my desire to do interdisciplinary research and my varied experiences in the lab. At Reed no one in the chemistry department seems to remember whether I'm a chemistry major or a BMB major because I spent the summer doing organic synthesis. I've been skating between the two departments and following my academic wanderlust since I got to college, and imagine myself doing the same afterwards.

But I worry. I have a few subjects that I am strong in and can be very enthusiastic, but I'm aware that the world is full of people smarter than me. My main strengths are enthusiasm, my breadth of curiosity, and the ability to get very interested in projects. I'm a good student, but not a great student and my transcript is far from perfect. I'm not really cutthroat and when I do well it's because I find some little area that interests me and just dive into it. There's a couple issues at play here: I know I love science enough to want pursue it further but a) do I look good enough on paper to get into good graduate programs? b) where is my place in the scientific community going to be? and c) am I of a competitive enough disposition?

While I feel like I have as solid of a training in organic chemistry as a chemistry major (what classes will I be missing when I graduate? quantum chem and physical chemistry lab) and as solid training in molecular biology as a biology major (I'm missing the population/organismal/evolutionary class requirement), I'm just definitely not (at least right now) approaching it in the traditional "get a grounding in one field and diversify from there" approach at all. The "what the fuck am I doing with my life" question is one I've thought about a lot, and generally all this sorts itself out so I'm not that concerned. But it seems like everyone has a different opinion on what the best way to go in the interdisciplinary sciences is in terms of training, where everything is headed, etc. Also--this is just undergrad--my professor likes to tell us that he studied chemistry (primarily inorganic) in undergrad, got a PhD in organic chemistry, did his postdoc in a physical chemistry group, and now teaches biochemistry and likes to emphasize that--at least in academia--you're constantly re-inventing yourself. My profs keep telling me that no one cares what your degree is called--they care about your research experience and coursework.

I also know I have a full year and a half of school left to ponder these things, and I will likely take time off after that. Fretting is not really productive, and life is full of surprises and changes of plans.

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.