She Blinded Me with Science

A dream is a wish your blog makes

2007-04-28T12:18:00.000-04:00

I've really let this blog go over the last while, haven't I? There are so many great new blogs out there that I haven't had the chance to link to. First off, I wanted to thank everyone who commented on my DOI post; the tips have made thesis-ing go a tad more smoothly. Second, I wanted to let everyone know what I'll be up to next. Soon, I'll no longer be qualified to write from the point of view of a grad student. I've been offered an Assistant Editor position with Chemical and Engineering News. I'm looking forward to getting started, even though the production schedule will mean that the bloggers will scoop me more often than not. :) It's likely that from now on, I'll be posting from meetings, and in another forum. So for now, "She Blinded Me with Science" will be on an indefinite hiatus, while I format margins, apartment hunt in DuPont Circle, and hone my craft at C&EN.*
I'll leave you with a deconstruction of one of the more hilarious commercials I've seen lately. Go to this link, then click the "see the Zoom! TV commercial" box, and prepare to be blown away.
Choice quotes:
"..an advance so profound, it took a team of scientists years to create."
This was noteworthy because apparently, a lot of scientific advances can be sorted out in a fortnight.
"the patented Zoom! light"
Can you really patent light? Can you forbid, say, the use of the 254nm wavelength without paying extensive royalties? My guess is that they've patented whatever lamp generates the UV light at a controlled intensity that's used in the procedure, but feel free to correct me if I'm wrong.
"breaking down the stains' double bonds"
I love how they threw that in there just to be sciencey. Evidently, the radicals generated by the Fenton reaction (which means the gel contains hydrogen peroxide and some kind of iron or other catalyst) are changing the structure of the stains so they no longer appear colored.

aside: I just did some demonstrations yesterday for 8th graders. Among other things, we bleached shredded carrots (aka, got rid of some of the double bonds.)

I'm really just concerned about the fallout for double bonds everywhere. I hope no one starts a smear campaign. (Double bonds aren't all bad, people! Gleevec's got 'em, hey, even Viagra's got 'em.)

Lastly, I know that when I go to the dentist's office, I wear my slinky little black dress. The black dress is, after all, a wardrobe staple.

Thanks for reading, everyone.

* If you do a Google Image Search for C&EN, you will find pictures that appeared in Chembark, Carbon-Based Curiosities, and the Lieber group webpage in the top hits.

Just try it.

2007-04-05T11:57:00.000-04:00

Try googling "masamune effect". It has to be in quotes for this to work. I was looking for a specific reference and was too lazy to go to Web of Science right away. I got a good chuckle for my efforts, but little else.
Sorry I haven't blogged in a bit. I'm recovering from an unfortunate turn of events that I'd prefer not to post about, and my computer time's being eaten up by other things these days.

..when you're done with that, read the real references, if you're so inclined. (I did have to go outside of Google to find them, since this work is mentioned offhand in many more recent papers.)
(a)W. Choy, L. A. Redd III., S. Masamune, J. Org. Chem. 1983, 48, 1137-1139;
(b) S. Masamune, L. A. Reed III., J. T. Davis, W. Choy, J. Org. Chem. 1983, 48, 4441-4444.

Satoru Masamune, while a professor of chemistry at MIT, made many contributions to the field of chemical synthesis. These two papers describe some of his contributions to the Diels-Alder reaction, one of my adviser's favorites.
The Diels-Alder reaction is artistic (it can let us sculpt 3D molecules out of flat precursors), it's green (no waste atoms lying around after the reaction, with just a few exceptions), and chemists have gotten pretty good at controlling and predicting its power.

Back to Masamune's papers. This work describes a small reactant with a defined 3D structure, which reacts very well at low temperatures, catalyst-free (green again, low energy requirement) with a variety of partners. The best part about this reactant was that one could predict the 3D structure of the products for the reaction. Masamune surmised that this was made possible by hydrogen bonding interactions occurring over the course of the reaction. That's a strategy taken straight out of the enzyme's playbook.

I picked the picture because I've always been fascinated by those desk toys. If you could turn the magnet on and off at will, I think it's a pretty decent basic illustration of the concept of building 3D things from flat things.

*UPDATE 4/28/07. Apparently, "She Blinded Me with Science" is now the top hit when you try googling "masamune effect". Neat.

Whither the protecting group?

2007-03-21T15:58:00.000-04:00

Kudos to Phil Baran's group, who have just published in the journal Nature describing protecting-group (PG) free syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families.
the ref: Nature 2007, 446, 404-408.
His group has published the enantioselective total synthesis of some of these compounds before (see, for instance, JACS 2005, 127, 15394-96.) but I'm guessing Nature deemed this worthy because of its unified application of a few big philosophies of organic synthesis (ie, atom economy and convergency) while trying to evaluate the pros and cons of going PG-free, as well as its overarching call for hearkening back to the early days, when men were men and syntheses were PG-free. That, and they optimized the routes to welwitindolinone and fischerindole to get higher yields.
So what is a protecting group? For organic chemists, they are a way of reining in the more unruly sections of the molecule you happen to be making. To be more specific, it's necessary to mask parts of the molecule that are likely to behave in some way other than what you'd like, or that refuse to "go along quietly" when some other part of your molecule needs attention.
For a great description, take a look here for Dylan Stiles' (aka Tenderbutton's) rather prescient article about the protecting group and some classic examples thereof.
Is the "PG-free way" really Mother Nature's way? If not, is her favorite protecting group the MOM group?
I think that some masked chemical reactivity exists in the biological world. I hope that my more scientifically inclined readers won't take offense at my stretching an analogy just a bit for the sake of a blog entry.
Take enzymes like proteases. Proteases break the bonds that link up the fundamental building blocks in proteins, and they're involved in many important roles in the body, from blood clotting to cell death. It's extremely important that proteases be exquisitely regulated, so that they don't start chopping up proteins willy-nilly. The "protecting groups" for proteases are in place at the beginning, during their production. Proteases are built as inactive forms known as zymogens, and in order to reveal the active protease, there's a little sliver of protein (called a peptide) that's got to get lopped off.
the ref: Nature 1999, 402, 373-376.
That isn't the only mechanism for regulating proteolysis. You can imagine that if a protease somehow gets activated at the wrong time, or in an out-of-control way, there would be dire consequences (ie, too much protease activity could contribute to stroke or alzheimer's).
When that happens, one natural defense mechanism is the serpin class of proteins. Serpins permanantly (covalently) inhibit proteases, mostly the serine type.

Incidentally, this is the most chemistry I've ever seen in an issue of Nature. Besides the Baran paper and the intro to it by Porco, there's a great piece by Bergman on C-H activation and a review by Toste. Plus, there's an article about chemistry in the NatureJobs section.
UPDATE 3/24: I should've realized Nature did that to coincide with the ACS national meeting.

Will DOI cure what ails me?

2007-03-20T22:55:00.000-04:00

As I mentioned on my last post, I've been busy reformatting tons of references, adapting something I've written before to satisfy a slightly different format.
Non-scientists, non-scholarly types: It's like writing that 8th grade term paper all over again, times 100. You know, the one where each of your sources for your bibliography had to be on a separate index card, and you had to get your mom to drive you to the Hackettstown Library to search (are you ready now?) the Readers' Guide to Periodical Literature for information on The Manhattan Project. I can't remember why I chose to write a term paper about the A-bomb at the tender age of 14, but a lot of what I read about for that paper still comes up.
But I digress.
The point is that reformatting references is unbelievably mundane work.
There is some computer software out there that's meant to take care of all that for you. The one I had started using is called EndNote. Endnote interfaces with Word, and it's smart enough to know that when you move text around, the numbers of your references will change if the order's been changed. It has templates for bibliographies in many different journals and can (supposedly) instantly reformat your references to a new journal.
Endnote didn't work well for me at all. I was working with a library of a couple hundred references for this review paper back in 2005. Unfortunately, I couldn't figure out a way to make the software format my references according to the specifications of the particular journal. So, once I was sure I was done shuffling text around, I switched my references to text-only and reformatted them manually, and now I'm reformatting once again.
Is there other, better software out there?
The biggest difference between now and when I was in eighth grade is the ease of access to the internet. One of the handiest technologies for keeping track of the scholarly literature is The Digital Object Identifier System, or DOI. DOI is like a homing device for a journal article, so that no matter where the content moves on the web, looking it up using a DOI locates it and retrieves it.
Recently, some Elsevier journals changed their web and old links no longer worked. If I'd set those links to the DOI of the journal article, they'd still be intact. That reminds me; I need to change my research group's "Publications" page so that everything is indexed by DOI.
What I'm wondering is whether there will come a point where DOI will become the universal reference citation standard, including in print. If that happened, I'd never have to worry about whether I should be using bold or italic font, or whether the authors' surnames come first or last, ever again. Just a simple URL would be all I'd need. However, part of me thinks that if journals (or is it the ACS Style Guidepeople?) were ever going to adopt uniform, URL-based standards, they would have done it a few years ago, at the relative "dawn" of the internet age.
What are the barriers to this, if any? Is it a content searching issue?
If you were going to pick a universal reference style, what would it be and why?

If I were going to Chicago...

2007-03-20T19:58:00.000-04:00

If I were going to Chicago, I'd probably be inspired to post something a little more imaginative.
I've been working on a research proposal (read: reformatting references) all week. My brain hurts.

It won't surprise anyone who knows me that I'd want to attend talks that walk the chemistry-biology tightrope. (Read: Jon Clardy, Dale Boger, Laura Kiessling, Sam Gellman, Carolyn Bertozzi, Anna Mapp, Xiaowei Zhuang, etc.)
Here are some of my less obvious go-to talks.

Sunday all day (intermittently): AGFD: Natural Products, Diets and Cancer Prevention. A friend from my last lab always made time to go to the talks from the Ag. and Food chemistry division. I like them, too, because, to me, they have a more "generalist" vibe, and sometimes there are some really interesting chemical structures that they throw up on a slide. You never know where the inspiration for the next target will come from. Not too long ago, there was a postdoc in my group who spent part of his Ph.D. synthesizing a molecule found in Roquefort cheese.

Monday AM: MEDI: Drugs from Academia: Marketed Drugs Discovered in Academic Labs
I'm curious what Bob Holton's going to do with the taxol $$. That, and I have to cheer on Princeton's own Edward C. "Ted" Taylor.

Monday lunch: CHED: Undergraduate Research Poster Session: Organic Chemistry
Mad props to Mike, my little bro, for being the first in the family to present a poster at an ACS meeting. I should probably have gotten more work done.

Monday PM: CHED: Research in Chemical Education
My friend Angie is a teaching postdoc and she's giving a talk about how to keep a lecture hall's worth of sophomores engaged in the organic chem course's subject material. My favorite quote from her teaching experiences is on my Facebook wall. "Sigh....I'm introducing the concept of "backside attack" to 260 college sophomores today. Pray for me." At her postdoc interview she had a week's notice to prepare a lecture on her assigned topic for another ~300 students.

Tuesday AM: PHYS: Xiaowei Zhuang's talk in ACS National Awards in Physical Chemistry
I know I said I wouldn't discuss an obvious one, but I've always really been intrigued by the idea of single molecule imaging studies. I was too afraid of math to take the plunge in a group like that, though. I like to think that one day we'll be able to make movies like this one. I don't think I've linked to that movie yet.

Wednesday AM:
9:55-10:35 ORGN: Biomimetic Natural and Unnatural Products Synthesis
Not a surprise that I'd go here. :)
I think the boss is talking about some new alkaloid-related work, but I'm not sure.

Wednesday PM: INOR: Coordination Chemistry: Characterization and Application
I want to listen to my friends Karl and Eli give talks about their work (or at least, my rudimentary, pop-science understanding of their work, judging by the link).

At some point: run up to Lincoln Park to get breakfast at The Bourgeois Pig, followed by research on, um, surface science at the Bliss Spa, paid for by my imaginary money.

Thursday PM: Nanoparticles: Synthesis, Passivation, Stabilization, and Functionalization
Nanotubes, biosensors, and a talk from someone in Chad Mirkin's group. What's not to like?
Chad Mirkin was here at Princeton a while ago and I regret skipping his talk because of labwork. His science reaches in so many directions.

Note to Anonymous

2007-03-14T08:20:00.000-04:00

this started as a reply to a comment on my last post, but it got so long i figured it deserved a post of its own. paul, excuse the lack of caps. i wrote this in the heat of the moment. i know how to diagram sentences, i swear. :)
anonymous,
i do agree with you that for grads busting their asses to pass quals (or get into a good group, or just getting stuff to work for once), the wining and dining days of recruiting are a distant memory. it's definitely true that fewer and fewer upper year students take part in the festivities, and with good reason...
i think that potential chemgrads need to go in well-informed about precisely what you said, and be open to (gasp!) other options. if you really really really want an industry job, they are tough to get these days. maybe the pendulum will swing back, maybe not.
and you're right, a survey can't be comprehensive if everyone isn't polled or doesn't respond, and they're reporting on survey data, so hopefully people trained as scientists know to take it with a grain of salt.
"The 2006 survey involved mailing questionnaires
to a random sample of 24,000
ACS members who were most likely to be
in the domestic workforce. They all resided
in the U.S., were under 70 years of age, and
were not in the emeritus, retired, or student
member categories." -C&EN 9/18/2006
The ACS has over 150,000 members, and it's been discussed at length in the blogs that many chemists don't join ACS at all, or their employers pay for it, so there's some overrepresentation there.
without real poll data, you risk jumping into that nebulous trend story fad. see here and here. so maybe their hands are tied to some extent. i don't think the stories on the survey data should be portrayed as indicative of anything wider. the question is, how could a good poll be properly conducted? with the status of postdocs being different almost everywhere, to cite one example, it would require extensive red-tape wading to reach everyone. on the other hand, since a lot of the job market stuff comes through word of mouth anyway, we could argue about where the best place is to disseminate this information in the first place. federal labor statistics?
i hear about industrial sites that are only hiring one person or two a year, and everybody has a fantastic pedigree. so, what happens to the others? some people are having to take a risk and take a job at a tiny company where they'd really need to stand out to ever be hired by a big guy.there are probably some success stories there, but i don't know as many working chemists as other bloggers. derek's situation is difficult, as well. it's economics driving that, plus perhaps preferring to train someone with less experience in your company's particular way of doing things?
when i got to grad school, i had blinders on. it's partially due to the fact that i went to a small school and didn't know any grad students, and that i had my "eyes on the prize" and didn't stop to think about the fact that i might be good at more than chemistry. my academic work was inextricably linked to my self-esteem back then. i think you can still go to grad school and work in a lab because you like chemistry. that's perfectly OK, but i think that people in this modern economy have to realize that a ph.d. in chemistry can be useful in plenty of different jobs, despite the traditionalists who regard those careers as "alternatives". i struggled with that idea for some time, but i keep hearing about my friends in the grad program that are going to go into consulting or work as a patent agent, two jobs i didn't know existed till grad school. some of them think that they might miss the lab, but maybe not. i even know someone who returned to the lab from an editorial position. it's tough, and you need to work hard to get back into the groove, but it's possible. reading "the world is flat" made me realize that everyone's going to have to work smarter and be creative in order to stay afloat.
the easiest jobs to look at are the ones for which you are supposedly directly trained. med school-> doctor. business school-> executive. law school-> lawyer. sally struthers school->medical assistant, electrician, business management, or accounting. chemistry grad school-> professor or lab chemist? yes, it's true that the other professions don't have the same kind of supply/demand issue in their job markets, but it's not something individuals have much control over, so i went for something different. maybe that's why when i hear about disgruntled grad students first thinking about other professions, those are often the things they gravitate toward at first. it takes real soul-searching to look beyond that. months and months of it, in my case, and if i'm not happy when i start working, i'm not afraid to start the process all over again.
i think the hardest part of the problem is that it's hard to explain this to the young-uns, because they think they have the answers and it won't happen to them, because we have somehow "failed" as chemists. i doubt i would have listened if "future me" went back in time to warn "young, idealistic, slightly cocky me" about such things.

whew. that's a manifesto-length post. speaking of which, if you haven't read milkshake's post, get thee to org prep daily. i learned a lot from it.

My favorite dog and pony show

2007-03-04T20:46:00.000-05:00

It's recruiting season at Princeton.
Typically, prospective students don't actually visit our department until they're already admitted, meaning that the department pulls out all the stops to bring in plenty of great people. I was admitted in the first year that Princeton started having a full recruiting weekend, instead of ad hoc visits to the department, and it made a huge difference (we had 1.5 times more people start than what had been common for the past 5 or 6 years). Every department does recruiting differently and presumably tries to do something distinctive/memorable, although I feel like most students come for a certain faculty member or two, not the department as a whole. Back when I was a senior in college, I remember that I had dinner at Yale's Peabody Museum (with the dinosaurs), but I think I heard that that hasn't been done in recent years. True? Also, does anybody know whether MIT still does the lobster bake? I've been told that TSRI does interview its students before admitting them, so the process is a little different there. What are some of the other well-known/ unique/ offbeat recruiting traditions?
The really interesting stuff happens after recruiting, when students commit to the university and then have to join a group. This tends to fuel the gossip for the better part of the fall semester. Who's going where, how many people is so-and-so taking, and the like. The department doesn't allow anyone to officially join a group until the end of November, although many students will start working in their lab of choice the summer before. During the fall semester, all first years attend all the research talks given by the faculty in one of our lecture halls. Unfortunately, as my years here have progressed, I've started to notice that the department's been providing less and less food at these events (we got free lunch and baked goods, the next year it was just baked goods, the year after that nothing at all.) My understanding is that at some places, the research talks are more of an "open house" setup, where interested parties listen to the faculty member discuss what's going on in the group. I've seen some of David Liu's open house posters, for instance. I understand why the department asks everyone to attend every talk, since there have been several occasions where students have switched fields completely at the beginning of grad school, and it's important to know what's going on outside of your field, but I also think that in an open house situation, there's likely to be more lively discussion, because everyone who's attending wants to be there.

Too bad Apple's got that name locked up

2007-02-22T13:52:00.000-05:00

I gravitated toward this paper's title, "Reversible, Erasable, and Rewritable Nanorecording on an H2 Rotaxane Thin Film".
the ref: JACS 2007 129, 2204-2205.
This paper's about a new material that makes a promising step toward atom-scale data storage devices. As computers store more and more large files (and I don't just mean home movies from your family trip to the world's largest ball of twine, I'm talking government use, scientific number crunching, and the like), the logical progression points to further miniaturized data drives.

Computers store data in bits and bytes, and the system boils everything down to a string of digits with only two possible values: zero or one. Because of this, the fundamental storage unit needs to be capable of switching reversibly between two different forms.

The authors of the paper pulled that feat off by making their new material from a molecule called a rotaxane, which is mechanically interlocked, like those metal toy puzzles that drive me crazy. Basically, the ring can move to each side of the dumbbell.

The "recording device", a scanning tunneling microscope, reminds me of a tiny turntable needle. This kind of microscope is a little different from the ones in every high school science classroom. It's used to measure properties at surfaces down to the nanometer (billionth of a meter) scale, and with an applied voltage, it can manipulate material down to individual atoms and molecules. Those school microscopes couldn't come close to being able to "see" something that small, and there's no voltage involved with them, either.

Put those two things together and the tiny tip can "move" the ring on the dumbbell molecule reversibly, which would translate to recording and erasing.

These researchers published a similar paper last year, but the new work tweaks the molecular structure of the dumbbell that makes erasing "data" easier. The next questions are ones of lifetime (how long-lasting is this material and how stable is the switch once it's put in position? etc.)

Death, Taxes, and Grad School

2007-02-18T21:58:00.000-05:00

One of the many differences between me and my friends who got "real jobs" after college is how Uncle Sam (and his state- and city-level brethren) decide we should be classified in the tax code. Since it's getting to be that time of year again, I figured I'd try to relate some of the confusion I've experienced because of the non-intuitive-ness of it all.
Back in high school and college, I got a W-2 at the end of the year for any job I held, listing how much had been withheld from my paycheck for federal and state tax, etc. All it took to do my taxes (and get my refund!) was the aptly named 1040-EZ.
In grad school, I was lucky enough to be awarded a fellowship. There is a difference in the way the federal government regards the various forms of grad-student income.
Princeton required me to TA for one semester, and that year I had a combination of fellowship and salaried income, so I remember that mess particularly fondly.
Permit me to explain:
If you're TA'ing a class (or, as Princeton calls it, acting as an AI or a preceptor), that is considered salaried work, so you still receive a W-2 and have federal and state taxes withheld. There is no money withheld from fellowship income at Princeton. (Is this different anyplace else?) That means I don't get a W-2.
Instead of the 1040-EZ, I have to use the tax tables to estimate what my tax will be for the coming year and send in a stub with a check to the U.S. Treasury quarterly. Then, I have to use a 1040-A form to report my estimated payments and deduct that from my calculated tax. There's a fine if you don't pay a certain amount of estimated tax in advance, so that's why I don't just pay up in one chunk on April 15th. The state-level taxes have the potential to add another layer of complexity, but I've been lucky because fellowship stipends are not taxable in the state of NJ, so I'd always get a little bit of a refund there. I grew up in NJ, so I didn't bother changing my residency or anything, either. (Now that I live in PA, I need to look into whether I'll owe tax at state level). City-dwelling grad students, how complicated is the tax situation for you?
Just for kicks, I'll link to Princeton's tax requirement sheet. I don't think you need to have an on-campus IP address to access it.
You always hear tell of random grad students who don't pay their taxes, figuring that it isn't worth the government's time to audit someone who only makes 19K a year. Good luck with that. I don't have the cojones for it.

The Grad Student Experience

2007-01-28T19:18:00.000-05:00

I've been out on the left coast for a while, indulging my desire to use a Pipetman, run pretty gels, and generate boatloads of mass spec. data.

While I've been here, I've started thinking about the differences in the graduate student experience at a university and at a research institute or a medical school. I applied to all three when I was an undergrad, although that probably doesn't happen often unless you have a biological bent in your research interests.

I'm floored by the facilities out here. They're really conducive to getting things done quickly. I've been to three or four other labs here to use some random instrument, and everyone's been very helpful. This equipment-sharing must just vary widely from department to department depending on how collegial a place is or how many levels of bureaucracy you need to get past to accomplish anything.

A couple years back, our department was actively recruiting a faculty member from a university that had a medical school campus. I can understand the challenges that would come with relocating to a university like Princeton with no professional schools at all. (The fictitious hospital where House works doesn't count). Even little things like access to the right set of journal articles can become a real hassle.

So why'd I go to a university? At the time I picked Princeton because it had the most PI's I'd want to work for. (Funny that none of them are there now.) I think that the shared experience my incoming class had (living in the grad dorm, working out at the gym on-campus, problem sets in the coffeehouse) gave us a real sense of community, which as a grad student is nice.

It's also important to me to socialize with nonscientists. I didn't know (or perhaps I should say didn't respect) very many humanities people in college, but the people I meet here are almost uniformly brilliant.

Maybe being a grad student outside of a university feels more like a real job, which is exactly what I was trying to put off?

Triangle Club**

2007-01-08T21:52:00.000-05:00

I wish I had the opportunity to learn more about concepts that are important to understand in developing a functioning drug. Derek's blog will have to suffice for now.
Today I'm posting about Naloxone and Naltrexone. They came up in a conversation about drug addiction (more on that later). These two molecules are opioid receptor antagonists that are strikingly similar in structure, but they're used in the clinic in different ways. An antagonist in the drug sense is something that binds to a receptor and stops the events/actions set in motion by another drug called an agonist. By itself, an antagonist doesn't do anything to the receptor.
(If you're lost and haven't read the links, suffice to say that the word "opioid" sounds like the word "opium" for a reason.)
See here for Molecule of the day's entry on Naloxone.
Naloxone clears your system more rapidly. It's given to patients who have overdosed on things like heroin or morphine. (I think the wikipedia entries I cited above may be confused here..) Naloxone essentially kicks the heroin/morphine off of the opioid receptor, and what you get is a rapid detox, complete with all the very painful symptoms of withdrawal. The detox process is almost instantaneous; the patient goes from completely passed out to completely awake in seconds. The process can also be done under anesthesia.
After detox, patients in rehab may take a once-daily pill of Naltrexone, which is much longer-acting. It'll keep any other opiates they may try to sneak from working.
The difference between the structures is actually really subtle. Note the cyclopropane Naltrexone substitutes for the Naloxone olefin. One extra carbon. Hmmm.
It's known in the literature that cyclopropanes can possess alkene-like reactivity.
What I'm not sure of (and don't have the time to look into in depth) are the differences in how they're metabolized. But here's something about metabolism of cyclopropanes that you can dig out of the literature pretty quickly:
The ref: Chem. Rev. 2003, 103, 1625-1647.

** and if you're into musical comedy and Ivy League tradition, see the Princeton Triangle Club's website.

More a hackneyed grad student joke than a science thing...

2007-01-06T15:38:00.000-05:00

The inventor of Instant Ramen and Cup Noodles has passed away. I actually haven't eaten the stuff in ages, because I have a kitchen now. When I was a first-year grad student, I had a case of ramen in my dorm room. I could never handle the whole "flavor packet", though, too salty. Usually I would add about half the packet. Oh, and Chicken Ramen was by far the best-tasting.

Acros starts 2007 off right (in my book, anyway)

2007-01-03T20:38:00.000-05:00

Today, we received an order from Acros that a former postdoc in the group originally placed in 2004 or so. It was one of the lab's occasional multi-bottle orders of 2.5 M n-butyllithium (n-BuLi) in hexanes.
(We order multiple 100 mL bottles, though some of our postdocs come from labs where one of the group jobs was to dole out the new n-BuLi into special sealed bottles from its big container. When I first joined the group, we had some shared 800 mL bottles, but that started to get unwieldy as we got more people.)
Anyway, soon after we placed that 2004 Acros order, we received a backorder notice, and the notices kept coming for a good while. We talked to our university's Fisher customer service rep to get to the bottom of the problem, and I believe we were told that because 2.5 M n-BuLi was manufactured in Europe, there was some new regulation on the books that made it very difficult to ship overseas. We had no problem getting 1.6 M Acros n-BuLi (anybody recall whether the suppliers are different for the two different concentrations?) and those that wanted it ordered 2.5 M n-BuLi from Aldrich (who I believe uses FMC Lithium) as a supplier, so I guess that order was relegated to the back of our heads until now. I have no idea what changed. Maybe some new law took effect Jan 1st (or 3rd, because of Gerald Ford). (**updated that link**) Our Fisher rep is usually around on Thursdays, so maybe I'll run into him tomorrow and find out.
For a trip down memory lane, see this post at Tenderbutton for a high-yield primer on the many ways to use an Aldrich or Acros Sure-Seal. You all remember the password, don't you?

Air out. Titanium tetrachloride in.

2006-12-22T19:22:00.000-05:00

I've been blogging sporadically lately; sorry about that. In the department of simple but really useful ideas, a postdoc in the lab next door is using a vacuum food sealer to package up some moisture-sensitive reagents. I can understand that he probably doesn't want to bother using our glovebox to store chemicals. Happy Chrismahannukwanzaakah to you all, and thanks for reading.

Busting out (cells) all over

2006-12-13T17:08:00.000-05:00

In keeping with the theme of Kyle's hilarious post, I'll throw in my own two cents. A couple of weeks ago some friends from the lab next door went to a Starbucks coffee tasting. It was one of the windiest, rainiest, nastiest nights in a while, so they apparently were the only ones there. By the way, the "Christmas Blend" is the same as the "Holiday Blend", in case you were wondering. Yes, the Starbucks people used a French press. The only nagging question I have is whether there is some cutesy urban legend about the connection between the coffee French press and the French press biologists use to gently crack open cells. Usually, when you want to recover a protein that you have manufactured in lab bacteria, you want a gentle method that won't damage your protein. You may also want to get at intact organelles, or something. In my very minimal protein purification experience, we would rapidly freeze, then thaw cells for a few cycles. For the proteomics I currently do, I use a Dounce homogenizer.
Here's a great basic reference for the ways to bust open cells.
Incidentally, I love Starbucks's eggnog lattes, but going to Starbucks in this town sometimes seems taboo, like you're getting your coffee from the man. Locals seem to prefer Small World coffee, and it's growing on me. Once Starbucks cans its seasonal beverage I might try to make the change permanent. (But yes, Jack, Halo Pub still makes the best mocha.) The Small World coffee tee shirt is one of the default gifts that grad students seem to get when they finish, regardless of whether they frequented the place or even whether they like coffee.

Trying not to use the obvious title joke here..

2006-12-08T15:34:00.000-05:00

I think my favorite science to read about is the type where the central idea is so elegant, you wonder why no one had thought of it already. PCR is like that, and in my mind, so is this recent JACS ASAP.

The ref: JACS 2006, DOI: 10.1021/ja0657307 (subscriber link)

The background:
I was in a bioinorganic/ biophysical chemistry lab a few years back, and the topic of FRET came up a lot. If you're unfamiliar, FRET stands for Förster resonance energy transfer (you'll also see fluorescence resonance energy transfer), and it is a convenient visual tool for measuring distances. This comes in handy when you want to learn more about protein-protein interactions, receptor-ligand interactions, and conformational changes.

You need 2 fluorescent dyes for a FRET experiment. In a simple case, you attach one dye to protein A and the other one to molecule B, and watch for changes in how they interact. If you did everything right, you'll see a different-colored glow depending on whether A is close to B.
Of course, you conscientiously selected your dyes so that their energy profiles overlapped just right. If A and B are close together, when you shine a light that would otherwise make A glow, what you see instead is mostly B glowing. That's because instead of glowing, A is able to hand off its energy to B in a way. That phenomenon is what's called FRET. Read this if you're interested in more details. Also, Lakowicz's Principles of Fluorescence Spectroscopy is an excellent book that discusses the field.

The ACTUAL PAPER:
The authors wanted an easy way to visualize a working enzyme in a living cell in real time. In other words, no additional prep time to wash out excess dyes, or having to bust the cells open to "see" the results.
Rather than bringing in two dyes on two separate molecules, the research team made a probe with two carefully chosen dyes built in.
When the target enzyme is catalytically active, it cleaves a protective group from a phenol to yield a quinone methide. There's a leaving group involved in generating the quinone methide. In this paper, the leaving group was one of the dyes. After the labeling event, the dyes aren't close together anymore, so no more FRET. (I can't remember where the liberated acceptor dye ends up, or whether that was mentioned.) The quinone methide that's left behind is a highly reactive alkylating agent that's known to latch onto any nearby nucleophile in a protein. Bingo, protein labeling and color change in one shot.

Whaddaya think's in the tacos?**

2006-12-06T23:30:00.000-05:00

The E. coli outbreak that swept central Jersey and surrounding states now seems to have been traced to green onions distributed to local Taco Bell restaurants. So, no Jersey jokes allowed.
Cue the renaissance of this 60's hit off the American Graffiti soundtrack.
I'm just glad reporters mostly shied away from the obvious "Run for the Border" headline.
Nothing's been confirmed, but Taco Bell's parent company is pulling all green onions from its shelves. For a slightly propagandistic (is that a word?) briefing on E. coli O157:H7, the virulent strain behind the food poisoning, pick yourself up a copy of Fast Food Nation.
What I remember from college is that this particular variety of E. coli produces a toxin that inhibits protein synthesis in a way similar to ricin, and often results in substantial kidney damage.
When I was a college freshman, we had case studies in our general chemistry course, and the one in the nuclear chemistry chapter was based on the Jack-in-the-Box E. coli outbreak of the 1990's. As I recall, we discussed the background of the case and debated the merits of beef irradiation.
This link about irradiated beef is pretty thought-provoking. Show me a guy who goes to McDonald's to boost his daily intake of essential vitamins, and I'll show you a doctor running a health website who does not believe in vaccinations or mammograms.
Quite a bit of the news coverage for this Taco Bell incident refers to Jack-in-the-Box, more so than the more recent E. coli outbreak in spinach. That doesn't make sense to me unless it's eventually demonstrated that the ground beef in the tacos is to blame. Maybe newswriters just think it's better to compare/ link fast food restaurants in their coverage.
I guess this is just a wake up call to me and any other non-red-meat eaters who are smugly thinking "this won't happen to me". I haven't eaten at Taco Bell in ages, but I got really cozy with arugula earlier this year.

** Hopefully a few people remember the TV show "You Can't Do That on Television"....

Pimp My Instrumentation

2006-11-29T19:52:00.001-05:00

With the arrival of the MacMillan group, change is sweeping our lil' department. We are getting three new NMR spectrometers to complement what we currently have. They won't be ready to use for a little while, but I'm really looking forward to the day when I will no longer have to wait in line to use the instrument and get the data I need to move forward.

NMR is short for Nuclear Magnetic Resonance. An NMR spectrometer is a machine that operates on the same principles as an MRI (magnetic resonance imaging). Don't get worried when you see the word "nuclear"; this instrument's no more dangerous than an MRI (unless you wear a pacemaker). We organic chemists use NMR several times a day to help figure out the chemical structure of the stuff we make.

Non-chemists, all you need to know is that compared to what we had before, this is frickin' sweet.

Now, for specifics:
Our old NMR's are Varian's and the new ones are Bruker's. Having only used Bruker as a biochemistry undergrad taking phosphorus NMR's, I can't really compare the experience. It seems like most organic chemists feel strongly that one is better than the other, and that Jeol is a distant third.
We get a couple of cryoprobes, specifically Bruker's TCI probe and QNP probe. The latter apparently allows users to switch by computer between 4 different nuclei without changing the probe tuning.
Also, we will have probes with heightened carbon sensitivity, meaning you can take a carbon NMR in the same time it would take for a proton (a couple minutes).
These instruments are actually located pretty close together and it's going to take some extra effort on Bruker's part to make sure everything works normally. Bruker may use our department to showcase their Ultrashield NMR's and the compact setup.
Each system is fully automated. We will just drop off our NMR tubes into the autosampler and the instrument will print out a spectrum and email the raw data and pdf of the spectrum to us.
There's a Bruker rep on campus every day setting up this instrument and its software, as well as the 2 other NMR's, which'll be in the next room. More as it develops.

And here's one of our babies as it stands now. (A big thank you to Istvan Pelczer for this photo.)
If you haven't seen one of these instruments before, the magnet in the instrument needs to be kept cold, so it's encased in an insulating metal container that's filled with liquid nitrogen and liquid helium. That's really cold, far below zero.

The big brother I never had

2006-11-22T19:44:00.000-05:00

Early yesterday morning, a few people came by the lab to install temporary mats by some of the hoods. The general idea is to monitor how much time we spend working at the hood each day. The mats sense our weight and record a length of time in a networked "box" just outside the lab. The compiled data get downloaded later.
No, it's not some passive-aggressive move on the part of my funding agency. Princeton Chemistry is breaking ground for a new building soon (our first new home since the Coolidge administration!) and an estimate of our time spent at the hood goes into choosing the best system of new hoods for the new building.
So let me back up a bit here and tell you what a hood is and why I use one.
Fume hoods are a mainstay of the organic chemistry lab. A hood is an enclosed workspace designed so that we can perform our experiments in a space that's fairly isolated from the air we breathe. Air flows up into the hood and away from the lab, sparing us from a lot of noxious fumes and small, potentially lung-coating particles. I work at the hood standing up, though I sometimes sit at a bar-stool height seat. The hoods in our lab are about 6 or 8 feet wide and pretty deep, longer than arm's length for me. They're outfitted with places to secure our flasks, vials, test tubes, whatever. Also in my hood are magnetic plates for stirring and heating, a couple of water taps, and a line for putting reactions under a vacuum or under an inert gas (see my entry on gloveboxes for a reminder about why that's important.)
You can imagine that several hundred of these hoods constantly sucking away air makes it costly to heat and cool a building. There have been improvements in hoods' energy efficiency with new designs, and we will be getting these "improved" hoods in the new building. The MacMillan labs are already equipped with new, energy efficient hoods. I guess they just want to get an idea of the volume of airflow that the we use in a given day, hence the mats.
One problem I see is that I'm not sure whether they are assuming that everyone closes their hood to save energy when they aren't working at them. Wishful thinking in this building. I know I'm not always very good about that.
The mats are about the size of a welcome mat and nondescript gray in color. Not nearly as nice as what I currently have attached to my XBox at home for playing Dance Dance Revolution. (You laugh, but try playing the advanced level. Tell me that's not a good workout.) This is kind of similar to what we got.
Needless to say, the mats spawned a couple of creative strategies in the group for "enhancing" the hour count, from moving our argon tanks on top of the mats to offering extra credit to undergrads to stand there for you.
So basically, it looks like I might soon be able to construct a bar graph like the one Kyle made here.

A Shot in the Arm

2006-11-17T17:01:00.000-05:00

I got my flu vaccine for free last week through Princeton Health Services. To encourage us to get vaccinated, there was an ad blitz campuswide for "FluFest", a two-day event at the student center which featured performances by our a cappella groups and free food.
I won't bother blogging about why you should get your flu vaccine, or complaining about misguided rants, because that's been done to death. Search blogger.com if you don't believe me.
For up-to-date information on the vaccine and the flu, click here to go to the Center for Disease Control's Website.
See here for more details about what's in the vaccine.
The two types of vaccine:
1) The trivalent inactivated influenza vaccine.--> I got this one.
"Trivalent" in this case means that the vaccine provides immunity to three different strains of the flu. The three strains in the vaccine change from year to year, depending on what health professionals have determined to be the most likely ones to be going around that particular flu season.
"Inactivated" means that the virus isn't infectious. You just get the parts of the virus that trick your immune system into doing its job. Mostly, that's the outer coating. It's like the story in the bible about how Jacob fooled his blind father Isaac into giving him the blessing intended for his hairier brother Esau, by wearing hairy goatskins.
2) The live, attenuated influenza vaccine.
"Attenuated" means weakened.
This vaccine is a nasal spray, not an injection.
The modified viruses for both types of the vaccine are grown in chicken eggs. This technology has been around since at least as far back as the 1950's, and it's why people with egg allergies shouldn't be given this kind of flu vaccine.
I searched PubMed for "embryonated hen's egg" and it looks like plenty of things can be grown in chicken eggs, like herpes simplex virus and hepatitis. I wonder why we still use this system. Seems to me like we should be able to make a synthetic, hypoallergenic cocoon for these things to grow by now.

I'll own up to it

2006-11-10T18:04:00.000-05:00

I shattered a dewar for a 500 mL round-bottomed flask today. I was wearing gloves and goggles, the dewar was in my hood at arm's length, and no one was hurt, but the BANG! was so loud that I was trembling for the next five minutes.
Here's a link to Princeton's lab safety website and its recommendations on dewars.
A dewar is an insulated container that I use for my cold baths in the lab. The most common cold bath I use is a mixture of dry ice and acetone, which has a temperature of 78 degrees below zero (Celsius). It's important to run some reactions in the cold to prevent uncontrolled reactivity.
Anyway, this particular dewar is made of glass that is lined with silver. The whole thing is surrounded by aluminum metal. The reason a dewar insulates so well is that it's a double layer flask with a space for a vacuum between the walls.
Dewars implode when they are broken, meaning that they collapse in on themselves instead of exploding outward. However, there's still a risk of small glass particles flying around and injuring someone.
The most famous dewar out there is the humble Thermos that you took to lunch every day in grade school.
In homage to the Tenderbutton style of blogging, I've posted pictures of the dewar so you can see the damage for yourself. I think I needed a better camera for this. The aluminum/ glass reflects light really well and is hard to photograph.
Here's a regular dewar.

Here's my shattered one.

Kids, don't try this at home. We're trained professionals.

Blogger Beta

2006-11-10T17:27:00.000-05:00

I finally made the switch to the beta version of the blogging website. There may be some bugs in the coming weeks (ie, in past weeks, other bloggers have not been able to see or post comments.)
So bear with me.

I Wish I Swore by Something with a Nice Fragrance

2006-11-08T11:28:00.000-05:00

Late fall is upon us, and the inevitable cold weather chapping and cracking of the skin on my hands has begun. The situation is exacerbated by having to wear gloves and wash my hands repeatedly at work. Proguard is a moisturizer that's available from the Fisher catalog, which is a one-stop shopping depot for general lab supplies, as well as direct from the Princeton Chem. stockroom. It is THE ONLY THING that ever keeps my skin from cracking. I use a little every time I wash my hands and it's fantastic; I even bought one for home (Jason wears gloves, too.) I hate to waste money on one of the cute little travel size packages of scented lotion for my purse because I know it'd be purely ornamental. I just throw some Proguard in a travel size case. Ideally, I'd like to be able to take my Proguard to something like The Body Shop and just blend it with any fragrance oil to use outside of lab. Come to think of it, that's something I'll have to try, but I doubt they'd help me out unless I was buying their brand of lotion. Proguard will definitely be one of the things I miss when I graduate. Maybe someone on the inside will be able to hook me up.
Just for fun, I thought I'd do a quick comparison of the main ingredients in Proguard ("P") versus my favorite scented moisturizer (we'll call it "WVS" for short, but those of you who know me should know what I'm talking about). I don't really have any sense of the percent composition of either lotion, because the ingredients are listed in descending order of percentage with no concrete numbers, as they'd be on food. I never stopped to think about moisturizer formulation before. Moisturizers have to multitask on the outermost layers of the skin, repairing damage and sealing in water, without triggering allergies or any other adverse reaction.

emollient (skin softener):
P = cetyl alcohol
WVS = cetyl alcohol, stearyl alcohol, petroleum jelly

silicone oils: (they form a protective layer)
P = dimethicone
WVS = same

humectant (hygroscopic substance, something that absorbs water):
P = sorbitol, propylene glycol
WVS = glycerin, propylene glycol

preservatives:
P = diazolidinyl urea (formaldehyde-releasing goodness!), methyl and propyl paraben, tetrasodium EDTA
WVS = basically the same

the ref: Characterization and chemistry of imidazolidinyl urea and diazolidinyl urea. Contact Dermatitis 2006 54, 50-58.
So all the key ingredients are nearly indistinguishable, but the scented stuff also contains vitamins, which I'm not sure would penetrate deep enough into my skin to do me any good anyway. (Anybody know about those properties for specific vitamins offhand?) The difference in cost is negligible when you factor in the size of the package and assume a little discount for buying in bulk.
With all this newfound knowledge of moisturizers, I'm not sure I buy into the Creme de la Mer craze, what with all their "miracle formula" sales pitch. "Even now, it is not entirely clear how Creme de la Mer works," they say. To me, it seems like the ingredients that work best in moisturizers are pretty cheap (dimethicone can be found in Silly Putty!). Anyhow, for some sciencey-looking stuff (fermentors!), I recommend you click the link labeled "The Miracle" and enjoy the movie.

Belated Halloween Edition

2006-11-06T22:03:00.000-05:00

Porphyrias are a family of relatively rare diseases that present symptoms reminiscent of the characters immortalized by Lon Chaney, Jr. and Bela Lugosi. There's ample discussion in the literature about whether these diseases spawned the myths we recognize today. Porphyria sufferers may have anemia, light sensitivity, and reddish colored urine, or excessive hair growth. The underlying problem has to do with how the body makes and utilizes porphyrin, part of an oxygen-carrying complex in our blood. The molecular underpinnings of the disease are largely unknown, but a recent Nature letter presents evidence that some porphyrias may be due to a defect in a specific protein.
the ref: Nature 2006, 443, 586-589.
This protein, called ABCB6, transports porphyrins to a place where they can bind to iron. This iron-porphyrin combo eventually ends up in hemoglobin. This work points out that it isn't necessarily just the production of porphyrins that's the problem, that getting porphyrins where they need to be so that they can do their job is equally important.
This idea reminds me a little of the distinction between Type I and Type II diabetes. The underlying theme that diseases with the same symptoms could come from "manufacturing" or "distribution" issues must be more common than I realize.
Type I diabetes: decreased or no insulin production
Type II diabetes: insulin's around, but the body isn't responding to it properly
There was supposed to be a chemistry grad student with porphyria beginning in my year, 2002. The department spent a sizable chunk of change renovating an entryway so that she could turn off all lights when she needed to, and they built her a private office and everything. (I think she would've been a computational chemist). She deferred enrollment for a year and then never arrived. Not sure where she is today.

Look, Ma, I'm a Citizen-Journalist

2006-10-26T23:43:00.000-04:00

I drove to Baltimore after work today to attend the National Association of Science Writers' 2006 meeting, Science in Society. There will be seminars with writing tips, networking lunches, and a "science cabaret" featuring what promises to be Lehrer-esque entertainment.
This year, the 500 science writers attending this meeting are going to be driving right into a story. See, when I was driving into Baltimore I was following the directions on the hotel website. Unfortunately, police had cordoned off one of my turn streets, so I had to drive around in circles for a while until I could figure out how to get to where I needed to go. I happened to notice white smoke emanating from manholes in the vicinity of the roadblock.
It turns out that two manhole covers popped open near one of the busiest intersections in the city, possibly due to a leak in a natural gas main. I'm lucky I got here way past rush hour. Reports here and here say that the Maryland Dept. of the Environment found low levels of natural gas using handheld meters. For an 88 page pdf discussing U.S. Department of Energy-sponsored development of a state-of-the-art natural gas detector, click here.
I'm too tired right now to do any back of the napkin math to figure out how much gas pressure would have to have built up to pop a manhole cover. Any takers?
Anyway, no one in the hotel where I'm staying knows what's going on, but maybe by tomorrow something will be in the news. I guarantee someone at this meeting's going to make a story out of it.

My Sincerest Apologies

2006-10-25T08:58:00.000-04:00

Devoted "She Blinded Me with Science" reader Ryan kindly pointed out that I didn't mention Mole Day, which happened on October 23rd. Shame on me. Ryan, did you play "Avogadro's Element Hunt"? It's on yesterday's link to the National Chemistry Week site. The mole is a fundamental unit of measurement in chemistry that lets us relate mass (something we can measure in the laboratory) to an amount of atoms or molecules (which we can't). When following chemical recipes, it's important to get the ratios of ingredients (molecules) correct. The "mole concept" is an extremely valuable tool that I use every day.
And now, for something completely different. One of the first things I learned about in Dr. Pearsall's Intermediate Inorganic Chemistry course was zinc phosphide, AKA "mole killer".

Here's how it works:
Zn₃P_2(s) + 6 HCl_(aq) ---> 3 ZnCl_2(aq) + 2 PH_3(g)

Zinc phosphide reacts with the water and acid in the digestive system, where it breaks down to zinc chloride and phosphine gas. Nice favorable reaction, entropy increases due to gas formation, yadda yadda.

I had scribbled in the margin of my notebook that day and it reads: phosphine, spontaneously flammable in air or moles. I also imagine that a rapidly expanding gas wouldn't be good for the circulatory system, either.
See here for a little more zinc phosphide backstory and information about other rodenticides.

Gold is Hot

2006-10-24T09:49:00.000-04:00

You might think, file that under "tell me something I don't know", but hear me out.
Yesterday, the American Chemical Society e-mailed me (and presumably all of its members with active e-mail accounts) a list of its "Hot Papers" to commemmorate National Chemistry Week. A quick glance at the hot papers in the journals clearly demonstrates gold's versatility as a catalyst and applications in materials science. If you're wondering why anyone would want to waste perfectly good gold on a chemical reaction, keep in mind that while gold is a rare element, it isn't as rare as a couple of other elements that organic chemists have put to good use, like rhodium. By the way, rhodium is often used to plate white gold jewelry.
a general ref: Org. Biomol. Chem. 2005, 3, 387-391.
See also this Tenderbutton commentary about a recent talk by F. Dean Toste, one of this field's more recognizable young researchers.
As a Jersey girl, I'm proud to note that my high school chemistry teacher helped us remember the symbol for the element gold by imitating a stereotypical mobster. I'll let you figure that one out.
The necklace, by the way, is sold in one of the more famous jewelry stores in St. Barts. The cutout is an accurate shape of the island.

Taking the Easy Way Out

2006-10-22T19:01:00.000-04:00

Yesterday, I presented my thesis research in a poster session that was open to the public. The organizers from Princeton's grad student government encouraged us to pitch our posters to a lay audience. Though we weren't really centrally located enough to attract the spillover crowds from the Princeton-Harvard football game, the locals who showed up were genuinely interested and asked questions. And therein lay the problem. Most of the questions I was asked were way beyond the scope of my research, because everyone was more interested in the potential applications of my work than in the work itself.
Maybe I'm being too hard on myself. It's possible that the crowd was already biased toward the biology end of things if they'd heard about the poster session from a relative or friend in the MolBio or EEB departments, who were vastly overrepresented. However, I copped out when I used 3/4 of my jargon-free abstract to describe a biological/medical problem that I thought more people would find familiar. The real challenge for me would have come up with a different way to explain what I do in the lab day in and day out. How do you explain the merits of synthesis to a lay audience? On the poster, I adapted the diagrams you can find on Phil Baran's or Scott Snyder's websites. Using color, I explained how organic chemists like to think backwards and why, if you need variety, it's good to build toward a couple of main components that you can snap together, as opposed to one long process. But it was too late. They'd read the abstract and wanted to know what I thought about the merits of Lysol sprays. I think I got a couple of sparks of interest when I said that many drugs are made using organic synthesis and I described what process chemistry is. It seemed like some people were under the impression that bioengineered bacteria did much of the grunt work.
This is something that'll probably gnaw at me for quite some time, as I struggle to find a voice as someone whose job it is to express why many different areas of science are important and relevant.

Knowing when to fold 'em

2006-10-09T23:59:00.000-04:00

Science news reports that a team based at U.Penn. School of Medicine has found some common ground between Lou Gehrig's disease and a specific kind of dementia. Their results have pinpointed a known protein, TDP-43, as a culprit for the disease, and their work may instigate a reevaluation about how these diseases are studied, in addition to highlighting a potential drug target. TDP-43 is a major player in the signature "clumps" that develop in different locations of the brain during these neurodegenerative illnesses.
Background info: Clumps in brain tissue are generally not good. The place where clumps end up seems to determine which disease will affect a patient. Frontotemporal lobar degeneration is the #2 cause of dementia after Alzheimer's in people under 65. In that case, the clumps hang out in the part of the brain that controls good judgement and good behavior. With Lou Gehrig's disease (aka amyotrophic lateral sclerosis), the problem might be closer to the section controlling motions.
The ref:Science 2006, 314, 130-133.
I guess hindsight must be 20/20 for this research team, because in the past doctors have sometimes seen patients with Lou Gehrig's disease develop this type of dementia, and vice-versa.

Again: The important take-home message is that the final folded state of proteins in the brain is crucial. Proteins usually start out as a chain of amino acids and eventually fold up into an orderly structure. If a protein doesn't fold correctly, chances are it's not going to function correctly, either. This is a theme that happens over and over again, in Alzheimer's, mad cow disease, you name it. What comes to mind for me are all those origami fortune-tellers and paper footballs I folded as a kid. You needed to fold it just right to get a good game of cafeteria table football started. Scientists know very little about how to tell at-a-glance what a protein's folded-up shape will look like. That knowledge would be a major step forward in treating these diseases, and there are several different approaches out there researchers are taking to figure it out.
Off the top of my head:
-You've got the camp that designs proteins from scratch to study what specifically in the amino acid sequence calls out for a given folding pattern.
-You've also got the researchers using computers to attack the question.
-See this recent post at In the Pipeline about a very ambitious Japanese research project that seems to be relying on building a database of structures to search for pattern recognition in the future.
I'll leave you with a factoid that combines Lou Gehrig AND science from my brother, who knows far more about baseball than I ever will (and is probably the only kid who grew up in NJ that is happy the Yankees lost).
The Iron Horse was an engineering major at Columbia.

Nobel Roundup

2006-10-04T10:19:00.000-04:00

The blogosphere lit up this week with rampant Nobel prize-related speculation and oddsmaking. So now that the big three science Nobels have been announced (sorry, economists), let me throw in my two cents.
It looks like RNA-related research projects are the leggings of the science community this fall. (I'll qualify that remark by saying that I have much more hope for the staying power of RNA research). The Nobels in Medicine and Chemistry both involve RNA in some way. You've almost certainly heard of DNA. I'll go out on a limb with an analogy here and liken RNA to DNA's free-spirited daughter. DNA usually is stably linked to another strand of its own kind, and it's always there when RNA is made. RNA is a more transient entity. It moves out of DNA's house in the cell's nucleus pretty quickly and promptly discloses all the family secrets. RNA has also been known to dabble in some funky activites, things like picking up habits from enzymes and dabbling in a little contortion.

The Chemistry prize was awarded for molecular-level snapshots of the "birth" of RNA, a process called transcription. The Medicine Prize was awarded for the discovery of RNA interference, an invaluable method for scientists trying to uncover a gene's function. Much of the media is framing both of the prizes as important for therapeutic applications, but we're still very far away from a real, live drug.

By the way, It seems like the Nobel committee is sweet on structural biology lately. The 2003 Nobel was awarded in part to another X-ray crystallographer. I blogged a little about X-ray crystallography here.

I was proud of myself this year, because I'm no physicist and it's the first time I can remember not having to read up on the science behind the prize. The Physics prize was awarded for work in cosmic microwave background radiation (CMB). Briefly, the CMB is a sort of residual signature of the Big Bang, and studying it has lent further support to the Big Bang theory and shed some more light (no pun intended) into the origins of the universe. I had read about CMB in a book, The Light at the Edge of the Universe, by my former science writing prof, Mike Lemonick. Looks like he has a little dirt on the Physics prize here.

In case you're wondering why I chose the title "Nobel Roundup", it's because I found this little gem while searching for a layperson-level RNA link. Giddyup!

Saturday morning cartoons

2006-09-28T14:20:00.001-04:00

While channel flipping on a recent Saturday morning, I happened upon a children's show called "The Zula Patrol". The characters on the cartoon, who I believe were aliens from the planet Zula, were trying to restore Earth's water supply, which had mysteriously gone missing. Apparently the Hydrogen family and the Oxygen family were embroiled in a Hatfield and McCoy-esque feud and couldn't stand to be near each other, so there was no H₂O anywhere to be found. In the end, Earth's water was recovered. The families got back together for the sake of two of their youngsters, who had fallen in love, or something like that. I can't remember whether the boy was oxygen and the girl was hydrogen, or whether it was the other way around. (I guess the writers tried to resolve the plot while glossing over the fact that the proper ratio is TWO hydrogen atoms to an oxygen atom. Good thing this show is aimed at kindergarteners.)
My impressions:
1) Cool! A TV show about chemistry!
2) Wait a minute. When I was growing up, Saturday morning cartoons were all about violence and slapstick. These kids are getting gypped.
3) I guess I'm a purist, but I don't like slick-looking computer animation as much as the lovingly hand-drawn kind.

I did a little digging on the web, and it turns out that "The Zula Patrol" aims to promote interest and understanding of science concepts to very young children, but also throws lessons in tolerance and advocates nonviolence. It was neat to read credits and see how many Ph.D.'s were involved in producing this cartoon. It looks like I caught one of only two episodes about chemistry-related topics, though. Most of the episodes are about space science, which makes sense given the setting and characters.

Dylan Tenders His Resignation

2006-09-19T11:39:00.000-04:00

I just wanted to salute Dylan Stiles over at Tenderbutton, who has decided to close down his blog over the next couple of months. He really has a gift for writing with panache about what can be a really inaccessible field, and he will be missed. He's certainly leaving on a high note, what with a profile in the Chemical and Engineering Newsblog. Hats off to you, Dylan, and good luck with finishing up your Ph.D.

Maybe I'll get your attention with a list post

2006-09-19T11:24:00.000-04:00

In honor of classes and labs starting up again for fall, and my colleagues in lab running off in the afternoons for their work as TA's (teaching assistants), I present:
"The All Time Top 3 Questions Students Asked Me in the Lab" blog entry.
Because of my funding situation, I've actually never TA'd a lab at Princeton (yes, we use "TA" as a verb). At Princeton, I lectured in weekly recitation/ problem solving sessions called precepts. I TA'd labs as an undergraduate; at my college many of the upperclass chemistry majors helped out around the general chemistry and organic chemistry labs to make a couple extra bucks, because there were no grad students.
Let me preface the list by saying that I thoroughly enjoyed being a TA. In fact, before stumbling onto this science writing gig, I wanted nothing more than to be a professor at a small college, milling about the labs every day. Even the most dedicated TA has to admit that redundant questions can be trying at times. I hope my post will help any gen chem/ orgo students that happen upon it (and maybe give all the current and former lab TA's out there a chuckle.)
If anyone has anything to add to my useful advice, please feel free to do so.
So, without further ado, the list of questions:
3. "Is this a precipitate?"
A precipitate is a product of a chemical reaction that is not soluble in the medium you've used to run the reaction. Precipitates come up in experiments that teach students important chemical concepts, like chemical equilibrium and general solubility properties of the elements. It can be tough to tell whether you've formed a precipitate when you've combined two solutions. It's important to make a note of the appearance of each solution before you combine them, and then compare to what you see afterward. I've seen precipitates range from cloudy white suspensions to yellow powder. Most of the time, the precipitate is more dense than the reaction solvent and sinks to the bottom of the test tube or beaker, but that's not always the case. This website has a couple of images of precipitates.
2. "Is this dry?"
In the organic chemistry lab, drying the solvent is one of the last steps in "working up" the product of the reaction, that is, isolating the product from the reaction medium and reagent byproducts. Many "workups" involve treating the reaction mixture with a solution of a base or an acid in water, and even if your organic solvent doesn't mix with water, there are probably small droplets of water that end up mingling with your solvent. You may be able to notice this if the solution is cloudy, or you see the droplets in there. To get rid of that residual water, we use "drying agents", a salt that absorbs the water. The drying agents I use these days are sodium sulfate and magnesium sulfate. At college, the labs stocked calcium chloride pellets. Regardless of what drying agent you use, the principle is the same.
-Make a note of your solution's appearance before adding drying agent. Is it cloudy?
-Add the drying agent a little at a time to the solution.
-Swirl the solution around for a little while (sodium sulfate is a little slower, so take your time there.)
-Watch for changes in cloudiness. If the solution's still cloudy, add a little more drying agent, etc.
-The best way someone's described how to tell when you're done is to look for "the snowglobe effect". Essentially, if the drying agent absorbs water, it clumps together at the bottom of the flask. If you add a little excess drying agent and the solution's dry, the drying agent swirls around like a snowglobe.
1. "Is this boiling?"
If you're asked this one, resist the urge to wonder whether your student has ever cooked pasta before. The evidence for boiling is usually the appearance of bubbles containing vapor from the liquid that rise to the liquid surface. Sometimes little bubbles form on the very hot bottom of the beaker before the liquid actually starts boiling, but don't be fooled.
See this wikipedia entry for a more detailed entry on boiling.

Finally, I think that the Not Voodoo website is a great resource for lab technique, and Zubrick's "Organic Chem Lab Survival Manual" is pretty good, too. If you're a little more experienced, I like "Advanced Practical Organic Chemistry" by Leonard, Gygo, and Procter.

More to Glove

2006-09-14T11:00:00.000-04:00

I've been using the glove box a lot lately. When my adviser moved to Princeton, he purchased a brand new one for the group with his startup funding from the University. It was one of our most expensive acquisitions, but the cost is well worth it. (Here's how much a used one of these puppies costs.)We use the glove box almost every day, when we work with air and moisture-sensitive materials.
If you were one of those lucky kids whose high school chemistry teacher showed you what happens when sodium metal reacts with water, then you understand the concern with keeping reactive chemicals isolated. Also keep in mind that in terms of flammability, toxicity, and general nastiness, sodium metal is barely even the tip of the iceberg. For example, we have a gas cylinder of trimethylgallium in our glove box. That stuff will ignite spontaneously in air. We don't work with a ton of very dangerous things, though; many of the chemicals we keep in our glove box just stay "fresh" longer than if we were to keep unscrewing the caps and exposing them to air.
The glove box (aka "dry box") is a sealed chamber with a window and an attached pair of arm-length gloves. The gloves are made of a very durable material that doesn't react with or absorb all the nasty chemicals (I'm not sure what the gloves attached to our box are made of... I'm guessing neoprene?) The chamber is filled with a gas that's not very chemically reactive (in our box, it's nitrogen, but apparently you can also use argon or helium). The box also has a vacuum pump and a sensor that detects vanishingly small concentrations of oxygen and water. It also has a gauge to control the gas pressure. Inside the box is a metal catalyst that scavenges residual oxygen, and zeolites to remove water. To get stuff into the box, there are two different-sized antechambers on its right hand side. The principle behind how they work is similar to that of an airlock. Just think of (insert name of your favorite space/ sci fi television show or movie here).
When I used the glovebox this AM, here's (in a nutshell) what I did. The most important thing is to be careful to prevent air and water from contaminating the box. I put my dry glass vial and spatula into the antechamber, and vacuum pumped out all the air/water, then refilled the antechamber with nitrogen. I repeat this a couple of times before it's safe to bring stuff into the box. Once the vial is in the box, I put my gloved hands into the big black gloves, which is annoying for me because the gloves are one size, so they have to be as large as possible. Also, sometimes people sweat in the gloves. I clumsily pick up the chemical from its shelf inside the box and weigh it out with the help of a little electronic gizmo that minimizes static, seal up my vial, and stick it back into the antechamber, where I do another cycle with the vacuum pump and the nitrogen before I can take it back out.
It takes about 45 minutes to do all that, and most of the time is taken up by vacuum pump/ refill cycles. Forty-five minutes to weigh one compound. Please consider this the next time you ask a chemist when he or she is going to graduate.

I try to update periodically

2006-09-01T16:59:00.000-04:00

Back when I was a junior in high school, much of my chemistry-related work entailed memorizing the periodic table. Elements 110 and 111 had been discovered in Darmstadt, Germany around that time, and my science teacher made a rather large fuss about it. My classmates made a rather large fuss about having to memorize one more element. I figured that after memorizing 109, the 110th was just a drop in the bucket, but my logic was lost on them. Unfortunately, these days the pickings are slim when it comes to discovering new elements that are stable. Scientists have isolated the elements that are available to us on earth, things like helium, tin, gold, and mercury. These elements are probably tangible to you; you can imagine a helium tank or some gold-plated jewelry. They're things that hang around; they aren't going anywhere. But elements like 110 and 111 are unstable, they can only survive for tiny fractions of seconds before decomposing to elements like lead. To understand why that is, we have to look at the problem at the atomic level. Every atom contains a nucleus composed of protons and neutrons. Protons have a positive charge and neutrons have no charge. Now, think about what it must take to tightly pack a bunch of protons together. They're all positively charged so they inherently repel, as though you forced together the wrong ends of two magnets. Physicists have described a force that keeps the nucleus from breaking apart, which solves the problem. Or does it?
It turns out that as elements become heavier (bigger than about 82 protons) and more protons are packed into that tiny little nucleus, the repulsion overwhelms the force that keeps the nucleus glued together. The story isn't quite that simple, however. For one thing, the number of neutrons also has an effect on how stable the nucleus is. Physicists have estimated that there are "magic combinations" of protons and neutrons that can confer stability even on superheavy elements. (I use "stability" loosely here. If element 110 and 111 last for only thousandths of a second, a lifetime of a day or two is very stable by comparison!) It's very challenging to do any experiments to verify and refine their calculations, but a paper published in Nature last week took a significant step in this direction.
The ref: Nature 2006 442, 896-899.
By probing how Nobelium (element 102) falls apart, researchers gained a window into the nucleus's underlying structure. They were able to hone in on numbers of protons and neutrons that they believe could exist stably.
I definitely wouldn't invest in Element 111 jewelry anytime soon, though. (Take a look at the periodic table; element 111 is located below copper, silver and gold and is likely to have similar properties.)

Image from http://www.dayah.com/periodic/

Snakes on my blog

2006-08-28T22:21:00.000-04:00

After going to watch "Snakes on a Plane" at my local multiplex, I was inspired to do some fact-checking on the screenplay by running a quick search of the literature.
(Here come the comments about selling out on blog topics too early in my fledgling career.)
My search engine of choice was PubMed, a government service with millions of journal article abstracts searchable by topic, author, etc.
To read about the premise of this cult thriller, click here. In short, the snakes on the plane became extremely aggressive and started attacking people because of a concentrated pheromone that was sprayed onto the passengers' leis. (The plane was en route to LA from Hawaii).
Here are some of the more interesting tidbits I dug up:
the ref: Science 1989, 245, 290-3.
The female pheromone of the Canadian red-sided garter snake is an intricate concoction of nonvolatile saturated and monounsaturated long-chain methyl ketones, and the corresponding male pheromone contains squalene (see figure), a compound I first learned about in my chemistry classes because of its role as a key intermediate in cholesterol biosynthesis.

So, did the mafia goons just spray one chemical onto those leis, or was it an "all purpose pheromone" that would "do it" for all of about twenty or thirty different species of snakes that were wreaking havoc on the plane? The snakes were from all over the world, as the actor playing the snake expert told us numerous times. I'd guess their pheromones were slightly different, but maybe not enough for it to matter?

Another thing: It's counterintuitive to me that pheromones from the opposite sex would trigger aggression. (I know, different strokes for different folks, but still...) It would make more sense that a pheromone from a member of the same sex would get the competitive juices flowing.
A 2002 paper suggests that a certain lizard species relies mainly on scent to determine the gender of an intruder. The authors experimentally manipulated the body markings and odor of the lizards in order to learn more about the interplay between sight and smell. Among other things, they observed that male snakes responded aggressively to a snake that smelled male, even if it was painted to look like a girl.
that ref was: Aggressive Behavior 2002, 28, 154-163.

Does that mean that to minimize confusion, all the snakes on that plane had to be the same sex? Or at the very least, there couldn't be any Black Adders.

I'll stop now, because this may just be the most thought anyone's ever given to the movie after having seen it, and that'll spoil the mood.

Quark Park: All of the Charm, a little of the Strange

2006-08-25T16:38:00.000-04:00

If you're in the Princeton area this fall, be sure to take some time for reflection at Quark Park, an innovative new sculpture garden opening September 8th. I read about the park here, here, and here, and there are plenty of links to other stories at the official Quark Park site.
A quark is one of the most fundamental units that make up matter (all the "stuff" in the universe around us). They're part of what atoms are composed of. (Yes, that's TINY! Quarks can't be seen.) The system that particle physicists came up with for naming quarks is one of the most interesting I've come across. I'm drastically oversimplifying the system (see here for more detail) but quarks can have any one of six "flavors":
up
down
top
bottom
charm
strange
The exhibits interweave the visions of local artists and scientists, and are meant to educate as well as inspire. For example, Princeton President Shirley Tilghman teamed up with a sculptor and an engineer to bring to life the complex networks through which we process smells. U.S. Congressman (and card carrying physicist) Rush Holt joined forces with emeritus physics professor Freeman Dyson and an architect to create a display about alternative forms of energy. The nonprofit group behind the park, Princeton Occasions, is still seeking funding to erect a stage in the park, which will be used for science demos, lectures, and performances. I work with the Chemistry department's outreach program and I think it would be lots of fun to electrocute pickles and make liquid nitrogen ice cream in a garden setting.
Unfortunately, the vacant lot where Quark Park stands is slated for condos in early 2007, so the park is only temporary (until late October or November, say the articles). Visit it while you can!

Platensimycin Redux

2006-08-21T16:28:00.000-04:00

Last Saturday, the Journal of the American Chemical Society published the isolation and structure determination of the natural product antibiotic platensimycin.
The paper can be found here.
I posted about this compound at this link. The new paper demonstrates that the potentially reactive alpha, beta-unsaturated ketone (enone, highlighted in red in figure) does not appear to contribute to platensimycin's chemical mechanism of action, but the conformation of the ring containing the enone does seem to play a role.
Platensimycin adsorbs well to the drying agent magnesium sulfate, perhaps a little too well, because it was impossible to recover product from it. The ortho-hydroxybenzoic acid chelates the magnesium. No problem with sodium sulfate, though. You called it, Jack.

Momma said knock you out

2006-08-20T22:25:00.000-04:00

I didn't want to miss the chance to blog about an anesthesia paper I saw in ACS Chemical Biology. :)
The ref:
ACS Chem. Biol. 2006, 1, 377-384.

A synthetic organic chemist may scoff at the structural simplicity of anesthetics like halothane and isoflurane (see figure), but there's no doubt that the effects they have on our physiology are very complex. These compounds bring on amnesia (unconsciousness/ unawareness), analgesia (pain relief), and paralysis, and all of these effects are completely reversible. When a new anesthetic emerges, it's important to figure out the molecular mechanisms behind its activity, but researchers are still very much in the dark in this area.

It doesn't help matters that these molecules are challenging to work with in the lab. They're volatile (evaporate easily), and they don't have a very strong binding affinity for their target(s). The latter is a good thing since you want your anesthetic to wear off!

There is some data available about binding sites and targets for older anesthetics called haloalkanes (halothane is in this category), but those molecules really aren't used in human patients anymore because of their toxicity profiles. The goal of this paper is to develop a tool to get the same kind of data on the stuff we're actually using, the haloethers (like isoflurane).

To solve the low binding affinity problem, Xi and colleagues designed an isoflurane mimic (see figure) that's photoactivatable. The molecule resembles isoflurane, but it contains some chemical bonds that will break down when you shine light of a certain energy on them. Once that happens, what's left is a reactive species that they anticipated would latch onto a target, allowing them to better examine the interaction.

The conclusion of the paper was that the photoactivatable isoflurane mimic is a valid tool for research in this area. It behaves similarly to isoflurane in the petri dish and in animal tests, and binds to a known isoflurane target in a very similar place.

I did notice a couple of minor nomenclature errors in the paper: Isoflurane is 1-chloro-2,2,2-trifluoroethyl difluoroMETHYL ether, and the analogous correction also goes for desflurane.

The reactive group that the researchers engineered is called a carbene. An explanation of what that is is beyond the scope of this blog, but not of this website. Maybe someone who remembers carbene reactivity better than I do can answer the question they pose in the text: Is there an amino acid residue with which the UV-generated carbene won't react? They propose mutagenesis experiments, and I'm sure you can just buy a kit somewhere that'll take care of that, but there must be some references are already out there on this. The whole train of thought began when they didn't see the expected reactivity with tyrosine. It seems like they're trying to determine whether it's a question of intrinsic reactivity or just the molecule's "fit" in the cavity.

To do: the authors mentioned that the more old-school haloalkane anesthetics like halothane were used to fish out potential targets for interaction through photolabeling in complex mixtures. I'd like to see that experiment done with this analog. This kind of experiment has already been done in many other systems (for example, see here). I guess it just depends on how easily they can incorporate a visualization element.

I work for peanuts

2006-08-10T10:48:00.000-04:00

I visited NYC after work last Saturday and supped at Spice, a Thai restaurant chainlet with a couple of locations in the city (I was on the Upper East Side). The decor was mod and minimalist and the food was great, but we limited our selection because one of my friends is highly allergic to peanuts.
Nature News ran an article a few weeks back that sheds a little more light on the mechanism behind anaphylactic shock. This is the most severe form of allergy, leading to a drop in blood pressure that is fatal if left untreated. We can treat someone who is in shock with a shot of epinephrine ("epi"), but this is more of a patchup; it doesn't get at the root of the problem and it can't prevent shock.
Here's the paper:
J. Clin. Invest. 2006, 116, 2244-2251.
In a nutshell (ha ha), the researchers confirmed previous reports that nitric oxide pathways are responsible, but the source of the nitric oxide wasn't the one they were expecting. They also pinpoint an often-studied signaling pathway (the PI 3-kinase pathway) as one of the orchestrators behind the whole nitric oxide-mediated shock response.
The PI 3-kinase pathway is involved in a large number of fundamental processes in our cells. A kinase is an enzyme that puts a tag (a phosphate group) on some other protein. The body uses phosphate groups as switches, adapters or handles for a ridiculous number of things. It's one of the ways the body physically transfers and amplifies a message. The authors conclude that it might be useful to look at the PI 3-kinase pathway as a way to intercept the shock response.
To demonstrate the involvement of PI 3-kinase, the researchers used wortmannin, my personal favorite inhibitor of PI 3-kinase. Wortmannin is a natural product made by fungi and it reacts with the business end of PI 3-kinase. For the mechanistically minded, I've included a figure.

The PI 3-kinase enzyme has a critical lysine involved in the phosphate transfer reaction, and wortmannin knocks that bad boy out of commission.

Promiscuous G, you're teasing me.

2006-08-09T18:42:00.000-04:00

I read this paper for a literature meeting nearly a month ago and I had meant to blog about it at the time. Here's the reference:
"Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake"
Science 2005, 310, 996-999.
Obestatin is a hormone that suppresses food intake and weight gain in mice (thanks to Harriet for the picture of the cute little mousie), so you can imagine that a lot of news outlets picked up the story when the paper came out last year. The message there was that finding obestatin provides a new drug target that could allow researchers and physicians to rein in that 10 AM candy bar craving in the not-too-distant future.

The work was fascinating to many researchers, not as the next big obesity cure, but because ghrelin and obestation come from the same gene and appear to have opposite effects! (Ghrelin increases body weight in mice.) The paper's authors first had a hunch that obestatin would exist because they performed a computer search of extensive genome sequence data for genes that look like they code for hormones. This touches off a debate on how much of an effect genomics has really had on the way we conduct research. See this post at In the Pipeline for commentary.

When I read this paper, I was drawn to the discovery that obestatin activates something called an "orphan G-protein-coupled receptor". Receptors are proteins that relay signals in the body in order to achieve some downstream effect, like muscle contraction. The human genome sequence has turned up a couple hundred genes that encode "G-protein-coupled receptors", a specific family of receptors with a track record of being valuable drug targets. Researchers don't yet know what interacts with "orphan receptors", but they'd eventually like to correlate them to a particular pathway or disease, so that they can eventually develop new and better drugs. That's why obestatin was such a big deal in the health field.

I guess this paper got me to thinking, "Isn't there a more proactive way to find the ligands (partners) for these orphan receptors instead of just waiting around for someone to publish papers like this one a couple of times a year?"

There are several ways that researchers go about this systematically. Scientists can take a little of the guesswork out of what the ligand is based on how similar the orphan receptor is to the ones we already know. Screening lots of potential partners at once is possible by coupling the receptor-ligand interaction to some kind of readout. The "adapter" they use is a G protein. Yes, these receptors are coupled to a G protein that sends out a message on its behalf. That's where the name "G-protein-coupled receptor" comes from.

So, why a promiscuous G protein? Promiscuous G's can speak for a wide range of receptors. It's much easier to set up the experiment if you don't have to change multiple components. Just get the new receptor that you want to test and all the other pieces are ready to go.

Unfortunately, there's no "universal adapter" quite yet. These screens are used often in drug discovery, but for now, scientists are getting by with an assortment of naturally occurring promiscuous G proteins and a few that they've engineered in the lab, and having to pick the one that works best for their system.

See these refs:
TRENDS Pharmacol. Sci. 2005, 26, 595-602.
Annu. Rev. Pharmacol. Toxicol. 2004, 44, 43-66.
Receptors and Channels 2002, 8, 297-308.
TRENDS Pharmacol. Sci. 2001, 22, 560-564.

Cramming for the test

2006-08-04T10:38:00.000-04:00

Steroids are in the spotlight this weekend, as we prepare for the results from the test of Floyd Landis's "B" sample. The issue at hand: Landis, the American winner of this year's Tour de France, tested positive for testosterone use after stage 17 of the Tour, which is where he mounted a dramatic comeback to retake the lead.

aside: Stephen Colbert's response a few days back, "Of course he tested high for testosterone! He's a red-blooded American!"

Cycling authorities state that Landis had provided a backup urine sample from that stage that is being tested as we speak to confirm the results and rule out contamination, etc. All this drama in a Tour de France already tainted by a doping scandal.

Testing for anabolic steroid abuse is a complicated process. Anabolic, by the way, loosely translates to constructive metabolism, "building up" or "reconstructing". Testosterone occurs naturally in the human body, but the levels vary enough from person to person that it's difficult to gauge what is normal. Instead, authorities test the ratio of testosterone to epitestosterone, nicknamed the T/E ratio. The chemical structures of the two are actually very similar, but right now, it's not clear what function epitestosterone might have. We know a lot about what testosterone does. Amazing what one little -OH group is worth.

There is a much better post here about the intricacies of conditions leading to low epitestosterone, anti-doping legislation and the testing involved.

An alternate test exists which uses mass spectrometry to distinguish synthetic testosterone from natural testosterone. A coworker of mine said that this had been mentioned in a news broadcast (can't remember where) and like good scientists, we were skeptical. Huh? How could that work? The masses should be the same! Turns out, it was just a case of oversimplification. Most people probably couldn't care less about the details, but I hold you to a higher standard, gentle reader.

The mass spectrometer can detect differences in the ratio of the two stable carbon isotopes, 13C and 12C. Isotopes of the same element have slightly different masses. Synthetic testosterone contains less 13C than the naturally occurring kind. Fox News says that most synthetic testosterone comes from soy. This post doesn't mention soybeans specifically, but goes into the details of how different plants end up with different 13C content based on how exactly they take in nutrients from photosynthesis.

The problem I see with measuring a ratio is that Landis's high reading could be due to high testosterone levels or a low excretion of epitestosterone. Also, I would think that if this were a case of doping, why couldn't he just administer epitestosterone, too? Anybody know the pharmacokinetic data for these? Maybe one's excreted much faster?

This paper describes how to use mass spectrometry to detect artificial epitestosterone.
Clinical Chemistry 2002, 48, 629-636.

It takes a little creativity to think of new tests, as there will always be new ways to mask cheating. Slightly off-topic: A college friend wrote her undergrad thesis in collaboration with the NJ State Police; she was trying to find a better way to test for gamma-hydroxybutyrate, a date rape drug.

Another test I thought was cool: Physicians can measure the levels of insulin C-peptide in patients with type 1 diabetes to see whether the pancreas is making any insulin on its own. The insulin that diabetics inject into their bodies is made without C-peptide, because it's not necessary for the insulin to work.

From MedLine Plus:
When insulin is synthesized by the beta cells of the pancreas, it is produced as a large molecule (a propeptide). This molecule is then split into two pieces: insulin and C-peptide. The function of C-peptide is not known.
Normal values in a patient requiring insulin injections indicate that the person's body is still producing some insulin. Normal values in a patient who has low blood sugar indicate that the patient is making too much insulin.
Low values (or no Insulin C-peptide) indicate that the person's pancreas is producing little or no insulin.
--------------------------
Update 8/9/06
I hadn't noticed that In the Pipeline blogged this a few days before. Read the post for some insight as to why the soy plant has a lower 13C content.

Your hairdryer knows more solid state chemistry than you do

2006-07-27T08:39:00.000-04:00

My favorite hairdryer finally kicked it on Wednesday morning, so now I'm in the market for a new one. My old $25 Vidal Sassoon lasted four years, and since then it seems there has been a quantum leap in hairdryer technology. A lot of the high-end and not-so-high-end gadgets feature "Tourmaline Technology". Tourmalines are a family of minerals with a very complex structure that could consist of up to about ten different elements, though all the members have the elements silicon, oxygen, aluminum, and boron in common. I don't know very much about solid state chemistry, but from what I just read, suffice to say that the structure of the mineral endows it with special properties. When heated, charges migrate within the crystals giving you positive charge at one end and negative charge in the other. A hairdryer with tourmaline crystals reduces frizz and static with the help of the charges emitted. Apparently these crystals give off infrared heat, too, but I haven't read anything about that yet. I'm looking forward to the informative pamphlet about the solid state chemistry of tourmalines that I'm certain will be included with my new hairdryer. ;)

The tastiest distillation there is

2006-07-26T23:21:00.000-04:00

Today I purified my product using the lab's Kugelrohr distillation apparatus. Unlike many of the concepts one comes across in the field of chemical synthesis, Kugelrohr distillation isn't named for anyone. Kugelrohr translates to "ball tube" or "ball pipe" in German. It's my favorite way of purifying solids with low melting points. The idea is that by applying a vacuum to a flask (round bottomed, ie ball-shaped) with the impure, oily solid in it, you lower the boiling temperature. If the boiling points of what you want to separate are different enough, the pure product distills over into a receiver flask (also ball-shaped) chilled with ice water.
There are other setups for distilling things, but the Kugelrohr setup is infinitely easier to handle when dealing with solids, IMHO.
Rotating or swiveling the flask gives you a more even boil, and in the early days of this technology this was accomplished using a windshield wiper motor connected to a tube or pipe.
See this reference:

Graeve, R.; Wahl, G. H. J. Chem. Ed. 1964, 41, 279.

Today you can buy a swanktastic Kugelrohr apparatus from Sigma-Aldrich and other fine retailers. The apparatus comes with a hot air oven to warm the impure sample and get it boiling. Just be careful not to heat your sample too much, or you'll char it.

Random thoughts:
Is there any etymological relationship to the tasty treat we call kugel?
I think one of the coolest-sounding named reactions (lots of organic chem. reactions are named after someone) is the Chichibabin reaction. My opinion changes often on this matter.

Lee Silver holds his own

2006-07-25T21:08:00.000-04:00

I finally got around to watching that Colbert Report episode with Prof. Lee Silver (thank you, TiVo!).
It's tough to get a word in edgewise with Colbert, but Silver took the offensive early, countering Colbert's bombast by politely asking him to lay out everything he knows about genetic engineering. "I'll ask the questions here," replied a clearly outmatched Colbert.
I think Silver was able to get his message out about balancing "nature" and "technology". My concern is that when the show describes him as believing that "cloning and gene splicing are the way of the future", that viewers will misunderstand the meaning of the words and mentally catalog Silver in the same cubby as the Raelians.
Anyway, the interview's hilarious. Watch it here.

Curb your enthusiasm?

2006-07-24T17:47:00.000-04:00

A lot of labs in my field are doubtless interested in a newly-reported compound, platensimycin, which showed potent antibacterial activity in the lab against pathogens that are resistant to multiple antibiotics. The structure is certainly intricate, what with five interlocking rings. Here's the reference:

Wang, J. et al. Nature 2006, 441, 358–361.

Researchers at Merck verified that platensimycin, which was isolated from a simple soil microbe in South Africa, inhibits a key enzyme that bacteria use to make fatty acids. This is cool because it's different from a lot of the antibiotics used in the clinic. Researchers realize that it's important to find new classes of antibiotics in order to stem the tide of resistance that's emerged due to widespread, indiscriminate drug use.

It's also significant that platensimycin is a natural product, that is, a compound crafted by an organism found in nature. Over the last ten or fifteen years, pharma companies had moved away from finding inspiration for new drugs in nature, preferring instead large collections of molecules stored in databases because they were more compatible with emerging high-tech discovery methods. (See this article in C&E News.)

I just thought I'd comment on the spate of articles that tout platensimycin as a potential cure for "the superbugs", as the multiply resistant bacteria have come to be called. (ei: See here and here.) My understanding has always been that if a pharmaceutical company publishes their results this early into the discovery process, it is because there are difficulties that are most likely going to prevent it from being a viable candidate. So while they almost certainly patent the compound, the paper puts the knowledge out there and the total syntheses and other studies can commence outside the company.

I think that the message of the Nature paper isn't really, "Hey everybody, here's platensimycin! It'll be the next magic bullet as soon as we test it in humans!" but rather, "Look, there are still useful ideas to be found by going back to nature and hunting in exotic places, instead of just sticking to libraries of compounds. Let's really dedicate some thought to targeting this fatty acid-making pathway. Nature's probably making compounds like platensimycin for a reason, and plus, it may take bacteria longer to adapt to a new kind of antibiotic." Hmmm.. maybe it doesn't sound as newsworthy that way. I do think that Nature got it right in this article, though.

Serotonin is a girl's best friend

2006-07-20T19:47:00.000-04:00

There's a cute profile in this week's Chemical and Engineering News about Raven Hanna, a Yale-trained molecular biophysicist who quit her postdoc to try science writing and eventually founded a company, Made with Molecules, to market her own line of jewelry. Her designs incorporate molecules like serotonin, acetylcholine, and dopamine, basically neurotransmitters that are known to have affect mood, concentration, etc. Neat concept. I myself am the proud owner of a double helix bracelet that I bought during a daylong conference at Cold Spring Harbor Lab. Some of the "DNA Apparel" on the latter website isn't really my cup of tea, but I suppose I'll run out of Christmas gift ideas sooner or later.

You get into Nature your way....

2006-07-19T21:33:00.000-04:00

Excuse the shameless self-promotion here. I've been featured in today's issue of Nature as part of their "Survive in Science" series. The article has advice and anecdotes about switching labs during your graduate career. You'll need to be somewhere with a subscription to the journal in order to view the article.
During my second year at Princeton, just after passing the Generals Exam (that's our qualifying exam), I switched from a biochemistry group to a synthetic organic chem lab, and I described the whole process to Kendall Powell, the freelancer who wrote the story. Kendall was a great interviewer; she was very easy to talk to and she even gave me some tips on breaking into the business.

Double Your Pleasure, Double Your Fun

2006-07-18T17:32:00.000-04:00

Every week, I look up papers about stuff that comes up in group meeting that I’m rusty at or haven’t heard of, and today I stumbled upon these gems while reading about phenol oxidations using hypervalent iodine.

Read:
Tet. Lett. 1988, 29, 677-680.
J. Chem. Soc. Perkin Trans. 1993, 1891-6.

They’re published five years apart, and the data tables are exactly the same, except for one new reaction. The person that ran that reaction wasn’t even granted authorship. The Perkin paper expands on the narrative a little, refers you to a few syntheses where the methodology was employed, and has a new scheme with a proposed mechanism, but no data to back up the proposal. At least it cites the Tet. Lett…

Ice-Nine for Proteins

2006-07-18T10:54:00.000-04:00

The BBC reports that researchers at Imperial College and the University of Surrey have found a material that can initiate formation of high quality protein crystals. The article emphasizes the finding's potential applicability in drug discovery but cautions that it isn't "one size fits all proteins".

I've really just scratched the surface in terms of my reading list, but it's not often I come upon an orphan news story. Perhaps this is a bit esoteric for the rest of the mainstream media outlets, but I was also curious why the report did not come out in January, which is when the article was published in PNAS. There's nothing the BBC says to suggest there's been any new advance since then.
Chayen, N.E.; Saridakis, E.; Sear, R. P. PNAS 2006, 103, 597-601.

*****Protein X-Ray Crystallography in a Nutshell*****
A protein crystal is a repeated array of a protein molecule, packed together in a regular pattern. Scientists in the field of x-ray crystallography bombard protein crystals with radiation and then determine the protein's 3D atomic structure.
This isn't trivial; proteins contain thousands of atoms. Nowadays, computers do much of the heavy lifting in terms of the math involved, but crystallographers guide the process the whole way through.

(See Dylan's blog for a snippet of a "classic" crystallography paper. It was a lot harder back in the day. That was just ONE AMINO ACID!)X-ray crystal structures of proteins can tell scientists how an enzyme works or how proteins interact with one another. Since these structures reveal the nooks and crannies of these proteins, they allow researchers to sculpt drug candidates that fit the mold.
*****

The BBC tidbit was near and dear to my heart, because when I was an undergraduate, I worked on part of my thesis research in a protein crystallography lab at a nearby pharma company. Though I'll be the first to admit that crystallizing an already-solved enzyme with a point mutant near the active site (a place less likely to perturb crystal packing) isn't the most challenging of projects, at the time I was really proud of having accomplished a little body of work that WORKED and provided some useful information.

My understanding is that crystallization remains the rate-determining step of solving structures. Rock candy this ain't. Any advance that provides a better microscopic picture of nucleation, the starting point for crystal formation, is going to be very helpful in the quest to crystallize "stubborn" proteins. It's known that introducing an external solid into the crystallization "broth" can produce better-ordered crystals. The material Chayen et al. found works because it has a wide distribution of pore sizes and shapes, making it more likely that a given pore will convince protein molecules to stick around and nucleate. If I had more time on my hands, I would check up on the proteins they crystallized using their method and see how diverse they are, or if any were known to be particularly challenging by traditional methods.

PS: The title refers to a material made up for Vonnegut's "Cat's Cradle". Ice-nine was supposed to be a high-melting allotope of water that would act as a "seed crystal" and instantly solidify your afternoon tea, and even (for those with visions of world domination) entire bodies of water.

Lee Silver on tonight's Colbert Report

2006-07-17T22:22:00.000-04:00

Tonight's Colbert Report will feature Princeton Molecular Biology's own Professor Lee Silver!
Incidentally, the Colbert Report is one of my favorite shows; I've been following Stephen's career since he was a brash but intrepid correspondent on The Daily Show. He's come so far, and made me so proud (tear).
I haven't read Lee Silver's book, but as the reviews encapsulate it, the book seeks to turn on its head the notion that what is natural necessarily equates to what is good, and explains that roadblocks to scientific advances are being put up from the political left just as much as from the right.
Read this article at The Scientist Magazine for more info.
Anyhow, my TiVo's set; it should be an interesting chat with Colbert about Silver's new book (no doubt he'll be gleeful that the left is getting an earful from Silver). I'll be sure to blog about my thoughts afterward.

Science Diet

2006-07-16T22:04:00.000-04:00

I've been influenced, nay, inspired, by the science-y and oft humorous commentary I read on a near-daily basis. Here's my own small contribution to the blogosphere. Take it for what you will.