Flourescent Protein Timers

Since Reed doesn't have a subscription to Nature Chemical Biology (I guess I could Interlibrary loan it if I'm really curious--but I still find that incredibly annoying), I'm stuck reading other blogger's accounts of the cool research in there. Like florescent proteins that work as a timer. As far as I can tell, they change color temporally, making them potentially a really powerful tool for cellular tagging and localization studies.

Seriously, though

Apologies for posting here so much; I'm on the last few days of winter break and have the time to do so, I suppose and I'm going a little stirr-crazy.

I was wondering if there are better RSS feeds than the one I have for PNAS, Nature, and Science. All of my ACS journal feeds are quite nice; it gives a full abstract as well as a graphical abstract and makes browsing really easy. And I recently managed to dig up a better feed for Angewandte Chemie (mostly due to reading chemistry blogs of other science people who spend far too much of their life on the interwebs). But I can't find an RSS feed for Cell, and Nature, PNAS and Science suck. No abstract, no nothing but the title and authors. Do biologists spend less time dicking around on the internet? I doubt it. There is way too much down time in molecular biology for that to be true. I gotta do some surfing around to find them.

Unrelated, but I also found it interesting that there was an extensive review article about RNA interference in Angewandte Chemie the other day. The borders of biology and chemistry are becoming very fuzzy indeed.

On Chemical Biology

So I think I mentioned earlier that I'm pretty sure I don't want to go into traditional biochemistry or structural biology because it's not exactly biology-meets-chemistry, it's kind of it's own thing. Here's excerpts from a PDF that I found on the UCSF website somewhere on one of their chemical biology pages:

Is there a problem?
Chemistry is a very mature science compared to biology.
Chemistry graduates continue to grow overall but at modest rates compared to biology graduates. What is making this happen?

...

What is Chemical Biology?
A paradigm shift in allowing scientists systematic access to chemical tools to probe important problems in biology.
It is not the same as biochemistry which uses chemical principles to probe biological molecules.
It is not the same as chemistry which is focused on synthesis and properties of small molecules.
It is not the same as molecular biology which modifies biomolecules to probe cells.

...

"It is different than molecular biology with the use of small molecules to probe biology offering numerous advantages to gene knockout and siRNA knock- downs, the modern tools used by molecular biologists. Proteins contain multiple functional sites and these"ablative tools" do not allow one to dissect individual functions. Moreover, cell signaling events occur quickly often with time-scales on the order of minutes. siRNA usually requires >24 hours to have its maximal effect and even then it usually only ablates 60-80% of the protein. Gene knockouts represent constitutive inactivation, unlike the acute inactivation that can be generated by a small molecule. Not surprisingly these different probes often generated different results. Small molecules represent rapid and dose-dependent probes of cellular function and the information that is generated is more relevant to drug discovery."

This is all very appealing to me. I'm all about small molecules and how they apply to biological systems. That, in my mind, is chemistry-meets-biology. I guess my main problem was that I read a lot of chemical biology papers that felt very...artificial. I think I describe it as "interdisciplinary for the sake of being interdisciplinary rather than having a point" somewhere on this blog, if not, if you know me in person those words definitely have come out of my mouth.

But I guess a lot of that has to do with the fact that trying to define chemical biology as a field is pretty new. I mean, the essence of what it is has been around for a long time called by different names. There has always been a chemistry-biology interface and medicinal chemistry has always been on it; this isn't exactly new. But defining this interface as a true discipline is, and trying to work more on the interplay between in vitro and in vivo with small molecules is definitely new.

I just need to find a corner of it that I feel like has a point and not, like, spend my life making aptamers that will never ever compete with real antibodies unless I find them to be extremely structurally interesting. Not that that is exactly a waste of time per say, just it doesn't seem satisfying to me. There's a lot of room to grow in this discipline, and I think interdisciplinary science is the way of the future.

Molecular imaging

The article in PNAS about using magnetic resonance to visualize a virus (which I originally heard about from Derek Lowe's blog In the Pipeline) seems to hit everywhere. I saw it in Nature News, and even in the New York Times. If you look at the image side to side with the electron micrograph, the quality of the image is spectacular. There's even talk about the idea of single-cell MRIs not being too far out of the realm of possibilities in the next ten, twenty years. Wouldn't that be fantastic?

It makes me wonder if crystallography is going to become obsolete at some point in my lifetime. Getting proteins to crystallize is time consuming and difficult (not that I have ever done it!). Not all proteins crystallize and then there's the whole issue of whether the crystallized conformation is really even biologically relevant or whether the crystal is good enough to justify a model, etc. etc. If biophysical imaging techniques at the nanoscale keep getting better and better, who knows what we'll be able to do in structural biology. All that time and energy spent trying to crystallize a protein can be spent studying structure at a different level. It could even be like the boom in the complexity of synthetic organic chemistry and natural products synth after high resolution NMR became widely available.

Maybe being able to read NMR spectra all together will become obsolete and we'll just pull up 3D images of the compounds on the computer after making something in lab. Who knows.

The scientific world is going to be so fantastic by the time I get to really enter it.

Education

There seems to be two camps of thinking about course decisions in my major. Biochem majors have a lot of requirements; it's the nature of being interdisciplinary. Some people in my major say "I'm probably going to grad school, I'm probably going to be thinking about science for the rest of my life and in a lab for the rest of my life, while I'm in undergrad I might as well take as much liberal arts stuff as I can." This seems legit, and this seems like where I thought I would be. After all, I'm the one who nearly didn't take gen chem my freshman year because I was ambivalent about the idea of studying science at a liberal arts school (and thought I was going to be just a biology major since I abhorred chemistry in high school). I get where that side's coming from.

But somehow, somewhere along the lines, I changed. I can't get enough science coursework. It's very strange. Every semester, there's another elective class that really want to take. Last semester I took advanced synthetic organic and a biochemistry seminar that fulfilled no graduation requirements. Next semester I'm taking advanced mechanistic organic, intro inorganic, and a biology seminar all of which do not fulfill any requirements. What is wrong with me? Am I becoming unbalanced?

And here's the thing: I love literature. I love music. I love history. I'd like to take some economics. I took a great religion class freshman year. I read novels and non-fiction unrelated to science voraciously during breaks. I like liberal arts classes, and there are any number of other things I am interested in beyond chemistry and biology.

So what changed? I guess part of it has to do with slogging through so much intro coursework to get here. Intro bio, intro chem, intro physics, even organic (as much as I liked it) was essentially an intro class. Now I am finally qualified to take small upper-level courses in my major with people who are serious about the subject matter, especially in elective courses. I know the professors and they know me, and it is all around a great experience usually. Seminars are great because they are more like journal clubs than classes. But you can't take those sorts of classes until you have the background.

The other thing is that I'm just do damn interested in everything. I seriously wish I could double chemistry & biology. It's the same side of me that wishes I could take everything under the sun that is not science that wants to take everything I can take in the two departments. Of courses, taking everything I would like to take is just simply impossible, but so it goes.

I'm also still discovering what exactly my scientific interests actually are. There's so much I just simply do not know, and the more I learn, the more I figure out what exactly it is that grabs me. For example, realizing that biochemistry is kind of it's own thing, and not exactly biology-meets-chemistry. Which is fine, great to learn about, and not what I want to do ultimately.

Sometimes I wonder, though, if I am jipping myself out of my last shot at taking liberal arts courses?

More on Watson

Actually, I take some of that last post back. Tying in that old reference from Chargoff that everyone else had forgotten was pretty clever. Also, saying that Linus Pauling's three helix model was a bunch of BS took balls (I mean, seriously, he's Linus Pauling). I guess he did have several moments of important insight that took the biophysical and biochemical data to incorporate it into a coherent model. I guess I shouldn't necessarily undervalue the big picture thinking. (I think I tend to do that because I tend to see big picture more intuitively than little details, and I immediately assume that the little details are always undervalued because they are harder for me personally. I suppose there are other people who feel like it's the opposite.)

He also took back some of what he said about Rosalind Franklin:

Rosy showed Francis her data, and for the first time he was able to see how foolproof was her assertion that the sugar-phosphate backbone was on the outside of the molecule. Her past uncompromising statements on this matter thus reflected first-rate science, not the outpourings of a misguided feminist.

Obviously affecting Rosy's transformation [in regards to the acceptance of the double helix model, which she had previously vehemently opposed] was her appreciation that our past hooting about model building represented a serious approach to science, not the easy resort of slackers who wanted to avoid the hard work necessitated by an honest scientific career. It also became apart that Rosy's difficulties with Maurice and Randall were connected with her understandable need for being an equal to the people she worked with. Son after her entry to the King's lab, she ad rebelled against its hierarchical character, taking offense because her first-rate crystallographic ability was not given formal recognition.

...Since my initial impressions of her, both scientific and personal (as recorded in early pages of this book) were often wrong, I want to say something of her achievements. The X-ray work she did at King's is increasingly regarded as superb. The sorting out of A forms and B forms, by itself, would have made her reputation; even better was her 1952 demonstration using Patterson superposition methods, that the phosphate group must be on the outside of the DNA molecule...

...we both [he and Crick] came to appreciate her great personal honesty and generosity, realizing years too late the struggles that the intelligent woman faces to be accepted by a scientific world which often regards women as mere diversions from serious thinking. Rosalind's exemplary courage and integrity where apparent to all, when, knowing she was mortally ill, she did not complain but continued working on a high level until a few weeks before her death.

Still a sexist (the woman had to prove herself to not only be competent, but first-rate, to be taken at all seriously), but the memoir was also meant to be told to reflect how they went through the process of figuring out the structure of the double helix, and those were his first impressions of her.

Interesting fellow, even if he is a raging bigot.

On Watson, Sexism, and Intellectual Laziness

I'm reading James Watson's account of discovering the structure of DNA with Francis Crick in his memoir The Double Helix. Watson has always struck me as kind of a racist d-bag, and I know part of it is being a man of his times. But the sexism is also killing me, just in how he talks about Rosalind Franklin:

...Maurice, a beginner in X-ray diffraction work, wanted some professional help and hoped that Rosy, a trained crystallographer, could speed up his research. Rosy, however, did not see the situation this way. She claimed that she had been given DNA for her own problem and would not think of herself as Maurice's assistant.

I suspect that in the beginning Maurice hoped that Rosy would calm down. Yet mere inspection suggested she would not easily bend. By choice she did not emphasize her feminine qualities. Though her features were strong, she was not unattractive and might have been quite stunning had she ever taken even a mild interest in clothes. This she did not. There was never lipstick to contrast with her straight black hair, while at the age of thirty-one her dresses showed all the imagination of English blue-stocking adolescents. So it was quite easy to imagine her the product of an unsatisfied mother who unduly stressed the desirability of professional careers that could save bright girls from dull marriages to dull men...

Clearly Rosy had to go or be put in her place. The former was obviously preferable because, given her belligerent moods, it would be very difficult for Maurice to maintain a dominant position that would allow him to think unhindered about DNA. Not that at times he didn't see some reason for her complaints--King's had two combination rooms, one for me, the other for women, certainly a thing of the past. But he was not responsible and it was no pleasure to bear the cross for the added barb that the women's combination room had remained dingily pokey whereas money had been spent to make life agreeable for him and his friends when they had their morning coffee.

Unfortunately, Maurice could not see any decent way to give Rosy the boot. To start she had been given to think she had a position for several years. Also, there was no denying she had a good brain. If she could only keep her emotions under control, there would be a good chance she could really help him...

...The real problem-then, was Rosy. The thought could not be avoided that the best home for a feminist was in another person's lab.

...Naturally I was delighted when Maurice said I would be welcome at Rosy's talk. For the first time I had a real incentive to learn some crystallography: I did not want Rosy to speak over my head.

We have certainly come a long way, that's for sure in terms of women in the sciences. I know sexism still exists (especially in regards to getting a post-doc and tenure with respect to wanting to have a family), but thank god for scientists like Franklin who cleared the way for us today.

The other thing that bothers me about Watson is that he seems intellectually lazy. He describes himself as a "mathematically deficient biologist" and claims to have never taken any organic chemistry or advanced chemistry or physics in college at all:

My interest in DNA had grown out of a desire, first picked up while a senior in college, to learn what the gene was. Later, in graduate school, it was my hope that the gene might be solved without my learning any chemistry. This wish partially arose from laziness since as an undergraduate at the University of Chicago, I was principally interested in birds and managed to avoid taking any chemistry or physics courses which looked of even medium difficulty. Briefly, the Indiana biochemists encouraged me to learn organic chemistry, but after I used a Bunsen burner to warm up some benzene, I was relieved from further true chemistry. It was safer to turn out an uneducated Ph.D. than to risk another explosion.

He goes on and on about how Crick understood the math and theory behind crystallography, and how he only acquainted himself with it on descriptive terms because it bored him to learn anything about biophysics or biochemistry. He talks about how studying the metabolism of the bases is boring, and how basically all biochemistry and organic chemistry is boring unless it applies to the gene.

He makes a good point when he talks about Linus' Pauling's discovery of the alpha-helix, which Pauling did on descriptive terms before confirming it theoretically; that playing with modeling kits and pictures can be a useful way to understand structural biochemistry and biophysics. It's not inherently the fact that he relies on descriptive terms that bothers me. After all, I operate on a diagrammatic, descriptive level and am aware of the fact that I don't understand most of the math that the computer does for me. A professor that came to give a chem talk at Reed once made the good point that you don't need to understand hardcore physical and quantum chemistry to have a good chemical intuition about reactivity; for example, understanding steric hindrance, ring strain, and favorable conformations are all things we tend to do at a descriptive level, even if there are computational reasons to back up the chemical intuition. So some scientists are quantitative types and others are more qualitative types, and yeah, it takes all different types to solve problems in science, fine. It's just this total irreverence for the fact that other fields are interesting and worth learning about that gets to me. I hate intellectual laziness. It's one thing to be deficient in some areas in your background--no one knows everything. It's a completely different to not be intellectually curious enough to want to know more about things you don't know much about.

Watson doesn't really seem like a complete genius. He seems like a guy who was really really into this one pet issue and was determined and lucky enough to fall into a crowd of exciting and talented people (like Crick, Rosalind Franklin, and Linus Pauling) who actually were brilliant. It angers me that Watson can be such a bumfuck, and Rosalind Franklin can be off in the lab, being brilliant, giving herself cancer, only to be viewed as a tool for the boys to understand DNA. She made it her project because she wanted to understand the structure of DNA too, not because she was trying to be spiteful and difficult. They just assume that they can use her expertise and her intellectual contributions as if she is just technical support.

This book is fascinating from a history of science perspective because he writes in his unabashedly caddish way about it all. About the politics and personalities of these people you read about in textbooks. About a time when science was even more of an old boys club than it is now.

Also, maybe you don't need to be brilliant to be a Nobel laureate, you just need to be mildly creative and fall into a good in-crowd.