Friday, December 7, 2007

Google is Amazing..."So what is it again you did in grad school?"

The other day, Erin asked me "So what is it you did again in grad school?" To be honest, it was hard for me to remember too. So I started poking around Google's site. They have quite a few "focused" search engines, one being called the "Scholar" search engine. I typed in my name to see if I could find my paper so I could explain what it was I did, cause it's hard to remember...sure enough, I found my paper.


Paper on Crystal Structure of Human Telomere DNA

Reading this paper brought back a lot of memories, and really made me appreciate completing that paper for reasons I will never be able to fully describe. But if you will allow an old man to share his memories with you, I would like tell you why an "ACCCT Telomeric DNA repeat is potentially important" based on what I learned at WSU (Go Cougs!).

When I entered Washington State's Ph.D. program for Biochemistry, I started my thesis work with Dr. Kang in his x-ray cystallography lab. In a nutshell, x-ray crystallography is a scientific method, whereby you shoot high-energy x-rays through a crystal of biological material (DNA, RNA, protein, etc.) It's no different than sitting in the dentist chair and getting your teeth x-rayed, for lack of a better analogy. After shooting the x-ray energy at the crystal, an x-ray diffraction pattern is produced. The most famous diffraction pattern is Watson-Crick/Rosalind Franklin's DNA diffraction pattern, which allowed them to later determine the structure of DNA as an alpha helix. (It wasn't the guys, it was a really smart woman who determined the structure of DNA...funny how they don't tell you that in school.)

The diffraction pattern that is generated represents an electron density map that you then used computer algorithms to solve the structure of the biological entity (DNA, etc) you are analyzing. The promise is that if you can determine the structure of a biological molecule, you may be able to design a drug that can interact with the target to effect a function (think "enzyme is involved in cancer progression --> this bad enzyme's structure or active site has a hole shaped like a triangle, lets design a bunch of drugs shaped like a triangle and see if it blocks the bad enzyme --> maybe this will slow down progression of disease because blocking site will make enzyme inactive").

So we purified a solution of the DNA repeating unit "ACCCT" which is present in all human chromosomal DNA. In fact, this particular repeat is present in the telomeres of human chromosomes. Telomeres are the tips or ends of chromosomes (see cartoon below). These telomeres are important because telomeres shorten during DNA replication, which occurs when a cell divides. At some point, the telomeres become too short, and the cell can no longer divide. At that point, a cell dies.

Guess what cells have telomeres that, for some reason, don't shorten??? Here's a hint, what cells are immortal, and characterized by uncontrolled growth??

Cancer cells.

So the thought is if you can understand the structure of telomeres, or the enzyme that keeps repairing and lengthening telomeres everytime DNA replicates, then you can design a drug that prevents this enzyme from working. Cancer cells die, and that's a good thing.

I'm oversimplifying things, because there are a lot of really smart people who are working on this therapeutic approach to treating cancer. The takeaway from solving the structure of ACCCT is that people think of DNA as a static molecule, but in fact, as the structure of ACCCT shows, unorthodox, but energetically favorable binding can occur between DNA base pairs. This higher order binding creates a "supersecondary" structure to DNA that perhaps stabilizes telomeric end units in chromosomes. Perhaps the enzyme that interacts with telomeres recognizes this supersecondary structure, or perhaps this non-traditional structure protects the ends from degradation and shortening. Only time will tell.

This was probably one of the most intellectually stimulating things I have ever been fortunate to do. Makes the portfolio asset allocation models we run at work seem a bit boring...

Cartoon Diagram of Telomeres















Link to NYTimes Interview with Grandmother of Telomere Biology Field:

Picture of a crystal, seen from under a microscope. To prepare the crystal for xray, you stand in a cold room, and use a 0.5mm glass capillary tube to grab one of these suckers and then stick on the x-ray machine.

Example of a diffraction pattern produced after shooting x-ray energy through a biological molecule...This particular diffraction pattern is the famous DNA pattern that Rosalind Franklin generated from DNA. Watson and Crick then used it to subsequently become famous...pretty unfair if you ask me.

Example of an electron denisty map around the carbon backbone of a molecule. It's a stereogram, so if you stare at it long enough, you'll see it in 3-D. (Like the popular "Magic Eye" posters, sans dolphin or dinosaur...) For ACCCT, I sat in front of a computer monitor with 3-D goggles to fit the structure to the density map my cystal generated.

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