Telomerase: Solving the High-Resolution Structure!
Since we reached our initial goal of $5,000 so quickly, we are going to go for a "push goal" of $10,000. This will allow us to buy a "block" of electron microscope time instead of buying it à la carte, therefore giving us more bang for our buck! Thanks everyone!
What is a telomere?
Each cell has a timer that says how many times it can divide, and this timer is called a telomere. You can think of it like the little plastic tip that seals the end of your shoelace. This little tip, known as an aglet, prevents the shoelace from fraying; a telomere is the DNA "tip" that prevents a chromosome from fraying.
Each time a cell divides, the telomere shortens by a set amount so that most cells in your body can only divide ~50 times before the end of the chromosome unravels.
So, what happens when a chromosome unravels?
Two major things. Obviously, important data stored near the end of the chromosome are lost, and second, things that clamp onto the telomere start floating around. That doesn’t sound too good, does it? It's not, and the cell freaks out! “Oh geez, all these telomere binding proteins are floating around, and I suddenly forgot how to make important things!" At this point, the cell throws up its hands and says, “Ok, I’m going to just stop doing anything and sit here.”
This is called cellular senescence, kind of like cellular “retirement”, which is the first thing that happens when a telomere gets too short. Eventually the cell either dies by committing suicide (apoptosis), or it just lives out the rest of its life telling stories that don’t go anywhere. This is how things work the VAST majority of the time...
OK, but what happens the other times? Cancer.
Normally your cells work together in harmony, with certain cells “retiring” after a set amount of time. This allows younger cells to "enter the workforce". But what happens if a cell decides, unilaterally, to just keep on dividing selfishly? That's cancer in a nutshell.
How does a cancer cell prevent its telomere from shortening?
Well, they have a little machine—an enzyme called telomerase—that elongates the telomere. After each division, this little machine comes along and adds DNA bases, which allows the cell to divide forever.
So if we stop telomerase, will that stop cancer?
The answer is probably. There are drugs being developed right now to do that, but the developers of these drugs are currently “shooting in the dark”.
What do I mean by shooting in the dark?
Most drugs are small molecules that exploit weaknesses in huge enzymes, and designing a drug is a lot like trying to find a single, 3-dimentional puzzle piece that fits into a 500 piece puzzle that is constantly moving. Imagine how much easier it would be to find that piece if you knew what the completed puzzle looked like? That is exactly what we are proposing: we want to figure out exactly what telomerase looks like.
Well, we recently solved the structure of Tetrahymena telomerase, which was published in Nature a couple months ago at ~25Å. And a recent publication has shown drugs that inhibit telomerase in Tetrahymena also frequently inhibit telomerase in humans. This further makes Tetrahymena a great model system for telomerase study.
What your donations will be used for.
To use the EM facility costs an hourly rate. Along with the supplies for making the samples and the instruments used to get them ready for analysis, the costs are quite high. Your donations will directly fund our time on the microscope and the supplies required to prepare the samples for analysis.
We are so excited about getting the high-resolution structure that we can hardly breathe! Any help you can give will lead directly to increasing the resolution, and so really you are helping acquire the structure too! Thank you so much!
For updates, check back here, your email, and r/solvethestructure.