Protein Angst

Wednesday, July 27, 2005

Harry Potter and the Order of the T Cells

Today, I bring you a story of why science is awesome. It is the story of Dr. K. George Chandy at the University of California at Irvine. I'll try to keep the technical terms to a minimum.

Our story begins about twenty years ago, when Dr. Chandy finds that T cells express Kv1.3, a potassium channel.

T cells are part of your immune system. They recognize things in your body that don't belong, and then they kill the crap out of them. There are three types of T cells important to this story. First, we have the naive T cells. As their name implies, they're pretty ignorant. They don't know anything. Once they encounter something potentially dangerous (an antigen), however, they become memory T cells. They remember what these foreign invaders look like so that, if they return, they're ready to kick them out again. Finally, there are effector memory T cells. These cells not only remember what invaders look like, but they will attack them themselves.

Now, see, in a normal, healthy person, there's no reason to have a bunch of effector memory T cells. You would only have a large supply if you were fighting a chronic infection, something that required a constant battle, something that demanded your immune system get involved.

Like, Dr. Chandy thinks, an autoimmune disorder. Multiple sclerosis, Type I diabetes, rheumatoid arthritis, etc. All these diseases have the immune system turning on itself, fighting foreign invaders that are actually the body's own tissue.

So he takes a look at the model. For a T cell to be activated, it must first recognize the antigen. When it docks with this cell, it triggers a release of intracellular calcium. But this isn't enough calcium for it to get jiggy with it, so it turns to Calcium Release Activated Calcium (CRAC), a channel that will allow more calcium into the cell.

There's a small problem, though. Calcium is positively charged, and since you've got all this calcium coming in, you need to get rid of some other positively charged ion to balance things out. This is where potassium channels come in. A T cell has two: Kv1.3 and KCa-something-or-other. In fact, we'll just call them Kv1.3 and The Other One. The key point here is that in order for this T cell to function, it needs at least one of these potassium channels.

Now, Dr. Chandy has this crazy theory, see. He thinks you can preferentially target the effector memory T cells (the ones actually responsible for hurting you if you have an autoimmune disorder) without taking out the naive and memory T cells (the ones responsible for protecting you).

So, to prove he's not on CRAC, he measures the expression of Kv1.3 and The Other One in all three cell types. And as it turns out, all three cells have fairly low expression of both channels when they're not activated. *yawn*

But! When the naive and memory T cells are activated, they make a whole lot more of The Other One. Effector memory T cells, on the other hand? Make a whole lot more of Kv1.3. That means if you block Kv1.3, effector memory T cells can't function because they don't have enough of The Other One to compensate, and the regular T cells can survive just fine with The Other One.

Dr. Chandy does about fifty thousand more experiments, and they all confirm his hypothesis. Blocking Kv1.3 is a totally awesome idea for fighting autoimmune disorders.

So he goes to the drug companies and asks them to make him a Kv1.3-specific inhibitor. And they all fail. One kills the mouse within ten minutes. One gives it heart problems. Others just aren't specific enough. Come on, drug companies!

Then one day he comes across an article in The Lancet from, like, 1983. This woman with multiple sclerosis was stung by a scorpion. And for about a day, she was kind of sick and all from being stung by a scorpion.

But then? Her multiple sclerosis symptoms went away. For two whole months, she was symptom-free. Or maybe it was two whole weeks. Then her symptoms came back, however.

Clearly, Dr. Chandy thinks, there was something in that venom. So he spends the next few years looking at venomous beasties, trying to find a Kv1.3 inhibitor.


No, seriously. A sea anemone from Cuba. It has this peptide that blocks Kv1.3 like whoa. It's like it was designed to sit right in the pore, held by the four subunits. The modeling they've done is just ridiculous. They know basically every interaction, and so they tack on an extra bit o' stuff to make it even more specific for Kv1.3 in the effector memory T cells. We're talking hundred- and thousand-fold specificity here.

So he starts playing with a mouse model. He gives some mice multiple sclerosis, and they exhibit symptoms and then die. He gives some mice multiple sclerosis, and he gives them this peptide, and they don't exhibit symptoms and then don't die. He can totally keep the mice from progressing to the full-fledged disease. Look, you can even watch the mice yourself, if you have PowerPoint.

Now, so far, he can't magically make the disease go away; he envisions it as an injection once a week or every two weeks for possibly the rest of your days. And he hasn't played with mouse models of the other autoimmune disorders to see whether this peptide could be a beautiful catch-all. But he's hoping for human tests within two or three years.

To sum up, then: intelligently constructed model -> wacky hypothesis -> wackily supported hypothesis -> unsuccessful drug companies -> crazy scorpion story from 1983 -> OMG SEA ANEMONE FROM CUBA -> magical peptide -> wonder drug.

And that is why science is awesome.