Sunday, September 26, 2010

What Have I Been Up To?

I haven't posted for a while. That's because I've become obsessed with my work in the lab, to the neglect of other aspects of life; a real lab rat.

When folks ask me to give an indication of my pursuits in the lab, it's often difficult to respond. As with many fields, layers of understanding are built on layers of understanding. How does one simplify this knowledge for the non-specialist? Well, with the aid of Joan Miro ("Harlequin's Carnival"), I'll try.

In the realm where humans operate, manipulating objects in a narrow range of size and mass and speed, mostly in a gaseous medium, keys don't spontaneously diffuse into locks, opening doors, allowing 100,000 balloons to occupy the room. The balloons are then not removed by grasping tendrils that emerge from the wall sockets, and all the above doesn't occur in less than a second.

But appearances change a bit in the tiny, enclosed, fluid environment of a cell. There, the size of a water molecule actually makes a difference. It's zigging and zagging at about 600 meters per second. Some say Einstein's observation of little pollen grains getting zigged and zagged by the zigging and zagging of water molecules ("brownian motion") was the final proof of the existence of atoms.

Bigger items like proteins and DNA also zig and zag, just more slowly. A reasonably sized protein might cover 1 meter in a second. That's still outrageously fast for something that's bottled up inside a space that human eyes can't perceive.

The universe inside the cell is also one of exquisitely tailored shapes of a huge range of stickiness. Whereas a high speed collision between two cars often results in death, destruction, and freshly-unusable parts flung in every direction, a collision between two proteins can initiate a chain of events that does something useful. You might imagine Miro's disembodied hand having a particular affinity for the window latch. Having twisted the latch, the window opens. The hand has no affinity for the latch once the window is opened, so it releases its grip. The little harlequin dude releases the cat-figure, which closes the window, which spontaneously latches, and then the disembodied hand performs its role again. This could repeat, say, 10,000 times in a second.

I should emphasize that there's a huge variety of stickinesses inside the cell. In our tedious realm, there's the stickiness of masking tape, the stickiness of gravity, and a few other sorts of stickiness. In the cell, though, you might have rules like "fish only interact with items found on the table, never elsewhere." And the cone can only stick to a perfectly cone-shaped hole in the wall.

There's a lot of stuff I'm ignoring here. What's to prevent events occurring in reverse? What powers all this motion? How do things change, say, if the disembodied hand gets tethered to the wall? What's going on in the next room? That's OK.

Point is, the universe inside the cell is one of interactions. I suppose the typical interaction between components in the cell is one of total indifference, the ladder not giving a crap that the dice just rolled into it. But the "productive" interactions are frequent enough to make all the difference. Some branches of modern biology (e.g. "systems biology") seek to understand the complete cell in terms of all these interactions. It's a huge task, with maybe 50,000 different proteins and RNA molecules, and a couple meters of DNA in your cell, all jostling and interacting with various degrees of stickiness. Part of me rebels against this mechanistic view, but I don't see a reasonable alternative. At some point in the future some commentator might scold this generation of biochemists for ignoring the "weak" (but frequent) interactions, but that would be wrong; it's hard enough to document all the strong ones right now!

There have been some amazing and inspiring animated attempts to simulate the life of a cell based on real knowledge of shapes and interactions. Such videos, however, can't possibly convey the speed at which these events occur. Nor do they show the myriad random, unsuccessful interactions that occur for every productive one...thus it appears that components are actually being attracted together, magnetic-like, over long distances. That's not the case.

So now, to move away from Miro and the abstract, what I'm trying to do is this: identify all interactions between human proteins and the RNA of a particular virus. Viruses aren't like Arnold Schwarzenegger announcing his presence with a minigun. They do their best to merge with the crowd, making it difficult for the cell to detect any unusual interactions. We're using a technology called the "three hybrid system." Basically, a protein latches to both DNA and RNA, and if that RNA latches onto another protein, that protein will latch onto another protein, which will make a different kind of RNA, which will interact with a ribosome and get translated into a new protein, which will interact with a small molecule and turn the yeast cell blue. The blue color, in turn, makes me happy. With the help of numerous other interactions, of course. I'm still boggled by the fact that the system works at all. There would seem to be too many points where the system could fail. This boggledness, however, suggests that even I, after all these years, still don't properly conceive of the universe inside a cell.