Drug Testers Think Small...continued
Worms as Workhorse and Test Subjects
For these reasons they have become the NemaPharm workhorse and test subject. "The essence of what NemaPharm is doing is to establish surrogates for human diseases [in worms] and then establish selections for drugs against those diseases," says Johnson. As the Prozac example shows, the surrogate may not be perfect, but that isnt necessarily a problem. The protein target of Prozac is involved in different behaviors in humans and worms, but what matters is that the same protein target is present in worms, and interfering with it causes some measurable symptom. Explains Johnson: "We are trying to use the same molecules and the pathways in C. elegans, not to reproduce the same behaviors."
An extreme example is the ras mutation, a genetic change that in humans can lead to cancer. In worms an over-active ras produces extra female reproductive structures, which are visible as bumps on the outside of the worm. The current screen for anti-ras chemicals involves looking for the disappearance of these bumps. Johnson hopes that he can automate this process soon.
Worms are not the ultimate solution for everything. They have a tremendous capacity for modifying and throwing out foreign chemicals, which may mask the effects of potentially useful drugs. And the differences between worm and human proteins are likely to be crucial in determining which is the perfect final drug.
But for the earlier stages of drug discovery, worms look like an excellent tool for picking the best target, and for finding a starting chemical for researchers to work on. Not all proteins are equally amenable to being shut off with a chemical. When Johnson looks for chemicals that shut off the over-active ras, he is really testing for a chemical that turns off either ras itself, or anything in its chain of command. If he finds that a lot of chemicals turn off another protein in this molecular pathway, that protein may make a better target for future screens.