Friday, September 14, 2007

Worms and the Human Brain

An experimental tool could help illuminate Parkinson's disease.

By Katherine Bourzac

Smart worms: MIT researchers have created a microfluidic chip for rapid whole-genome screens and for testing large numbers of therapeutic compounds in live worms. Neurons in this worm, the millimeter-long nematode C. elegans, are labeled green. Credit: Mehmet Fatih Yanik, MIT

There are no cures for debilitating neurodegenerative diseases such as Parkinson's, and researchers still don't understand what causes brain cells to die in patients suffering from these diseases. But MIT researchers hope to speed up the quest for answers and the search for therapies in an unlikely test subject: worms.

Mehmet Fatih Yanik, assistant professor of electrical engineering and computer science at MIT, is developing microfluidic devices that could greatly facilitate experiments, including whole-genome screening and drug testing, on small nematode worms called C. elegans. They are a favorite subject of biologists and medical researchers because the worms are tiny and transparent, and researchers can do experiments with them that are not possible with larger animals.

Yanik's polymer chips have two layers of channels. One layer is "like a maze," he says. In this layer, the one-millimeter-long worms are shuttled and sorted at high speed. The channels are only a few hundred micrometers wide and hold very small volumes of liquid. The upper layer is what Yanik calls "the plumbing." It contains valves that control the flow of liquid and worms.

Suction channels allow researchers to immobilize the worms for imaging on a high-resolution microscope. The nematode worms are made up of fewer than one thousand cells, each of which can be seen under the microscope. Using Yanik's chip, "you can see neurons die in real time" in the live animals, says Richard Nass, assistant professor of pediatrics and pharmacology at Vanderbilt University Medical Center. Imaging at this level of detail and speed is impossible in larger animals, and older worm systems can provide blurry images because the worms are free-swimming.

Nass developed the first worm model of Parkinson's disease. In it, the animals are treated with a toxin that kills dopamine neurons. On the chip, worms can be sorted using visual signs of how the toxin affects their nerves. Such an experiment takes about six months using conventional techniques, says Nass. On Yanik's chip, it takes one month.

As part of a collaboration with a major international drug company, Nass is using the chips and his worms to discover possible Parkinson's therapies. Humans have tens of thousands of dopamine neurons connected to tens of thousands of other neurons, says Nass. The worms only have eight dopamine neurons, yet "at the molecular level, their nervous system is almost identical to the human nervous system."

In one type of experiment possible with the new microfluidic device, worms on the chip can be treated with compounds for high-throughput drug screens. Such automated drug screens, which are currently performed on single cells, have not been practical in whole, live animals in the past.