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.
Yanik’s chip should also speed up whole-genome screens that help researchers understand which genes are necessary for vital processes, such as the ability of nerve cells to recover from injury. “A lot of the genes in worms … function in the same way as they do in higher organisms,” says Richard Roy, associate professor of biology at McGill University. Specifically, Yanik’s chip could help speed up experiments in which researchers silence every single worm gene and watch what happens to determine which genes are necessary for which physiological processes.
Yanik is using the chips to study the genetics of nerve regeneration. He developed a highly precise, intense laser for performing microsurgeries on the worms. The laser allows him to very precisely sever a single branch of a neuron without damaging the surrounding tissue. Yanik silences each gene in the worm’s entire genome, one gene at a time, then severs neurons in each worm and watches the outcome. If a worm with a particular silenced gene can’t heal the damaged nerve, that suggests that the gene plays an important role in the healing process.
Speeding up studies of the worms could have broad implications for genomic medicine. The worms provide a particularly good model of the human nervous system, and they’re also widely used to study development, with implications for human developmental disorders and cancer, Roy says. Yanik’s chips, if they live up to their promise, would be a huge improvement in speed, volume, and precision over what’s currently available.