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Thomas Schwarz, PhD, is gentle, modest and congenial, but when he's extolling the virtues of his favorite research subject, his tone becomes almost reverential. Schwarz is passionate about his fruit flies, or Drosophila melanogaster, as he affectionately calls them. In his research laboratory at Children's Hospital Boston's Neurobiology Center, Schwarz and his team of researchers experiment on millions of fruit flies to study genes involved in forming and maintaining the synapses between nerve cells—in other words, helping neurons talk to each other. For him, it's a dream come true, partly because it allows him to marry his dual interests of neurobiology and genetics, but also because he's able to indulge his curiosity about this singular species. "I love my flies," he says, grinning. "They're pretty smart little guys. They have intricate courtship rituals in which they sing to each other by vibrating their wings, very stylized ways of fighting over mates and food—and a really incredible sense of smell."
Listening to Schwarz wax poetic about Drosophila, which sounds like an exotic woman's name when it rolls off his tongue, it's clear why fruit flies have been so valuable to researchers for the past century. Their genomes are remarkably similar to those of humans, they breed quickly (thereby creating innumerable new research subjects) and, most interesting to Schwarz, have quite sophisticated nervous systems. "They can fly—which humans can't," he says. "They can steer themselves toward a specific object in the face of wind currents and avoid the swat of your hand, which requires a huge amount of darting. And they coordinate walking with six legs. They may not publish scientific articles or compose operas, but the calculations their brains have to do are amazing."
Stacked high on shelves in Schwarz's lab are thousands of vials, most containing mutant breeds of flies that he's genetically manipulated. The flies—the same kind that buzz around your bananas—will live for about two months, depending, Schwarz says, on how happy they are. Most of them find regular room temperature to be satisfactory, but the more sensitive stocks get incubators. "We pamper them," Schwarz says.
Until, of course, it comes time to study them. Sometimes the researchers examine the barely visible embryos, which are the size of a pin's head; other times they dissect larvae, which are the size of a grain of rice. For some experiments, Schwarz and his team insert glass microelectrodes into flies' muscle fibers—which can be as small as a hundredth of a millimeter across—and stimulate those nerves while recording how their synapses work.
Schwarz became interested in fruit fly genetics as an undergraduate at Harvard in the 1970s. It was, as he says, "the dawn of molecular biology," when it was just becoming possible to start with a mutated fly and work backward to see which gene was responsible for the mutation. "It reminded me of when TVs had tubes in them, and you could take a tube out and figure out how the TV worked by seeing what went wrong," he says. "The logic of genetics research was beautiful and appealing in the same way."
Now that he has a lab of his own, Schwarz conducts much of his research using this approach, starting with a so-called mutant screen. "Basically, we mutate flies at random, trashing genes left and right, find the interesting ones and ask, 'What was it we screwed up in this fly?'" he says. The odder the fly, the more potential it has for research: Those with physical abnormalities, who have trouble hatching or flying, hold their wings strangely or exhibit unusual reproduction habits, such as failure to produce the right courtship song, make prime research subjects.
For Schwarz, some of the appeal of this method is its inherent element of surprise. "There's a joke in the fly world that with a mutant screen, you always find what you're looking for—you just didn't know that this is what you were looking for," he says.
One study yielded especially unexpected results. Schwarz started with a million flies whose photoreceptors were genetically manipulated, making them blind. Then he zeroed in on a few hundred flies whose eyes looked normal and whose retinas responded to light, but somehow couldn't transmit vision signals to their brains. He named one new mutant Milton, after the blind poet (he credits his wife, an English professor). "We always hope to find something new with a mutant screen, but we don't necessarily know where to go with it once we do," says Schwarz. "It was a long time before we figured out what was wrong with those Milton flies."
Puzzling this out took several years, even after his team identified the gene that was responsible. As it turned out, the problem wasn't how cells' synapses formed, as he'd supposed. Instead, microscopic examination of the sightless flies' neurons revealed that the mitochondria that power them couldn't move around inside the cells. The synapses weren't working properly because the mitochondria were trapped, unable to get to cells' peripheries and supply them with energy. "We had no idea we were looking for things that controlled how mitochondria moved around," Schwarz says. "I hadn't thought about mitochondria in 20 years, and then there they were."
That discovery led Schwarz out of fly genetics and into research on neuro-degenerative diseases. Neurons are the most elongated cells in our bodies; a single cell can reach from the spinal cord into the muscles of our legs and arms. That means that mitochondria need to move long distances to supply energy to the nerve endings, and if they don't, that cell may degenerate. Serendipitously, the nearby lab of Dennis Selkoe, MD, at Brigham and Women's Hospital, had found that an enzyme that interacts with Milton and the motor proteins Schwarz was studying is mutated in some families with Parkinson's disease. Schwarz's team is now finding that this enzyme stops mitochondria from moving. "We started out trying to learn basic things that affect how nerve cells work," he says. "But we got to this amazing piece of cell biology, figured out how mitochondria move around and, as it turned out, linked it to a crucial part of the pathology of Parkinson's disease."
Another family of mutant flies in the lab start to form synapses but then stop, causing the circuits of their brains to be underdeveloped. Schwarz thinks that the process will shed light on developmental brain disorders such as retardation and autism. "Those are mutants we're feverishly pursuing," he says.
Despite these kinds of advances, Schwarz sometimes finds himself in the position of defending his choice to study such seemingly insignificant creatures—and the dig Sarah Palin made about public money being wasted on fruit fly research during the Presidential election campaign still stings. "She was actually making fun of the species that damages olives, but still, it was a cheap shot," he says. His enthusiasm for Drosophila is undiminished. "We work with every aspect of a fly, from how they act to their molecules—we get to learn about what really makes the fly a fly," he says. "People tend to think of fruit flies as being a lower organism and humans a higher one. I'm not sure the flies would agree with us." |
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