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Fruit Fly Research Illuminates Human Health

By Alison Davis

To many Americans, fruit flies are the annoying consequence of buying too many on-sale bananas.

Yet these tiny red-eyed animals — known to scientists as the species Drosophila melanogaster — are essential workhorses in thousands of biomedical research laboratories around the world. Decades of study have revealed that the tiny insects, which bear little resemblance to people, nevertheless share much of our genetic heritage. Fruit flies possess strikingly similar versions of the genes that promote normal human development and, when altered, contribute to disease.

"Nobody would have predicted that an arcane fruit fly that had a leg sticking out of its head would have revealed fundamental secrets about the development of human embryos," said Charles Zuker, a neuroscientist at the University of California, San Diego.

On Sept. 6 at the Howard Hughes Medical Institute campus in Chevy Chase, Zuker and a distinguished group of researchers joined forces to extol the virtues of the fruit fly as a model system in biomedical research. The meeting, "Drosophila: Direct Flight to Understanding Human Disease and Behavior," was cosponsored by HHMI and three NIH components: the National Institute of General Medical Sciences, the National Institute of Child Health and Human Development, and the National Institute on Alcohol Abuse and Alcoholism. Coordinating the meeting were Laurie Tompkins, a program director at NIGMS, Gerald Rubin, HHMI's vice president for biomedical research, and Tom Kornberg, a fly geneticist at the University of California, San Francisco.

Photo of the fruit fly, Drosophila melanogaster, by Jay Hirsh, an NIGMS grantee at the University of Virginia.

"The time is ripe now — the tools are there," said Rubin, a recognized leader in the tightly knit fruit fly research community, and collaborator with Celera Genomics' Craig Venter in sequencing the Drosophila genome this past spring. "Drosophila is the organism closest to humans where it's still possible to do [in-depth] genetic studies."

What kind of genetic studies? The list of human-related topics fruit fly researchers are currently working on is surprisingly broad in scope: cancer; birth defects; development of the respiratory and circulatory systems; cardiovascular development and disease; taste, sight, smell and hearing; learning and memory; brain disease; sleep; drug abuse; aging; and diabetes.

Those were just the topics covered at the meeting. Missing from the list, but currently under investigation by scientists using fruit flies as a model, are eye development, circadian rhythms, blood cell development, malaria and Parkinson's disease, to name a few.

Over the years, researchers have learned that even though flies do things very differently from more evolved organisms such as humans, the core signaling pathways in which cells form and carry out their duties as part of functioning organs are remarkably similar throughout the biological kingdom. In so-called model organisms such as flies, often these pathways are much simpler, making them much easier to study.

Take diabetes, for example. Flies don't get this debilitating disease, and their bodies don't even make glucose (they produce a different sugar called trehalose instead). Yet almost all of the insulin-signaling circuits that become disordered in diabetes exist in the bodies of flies, a feature rendering them potentially useful test systems for probing the causes of diabetes as well as for finding potential treatments.

The future already looks bright. "We've gone from a simple insect to three new drug targets in 2 years," said geneticist Geoffrey Duyk, chief scientific officer of Exelixis Pharmaceuticals of South San Francisco, Calif.

Remarkably, despite the fact that flies don't even have hearts (at least not multi-chambered organs like humans), Drosophila researchers have begun to untangle the fundamental steps involved in heart development. "The heart is a wondrous and mystical organ, but so little is known about it at a molecular level," said Eric Olson, a molecular biologist at the University of Texas Southwestern Medical Center at Dallas. His group has made recent strides in identifying new genes — in flies and mammals — that play a role in this process.

Other talks at the meeting summed up recent progress in researchers' quest to use Drosophila to probe the mysteries of the brain.

For example, according to Tim Tully of Cold Spring Harbor Laboratory, fruit flies are revealing secrets about how the brain processes memories. Tully, who has set up an experimental system he calls "Pavlov's flies," recounted the similarities between the "brains" of flies and those of people. (Tully's fly work is analogous to the classic learning experiments with dogs performed by Ivan Pavlov around the turn of the 20th century, involving so-called conditioned responses to various stimuli.)

"Humans have circuits like a Macintosh computer, whereas a fly has a Philco radio," he said, "but there are still transistors and resistors [that make them work]." Tully and his coworkers have unearthed a molecular "switch" in flies called CREB that appears to convert incoming information into long-term memory. The molecule also exists in humans.

The past few years have witnessed an explosion of findings about the inner workings of fly biological clocks, information that has demonstrated a nearly identical set of working parts in higher organisms such as mice and people. Building on the success of these genetic studies, veterinarian Joan Hendricks, a sleep researcher at the University of Pennsylvania, has turned to Drosophila to study sleep.

"Some of the most fundamental questions [about sleep] haven't even been asked," said Hendricks, conceding that scientists don't even know whether sleep is something only mammals and birds do. In part because of the legacy of research on circadian rhythms in flies, she is hopeful that insects may be a useful genetic model system for studying normal rest as well as sleep disorders.

Other scientists at the meeting spoke of using fruit flies to study drug abuse and addiction.

Ulrike Heberlein, a Drosophila geneticist at UCSF, told the audience about her studies of the molecular roots of drug abuse, particularly behaviors that result from short- and long-term exposure to alcohol in flies. According to Heberlein, fruit flies, just like people, develop a tolerance to alcohol over time — and require higher concentrations of alcohol to produce a behavioral effect.

Also similarly to people, flies lose their balance and postural control after ingesting alcohol, she said, describing previous studies performed with an elaborate laboratory device called an "inebriometer," a vertical series of cones that flies fall through after being exposed to varying doses of alcohol (the ones that fall through fastest are the most affected; they are subjected to further study and genetic analysis).

This approach, and a more recent refinement of the method in which Heberlein exposes flies to alcohol and then places them on a tray connected to a computer that generates a digital tracing of the flies' movements in response to different amounts of alcohol, has enabled her to link certain fly genes with sensitivity to alcohol. In a surprising twist, she and her colleagues have found an astonishing overlap between fly genes involved in sensitivity to alcohol and learning and memory.

In concluding remarks, Rubin echoed the comments of many of the day's speakers.

"No one could have predicted, or appreciated, the incredible amount of [evolutionary] conservation between fruit flies and humans," he said, adding that armed with the power of Drosophila genetics and the recently decoded Drosophila genome sequence, scientists using flies "can go after a problem without knowing anything about it."

Veteran fruit fly researcher Matthew Scott, a developmental biologist at Stanford University who has forged links between key molecules in fly development and birth defects and cancer in humans, remains fascinated by the game itself.

"Connecting things we didn't think were connected makes science so much fun," he said.

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