Little flies suggest big cures


Sehgal with flies.

Photo by Candace diCarlo

For lonely night owls married to early birds, a new day may be about to dawn. Some new basic research conducted at the Medical Center on fruit flies may one day help scientists to reset the internal clocks of humans.

The mechanisms that regulate the circadian rhythms of humans and other life forms, including even tiny bacteria, are similar to those regulating the fruit fly’s, explained Amita Sehgal, Ph.D., who heads a team investigating fruit fly internal clocks. And understanding those mechanisms may lead to solutions for human problems like jet lag; sleepiness in workers, pilots and soldiers on the night shift; and maybe even some forms of depression, Sehgal said.

“We’re finding out every day that more and more in the human system might be controlled by our internal molecular clock, everything from our thresholds for pain, blood pressure and basal body temperatures to hormone cycles,” she said.

Sehgal, an associate professor of neuroscience and a Howard Hughes Medical Institute (HHMI) assistant investigator, is senior author of an article published in the Sept. 10 issue of Science, which explained the molecular intricacies of how a fruit fly synchronizes its physical functions with the daily cycle of light and dark.

The team zapped fruit flies with light pulses and analyzed the consequences.

Three years ago, Sehgal’s team showed that a protein with the confusing – and amusing – name of “timeless,” or TIM for short, decreased after a photoreceptor in the fly perceived light.

“This year, we figured out how TIM goes away in response to light,” she said. About 20 minutes after light hits the photoreceptor, the body adds phosphates to the TIM protein, which starts to break down. The team showed that fly cells then flag TIM for destruction, and then a protease system, alerted by the flag, completes the breakdown.

“The [protease] system [which breaks down proteins] is not unique to circadian rhythms,” Sehgal said. “It’s implicated in some cancer-causing pathways, and in cell cycles and cell division. The work has broad applications. We now have proteins or systems that you can target to reset your biological clock.”

That’s something that might come in handy for something as silly as the scheduling problems experienced by morning people married to night owls. Or it may help in something as serious as timing the delivery of highly toxic drugs, such as cancer drugs, which may be more effective and cause fewer side effects when given at a specific time of day. “Since so many human hormones rise and fall in circadian cycles, this effect on drug therapy seems to make perfect sense,” Sehgal said.

Sehgal, a native of New Delhi, began her study of the circadian rhythms of fruit flies partly because scientists already had an inkling of their molecular basis. “The tools were there, the genetic tools,” she said. What intrigued her was a chance “to find the molecular basis of behavior.”

Originally published on October 28, 1999