Molecular Biology, Neuroscience
University of Pennsylvania
Dr. Sehgal is also John Herr Musser Professor in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania.
Circadian Rhythms and Sleep
Sometimes, the most surprising scientific discoveries are the simplest. Flies sleep, Amita Sehgal found. And with that, she opened the door to new possibilities for research on the molecular basis of behavior—specifically, an organism's enigmatic need to sleep.
Fruit flies sleep differently than we do. They don't close their eyes, and from what scientists can tell, they don't go through different stages of sleep like mammals do. However, their rest periods resemble human sleep in many ways, and they are active during the day, like us. Researchers know that flies need sleep because the insects stay still for several hours at night, during which their response to sensory stimuli is reduced. Flies that are sleep deprived also respond sluggishly to stimuli, and will make up lost rest during the day when they would normally be active.
Sehgal has identified the chain of biochemical reactions, known as a signaling pathway, that controls rest in fruit flies. The pathway, she discovered, leads to an area of the brain called the mushroom body, which also regulates learning and memory. Her findings meant that scientists could use Drosophila melanogaster, the genetically tractable fruit fly, to study sleep in humans.
Sleep is absolutely essential for fruit flies and the sleeping species they model. Sehgal says, "In all animals, where the experiment has been done, if you don't allow them to sleep, they die."
Nobody knows why. But Sehgal and colleagues are trying to break sleep down into its molecular and genetic components. They study how an organism's sleep cycle falls into its circadian rhythm—the inherent daily cycle of physiological processes including sleep, metabolism, and blood flow.
Using the fruit fly model, Sehgal and her lab members have found that genes called period and timeless control the circadian rhythm in both flies and humans. The timeless gene synchronizes the organism's 24-hour physiological cycle with environmental cues—in this case, daylight. Lack of the gene disrupts the internal clock's ability to keep time. The period gene determines the length of the cycle. Scientists can tweak the gene so that mutant flies will have a cycle that lasts 19 hours instead of 24. This mutation in period produces a 19-hour cycle in any fly, suggesting that the time span of the molecular clock is a strictly genetic phenomenon.
This clear relationship between genetics and behavior attracted Sehgal to the study of circadian rhythms. She worked as a postdoc from 1988 to 1993 at Rockefeller University with Michael Young, who studied both circadian rhythms and neuronal development. Sehgal assumed she would work with the latter when she applied for the job, since she had studied a factor required for neuronal development for her Ph.D. But Young gave her a paper that he was about to publish about "the clock side of things."
Earlier in her career, Sehgal had found changes in behavior subtle and difficult to quantify. "Having been trained as a molecular biologist, where either you have a band on a gel or you don't, I was not comfortable with these little quantitative changes you had to look for in behavioral assays," she says. "But when I read this paper, I realized that circadian rhythms were different from any other behavior in that these phenotypes are very strong, their assay is very robust, very reliable, very consistent, and very genetically manipulable."
Sehgal didn't fully realize her interest in science until graduate school. She grew up in India, and went to undergraduate school in New Delhi, where the top students were expected to pursue math and science careers. Sehgal herself was more interested in literature and law. "It wasn't as though there was active pressure on me, but I went into science because of how things were viewed in society."
After she finished her studies in India, she volunteered in a lab in Australia, where her father was in the country, working for the Indian government and promoting Indian tourism. In the lab, Sehgal worked on a project to determine if DNA repair was affected in people with muscular dystrophy. She had hoped that the experience would help her decide whether to follow a career in science. "To be perfectly honest, I hated it," she says.
She didn't feel useful as a young volunteer because she was only sporadically assigned to work on surface-level aspects of the project. Sehgal comments, "I think that's something to keep in mind when we're training people, that until they get really involved and are doing much more on their projects, you can't expect them to get excited about it."
She went to graduate school in science anyway, because she felt it was the most straightforward career path. She started at Cornell in 1983, began working on a human neuronal growth factor, and loved it. "At that point I was really investigating it in some depth. And that made a huge difference. Once you get turned on by the research, then you're in it, then you're hooked."
Sehgal has stayed hooked as she investigates the cadence of natural rest and active cycles. "The very fact that we don't know why they're so important is keeping us really enthralled," she says. We all have clocks within us. Sehgal wants to pick them apart, cog by molecular cog, to figure out how our bodies know that in order to survive, every so often, we should lie down and sleep.