Three Americans recognized for discovering the cellular gears that drive circadian rhythms
From left to right: Courtesy of Brandeis Univ., Mike Lovett/Brandeis Univ. and Mario Morgado/The Rockefeller Univ.
These three Americans were honored October 2 by the Nobel Assembly at the Karolinska Institute in Stockholm for their work in discovering important gears in the circadian clocks of animals. The trio will equally split the 9 million Swedish kronor prize — each taking home the equivalent of $367,000.
The researchers did their work in fruit flies. But “an awful lot of what was subsequently found out in the fruit flies turns out also to be true and of huge relevance to humans,” says John O’Neill, a circadian cell biologist at the MRC Laboratory of Molecular Biology in Cambridge, England. Mammals, humans included, have circadian clocks that work with the same logic and many of the same gears found in fruit flies, say Jennifer Loros and Jay Dunlap, geneticists at the Geisel School of Medicine at Dartmouth College.
Circadian clocks are networks of genes and proteins that govern daily rhythms and cycles such as sleep, the release of hormones, the rise and fall of body temperature and blood pressure, as well as other body processes. Circadian rhythms help organisms, including humans, anticipate and adapt to cyclic changes of light, dark and temperature caused by Earth’s rotation. When circadian rhythms are thrown out of whack, jet lag results. Shift workers and people with chronic sleep deprivation experience long-term jet lag that has been linked to serious health consequences including cancer, diabetes, heart disease, obesity and depression.
Before the laureates did their work, other scientists had established that plants and animals have circadian rhythms. In 1971, Seymour Benzer and Ronald Konopka (both now deceased and ineligible for the Nobel Prize) found that fruit flies with mutations in a single gene called period had disrupted circadian rhythms, which caused the flies to move around at different times of day than normal.
“But then people got stuck,” says chronobiologist Erik Herzog of Washington University in St. Louis. “We couldn’t figure out what that gene was or how that gene worked.”
At Brandeis University in Waltham, Mass., Hall, a geneticist, teamed up with molecular biologist Rosbash to identify the period gene at the molecular level in 1984. Young of the Rockefeller University in New York City simultaneously deciphered the gene’s DNA makeup. “In the beginning, we didn’t even know the other group was working on it, until we all showed up at a conference together and discovered we were working on the same thing,” says Young. “We said, ‘Well, let’s forge ahead. Best of luck.’”
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Night and day
At night, the period gene is active, making period mRNA that heads to the cell’s cytoplasm to direct production of PER, the period protein. Newly named Nobel laureates Jeffrey C. Hall and Michael Rosbash discovered that once enough protein builds up, it somehow enters the cell’s nucleus. There, PER blocks its own gene from continuing production. The protein degrades during the day, and once it’s gone, its gene starts up again.
It wasn’t immediately apparent how the gene regulated fruit fly activity. In 1990, Hall and Rosbash determined that levels of period’s messenger RNA — an intermediate step between DNA and protein — fell as levels of period’s protein, called PER, rose. That finding indicated that PER protein shuts down its own gene’s activity.
A clock, however, isn’t composed of just one gear, Young says. He discovered in 1994 another gene called timeless. That gene’s protein, called TIM, works with PER to drive the clock. Young also discovered other circadian clockworks, including doubletime and its protein DBT, which set the clock’s pace. Rosbash and Hall discovered yet more gears and the two groups competed and collaborated with each other. “This whole thing would not have turned out nearly as nicely if we’d been the only ones working on it, or they had,” Young says.
Since those discoveries, researchers have found that nearly every cell in the body contains a circadian clock, and almost every gene follows circadian rhythms in at least one type of cell. Some genes may have rhythm in the liver, but not the skin cells, for instance. “It’s normal to oscillate,” Herzog says.
Cease with assist
Newly named Nobel laureate Michael W. Young discovered that TIM, the timeless protein, pairs up with PER, the period protein. That pairing helps PER go into the cell’s nucleus to turn off the period gene. Period and timeless are two of the molecular gears of the circadian clock in fruit flies. Most of timeless’s job is performed by Cryptochrome in mammals’ clocks.
Trouble arises when those clocks get out of sync with each other, says neuroscientist Joseph Takahashi at the University of Texas Southwestern Medical Center in Dallas. For instance, genes such as cMyc and p53 help control cell growth and division. Scientists now know they are governed, in part, by the circadian clock. Disrupting the circadian clock’s smooth running could lead to cancer-promoting mistakes.
But while bad timing might lead to diseases, there’s also a potential upside. Scientists have also realized that giving drugs at the right time might make them more effective, Herzog says.
Rosbash joked during a news conference that his own circadian rhythms had been disrupted by the Nobel committee’s early morning phone call. When he heard the news that he’d won the prize, “I was shocked, breathless really. Literally. My wife said, ‘Start breathing,’" he told an interviewer from the Nobel committee.
Young’s sleep was untroubled by the call from Sweden. His home phone is the kitchen, and he didn’t hear it ring, so the committee was unable to reach him before making the announcement. “The rest of the world knew, but I didn’t,” he says. Rockefeller University president Richard Lifton called him on his cell phone and shared the news, throwing Young’s timing off, too. “This really did take me surprise,” Young said during a news conference. “I had trouble even putting my shoes on this morning. I’d go pick up the shoes and realize I needed the socks. And then ‘I should put my pants on first.’”
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