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From left to right: Michael Young, Jeffrey Hall, and Michael Rosbash.

CUHK; Gairdner Foundation; Gruber Foundation.

Timing is everything: U.S. trio earns Nobel for work on the body’s biological clock

Discoveries about how organisms stay in sync with Earth’s rhythm of day and night have won this year’s Nobel Prize in Physiology or Medicine.

Jeffrey Hall and Michael Rosbash of Brandeis University in Waltham, Massachusetts, and Michael Young of The Rockefeller University in New York City share the prize equally for their work on how several genes work together to control the basic circadian clock, encoding proteins that build up during the night and are broken down during the day. These clocks are ticking inside plants, fungi, protozoa, and animals. In recent years, researchers have found that the clock is related not only to our sleep cycle, but also to metabolism and brain function.

Circadian, or daily, rhythms are “just as fundamental as respiration,” says Charalambos Kyriacou, a molecular geneticist at the University of Leicester in the United Kingdom. “There isn’t any aspect of biology that circadian rhythms aren’t important for. They are totally fundamental in a way that we didn’t anticipate” before the discoveries honored today.

The presence of a biological clock was already surmised in the 18th century. In 1729, French astronomer Jean Jacques d'Ortous de Mairan showed that mimosa leaves, which open at dawn and close at dusk, continued this cycle even when kept in darkness. But it wasn't until the 20th century that the idea of an internal clock—as opposed one that responds to external cues like light—was settled.

The genetic basis for a daily physiological cycle was first discovered in fruit flies in the 1970s. Seymour Benzer and Ronald Konopka at the California Institute of Technology in Pasadena created mutant flies that had abnormal biological clocks. One type had a broken clock—its patterns of activity became arhythmic—whereas the others now had either a 19-hour or a 28-hour cycle. Benzer and Konopka showed the mutations all had hit the same gene, presumably in different ways. They and other researchers homed in on a gene called period.

Hall and Rosbash finally sequenced the gene in 1984, as did Young. Hall and Rosbash showed that its protein, called PER, rose and fell over 24 hours, peaking at night. They suspected the clock was driven by a feedback loop, with the protein PER interfering with the period gene. (“It makes you scratch your head and wonder if it’s even possible,” Young said in a 1985 news story in Science about the discovery.)

For the clock to work, PER had to get into the nucleus. Young figured out how that happened. In 1994, he and colleagues discovered a second clock gene, timeless, that allowed PER to enter the nucleus and stop period from making more. (Their paper was published in Science.) 

There isn’t any aspect of biology that circadian rhythms aren’t important for. They are totally fundamental.

Charalambos Kyriacou, University of Leicester

Researchers have since found half a dozen more genes that influence the cycle. For example, period and timeless are turned on by clock, discovered in 1997 by Joseph Takahashi, now at UT Southwestern in Dallas, Texas, and his colleagues. Within a year, this group discovered another key part of the feedback loop: When PER and TIM get into the nucleus, they also curtail the activity of clock.

Clock genes are extremely influential, affecting the activity of most other genes in the body in one way or another. Circadian mechanisms influence metabolism—how our body uses and stores energy—blood pressure, body temperature, inflammation, and brain function. Time of day can influence the effectiveness of drugs and their side effects. And mismatches between the clock and the environment, for instance as a result of jet lag or shift work, have been shown to play a role in mood disorders and even cancer risk.

“Since the seminal discoveries by the three laureates,” the Nobel Assembly said in its press release today, “circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.” (An extensive discussion about the trio’s work is available from the Nobel Assembly here; watch a video of this morning’s announcement here.)

The award came as a complete surprise to one of the Nobelists. “You are kidding me,” Rosbash said this morning after he was called and notified of the honor, Thomas Perlmann, the Nobel Commitee’s secretary, told journalists this morning.

The Nobel Prize comes with 9 million Swedish Kronor ($1.1 million), which Hall, Rosbash, and Young will share. The amount went up from 8 million kronor last year, an increase of 12.5%.

Related Science papers

D. Rogulja, M. W. Young, "Control of sleep by cyclin A and its regulator," Science 335, 6076 (30 March 2012)

P. Meyer, L. Saez, M. W. Young, "PER-TIM interactions in living Drosophila cells: An interval timer for the circadian clock," Science 311, 5758 (13 January 2006)

S. A. Brown et al., "PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator," Science 308, 5722 (29 April 2005)

A. Busza et al., "Roles of the two Drosophila CRYPTOCHROME structural domains in circadian photoreception," Science 304, 5676 (4 June 2004)

J. D. Levine et al., "Resetting the circadian clock by social experience in Drosophila melanogaster," Science 298, 5600 (6 December 2002)

J. D. Plautz et al., "Independent photoreceptive circadian clocks throughout Drosophila," Science 278, 5343 (28 November 1997)

M. P. Myers et al., "Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock," Science 271, 5256 (22 March 1996)

M. P. Myers et al., "Positional cloning and sequence analysis of the Drosophila clock gene, timeless," Science 270, 5237 (3 November 1995)

A. Sehgal et al., "Rhythmic expression of timeless: A basis for promoting circadian cycles in period gene autoregulation," Science 270, 5237 (3 November 1995)

N. Gekakis et al., "Isolation of timeless by PER protein interaction: Defective interaction between timeless protein and long-period mutant PERL," Science 270, 5237 (3 November 1995)

Z. J. Huang, K. D. Curtin, M. Rosbash, "PER protein interactions and temperature compensation of a circadian clock in Drosophila," Science 267, 5201 (24 February 1995)

J. C. Hall, "The mating of a fly," Science 264, 5166 (17 June 1994)

A. Sehgal et al., "Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless," Science 263, 5153 (18 March 1994)

L. B. Vosshall et al., "Block in nuclear localization of period protein by a second clock mutation, timeless," Science 263, 5153 (18 March 1994)

I. Edery, J. E. Rutila, M. Rosbash, "Phase shifting of the circadian clock by induction of the Drosophila period protein," Science 263, 5144 (14 January 1994)

D. A. Wheeler et al., "Molecular transfer of a species-specific behavior from Drosophila simulans to Drosophila melanogaster," Science 251, 4997 (1 March 1991)

C. P. Kyriacou, J.C. Hall, "Interspecific genetic control of courtship song production and reception in Drosophila," Science 232, 4749 (25 April 1986)