The 2017 Nobel Prize in Physiology or Medicine - Press Release: The Nobel Assembly atKarolinska Institutet has today decided to award the 2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecularmechanisms controlling the circadian rhythm

(原英文报道见：https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html)

Summary

Life on Earth is adapted to the rotation ofour planet. For many years we have known that living organisms, including humans, have an internal, biological clock that helps them anticipate and adaptto the regular rhythm of the day. But how does this clock actually work?Jeffrey C. Hall, Michael Rosbash and Michael W. Young were able to peek insideour biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that itis synchronized with the Earth's revolutions.

Using fruit flies as a model organism, this year's Nobel laureates isolated a gene that controls the normal dailybiological rhythm. They showed that this gene encodes a protein that accumulates in the cell during the night, and is then degraded during the day. Subsequently, they identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. We now recognize that biological clocks function by the same principles incells of other multicellular organisms, including humans.

With exquisite precision, our inner clockadapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels,  sleep, body temperature and metabolism. Our wellbeing is affected when there is atemporary mismatch between our external environment and this internal biological clock, for example when we travel across several time zones and experience "jet lag". There are also indications that chronic misalignment between our lifestyle and the rhythm dictated by our innertimekeeper is associated with increased risk for various diseases.

Ourinner clock

Most living organisms anticipate and adapt todaily changes in the environment. During the 18th century, the astronomer Jean Jacques d' Ortous de Mairan studied mimosa plants, and found that the leavesopened towards the sun during daytime and closed at dusk. He wondered what would happen if the plant was placed in constant darkness. He found that independent of daily sunlight the leaves continued to follow their normal dailyoscillation (Figure 1). Plants seemed to have their own biologicalclock.

Other researchers found that not only plants, but also animals and humans, have a biological clock that helps to prepare ourphysiology for the fluctuations of the day. This regular adaptation is referredto as the circadian rhythm, originating from the Latin words circameaning "around" and dies meaning "day". But justhow our internal circadian biological clock worked remained a mystery.

Figure 1. An internal biological clock. The leaves of the mimosa plant open towardsthe sun during day but close at dusk (upper part). Jean Jacques d'Ortous deMairan placed the plant in constant darkness (lower part) and found that theleaves continue to follow their normal daily rhythm, even without anyfluctuations in daily light.

Identificationof a clock gene

During the 1970's, Seymour Benzer and his student Ronald Konopka asked whether it would be possible to identify genes that control the circadian rhythm in fruit flies. They demonstrated that mutations in an unknown gene disrupted the circadian clock of flies. They namedthis gene period. But how could this gene influence the circadianrhythm?

This year's Nobel Laureates, who were also studying fruit flies, aimed to discover how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash, working in close collaboration at Brandeis University in Boston, and Michael Young at the Rockefeller University in NewYork, succeeded in isolating the period gene. Jeffrey Hall and Michael Rosbash then went on to discover that PER, the protein encoded by period, accumulated during the night and was degraded during the day. Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm.

A self-regulating clockwork mechanism

The next key goal was to understand how suchcircadian oscillations could be generated and sustained. Jeffrey Hall and Michael Rosbash hypothesized that the PER protein blocked the activity of the period gene. They reasoned that by an inhibitory feedback loop, PER protein could prevent its own synthesis and thereby regulate its own level in a continuous, cyclic rhythm (Figure 2A).

Figure 2A. A simplified illustration of thefeedback regulation of theperiod gene. Thefigure shows the sequence of events during a 24h oscillation. When the period gene is active, period mRNAis made. The mRNA is transported to the cell's cytoplasm and serves as templatefor the production of PER protein. The PER protein accumulates inthe cell's nucleus, where the period gene activity is blocked. Thisgives rise to the inhibitory feedback mechanism that underlies a circadianrhythm.

The model was tantalizing, but a few piecesof the puzzle were missing. To block the activity of the period gene, PER protein, which is produced in the cytoplasm, would have to reach the cell nucleus, where the genetic material is located. Jeffrey Hall and MichaelRosbash had shown that PER protein builds up in the nucleus during night, but how did it get there? In 1994 Michael Young discovered a second clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. Inelegant work, he showed that when TIM bound to PER, the two proteins were ableto enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop (Figure 2B).

Figure 2B. A simplified illustration of themolecular components of the circadian clock.

Such a regulatory feedback mechanism explained how this oscillation of cellular protein levels emerged, but questions lingered. What controlled the frequency of the oscillations? MichaelYoung identified yet another gene, doubletime, encoding the DBT proteinthat delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle.

The paradigm-shifting discoveries by the laureates established key mechanistic principles for the biological clock. During the following years other molecular components of the clock work mechanism were elucidated, explaining its stability and function. For example,this year's laureates identified additional proteins required for the activation of the period gene, as well as for the mechanism by whichlight can synchronize the clock.

Keepingtime on our human physiology

The biological clock is involved in manyaspects of our complex physiology. We now know that all multicellularorganisms, including humans, utilize a similar mechanism to control circadianrhythms. A large proportion of our genes are regulated by the biological clockand, consequently, a carefully calibrated circadian rhythm adapts ourphysiology to the different phases of the day (Figure 3). Since the seminal discoveries by the three laureates, circadian biology has developedinto a vast and highly dynamic research field, with implications for our health and well being.

Figure 3. The circadian clock anticipates andadapts our physiology to the different phases of the day. Our biological clock helps to regulate sleeppatterns, feeding behavior, hormone release, blood pressure, and bodytemperature.

Jeffrey C. Hall was born 1945 in New York, USA. He receivedhis doctoral degree in 1971 at the University of Washington in Seattle and wasa postdoctoral fellow at the California Institute of Technology in Pasadena from1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974.In 2002, he became associated with University of Maine.

Michael Rosbash was born in 1944 in Kansas City, USA. Hereceived his doctoral degree in 1970 at the Massachusetts Institute ofTechnology in Cambridge. During the following three years, he was apostdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, hehas been on faculty at Brandeis University in Waltham, USA.

Michael W. Young was born in 1949 in Miami, USA. He receivedhis doctoral degree at the University of Texas in Austin in 1975. Between 1975and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto.From 1978, he has been on faculty at the Rockefeller University in New York.