生物钟—2017年诺贝尔生理学奖

原文来自诺贝尔奖官网 （未完待续）

瑞典卡罗林斯卡医学院2日在斯德哥尔摩宣布，2017年诺贝尔生理学或医学奖由杰弗里·霍尔、迈克尔·罗斯巴什和迈克尔·扬三位美国科学家分享，以表彰他们在研究生物昼夜节律分子机制方面的杰出贡献。

Summary

综述

Life on Earth is adapted to the rotation of our planet. For many years we have known that living organisms, including humans, have an internal, biological clock that helps them anticipate and adapt to 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 inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth's revolutions.

生活在地球上的生物因长期进化，适应了地球的自转，对于昼夜的交替和日常环境的变化能够通过内部的生物钟进行调节，使自身的生理活动与其匹配，生物的这种对应于一天24小时的活动适应能力就称为昼夜节律。最常见的昼夜节律现象就是动物和人类的睡眠、呼吸等变化以及向日葵的转向行为等。从科学上的意义来说，节律只是生物钟的外在表现，深入研究节律可以帮助人类加深对于生物钟内在调节控制机制的认识。评奖委员会表示，今年获奖者的研究成果解释了许多动植物和人类是如何让生物节律适应昼夜变换的。

Using fruit flies as a model organism, this year's Nobel laureates isolated a gene that controls the normal daily biological 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 in cells of other multicellular organisms, including humans.

通过利用果蝇作为模式生物，今年的诺贝尔奖获得者们分离出了一个能够控制日常生物节律的基因。他们揭示了这个基因能够编码一个蛋白质，这个蛋白质夜间能在细胞中积累，而在白天减少。随后，他们识别出了该机制其他的蛋白质部件，展示了在细胞中管理自维持生物钟的机制。我们现在识别出在其他的多细胞有机体（包括人类）中的细胞中存在着同样的生物钟机制。

With exquisite precision, our inner clock adapts 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 a temporary 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 inner timekeeper is associated with increased risk for various diseases.

我们内部的时钟拥有着精巧的精度，它调节着我们的生理以适应一天中剧烈不同的阶段。这个时钟调节人体的关键功能，如行为、荷尔蒙水平、睡眠、体温和新陈代谢。当我们的外部环境和内部时钟不匹配时，我们的健康就会受到影响，例如我们穿越几个地球时区，体验到“时差”时。同样有迹象表明各种疾病风险的增加跟生活方式和人体内部时钟决定的昼夜节律长期不匹配有关。

Our inner clock

我们的内部时钟

Most living organisms anticipate and adapt to daily changes in the environment. During the 18th century, the astronomer Jean Jacques d'Ortous de Mairan studied mimosa plants, and found that the leaves opened 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 daily oscillation ( Figure 1 ). Plants seemed to have their own biological clock.

大多数生命体预测和适应日常环境的变化。在18实际，天文学家Jean Jacques d'Ortous de Mairan研究了含羞草植物，发现了白天它们的叶子朝向太阳打开，傍晚闭合。他猜想如果把这种植物放在长期黑暗下会发生什么。他发现与每天的太阳无关，这些叶子继续遵从他们正常的每日振荡（开合）。（图1）植物们似乎拥有他们自己的生物时钟。

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

其他研究者发现，不仅植物，动物和人类也有生物钟，为了应对一天的波动而帮助我们准备我们的生理机能。

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

图1. 一种内部生物钟。含羞草的叶子白天朝向太阳展开，但傍晚合上（上边的图）。 Jean Jacques d'Ortous de Mairan把这个植物放在恒定的黑暗中（下图），发现叶子继续遵从他们通常的每日节律，即使在没有任何每天光照波动的黑暗环境下。

Identification of a clock gene

一个时钟基因的识别

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 named this gene period . But how could this gene influence the circadian rhythm?

在20世纪70年代，Seymour Benzer和他的学生Ronald Konopka问到有没有可能从果蝇身上找到控制昼夜节律的基因。他们证明了在一个未知基因中的变异破坏了果蝇的时钟节律。他们把该基因命名为period(周期)。但是这个基因如何影响昼夜节律呢？

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 New York, 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.

今年的诺贝尔奖获得者们，同样也是研究果蝇，目标是发现生物钟究竟如何运作。1984年，Jeffrey Hall和Michael Rosbash进而发现了period基因所编码的PER蛋白质晚上增加，白天减少。所以，PER蛋白质的数量以24小时为循环振荡，这与昼夜节律同步。

A self-regulating clockwork mechanism

自调节时钟机制

The next key goal was to understand how such circadian 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 ).

下一个关键目标是理解这样的生理振荡是如何产生和维持的。Jeffrey Hall 和Michael Rosbash假设PER蛋白质阻塞了period基因的活动。他们推断通过一个抑制性的反馈回路，PER蛋白质能够阻止它自身的合成，因而能够连续的周期性的调节它自己的数量。

Figure 2A. A simplified illustration of the feedback regulation of the period gene.

图2A. 一个简化的周期基因反馈调节示意图

The figure shows the sequence of events during a 24h oscillation. When the period gene is active, period mRNA is made. The mRNA is transported to the cell's cytoplasm and serves as template for the production of PER protein. The PER protein accumulates in the cell's nucleus, where the period gene activity is blocked. This gives rise to the inhibitory feedback mechanism that underlies a circadian rhythm.

这幅图展示了24小时周期内的各个事件的发生次序。当周期基因活动时，就产生了周期基因的信使RNA(mRNA).

The model was tantalizing, but a few pieces of 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 Michael Rosbash 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. In elegant work, he showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop ( Figure 2B ).

Figure 2B. A simplified illustration of the molecular 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? Michael Young identified yet another gene, doubletime , encoding the DBT protein that 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 clockwork 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 which light can synchronize the clock.

Keeping time on our human physiology

The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day ( Figure 3 ). Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

Figure 3. The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.

Key publications

主要论文

Zehring, W.A., Wheeler, D.A., Reddy, P., Konopka, R.J., Kyriacou, C.P., Rosbash, M., and Hall, J.C. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39 , 369–376.

Bargiello, T.A., Jackson, F.R., and Young, M.W. (1984). Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312 , 752–754.

Siwicki, K.K., Eastman, C., Petersen, G., Rosbash, M., and Hall, J.C. (1988). Antibodies to the period gene product of Drosophila reveal diverse tissue distribution and rhythmic changes in the visual system. Neuron 1 , 141–150.

Hardin, P.E., Hall, J.C., and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343 , 536–540.

Liu, X., Zwiebel, L.J., Hinton, D., Benzer, S., Hall, J.C., and Rosbash, M. (1992). The period gene encodes a predominantly nuclear protein in adult Drosophila. J Neurosci 12 , 2735–2744.

Vosshall, L.B., Price, J.L., Sehgal, A., Saez, L., and Young, M.W. (1994). Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263 , 1606–1609.

Price, J.L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B., and Young, M.W. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94 , 83–95.

Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 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. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.

Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 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.

Illustrations: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of mankind.

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