The Workings of Our Inner Clock – Nobel Prize in Physiology or Medicine 2017

2017 Nobel Laureates in Physiology or Medicine: Jeffrey C. Hall, Michael Rosbash and Michael W. Young. Illustration: Niklas Elmehed. Copyright: Nobel Media AB 2017

2017 Nobel Laureates in Physiology or Medicine: Jeffrey C. Hall, Michael Rosbash and Michael W. Young. Illustration: Niklas Elmehed. Copyright: Nobel Media AB 2017

 

Our body functions differently during the day than it does during the night – as do those of many organisms. This phenomenon, referred to as the circadian rhythm, is an adaptation to the drastic changes in the environment over the course of the 24-hour cycle in which the Earth rotates about its own axis. How does the biological clock work? A complex network of molecular reactions within our cells ensures that certain proteins accumulate at high levels at night and are degraded during the daytime. For elucidating these fundamental molecular mechanisms, Jeffrey C. Hall, Michael Rosbash and Michael W. Young were awarded the Nobel Prize in Physiology or Medicine 2017.

Already in the 18th century, the astronomer Jean Jacque d’Ortous de Mairan observed that plants moved their leaves and flowers according to the time of the day no matter whether they were placed in the light or in the dark, suggesting the existence of an inner clock that worked independently of external stimuli. However, the idea remained controversial for centuries until additional physiological processes were shown to be regulated by a biological clock, and the concept of endogenous circadian rhythms was finally established.

 

Simplified illustration of the feedback regulation of the period gene.  Illustration: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén

Simplified illustration of the feedback regulation of the period gene. Illustration: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén

The first evidence of an underlying genetic programme was found by Seymour Benzer and Ronald Konopka in 1971 when they discovered that mutations in a particular gene, later named period, disturbed the circadian rhythm in fruit flies. In the 1980s, the collaborating teams of the American geneticists Jeffrey C. Hall and Michael Rosbash at Brandeis University as well as the laboratory of Michael W. Young at Rockefeller University succeeded in deciphering the molecular structure of period. Hall and Rosbash subsequently discovered how it was involved in the circadian cycle: they found that the levels of the gene’s product, the protein PER, oscillated in a 24-hour cycle, and suggested that high levels of PER may in fact block further production of the protein in a negative self-regulatory feedback loop. However, how exactly this feedback mechanism might work remained elusive.

Years later, the team of Michael W. Young contributed the next piece to the circadian puzzle with the discovery of another clock gene, named timeless. The protein products of period and timeless bind each other and are then able to enter the cell’s nucleus to block the activity of the period gene. The cycle was closed when, in 1998, the teams of Hall and Rosbash found two further genes, clock and cycle, that regulate the activity of both period and timeless, and another group showed that vice versa the gene products of timeless and period control the activity of clock. Later studies by the laureates and others found additional components of this highly complex self-regulating network and discovered how it can be affected by light.

The ability of this molecular network to regulate itself explains how it can oscillate. However, it does not explain why this oscillation occurs every 24 hours. After all, both gene expression and protein degradation are relatively fast processes. It was thus clear that a delay mechanism must be in place. An important insight came from Young’s team: the researchers found that a particular protein can delay the process and named the corresponding gene doubletime.

It has since been discovered that the physiological clock of humans works according to the same principles as that of fruit flies. To ensure that our whole body is in sync, our circadian rhythm is regulated by a central pacemaker in the hypothalamus. The circadian clock is affected by external cues such as food intake, physical activity or temperature. But how does the circadian clock affect us? Our biological rhythm influences our sleep patterns, how much we eat, our hormone levels, our blood pressure and our body temperature. Dysfunction of the circadian clock is associated with a range of diseases including sleep disorders, depression, bipolar disorders and neurological diseases. There is also some evidence suggesting that a misalignment between lifestyle and the inner biological clock can have negative consequences for our health. An aim of ongoing research in the field of chronobiology is thus to regulate circadian rhythms to improve health.

 

Lisa Vincenz-Donnelly

About Lisa Vincenz-Donnelly

Lisa Vincenz-Donnelly is a member of the communications team of the Lindau Nobel Laureate Meetings. Before joining the Lindau team, she studied Chemistry and Biochemistry in Galway, Ireland, and completed her doctoral degree in the lab of F. Ulrich Hartl at the Max Planck Institute of Biochemistry in Martinsried, Germany.

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