The Nobel Prize in Physiology or Medicine 2017

The 2017 Nobel Prize in Physiology or Medicine is awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms that control circadian rhythms. Circadian rhythms are driven by an internal biological clock that anticipates day/night cycles to optimize the physiology and behavior of organisms. Observations that organisms adapt their physiology and behavior to the time of the day in a circadian fashion have been documented for a long time, but the existence of an endogenous circadian clock would only finally become established well into the 20th century. In 1971, Seymour Benzer and Ronald Konopka identified mutants of the fruit fly Drosophila that displayed alterations in the normal 24h cycle of pupal eclosion and locomotor activity. Experiments suggested that the mutations involved the same gene, later named period.

A decade later, Hall and Rosbash, collaborating at Brandeis University, and Young, at Rockefeller University, isolated and molecularly characterized the period gene. However, its structure and sequence did not immediately suggest a molecular mechanism for the circadian clock. A series of breakthroughs, including the identification of other genes that partner with period, from Hall, Rosbash and Young eventually led to the notion of a TranscriptionTranslation Feedback Loop (TTFL). In this mechanism, the transcription of period and its partner gene timeless are repressed by their own gene products – the PERIOD (PER) and TIMELESS (TIM) proteins, generating an autonomous oscillation. At the time, a transcriptional mechanism was not obvious, and the discovery of the self sustained circadian TTFL was a new paradigm.

Further studies revealed a series of interlocked transcription-translation feedback loops, together with a complex network of reactions. These involve regulated protein phosphorylation and degradation of TTFL components, protein complex assembly, nuclear translocation and other post-translational modifications, generating oscillations with a period of ~24 hours. Circadian oscillators within individual cells respond differently to entraining signals and control various physiological outputs, such as sleep patterns, body temperature, hormone release, blood pressure, and metabolism. The seminal discoveries by Hall, Rosbash and Young have revealed a crucial physiological mechanism explaining circadian adaptation, with important implications for human health and disease.

The discovery of self-sustained transcription/ translation feedback loops as the central component of the molecular mechanism by which clock genes control circadian oscillations in cells and tissues has led to a new paradigm in our understanding of how organisms anticipate and adapt to the regular daily environmental cues such as light. Since the seminal discoveries by the three laureates, elucidating a fundamental physiological mechanism, circadian biology has developed into a vast and highly dynamic research field, with important implications for our health and wellbeing.

Circadian clock

The circadian clock has an impact on many aspects of our physiology. This clock helps to regulate sleep patterns, feeding behaviour, hormone release, blood pressure and body temperature. A large proportion of our genes are regulated by the clock.

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