Circadian Biology: The Noble Prize Winning New Interdisciplinary Branch Of Science

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 Transcription-Translation 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.