Circadian Rhythm

The biology of body clock influences everything we do.

Image was taken from Wikipedia; work by YassineMrabet.

Oct 2, 2017, the Nobel Prize of Physiology or Medicine was awarded to three American scientists, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, in honor of their discovery of the molecular mechanism underpinning circadian rhythm.

All of a sudden the term “circadian rhythm” becomes a buzzword in the Internet. Here is a very brief perspective on the fascinating research field.

The word circadian originates from the Latin words Circa, meaning “around”, and dies, meaning “day”. Circadian rhythm is the biological process that displays an endogenous (built-in or self-sustained), entrainable (self-adjusted) oscillation of about 24 hours. These 24-hour rhythm are driven by a biology clock, and it has been widely observed in plants, animals, fungi, and cyanobacteria. (From Wikipedia) The body of research on biological rhythms is called Chronobiology.

“Ever since the emergence of life on earth, about four billion years ago, evolving life forms had to adapt to the rotation of our planet. This ability to prepare for the daily fluctuations is crucial for all life forms”. --Thomas Perlmann, professor and secretary of the Nobel committee for Physiology or Medicine.

So how does the adaption work?

The key discoveries date back to the 1970s and resulted from studies on fruit flies. At that time Seymour Benzer and his student Ronald Konopka identified an unknown gene, the mutations of which disrupted the circadian clock of flies. The gene was named period. [1] It was the first clock gene identified. In 1980s, Nobel Laureates, Jeffrey Hall and Michael at Brandeis University, and Michael Young at Rockefeller University, successfully cloned and isolated the period gene… a big deal in those days [2, 3]. Jeffrey Hall and Michael Rosbash then went on to discover PER, the protein encoded by period. It was observed that protein PER accumulated in cell nuclei during the night and was degraded during the day. [4, 6] The protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm.

Follow-up research found that the fluctuating protein levels were a consequence of, and contributed to, the fluctuating mRNA levels of period [5]. As RNA goes up, protein comes down and vise versa, suggesting a negative feedback mechanism.

Figure 1. The feedback mechanism in the fruit fly circadian rhythm

During the following years more molecular components of the transcriptional machinery were elucidated. In 1994 Michael Young discovered a second gene, timeless, that was essential for the circadian rhythm. It was found that TIM, the protein coded by timeless, physically associated with PER in the cytosol and entered the cell nuclei, where they repressed the transcription of period and blocked the gene transcription, thereby closing the inhibitory feedback loop. [7]

Figure 2. A simplified illustration of the molecular mechanism of period regulation

Since the seminal discoveries by the three laureates, chronobiology has developed into a vast and highly dynamic research field, with wide implications for human and animal health.

More information and resources about the biological time could be found at HHMI's BioInteractive Blog.

References

[1] Konopka R. J. and Benzer S. (1971) Clock mutants of Drosophila melangogaster. Proc. Nat. Acad. Sci. USA 68, 2112-2116.

[2] 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.

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

[4] 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.

[5] 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.

[6] 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.

[7] 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.