A Timely Award: On Circadian Rhythms

The 2017 Nobel Prize in Medicine or Physiology was awarded this month to American researchers Jeffrey Hall, Michael Rosbash, and Michael Young for their work on circadian rhythms. The circadian rhythm, often described as an internal body clock, is best known as the explanation for jet lags and is a biological system that has long since captured the interest of both scientists and the public alike.

According to the National Institute of General Medical Sciences, circadian rhythms—derived from the Latin circa, meaning approximately, and diem, meaning day—are physical, mental, and behavioral changes that follow an approximate 24-hour cycle. The daily rotation of the Earth causes changes in light and temperature levels, and many life forms have adapted to these oscillations by developing biological clocks that help regulate important physiological and behavioral rhythms such as sleep, metabolism, temperature, and hormone release. Found not only in animals, but also in plants, fungi, and some species of bacteria, circadian rhythms also exist in organs and cells, such as the heart, liver, neurons, and even red blood cells.

An important defining factor of circadian rhythms is that they are endogenous, meaning that they are internally generated and persist even in the absence of external cues. French astronomer de Mairan discovered the endogenous nature of these rhythms when he found that the daily opening-and-closing leaf movements of Mimosa pudica plants continued even when the plants were subjected to constant darkness. However, circadian rhythms face the risk of becoming obsolete if they cannot adjust to environmental changes, such as alterations in length of the day according to seasonal changes; therefore, external cues called zeitgebers act to synchronize circadian rhythms to the surrounding environment. Although light is clearly the most important zeitgeber, temperature, exercise, and social cues have also been identified as factors that influence circadian rhythms.

In mammals, circadian rhythms are controlled by the suprachiasmatic nucleus (SCN), a tiny region located in the hypothalamus. Researchers discovered the role of the SCN as a ‘master clock’ when they found that SCN removal in rats resulted in disrupted daily hormonal and behavioral rhythms, while SCN transplants restored broken rhythms. As mentioned before, circadian rhythms exist in peripheral cells and organs as well, and the SCN is believed to coordinate these independently local oscillations so that the circadian rhythm is functioning properly at an organismal level.

The mechanism of circadian clocks inside cells is where this year’s Nobel prize winners come in. Through studying fruit flies (Drosophila melanogaster), Hall and Rosbash succeeded in isolating the period — often abbreviated into per — gene, a key component in regulating the circadian rhythm. They also discovered that the per gene produces a type of protein called PER, which accumulates in cells overnight and degrades during the day. This led to a hypothesis that the PER protein inhibits the per gene from producing more PER; once PER levels subsequently degrade, per is again free to generate more PER, and this repeats in a continuous feedback loop. Michael Young, on the other hand, discovered another clock gene named timeless (tim) responsible for the production of the TIM protein. TIM paired up with PER to enter the cell’s nucleus and prevent per gene activity, resulting in the aforementioned continuous daily cycle. Many new clock genes have been discovered over the years; doubletime (dbt), Clock (Clk), and cycle (cyc) genes were found in further studies on fruit flies, while research involving mice revealed that mice possessed three different types of period genes (Per1, Per2, and Per3) along with other clock genes such as Bmal1 (the mouse equivalent of cyc in fruit flies) and Clock.

Disruptions in circadian rhythms have been associated with various physical and mental health conditions in humans, and some studies suggest that working night shifts may be related to a higher risk of developing cancer or depression. However, circadian rhythms are highly adaptable, and cases exist where organisms have altered or even eliminated parts of their circadian rhythms. One example of this has been found in the reindeer (Rangifer tarandus); in the arctic regions where it dwells, summer entails months of constant daylight, while winter brings the opposite. The reindeer have adapted themselves to these extreme conditions through developing a highly sensitive circadian rhythm; regular rhythms can be observed during the short periods of fall and spring, where the duration of day and night are similar in a 24-hour-cycle, but they lose these rhythms in summer and winter and display unpredictable bouts of rest and activity. A group of researchers (Lu, Meng, Tyler, Stokkan, and Loudon) hypothesized that reindeer activity and melatonin levels were directly influenced by the presence of light instead of being regulated by circadian rhythms; to test this out, they exposed a group of reindeer to short 2.5-hour-cycles of light and dark. Melatonin is a hormone that helps regulate sleep and wake cycles, and in the reindeer’s case, it took less than 15 minutes of darkness to result in a sharp increase of melatonin. Once the lights were back on, however, melatonin levels abruptly plummeted within the span of 30 minutes. Research concerning the clock genes themselves further supported the hypothesis, which demonstrated that reindeer clock gene oscillations were significantly weaker and more arrhythmic than those seen in mice. A possible explanation for these findings is that the arctic is an environment where specialized adaptive functions can often be found, and circadian rhythms may not be an exception; in the reindeer’s case, there would be little value in maintaining a 24-hour rhythm in an environment where 24-hour cycles do not persist for the most of the year. Such modified or diminished circadian rhythms are more common than generally thought and can be seen in a variety of organisms such as honeybees, sharks, and migratory birds. Examples of animals with modified circadian rhythms in response to specialized environments support the notion of the adaptive and evolutionarily dynamic nature of circadian rhythms, and further research may yield a deeper understanding of crucial questions regarding circadian rhythms such its origins and evolutionary benefits in possessing them.

The circadian rhythm is fascinating on molecular, genetic, and evolutionary levels, and the more we discover, the more relevant it becomes to human life and wellbeing. We now know that medications and drugs should be taken at the right time to maximize effectiveness; for example, research on liver circadian rhythms have revealed that statins are best taken before bedtime, as cholesterol production in the liver is highest after midnight and lowest during the morning and early afternoon.