What Makes Us Tick?

Katie Lowles is a PhD student at the University of Manchester investigating the interaction between immune cells and the circadian rhythm, and how they together influence the extracellular matrix homeostasis in health and disease. She was highly commended in the 2021 Bio-Rad Science Writing Competition. In this guest blog, Katie discusses the circadian clock and why it is important for human health.

Not all biological processes are equally important at all times during a 24-hour period. We are generally most active during the day and glucose utilization and metabolism must increase to meet our energy demands. Conversely, in the evening, melatonin hormone production increases to promote sleep. In fact, many homeostatic processes, such as eating habits, digestion, and body temperature must be temporally regulated throughout a 24-hour period in order to maintain a stable internal bodily state. It is the role of the body’s natural timing device, the circadian clock, to ensure this is the case.

The circadian clock provides organization to biological processes and allows us to adjust to daily environmental changes and respond to external cues that correspond to the light-dark cycle. The clock’s rhythm is set by light exposure, meaning that our internal day coincides with the external day. A synchronized circadian clock is pivotal to our physical and mental health.

Setting the Circadian Rhythm

Driving the circadian rhythm are the master oscillator and slave oscillators. The master oscillator is located in the suprachiasmatic nucleus (SCN) of the brain hypothalamus and functions to set the phase and period of the circadian rhythm. The SCN receives light inputs from photosensitive retinal ganglion cells. It then entrains slave oscillators, which are cell-autonomous, self-sustained peripheral clocks found in most cells of the body. Slave oscillators are responsible for inducing circadian rhythm in local tissue.

On a molecular level, circadian rhythms are controlled by fluctuating gene expression throughout a 24-hour time frame. Pioneering work done by Benzer and Konopka in 1971 showed that mutations in a gene called period altered the circadian cycle in fruit flies – their normal 24-hour cycle was shortened or lengthened depending on which part of the gene was mutated. It was clear that period played a central role in controlling the circadian rhythm in fruit flies.

Award-Winning Circadian Discoveries

A decade later, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young determined that the protein which the period gene encodes was highly abundant at night but not during the day - suggesting that expression of the period gene is synchronized with the external day-night cycle. This led them to the notion that the PERIOD protein was its own switch-master in a transcription-translation feedback loop (TTFL); PERIOD accumulates at night and inhibits its own transcription during the day.

Hall, Rosbash, and Young were awarded the Nobel Prize in 2017 for elucidating the molecular mechanisms controlling circadian rhythms. Their seminal discoveries advanced the field of chronobiology significantly and their work is often considered remarkable as, at the time, the concept of TTFL was a new paradigm and would not have been the obvious mechanism of circadian rhythm control.

Chronodisruption

Our circadian rhythm is set daily by cyclic environmental cues called zeitgebers. Probably the most crucial zeitgeber is the light-dark cycle. It synchronizes the SCN and entrains it to the 24-hour biological day. Ideally, we would all be exposed to strong light in the morning and sleep in dark bedrooms at night. However, for many of us, our light exposure does not reflect natural light levels during a 24-hour solar day. We spend lots of time in artificially lit homes and looking at smartphones - particularly during the evening hours when the circadian rhythm is particularly sensitive to light-induced phase delays. The result is misalignment between the timing of our circadian clocks and the external day, which is often referred to as chronodisruption.

There is a strong link between chronodisruption and health. As well as a reduction in sleep quality, mood, and general well-being, prolonged circadian disruption has been linked to increased likelihood of cardiovascular disease, metabolic disorders, and certain cancers (James et al. 2017). This can have big implications for someone with a constantly changing wake/sleep cycle, such as shift workers.

The importance of entraining the SCN to the 24-hour biological day can be further demonstrated by the results of studying the circadian clock in blind people with no light perception. Instead of having a 24-hour clock which is reset by external light each day, their bodies follow their own intrinsic clock, which often has a period longer than 24-hours (Quera Salva et al. 2017). Therefore, each day their wake/sleep cycle is shifted in a phenomenon called “free-running”. Sleep disturbance and sleepiness throughout the day decrease the quality of life in those with a free-running circadian clock.

Urinary melatonin is often used as a circadian biomarker to diagnose people with free-running disorders. Melatonin synthesis is inhibited by light, meaning in individuals with a normal 24-hour circadian clock, melatonin concentration peaks at night to promote sleep. In individuals with free-running disorders, it peaks later and concentrations during the day are abnormally high, causing drowsiness during the day and difficulty falling asleep at night (Zisapel 2018). To treat patients, FDA-approved melatonin receptor agonist, tasimelteon is used and has been proven effective for reducing free-running in totally blind patients (Johnsa and Neville 2005).

The Importance of Chronotype

Even if two sighted people were exposed to the same environmental factors, including light levels and temperature changes, one of them may feel tired and fall asleep at midnight, while the other might fall asleep on the sofa in the early evening. The explanation for differences in a person’s natural inclination to sleep or do activity is their chronotype. Chronotype is dependent on genetic, environmental, and age-related factors (Bauducco et al. 2020). During teenage years, adolescents tend towards a delayed chronotype, meaning they go to sleep and wake up later. This often changes as we age, with a shift towards a "morning lark"chronotype. Increased awareness of the existence of chronotypes is sparking conversations about altering the timings of school or work days to suit our natural body-clocks.

When properly synchronized with the environment, the circadian clock keeps many physiological processes running smoothly - leading to an overall healthier body and mind. In today’s fast-paced society, where huge emphasis is often placed on maximizing productivity, it is important that we make time to step away from the screen, go outside, or have an early night to let our circadian clock catch up.