Circadian Rhythm Research Earned the 2017 Nobel Prize. What’s the Upshot for the Sleep Disorders Field?

A conversation with researcher and clinician Reena Mehra, MD, MS

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The 2017 Nobel Prize in Physiology or Medicine was awarded in October to three American investigators — Jeffrey C. Hall, Michael Rosbash and Michael W. Young — for their discoveries of the molecular mechanisms governing circadian rhythms.

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Consult QD asked Reena Mehra, MD, MS, Director of Sleep Disorders Research at Cleveland Clinic and Professor of Medicine, for her take on what this prize means to the field of sleep medicine.

Q: Why are circadian rhythms important?

Having an internal clock allows life forms to regulate physiological processes to optimize activity during the time of day when they can best take advantage of the environment, and to have a period of quiescence to rejuvenate at other times.

Circadian rhythms are internal variations in our physiology with an approximate cycle length of 24 hours in humans. The master pacemaker of the circadian rhythm is the suprachiasmatic nucleus, which resides in the hypothalamus. This pacemaker receives environmental cues to synchronize to the 24-hour light-dark cycle and relays this timing information to peripheral clocks in our organs, tissues and cells via endocrine and autonomic pathways. Desynchronization of these rhythms is now pervasive in our society, given exposure to light at night and disruptive sleep schedules.

Q: Tell us a bit about the research that led to the Nobel Prize.

Although the discovery of circadian rhythms, and even a bit of their underlying genetic basis, preceded the work of the Nobel Prize winners, their research was the first to work out the autonomous feedback loop that forms the basis of the continuously oscillating nature of a biological clock. Investigating fruit flies, Drs. Hall, Rosbash and Young discovered a “period” gene that encodes for the PER protein, which accumulates in cells during the day and degrades at night. TIM proteins from the “timeless” gene interact with the PER proteins when their level becomes too high to repress PER gene activity.

The actual picture is more complex, but this simplified model illustrates the self-regulatory, approximate 24-hour feedback loop essential to the workings of circadian clocks.

Circadian oscillators are not completely automatic; they are sensitive to internal and environmental signals or cues (i.e., zeitgebers or “time-givers”), such as light, activity, sleep, food and hormone levels.

Q: We now live in a somewhat artificial world where we can regulate light and determine when we work, play and access resources. Are circadian rhythms still relevant?

Definitely. Many biological processes have been established through evolution to ensure that our bodies have a regular, approximate 24-hour rhythm. Substantial disruption to that has real health impacts that are increasingly being recognized.

Cleveland Clinic has a very active Sleep Disorders Center, where we see many patients with sleep disorders and those who are out of sync with their circadian rhythm. Circadian rhythm disorders stem from having a natural clock that is different from others, such as advanced sleep phase syndrome (“morning lark syndrome”) or delayed sleep phase syndrome (“night owl syndrome”), both of which cause chronic sleep disruption when natural rhythms conflict with work or social activities. Another type of circadian rhythm disorder occurs when there’s misalignment of the internal rhythm and the environment, as seen in shift workers and frequent air travelers, who can feel like they’re in a constant state of jet lag. In shift work sleep disorder, emerging data show associations with cancer, metabolic dysfunction and alterations of mood and cognition due to prolonged shift work schedules.

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Impacts on health are compounded when circadian rhythm disorders occur with other sleep disorders, such as sleep apnea.

Q: What can be done about circadian rhythm sleep disorders?

There’s no magic bullet, but we do offer our patients a variety of management techniques. So-called sleep hygiene is important, which emphasizes maintaining a consistent daily sleep schedule and avoiding known sleep disruptors several hours before bedtime, including alcohol, caffeine and device screens. Phototherapy — with specific attention to the timing, intensity and duration of light exposure — in addition to re-entrainment techniques and melatonin can also help.

Q: What’s on the horizon in circadian rhythm sleep research?

At Cleveland Clinic we’re investigating diurnal patterns of paroxysmal atrial fibrillation and how this relates to sleep-disordered breathing. Our previous research uncovered interesting links between obstructive sleep apnea and atrial fibrillation, but diurnal associations have not been well-studied and could provide insights into underlying circadian-related triggers to heart arrhythmias.

Understanding chronobiology of medical disease has the potential to elucidate mechanistic underpinnings that may allow for identification of circadian therapeutic targets. Chronotherapeutics is an exciting, largely untapped field that’s likely to be the focus of much future research. Knowing that biological processes have a circadian rhythm, it makes sense to look into optimizing the effects of medications by more carefully timing dosing. For example, a heart medication may be more effective if taken in the morning than at night, but without experimental evidence, there’s no way to know.

Clinical trials rarely report — or even record — the time of day interventions are administered or when blood samples are collected, and the timing of data collection for end points such as blood pressure is often not standardized. Not taking timing into account increases the likelihood of inaccurately interpreting findings from these studies.

This recent Nobel Prize has expanded awareness of the importance of circadian rhythms. Those of us who specialize in sleep and circadian rhythm disorders have high hopes that the work culminating in this distinction will have significant impacts in the neurosciences and beyond.

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