Circadian Rhythm & Disease

AND THE BEAT GOES ON

Earlier this week, most areas of North America and Europe observed the annual ritual of “springing forward.” People started setting their clocks ahead one hour in the U.S. in 1918. The federal government aimed to save electricity and increase productivity for the war effort. The disruption of daily routines and sleep that comes with Daylight Saving Time is unwelcome to many. Opposition to the concept runs so strongly that last year, California voters passed a statewide proposition to end the twice-yearly clock change.

Maybe you’re wondering if there’s anything more to the yearly time change than inconvenience. In this issue, we’ll examine circadian rhythms, explore their links to different health conditions, and find out ways drug discovery researchers are delving into taking this biological phenomenon into account. Next week, we look into some of the latest thinking on how we can improve our health by paying attention to our bodies’ ebb and flow.

We’ve Got Rhythm

What are circadian rhythms though? Basically, they are the internal clock that governs the lives of most living organisms—Donald Trump, Nancy Pelosi, trees, flowers, your dog or cat, even some microbes. The roughly 24-hour cycles of physical activity are set primarily by light and darkness. These primordial rhythms play a vital role in human health.

Disrupting circadian rhythms can cause more problems than a few days of fatigue. Abnormal circadian rhythms correlate not just with insomnia, but also with diabetes, heart problems, some cancers, Parkinson’s disease, and more. (Article continues below)

Rocking Around the Clock with Proteins?

Circadian rhythms are regulated not only by cycles of light and dark around us, but also by our own internal cues. These “biological clocks” are groups of related proteins in cells throughout our bodies.

Scientists call the most extensively studied of these cues Clock proteins. They interact with each other and govern the expression of other proteins every 24-hours or so. Consequently, most people feel discombobulated after staying up all night or traveling through several time zones regardless of how much they sleep. Our tiny molecular timekeepers keep signaling us that it’s earlier in Waikiki than Chicago, for example. So a whole range of physiological functions, from temperature to heart rate, blood pressure, and alertness respond as if we’re getting ready for bed in Chicago when instead we’re at a luau on the beach.

Clock proteins, in turn, are regulated by the brain’s master timepiece—the suprachiasmatic nucleus. This region consists of about 20,000 nerve cells. It’s just above where the optic nerve crosses into the brain. This location, called the optic chiasm, explains why so many of these neurons respond to light.

Available Now: Hetlioz

The inability to see light causes many blind people serious problems. Their brains don’t receive the proper input to “set” the suprachiasmatic nucleus. As a result, they experience non-24-hour sleep-wake disorder. Sufferers find it virtually impossible to sleep at standard times. This inability makes holding traditional jobs and maintaining stable relationships extremely difficult.

Help is available, thankfully. In 2014, the FDA approved Vanda Pharmaceuticals’ (Washington, DC) Hetlioz for non-24-hour sleep-wake disorder. Hetlioz is an agonist; it binds directly to and activates the melatonin receptor. You may think of melatonin as an over the counter sleep aid, but nature made it first! Levels of this sleep-inducing hormone normally rise as darkness falls. Completely blind people can’t regulate melatonin production, so Hetlioz aims to normalize sleep patterns.  Synthetic melatonin receptor activators such as Hetlioz are designed to be more stable than the melatonin available at your local pharmacy.

Coming Soon

Aptly-named Synchronicity Pharma (South San Francisco, CA) is focusing on how circadian-rhythm disruptions relate to a range of health disorders including type 2 diabetes, Cushing’s syndrome (elevated cortisol levels), high blood pressure, obesity, sleep apnea, cancer, and inflammation. Scientists at Synchronicity have identified potential circadian-modulating compounds and begun testing the most promising, SHP-1705, in Phase 1 clinical studies.

In the Lab: Busting the Cancer Clock

A possible link between circadian rhythm dysfunction and cancer is inspiring the development of another drug. Clock proteins dictate the timing of cell division. This may mean that circadian disruptions also govern when cancer cells divide. Researchers at the University of California, Santa Cruz are zeroing in on the protein PASD1, which appears in many different cancer cell lines. PASD1 interacts with the Clock proteins, essentially shutting them down. Early preclinical work suggests that inhibiting PASD1 causes the Clock proteins to reactivate—making PASD1 a possible drug target.

Time is of the Essence

Taking medicine at the same time every day can help make sure a dose isn’t forgotten. In certain cases, however, medication timing may also influence how well it works.

For example, blood pressure is tied to circadian rhythm. It naturally falls between midnight and 3 a.m. in most healthy adults. For those with hypertension, however, this drop often fails to occur. Patients can restore this normal rhythm by taking their blood pressure medicine at night.

Dosage timing may also influence the effectiveness of some cancer drugs. For example, PARP1 inhibitors shut down a DNA repair enzyme in malignant cells. The shutdown damages cell DNA so much that they initiate apoptosis—a process in which cancer cells pretty much self-destruct. Researchers at University of North Carolina (Chapel Hill, NC) have learned that DNA repair enzymes are more active later in the day. That behavior means that PARP1 inhibitors may be more powerful if patients take them in the morning because inhibiting the enzymes should be easier when they are less active.

Circadian rhythms govern more than the 24 hours of our days. Uncovering the cellular mechanisms of the sleep-wake cycle might open up new treatment avenues for an array of diseases. Next week, we’ll look at recent research that can help optimize your own circadian rhythms.