Dancing to the circadian rhythm: NHLBI researcher finds new genes for body’s internal clock

Might lead to better understanding of sleep disorders, heart disease, and more

If you feel energized or tired around the same time each day, or routinely get up early or stay up late—the familiar ‘early riser’ or ‘night owl’ syndrome—you are witnessing, in real time, your circadian rhythm at work. That’s the 24-hour internal body clock which controls your sleep/wake cycle. 

Circadian rhythms have long fascinated researchers—decades ago three of them marked a critical milestone when they discovered the molecular components behind that mysterious timing cycle. For this game-changing finding, the trio recently was awarded the 2017 Nobel Prize in Physiology or Medicine. Since their discovery researchers have come to know that the circadian clock affects not just sleep, but hormone production, eating habits, body temperature, heart rate, and other biological functions.

Yet, for all these advances, scientists still know relatively little about the clock’s genetic underpinnings. Now a team of NHLBI researchers is working to change that with the discovery of scores of new genes they say have a profound impact on the circadian rhythm. These researchers say these genes could hold the key to a new understanding of a wide range of health conditions, from insomnia to heart disease, and perhaps pave the way for new treatments for them.

NHLBI researcher Dr. Susan Harbison displays a device used to record sleep and activity in fruit flies. Photo credit: Yazmin Serrano Negron, NHLBI.

For sure, the studies are slowly unfolding. For example, long-term night shift work has been associated with an increased risk of high blood pressure, obesity, and heart disease. Some studies have shown a link between circadian rhythm changes and cancer.  And a recent study by researchers in France found that heart surgery is safer in the afternoon than in the morning, a phenomenon they attribute to the body’s circadian clock having a better repair mechanism in the afternoon than in the morning.

Now, thanks to Harbison and her research team, new insights into why some people experience longer or shorter periods of wakefulness or sleepiness than others—and what it might mean for a host of health conditions—could be on the horizon.

To explore this line of research more deeply, Harbison is working with a favorite laboratory model of sleep researchers: Drosophila melanogaster, the common fruit fly.  While this little fly may seem like an unlikely choice, it turns out to be an appropriate stand-in for humans.

“The clock mechanisms regulating circadian rhythm in humans and fruit flies are remarkably similar,” Harbison said. “They both have biological rhythms of about 24 hours. In fact, the genes involved in mammalian circadian rhythms were first identified in flies.”

Previous studies by other researchers had identified approximately 126 genes for circadian rhythms in fruit flies.  In recent studies using a natural population of flies, Harbison’s group estimates that there are more than 250 new genes associated with the circadian clock, among the largest number identified to date.  Many of the genes appear to be associated with nerve cell development—not surprising, she said, given the wide-ranging impact of circadian rhythms on biological processes.

In addition to finding this treasure trove of clock-related genes, Harbison’s group also found that the circadian patterns among the flies were highly variable, and that some of the genes code for variability in the circadian clock. Some flies had unusually long circadian periods—up to 31 hours—while others had extremely short circadian periods of 15 hours.  In other words: Just like people, there were ‘early risers’ and ‘night owls’ and long sleepers and short sleepers among the fruit flies.

“Before we did our studies, there was little attention paid to the genes responsible for variability in the circadian period,” noted Harbison, who is also looking at environmental factors that might influence these genes, such as drugs like alcohol and caffeine. “We now have new details about this variability, and that opens up a whole new avenue of research in understanding what these genes do and how they influence the circadian clock.”

Credit: Courtesy of Susan Harbison, NHLBI.

This graph shows rest and activity patterns for two different fruit flies. The graph on the left shows the rest and activity of a fly with a normal circadian period (about 24 hours). Vertical blue bars show the fly's activity during the day (yellow horizontal bars) and night (black horizontal bars). The graph on the right shows the rest and activity of a fly with an abnormal circadian period (about 31 hours). The abnormal pattern is similar to an individual with a circadian rhythm disorder. Graphic courtesy of Susan Harbison, NHLBI.

Harbison says that for most people, disruptions to the circadian clock have a temporary effect, as occurs with daylight saving time or jet lag from overseas travel, when a person may experience short-term fatigue as they adjust to a time change or new time zone. But for some, disruptions to the clock are associated with chronic health effects, as occurs with night shift workers. Others who suffer from certain circadian rhythm disorders— such as delayed sleep phase disorder—may find it extremely difficult to fall asleep at a desired time.

“The clock architecture is not set in stone and is not a ‘one size fits all’ device,” she noted. “What we’re finding is that the effect of disrupting the circadian clock differs depending on the genetic makeup of the individual. Just as human height and other traits are variable, the same is true of circadian traits among different individuals.”
 
In the future, Harbison hopes that these newly identified genes might ultimately be linked to specific disease processes in humans. Her findings could lead to the discovery of new biomarkers for diagnosing circadian disorders and lay the groundwork for new treatments for sleep and circadian disorders in humans.