Individual Circadian Clocks Might Be the Next Frontier of Personalized Medicine

For as long as Seemay Chou can remember, she has gone to bed at midnight and woken around 4:30 a.m. Chou long assumed that meant she was a bad sleeper. Not that she felt bad. In fact, sleeping just four hours a night left her feeling full of energy and with free time to get more done at her job leading a research lab that studies bacteria. “It feels really good for me to sleep four hours,” she says. “When I’m in that rhythm, that’s when I feel my best.”

Still, in an effort to match the slumber schedules of the rest of the world, she would sometimes drug herself–with melatonin, alcohol or marijuana edibles–into getting more sleep. It backfired. “If I sleep seven or eight hours, I feel way worse,” she says. “Hung over, almost.”

Although the federal government recommends that Americans sleep seven or more hours per night for optimal health and functioning, new research is challenging the assumption that sleep is a one-size-fits-all phenomenon. Scientists have found that our internal body clocks vary so greatly that they could form the next frontiers of personalized medicine. By listening more closely to the ticking of our internal clocks, researchers expect to uncover novel ways to help everybody get more out of their sleeping and waking lives.

Human sleep is largely a mystery. We know it’s important; getting too little is linked to heightened risk for metabolic disorders, Type 2 diabetes, psychiatric disorders, autoimmune disease, neurodegeneration and many types of cancer. “It’s probably true that bad sleep leads to increased risks of virtually every disorder,” says Dr. Louis Ptacek, a neurology professor at the University of California, San Francisco (UCSF). But details about what’s actually going on during shut-eye are sparse. “We know almost nothing about sleep and how it’s regulated,” says Ptacek.

Some people are morning larks, rising early, and others are night owls, who like staying up late. Those patterns are regulated by the body’s circadian rhythm, a 24-hour internal clock. People can manipulate their circadian rhythm through all kinds of external factors, like setting an alarm clock or exposing themselves to light. But the ideal sleep duration has long been thought to be universal. “There are many people who think everyone needs eight to eight and a half hours of sleep per night and there will be health consequences if they don’t get it,” says Ptacek. “But that’s as crazy as saying everybody has to be 5 ft. 10 in. tall. It’s just not true.”

Ptacek and his wife Ying-Hui Fu, also a professor of neurology at UCSF, are pioneers in the relatively new field of sleep genetics. About a decade ago, Fu discovered the first human gene linked to natural short sleep; people who had a rare genetic mutation seemed to get the same benefits from six hours of sleep a night as those without the mutation got from eight hours. In 2019, Fu and Ptacek discovered two more genes connected to natural short sleep, and they’ll soon submit a paper describing a fourth, providing even more evidence that functioning well on less sleep is a genetic trait.

The researchers are now collecting data on short sleepers in order to figure out just how rare these mutations are. “If we can get a better understanding of why their sleep is more efficient, we can then come back and help everybody sleep more efficiently,” Fu says. Among the participants is Chou, who also happens to work at UCSF. One day at a faculty meeting, she and Ptacek chatted about his work. She immediately recognized herself when he described short sleepers. “I had never heard of this. But once I started reading about it, it was sort of an epiphany.”

Chou doesn’t know yet if she has the identified genetic variants. But after the researchers interviewed her about her family’s sleeping patterns, she realized her mom is also a short sleeper. “I have memories of when I was younger, and my dad being frustrated with her for staying up really late, but she always seemed fine,” she says. The researchers took blood samples from both women.

Doctors once dismissed short sleepers like Chou as depressed or suffering from insomnia. Yet short sleepers may actually have an edge over everyone else. Research is still early, but Fu has found that besides being more efficient at sleep, they tend to be more energetic and optimistic and have a higher tolerance for pain than people who need to spend more time in bed. They also tend to live longer. Chou says the first three hold true for her; by nature, she is sunny and positive, and though she often finds bruises on her body, she usually doesn’t remember getting them. “I find it annoying how much people complain about little physical pains,” she says.

So far, these are just intriguing observations. But by studying genetic short sleepers, Fu and Ptacek believe they’ll eventually learn lessons for the rest of us. “As we identify more and more genes and we think about the pathways in which they function, at some point, a picture is going to emerge, and we will begin to have an understanding of how sleep is regulated in greater detail,” Ptacek says. This, they hope, will lead to targeted treatments, like pills or vitamins, to improve sleep efficiency in everyone.

Researchers are also looking beyond sleep to other circadian bodily processes that might benefit from a personalized or targeted approach. While a master clock in the brain acts like a conductor, setting time for the whole body, the rest of the body is like orchestra players with clocks of their own. “All your organs have rhythms,” says Steven Lockley, an associate professor of medicine at Harvard Medical School who studies circadian rhythms and sleep. “There’s a clock in your heart, a clock in the lungs, a clock in the kidneys.” Just about everything in the body–metabolism, hormones, the immune system, reproductive function and the way DNA is translated–is influenced by a circadian rhythm, he says.

And not everybody’s is the same. People’s internal clocks are often hours off from one another, Lockley says. “The range of individual differences is much bigger than anyone really understands yet.”

The body’s complex clock system has implications for both healthy people and those with medical conditions, and scientists are already seeing glimpses of how they can time certain tests and treatments to get more accurate or potent results. A cholesterol reading, for example, might be affected by what time of day you go to the doctor’s office, because the liver (which makes cholesterol) has a circadian rhythm. “The time of day at which you measure something could make someone look clinically abnormal, even though they’re not,” Lockley says.

Medicine might also be more effective if taken at a certain time. Because they’re metabolized in the liver, “drugs change their effects throughout the day,” Lockley says. Other circadian bodily processes, like cell function, can also affect how medication acts. Early research suggests certain drugs–including some for colorectal cancer, pain and asthma–perform better or are less toxic when taken at different times of day.

Exercise, which can be as powerful as medicine for some conditions, is good for you whenever you do it. “But I do think that the time of day may have an influence, on top of the effects of exercise, on our metabolic health,” says Juleen Zierath, professor of physiology at Karolinska Institute in Sweden. In one small study published in 2018 in the journal Diabetologia, Zierath and her team started 11 men with Type 2 diabetes on a high-intensity interval training program. The men exercised either in the morning (around 8 a.m.) or the afternoon (4 p.m.) for two weeks, then switched schedules. The researchers expected that regardless of the time of day, men in both groups would see improvements in blood-sugar levels. But “when they exercised in the morning, they actually had slightly higher levels of blood sugar [than baseline], which we didn’t expect at all,” Zierath says. It’s not clear to what extent the type of exercise and other variables matter, but the study provides an intriguing hint that time of day might make a difference for exercise.

Scientific knowledge is nascent when it comes to optimizing testing and treatment by the clock. Our understanding of individual circadian time is even more primitive. But Lockley believes it’s the key to personalized medicine; he and others are exploring ways to measure a person’s internal circadian time through simple clinical tests. “Hopefully in the next five to 10 years, you’d go to the doctor, give a breath test or a pee sample, and the doctor would know your biological time,” he says. “Then all your test results and treatments could be based on your real internal time, which is going to be very different between you and me based on our internal clocks.”

For now, even the understanding that our bodies often operate according to different clocks is a big scientific advance. It’s already changed the way Chou sleeps, lives and works. “I’ve just become more comfortable with accepting my sleep,” she says. She now asks her employees about their sleep schedules to anticipate when each will be at their peak. She also informs everyone about her own abbreviated schedule, so they know she doesn’t expect an immediate response to an email she sends at 4:05 a.m. “That’s just when my brain is working,” she says.