Posted on by Dr. Francis Collins
Some people are early risers, wide awake at the crack of dawn. Others are night owls who can’t seem to get to bed until well after midnight and prefer to sleep in. Why is this? An NIH-funded team has some new clues based on evidence showing how a molecular “switch” wired into the biological clocks of extreme early risers leads them to operate on a daily cycle of about 20 hours instead of a full 24-hour, or circadian (Latin for “about a day”), cycle .
These new atomic-level details, shared from fruit flies to humans, may help to explain how more subtle clock variations predispose people to follow different sleep patterns. They also may lead to new treatments designed to reset the clock in people struggling with sleep disorders, jet lag, or night-shift work.
This work, published recently in the journal eLIFE, comes from Carrie Partch, University of California, Santa Cruz, and her colleagues at Duke-NUS Medical School in Singapore and the University of California, San Diego. It builds on decades of research into biological clocks, which help to control sleeping and waking, rest and activity, fluid balance, body temperature, cardiac rate, oxygen consumption, and even the secretions of endocrine glands.
These clocks, found in cells and tissues throughout the body, are composed of specialized sets of proteins. They interact in specific ways to regulate transcription of about 15 percent of the genome over a 24-hour period. All this interaction helps to align waking hours and other aspects of our physiology to the 24-hour passage of day and night.
In the latest paper, Partch and her colleagues focused on two core clock components: an enzyme known as casein kinase 1 (CK1) and a protein called PERIOD. Clock-altering mutations in CK1 and PERIOD have been known for many years. In fact, CK1 was discovered in studies of golden hamsters more than 20 years ago after researchers noticed one hamster that routinely woke up much earlier than the others [2,3].
It turns out that the timing of biological clocks is strongly influenced by the rise and fall of the PERIOD protein. This daily oscillation normally takes place over 24 hours, but that’s where CK1 enters the picture. The enzyme adjusts PERIOD levels by chemically modifying the protein at one of two sites, thereby adjusting its stability. When one site is modified, it keeps the protein protected and stable. At the other site, it leaves it unprotected and degradable.
Many of these details had been worked out over the years. But, Partch wanted to drill even deeper to answer an essential question: Why does this process normally take 24 hours, which is remarkably slow biochemically? And, what changes in those whose daily cycle gets cut far short?
To find out, her team performed a series of protein structure and biochemical analyses of the CK1 mutation originally found in hamsters, along with several other clock-altering versions of the enzyme found in organisms ranging from flies to humans. What they’ve discovered is a portion of CK1 acts as a switch. When this switch functions normally, it generates a near-perfect 24-hour cycle by keeping PERIOD’s stability just right. In this case, people easily and correctly align their internal clocks to the daily coming and going of daylight.
If the switch favors a faster breakdown of the protein, the daily cycle grows shorter and less tightly bound to daylight. For these early risers, it’s a constant struggle to adjust to life in a 24-hour world. Though they try to get in sync, these early risers are never able to catch up. Conversely, a switch that favors a slower breakdown will lengthen the clock, predisposing some to be night owls.
Such shifts in clock timing can arise from alterations either to the CK1 enzyme or the PERIOD protein. In fact, people with an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome carry a mutation in the PERIOD protein at one of the places that CK1 modifies. The new work shows that this change makes PERIOD more stable by interfering with the enzyme’s ability to mark the protein for degradation.
One thing that makes the CK1 enzyme so fascinating is that it’s extremely ancient. A nearly identical version of the enzyme to the one in humans and hamsters can be found in single-celled green algae! It’s clear that this enzyme and its function in biological clocks is, evolutionarily speaking, rather special. And at one level, that makes total sense—our planet has operated on a 24-hour clock for the entire span of evolutionary time.
The versions of CK1 that Partch’s team studied here are rare in people. She now plans to study other variations that turn up in humans much more often.
Her discoveries are sure to offer a fascinating view on these internal clocks and, pardon the pun, how they make us all tick. She hopes they’ll lead to new ways to adjust the clock in those with sleep disorders and even the means to reset the clock in people who regularly travel overseas or work the night shift.
Ultimately, Partch would like to tap into the crosstalk between biological clocks and the ability of cells to repair their DNA. She wants to see if clock disruptions have any implications for cancer susceptibility. And yes, now’s a good time to find out the answer.
 Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. Philpott JM, Narasimamurthy R, Ricci CG, Freeberg AM, Hunt SR, Yee LE, Pelofsky RS, Tripathi S, Virshup DM, Partch CL. eLIFE. 2020 Feb 11;9.
 A mutation of the circadian system in golden hamsters. Ralph MR, Menaker M. Science. 1988 Sep 2;241(4870):1225-7.
 Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Science. 2000 Apr 21;288(5465):483-92.
Circadian Rhythms (National Institute of General Medical Sciences/NIH)
Advanced Sleep Phase Syndrome, Familial (Genetic and Rare Disease Center/NIH)
Partch Lab (University of California, Santa Cruz)
NIH Support: National Institute of General Medical Sciences; Office of the Director
Posted on by Dr. Francis Collins
This past weekend, I attended a scientific meeting in New York. As often seems to happen to me in a hotel, I tossed and turned and woke up feeling not very rested. The second night I did a bit better. Why is this? Using advanced neuroimaging techniques to study volunteers in a sleep lab, NIH-funded researchers have come up with a biological explanation for this phenomenon, known as “the first-night effect.”
As it turns out, the first night when a person goes to sleep in a new place, a portion of the left hemisphere of his or her brain remains unusually active, apparently to stay alert for any signs of danger. The new findings not only provide important insights into the function of the human brain, they also suggest methods to prevent the first-night effect and thereby help travelers like me in our ongoing quest to get a good night’s sleep.
Posted on by Dr. Francis Collins
As this LabTV profile of an outstanding nurse-scientist shows, there are many different paths to a career in biomedical research. Leorey Saligan grew up in the Philippines, where the challenges and rewards of caring for sick family members inspired him to become a nurse. His first job was at a nursing home in Midland, TX, and the next at a nearby hospital. Later, Saligan moved to Norfolk, VA, where as a nurse practitioner he began caring for people with sarcoidosis, an inflammatory disease that affects several organ systems.
Saligan went on to pursue a Ph.D. in nursing at Virginia’s Hampton University, writing his dissertation on the chronic vision problems associated with sarcoidosis. To gather more data on such problems, he joined NIH’s National Institute of Nursing Research in Bethesda, MD, and, with the help of colleagues, carried out a clinical study. To Saligan’s surprise, the data showed that fatigue, rather than poor vision, was the top concern of people with sarcoidosis. That discovery sparked his research interest in fatigue—an interest now focused on the intense, often debilitating fatigue that many people with cancer experience both during and after treatment, particularly radiation therapy.
Like people with sarcoidosis, people undergoing cancer treatment report that fatigue is the symptom that most negatively affects their quality of life. Many find the fatigue so distressing that their treatment regimens have to be reduced or even halted—actions that may have a negative effect on the cancer-killing power of such treatments. And, for some folks, the fatigue can be long lasting, persisting for months or even years after cancer therapy ends.
By analyzing blood and tissue samples donated by volunteers who are undergoing or who have undergone cancer treatments, Saligan and colleagues from NIH’s Clinical Center and National Cancer Institute have uncovered several promising leads in their effort to gain a better understanding of the molecular mechanisms of treatment-related fatigue. He is also working with behavioral researchers to explore the relationship of fatigue with pain, depression, anxiety, sleep disturbances, and other symptoms. Ultimately, this NIH tenure-track investigator (who also happens to be an officer in the U.S. Public Health Service) wants to see this scientific knowledge translated into effective ways of treating or preventing the fatigue that is a most unfortunate side effect of potentially life-saving cancer therapies.
Effect of Ketamine on Fatigue Following Cancer Therapy (ClinicalTrials.gov/NIH)
Science Careers (National Institute of General Medical Sciences/NIH)
Careers Blog (Office of Intramural Training/NIH)