Keeping the Body Ticking

Newswise — SINGAPORE – Tick tock. Tick tock. A team of scientists from Duke-NUS Graduate Medical School Singapore (Duke-NUS) and the University of Michigan at Ann Arbor have discovered a molecular switch that regulates the body’s circadian clock and allows it to keep time. This switch could be a potential drug target to treat circadian rhythm disorders caused by jet lag, shift work or metabolic disorders. Normally, the circadian body clock (24-hour cycle) is synchronized with the rising and setting of the sun, ensuring that we sleep at night. One of the reasons this is possible is because the body clock is relatively insensitive to small changes in temperature. This is important because otherwise, the body clock could run too fast when it is hot or too slow when it is cold. A long-standing scientific mystery is how our body clock compensates for changes in temperature and maintains its speed. Over the past few decades, research has advanced our understanding of the circadian clock. One of the proteins critical for determining the timing of the clock, as well as the timing of sleep, is Period2 (PER2). In the current study, published October 1 in the journal Molecular Cell and led by David Virshup, M.D., from Duke-NUS and Daniel Forger, Ph.D., from Michigan, the findings shed light on how PER2 regulates our circadian clock. It also clarifies how the clock adapts to diverse conditions such as temperature and metabolic changes. The research team found that the stability of PER2 is dependent on a process called phosphorylation, in which phosphates are added at key sites to influence the function of PER2. Virshup and the team discovered that phosphorylation acts as a switch. This “phosphoswitch” leads to two alternative fates for PER2: increased stability or increased degradation. The researchers report that this phosphoswitch is sensitive to changes in temperature and metabolic signals and so it fine-tunes clock speed as needed. Usually, the rate of a biochemical reaction increases as the temperature rises, so in this case the speed of the body clock should increase if the temperature rises. However, the team showed that at higher temperatures, the phosphoswitch ensures that degradation of PER2 is slower, therefore maintaining the speed of the body clock. “This study sheds light on one of the biggest mysteries of the circadian clock in the last 60 years and has helped to explain some of the basic mechanisms that govern the timing of the clock,” explained Virshup, director of the Cancer and Stem Cell Biology Programme at Duke-NUS and professor of pediatrics at the Duke University School of Medicine. “By using both biochemical analysis and mathematical modeling we demonstrated how the core circadian clock keeps to a 24-hour cycle despite temperature changes and metabolic changes.” The findings have several implications. The phosphoswitch gives researchers and scientists a potential drug target to influence the behavior of the circadian clock. This new target may make it possible to counter the effects of jet lag, shift work and, perhaps, seasonal affective disorder. The study also provides a mathematical model that accurately predicts the behavior of the clock under different circumstances. This model will be useful in determining when drugs should be administered to modify circadian rhythms so that they are most effective. The next step for the team is to test their predictions in an animal model. They plan to explore more about how phosphatases, an enzyme found in the body, and other kinases may be important in regulating the circadian clock. Their current hypothesis is that the interplay of these systems will regulate the sleep and wake cycle. In addition to Virshup and Forger, study authors include first author Duke-NUS research fellow Min Zhou and KAIST mathematician assistant professor Jae Kyoung Kim. This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Investigator Research Grant. About Duke-NUS Graduate Medical SchoolThe Duke-NUS Graduate Medical School Singapore (Duke-NUS) was established in 2005 as a strategic collaboration between the Duke University School of Medicine and the National University of Singapore (NUS). Duke-NUS offers a graduate-entry, four-year M.D. (Doctor of Medicine) training program based on the unique Duke model of education, with one year dedicated to independent study and research projects of a basic science or clinical nature. Duke-NUS also offers M.D./ Ph.D. and Ph.D. programs. Duke-NUS has five signature programs: Cancer and Stem Cell Biology, Neuroscience and Behavioural Disorders, Emerging Infectious Diseases, Cardiovascular and Metabolic Disorders, and Health Services and Systems Research. This year, Duke-NUS celebrates its 10th anniversary. In this time, Duke-NUS and SingHealth have established a strategic partnership in academic medicine that will guide and promote the future of medicine, combining the collective strengths of SingHealth's clinical expertise and Duke-NUS' biomedical sciences research and medical education capabilities. For more information, please visit www.duke-nus.edu.sg