The study, which appeared in the early online edition of the Proceedings of the National Academy of Sciences, found that mice lost 85 percent of their hair if they received radiation therapy in the morning, compared to a 17-percent loss when treatment occurred in the evening.
Researchers from USC, the Salk Institute for Biological Studies and the University of California, Irvine (UCI), worked out the precise timing of the hair circadian clock as well as uncovered the biology behind the clockwork — the molecules that tell hair when to grow and when to repair damage. The researchers then tested the clock using radiotherapy.
“These findings are particularly exciting because they present a significant step toward developing new radiation therapy protocols that include minimizing negative side effects on normal tissues, such as hair or bone marrow, while maintaining the desired effects on cancer cells,” said the study’s first author Maksim Plikus, formerly a postdoctoral fellow at USC and now an assistant professor of developmental and cell biology at UCI. “We will now apply our findings to design novel circadian rhythm-based approaches to cancer therapy.”
The scientists can’t say their findings will directly translate to human cancer therapy because they haven’t yet studied that possibility. But they say it is becoming increasingly clear that body organs and tissues have their own circadian clocks that, when understood, could be used to time drug therapy for maximum benefit.
“This suggests that delivering a drug to an organ while it is largely inactive is not a good idea. You could do more damage to the organ than when it is awake, repairing and restoring itself,” said the study’s co-lead investigator, Satchidananda Panda, an associate professor in Salk’s Regulatory Biology Laboratory and an expert on circadian rhythm. “If you know when an organ is mending itself, you might be able to deliver more potent doses of a drug or therapy. That might offer a better outcome while minimizing side effects.”
Cheng-Ming Chuong, professor of pathology at the Keck School of Medicine of USC and the study’s co-lead investigator, and Plikus are experts on hair regeneration. Panda uses genetic, genomics and biochemical approaches to identify genes under circadian regulation in different organs and to understand the mechanism of such regulation. They teamed together to find and then take apart the mouse hair circadian clock. It was a long and difficult study, according to Chuong.
“Hair is a very complicated organ, featuring different types of cells going through different stages in the life cycle in a very tiny space,” he said. “We found that hair in mice grows fast in the morning and slows down at night, engaging a very powerful clock.”
Every time hair cells divide, they pick up DNA damage that needs to be repaired. The scientists discovered that mice hair cells repair the damage primarily in the evening.
Radiotherapy damages DNA in cells that divide rapidly, which is why it is used against growing cancer cells. That means DNA damage to hair cells from radiotherapy delivered in the morning is not repaired until the evening, leading to hair loss. Damage from radiotherapy at night, however, is minimized because hair cells, already in the process of repairing DNA, can quickly heal.
“While we don’t yet know if human hair follows that same clock we found in mice hair, it is true that facial hair in men grows during the day, resulting in the proverbial 5 o’clock shadow. There is no 5 a.m. shadow if you shave at night,” Panda said.
Scientists know for certain that other organs, such as the liver, use a circadian clock, and they suspect that all human tissue is similarly regulated, though the clocks may be timed differently. According to Chuong and colleagues, the clinical implications for these various internal clocks may go beyond timing of drug therapy.
“For example, some researchers suspect that obesity and diabetes occur when an organ or organs — perhaps the liver or stomach or pancreas — should be sleeping, but is awoken by food that needs to be processed,” Panda said.
Other contributing authors on the study were Damon de la Cruz from USC, Christopher Vollmers and Amandine Chaix from Salk, and Raul Ramos from UCI.
The study was supported by grants from the National Institutes of Health (grant numbers AR42177, AR47364, DK091618 and P30 CA014195), The Leona M. and Harry B. Helmsley Charitable Trust, The Charles A. Dana Foundation, the Glenn Foundation for Medical Research and the Edward Mallinckrodt Jr. Foundation.