Many tiny ‘watches’ keep body’s time

The daily rhythms of the body – once thought to be strictly governed by a master clock lodged in the brain – appear to be driven to a remarkable degree by tiny timepieces pocketed in organs all over the body. What’s more, these peripheral timepieces appear to be strikingly idiosyncratic in appearance – more like Swatch watches than the classic Timex. Clocks located in the liver and heart appear to use very different sets of genes to perform essentially the same functions, researchers at the Medical School (HMS) and the School of Public Health (SPH) report in the April 21 Nature online.

The study, among the first to explore circadian time mechanisms outside the brain, could have a potentially broad impact on the burgeoning fields of circadian medicine and postgenomic science.

Clinicians have known for years that organs perform their varied functions at different rates – the heart beats; kidneys transport ions and electrolytes; the liver metabolizes lipids, sugars, and amino acids differently over the course of the day – and have used this knowledge to design more effective drug regimens for patients. A better understanding of what drives those local rhythms, and how they go wrong, could aid physicians’ efforts.

The discovery that different genes perform similar circadian functions also bears on attempts to move beyond the Human Genome Project, to find functions for the tens of thousands of newly described genes. “There is a lesson here beyond clocks, and that is that the relationship between gene regulation and physiology has a giant black box,” said the study’s principal investigator, Charles Weitz, associate professor of neurobiology at HMS.

The existence of peripheral timepieces had been suspected but no one knew how much control they actually had or why they were in organs such as the heart, lungs, and liver in the first place. Using newly developed gene chips, Weitz, Kai-Florian Storch, research fellow in neurobiology at HMS and lead author of the study, and colleagues monitored the activity of 12,000 genes – one-third the entire mouse genome – in the hearts and livers of mice at various points during the day. Mathematical models developed by Wing Wong, professor of computational biology at SPH, revealed that 8 to 10 percent were expressed in a markedly circadian rhythm in both the heart and liver. “That is a pretty big chunk of the genome,” said Weitz.