Our body clocks tell us a lot more than whether we're hungry or tired. One of the leading researchers into 'clock genes', Prof Garret FitzGerald, talks to Dick Ahlstrom
Time is a spur that gets us up for work, stresses us if we are late and tells us when we should eat or sleep. But forget about the clock you wear on your wrist, the real clock that controls our lives is hidden inside.
Scientists are learning more every day about the internal "clock genes" that influence functions such as metabolism, heart rate and blood pressure. These genes set themselves via cells in the eyes that respond to sunlight, but that have nothing to do with vision.
But what influence might the clock genes have on less desirable events such as heart attacks and strokes? And can we learn to reset our biological gene-driven clocks to improve the effectiveness of drugs or stop jet-lag?
The chairman of the department of pharmacology at the University of Pennsylvania, Prof Garret FitzGerald is attempting to answer some of these questions. FitzGerald is a Dubliner who in 2005 won the Boyle Medal award for scientific excellence, given by the Royal Dublin Society and The Irish Times, and who also heads the Institute for Translational Medicine and Therapeutics at UPenn. There he has a group studying clock genes and their influence on our physiological systems.
The team recently published a study in the prestigious US journal Proceedings of the National Academy of Sciences with collaborators in the Salk Institute for Biological Studies in San Diego, California.This study looked in particular at the daytime variation in the incidence of heart attack and stroke. The onset of both these dramatic conditions occurs more frequently in the early morning than at other times of the day.
They also seem to coincide with the early morning rise in clock gene activity which stresses a whole range of bodily functions, including heart rate and blood pressure. The question to be answered was whether the morning spike in heart attack and stroke could be linked to our biological clocks and/or to the stresses associated with waking and getting moving in the morning.
"We decided to look at the key genes in the clock," Prof FitzGerald says. The work was made more complex given it is now understood that while the "master" clock is located in an area of the brain called the suprachiasmatic nucleus in the hypothalamus, most other peripheral tissues also have their own "local" molecular clocks that run in synchrony with the master. The researchers were able to establish how mouse metabolism varied when certain clock genes were blocked. They could also gauge how the impact of stress might become amplified through the influence of clock genes.
They found that in fact clock gene activity plus stress delivered more of a physiological impact. "The most pronounced response to stress occurred in mice at the nadir of the rhythm, corresponding to the early morning hours when clinical vascular events begin to peak," the group writes in PNAS.
"Indeed, one might expect this effect to be pronounced in patients with [high blood pressure] in whom the amplitude of the diurnal variation in blood pressure is exaggerated or in those individuals who do not lower their blood pressure at night."
They argue there is growing evidence that clock gene activity could help produce this spike in cardiovascular events and also that the addition of stress increases the risk of these events. "The early morning hours give the largest response to stress. It is a time-dependent influence on the stress response," says Prof FitzGerald. Learning about how the clock functions opens up lots of therapeutic opportunities. "This raises the prospect of setting the clock in tissue-specific areas."
Certain drugs work better at different times of the day, depending on what the background metabolism is doing. The goal would be to "reset the clock in different tissues" as a way to improve response to a drug. There is also the possibility of reducing the influence of clock-driven stress as a way to lower the burden of heart attack and stroke early in the morning. "I think there is everything to play for," says an optimistic FitzGerald.