Telling Body Time

A new method could make assessing a person’s circadian rhythms easier, paving the way for increased drug effectiveness.

By Hayley Dunning |

FLICKR CREATIVE COMMONS, AARON GELLER

Circadian rhythms dictate the 24-hour shifts in gene expression, protein levels, and various cellular processes throughout the day, such as melatonin affecting our sleep-wake cycle. Such changes in cell activity—in particular, cyclical changes in metabolism— can greatly influence the effectiveness of a drug and the severity of its side effects, depending on when it is administered.

However, each individual has unique circadian timing, with “body time” being offset by as much as 6 hours between people, making it difficult—if not impossible—for doctors to consider when giving drugs. Previous attempts to assess a person’s body time have relied on intense, repeated sampling procedures impractical for clinical applications. But in a study published yesterday (August 27) in the National Academy of Sciences proceedings, researchers have demonstrated a new method that requires only two blood samples taken 12 hours apart.

“Due to a combination of genetics and environment, there is a wide diversity of clock times among humans, from morning larks to night owls,” chronobiologist Steven Brown of the University of Zurich, who was not involved in the study, said in an email. “It would be advantageous to have a simple method to accurately determine clock time before a particular treatment, particularly for a toxic one like chemotherapy of cancer.”

Determining where in the cycle a person’s body clock is at any given time typically involves measuring melatonin and/or cortisol levels. These chemicals show robust patterns over a 24-hour period. However, random sampling must be done continuously for more than a day under controlled environmental conditions to determine the patient’s baseline levels. In the new study, Hiroki Ueda and colleagues at the RIKEN Center for Developmental Biology in Kobe, Japan, measured as many oscillating metabolites as possible to create a chart of how they fluctuate in proportion.

The concept is based on 16th-century botanist Carolus Linnaeus’ flower clock. “Each flower has different timing for opening and closing,” said Ueda. Linnaeus reasoned that if he knew when a range of flowers opened and closed in a day, he could create a garden to tell the time. “Likewise,” Ueda said, “each metabolite has different timing, so I applied this concept to the human body.”

Three study participants had blood samples taken every hour for 1.5 days, under normal sleep-wake conditions and then again after their normal cycles had been disrupted by a forced 28-hour sleep-wake schedule. Such disruption of natural circadian cycles is known to occur in shift workers or people travelling between time zones, and can cause weight gain and obesity, metabolic abnormalities and diabetes, and even heart disease.

The researchers measured the levels of 58 metabolites by liquid chromatography-mass spectrometry and used radioimmunological assays to assess cortisol and melatonin levels. The metabolites, whose levels cycled in participants during their normal cycles, were tracked against patterns of melatonin and cortisol to calibrate the metabolite levels with the body clock. The researchers then drew up a table based on the proportions of metabolites across body times, and used it to estimate the body time of study participants using just two samples taken 12 hours apart. During both disrupted and normal cycles, the team estimated body times within 3 hours of real body time, as shown by the traditional cortisol/melatonin method involving sampling as often as every 20 minutes.

“In principle, the method holds great promise to replace the cumbersome melatonin assay,” said Brown. “In practice, however, the method is still in its infancy.” The method has still limited the accuracy of liquid chromatography-mass spectrometry, for example, and more work is required to verify this proof of concept result.

But Ueda hopes he can move forward and scale up the study to track the metabolites of thousands of participants and build a comprehensive metabolite timetable. Such a massive dataset could reduce body clock estimation to a single sample per patient, and may help make the practice common in clinical settings. “My small dream is that internal body time is going to be one of the ways for your health to be checked,” he said.

T. Kasukawa et al., “Human blood metabolite timetable indicates internal body time,” Proceedings of the National Academy of Sciences, doi: 10.1073/pnas.1207768109, 2012.

Source: TheScientist
http://the-scientist.com/2012/08/28/telling-body-time/

Posted by
Robert Karl Stonjek