Ironically, Erik Herzog was experiencing jet lag when he sat down to discuss his new Children’s Discovery Institute grant to study circadian rhythms.  “Jet lag is an example of what happens when your biological clock is out of synch with local time,” he said.  “It’s a good illustration of the power of circadian rhythms on our body processes.”

Dr. Herzog, Associate Professor of Biology at Washington University, had just returned from Japan, where he had given a series of talks about new research into understanding the molecular mechanisms of circadian rhythms in the brain.

The term circadian comes from the Latin circa (around) and diem (day).  Most body processes such as sleep-wake cycles, hormone secretion, and even the rate of cell division are on roughly a 24-hour time clock. Changes in brain wave activity, body temperatures, and other physiological reactions link closely to this cycle.

 “It has been shown that single cells also exhibit these daily oscillations, and there is a cause-effect relationship between abnormal body rhythms and health problems - including cancer,” said Dr. Herzog.

 Therein lies the reason for the CDI grant award.  Approximately 3,200 children are diagnosed with brain cancer every year.  While some of these children are cured of their tumors, they often suffer chronic illnesses, and even second cancers because of the toxicity of their treatment. 

Pediatric oncologist Dr. Josh Rubin, who is collaborating with Dr. Herzog in the grant, cares for children with brain tumors every day in his practice.  In his own research, Dr. Rubin pursues novel treatments to stop these cancers.  The collaborators met at a neuroscience retreat more than a year ago and immediately recognized the synergistic value of combining their efforts.

The partnership between Drs. Herzog and Rubin on this CDI-funded project was born of the shared belief that, because much of our body function varies with time of day, cancer outcomes can be improved by understanding how circadian rhythms regulate cell division.

 “Each child’s body may have a best time of day for killing cancer cells,” said Dr. Rubin. “Likewise, there may be a time of day when that child’s body is best able to detoxify, to rid itself of the effects of drugs. If we can find a way to zero in on those optimum times, we can administer therapies that dramatically increase efficacy and reduce adverse reactions.”

Identifying treatment schedules and anti-cancer drugs that can slow or destroy fast-dividing brain cells is the focus of the collaboration.  Underpinning the project are sophisticated imaging equipment and computer programs in the Herzog and Rubin laboratories.  These exciting new technologies enable the researchers to monitor real-time tumor growth and events within single cells.

Working with Dr. Luciano Marpegan, a postdoctoral fellow, Drs. Herzog and Rubin have begun to examine daily rhythms in cells that can go bad in the most common pediatric brain cancer.  These cells, called glial cells, become gliomas when they divide at pathological rates.  The team has begun to ask whether circadian rhythms in gliomas differ from normal glial cells.

Of particular interest is the effect of a molecule called cyclic adenosine monophosphate or cAMP on cell division.  The concentration of cAMP in normal brain cells is higher than in cancerous cells.  Dr. Rubin’s laboratory has found that manipulating cAMP levels in cells can start or stop pathological cell division.  Recent evidence from Dr. Herzog’s lab has indicated that the circadian clock normally regulates cAMP in cells. 

The investigators will measure cAMP levels in normal and cancer cells over the day and in response to candidate drugs.  These experiments may lead to the development of novel drugs that work by elevating cAMP at critical times to suppress tumor growth.

Drs. Herzog and Rubin believe that their collaboration will significantly advance the search for cancer treatments best suited for each individual’s biological clock.