Back in 1960, researchers discovered that a specific toxin, given to a mouse at one time of the day, would kill it. Administer the same poison at a different time, and the mouse was fine.
The study of mammals’ circadian rhythms has come a long way since then, but in humans, circadian medicine is still in its infancy. However, understanding how our bodies rhythms influence our receptivity to chemicals could have big effects. Researchers at Cincinnati Children’s Hospital Medical Center have created a “human circadian atlas” with information about how our circadian rhythms affect different parts of the body. They hope it will help make the idea of personalized medicine built around the body clock more mainstream, and improve patient outcomes.
Not all genes are driven by the clock. Some do the same processes, producing the same chemicals, all the time. But half of your genome—the genetic information in your body—is regulated by your body clock. That can have important implications, especially for medicine. Studying different kinds of animals has produced databases of how their body clock affects different kinds of tissues in the body. But until now, there’s been no such database for humans—and no explicit confirmation that half our genome, as with other mammals, relies on the clock. In this study, “we were interested in identifying the molecular rhythms of different human tissues,” first author Mark Ruben says. They reported back on 13 different types of human tissue, including colon, thyroid, and several different heart tissues.
An example of when this knowledge might be useful is in administering chemotherapy drugs like streptozocin, which is used to treat a certain kind of pancreatic cancer. “It’s a pretty effective drug, but its major downside is the toxicity,” says coauthor John Hogenesch. It’s toxic to both the liver and kidneys. But the drug has a half-life of only 15 minutes, which means if it’s administered at the right time, it can treat the pancreas when the kidneys and liver are least susceptible to it.
But although tissues are all driven by the body clock, they’re doing different things at different point in the day. Using an algorithm called CYCLOPS (cyclic ordering by periodic structure), the team was able to figure out the rhythms of 13 different kinds of tissue in the body—including the liver and kidneys. All of these tissue types are medically important, and a database like this opens up new avenues for personalized treatment, because some drugs designed are more effective—or do less damage—at certain points in the tissue’s rhythm.
“What I think is probably the most interesting finding [of the study] is that this data was preserved at the population level,” says Hogenesch. That means regardless of who you are—your race, age, or health status—your tissues follow the same rhythms. It makes the prospect of tackling actually figuring out the optimal point in the rhythm to administer drugs much less daunting, he says.
“We know that circadian rhythm is very important from a medical treatment perspective,” says University of California at San Francisco molecular biologist Ying-Hui Fu, who was not involved in the study. This paper “comes at a big gap,” she says, and will hopefully demonstrate to doctors the value (and feasibility) of thinking about circadian rhythms during treatment.
“I think this is a part of medicine that hasn’t really been embraced yet,” says Kenneth Wright, a University of Colorado neuroscientist who was not involved with the study. But that may be changing, he says. Three American scientists won the Nobel Prize in Physiology or Medicine last year for their discovery of the molecular mechanisms underlying circadian rhythm, and he says the field is gaining wider recognition. “Where we’re at right now is this opportunity in the field to translate this information into medicine,” he says.
Currently, of the approximately 2,000 drugs approved by the FDA for use in humans, only around 40 have been tested for their optimal circadian time of use. Hogenesch and Ruben hope to change that. “If we could get five to 10 clinical trials a year,” Hogenesch says, then their research would be effective. “I will feel better six months to a year from now,” he says, when it’s possible to see if their atlas is being used.
