Top Breakthrough Discovery | Published September 2018 in Science Translational Medicine

A photo of Marc Ruben, PhD, and John Hogenesch, PhD.

Marc Ruben, PhD, and John Hogenesch, PhD

Using new bioinformatics tools to analyze thousands of human tissue samples, researchers at Cincinnati Children's created a new database of daily rhythms in human gene activity—including many genes that regulate how drugs work.

Reporting in Science Translational Medicine, researchers say their results could have significant implications for a growing field of study called circadian medicine—timing the administration of drugs or other therapies to coincide with the body’s internal clock.

The Cincinnati Children’s research team included first author, Marc Ruben, PhD, and senior author John Hogenesch, PhD; both of the Division of Human Genetics; and co-author David Smith, MD, of the Division of Pediatric Otolaryngology.

"We identified rhythms in gene expression across the body in a large and diverse group of people,” Hogenesch says. “It doesn’t matter if you’re male, female, young or old, or what your ethnicity is, your body’s internal clock regulates half your genome. This includes drug metabolizing enzymes, transporters, and targets. Now we are learning which drugs hit clock-regulated products and may benefit from optimizing administration time in people.”

Applying CYCLOPS

One challenge to applying biological time in clinical practice is the lack of knowledge about how the circadian clock controls rhythms in humans. Until now, scientists relied on animal models to study circadian biology, but with little translational impact.

To fill the knowledge gap, the researchers used a population-based approach in developing their computer algorithm called “cycling ordering by periodic structure,” or CYCLOPS.

“Overall this connects thousands of different drugs, both approved and experimental, to nearly 1,000 cycling genes.”

Hogenesch and his team used CYCLOPS to analyze the timing of gene-to-tissue interactions in 13 tissue types from 632 human donors. Raw data about the samples came from the Genotype-Tissue Expression (GTEx) Consortium, funded by the National Institutes of Health.

Of the thousands of genes that cycled rhythmically in the different human tissues, core clock genes were among the most robust. This finding also aligned with earlier studies in other vertebrates. Of these, 917 genes code for proteins that help transport or metabolize drugs or are themselves drug targets. Some of the circadian effects detected by this study were so large that genetic influences on drug efficacy and tolerance may have been masked in past studies.

“Overall this connects thousands of different drugs, both approved and experimental, to nearly 1,000 cycling genes,” explains Ruben, the study’s first author and a research fellow. “This includes genes that cycle in the human cardiovascular system and many of the drugs used to treat heart disease.”

Heart of the Matter

The researchers report 136 drug targets rhythmically cycling in at least one of four cardiac tissues, the atrial chamber, aorta, coronary artery, and the tibial artery. Many of these are “standard-of-care” targets for drugs, including an entire family of calcium channel blockers. While the database represents a major step forward, challenges remain in putting these ideas in practice.

“It’s not as simple as taking your medication in the morning,” Ruben says. “One in six US workers are now shift workers, so while it may be morning for most, it is bedtime for some. We need a robust way to measure body time to account for this.”

Circadian Medicine Moving Forward

“The industry trend toward sustained-release formulations, although good for patient adherence, can be problematic from the vantage of circadian biology.”

Since publishing this database, Hogenesch, Ruben, Smith, and first author Gang Wu published an article Nov. 27, 2018, in PNAS reporting that numerous cycling genes are expressed in the skin. In fact, a person’s body clock can be measured through skin testing within three hours—a better tool than blood testing.

Hogenesch and Ruben went on to co-author a widely-shared perspective article in Science entitled “Dosing Time Matters.” Hogenesch, Ruben, and Smith also reported Oct. 1, 2019, in PNAS on how caregivers may be missing the beat on a dozen cyclic medications commonly used in hospital settings.

Hogenesch and Ruben contend that harmonizing the timing of medication dosing, radiation therapy—even surgical procedures—with the patient’s body clock will improve outcomes for numerous conditions. Circadian medicine data may even challenge some long-standing best practices.

“The industry trend toward sustained-release formulations, although good for patient adherence, can be problematic from the vantage of circadian biology,” the co-authors stated in the Science perspective. “Drug exposure is constant over 24 hours, but its target(s) may not be. Flattening a process that is normally rhythmic may be maladaptive.”

Looking forward, the new critical care tower at Cincinnati Children’s will play a role in future circadian medicine research. A block of new intensive care suites will feature a new, highly adjustable lighting system that will allow deeper study of emerging light-therapy approaches that could help prevent retinopathy of prematurity, speed wound healing, and produce other benefits.