Building circadian medicine at a pediatric hospital

Research on the genetic basis of the mammalian circadian clock that has been central to progress in the field of chronobiology will be featured at the next University at Buffalo Clinical and Translational Science Institute (CTSI) Distinguished Speaker Seminar.

John B. Hogenesch, PhD, Professor of Pediatrics, Divisions of Human Genetics and Immunobiology; Genetics Chair, Systems Biology; Interim Director, Division of Human Genetics; and Director, Center for Circadian Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati, will present “Building Circadian Medicine at a Pediatric Hospital” online via Zoom from 4 to 5 p.m. on Wednesday, June 1. Register here to watch the Zoom live.

Recent decades have seen an explosion of growth in mechanistic understanding of circadian clocks in several model organisms and in humans. However, translation of that knowledge into actionable medical interventions has been slow. In his seminar, Hogenesch will discuss efforts to develop circadian medicine in a pediatric hospital; will detail recent progress in understanding the molecular output of the clock in the mouse and humans, including identifying new opportunities for circadian dosing time in improving drug action; will talk about efforts to test these hypotheses prospectively in model organisms and retrospectively in large clinical databases; and will discuss future opportunities and challenges.   

“The work by John and his team is particularly interesting as it applies translational research to a systems level,” says Jessica L. Reynolds, PhD, Associate Director of the CTSI’s Workforce Development Core, co-investigator of the CTSI K Scholar Program, and Associate Professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences. “It is not often we see such broad implementation of translational research.”

Translating research into patient care

In a recent interview to discuss his upcoming seminar, Hogenesch outlined several reasons why researching circadian medicine and studying the circadian clock in a pediatric hospital setting are so important.

“First, the clock regulates much of our physiology and behavior — for example, blood pressure and heart rate, cortisol, growth hormone,” he says. “So, interpreting these values should take into account when they are measured. Second, hospitals operate in a rhythmic fashion. Samples are collected and sent to the lab prior to morning rounds so they can be interpreted. At rounds, decisions are made, and, with a delay, the pharmacy fills orders and medicines are administered. This happens every day, 24/7, 365.”

In addition, Hogenesch says there are many patients with circadian disorders like delayed sleep-wake phase disorder — “something like 9% of all adolescents. Here, we see those patients and also those with genetic disorders that accompany clock and sleep problems.”

Hogenesch is optimistic that research on the circadian clock will have an impact on improving drug action and developing new medical interventions.

“My hope is that there is a recommendation accompanying every drug that is prescribed about when to take it,” he says. “For example, I am on low dose aspirin and take it prior to sleep. It turns out that taking it then both lowers blood pressure and preserves its anti-thrombotic effects.”

The importance of mentorship

Hogenesch is a strong advocate for the value of mentorship, and credits a series of mentors for influencing his interest in how genes regulate behavior. The guidance and support he received still influences his work.

“I’ve been lucky to have some amazing mentors,” he says. “I started at Northwestern University as a technician with now UB’s Margarita L. Dubocovich, PhD, SUNY Distinguished Professor, Department of Pharmacology and Toxicology, Senior Associate Dean for Diversity and Inclusion, Jacobs School, where I learned about melatonin and its pharmacology. I took my first class in graduate school from Joseph Takahashi, PhD, who taught behavioral genetics. I did my PhD with Christopher Bradfield, PhD, where I discovered many bHLH-PAS domain transcription factors, including Bmal1, the key regulator of the circadian clock, but also Hif1a, Hif2a, and Hif3a, which regulate response to low oxygen. I did my postdoc with Steve Kay, PhD, and Peter Schultz, PhD, at Novartis, San Diego. There I learned and developed genomics methods and built large-scale resources like the Gene Atlas.”

Dubocovich, the Director of the CTSI Workforce Development Core, CTSI K Scholar Program Lead, and KL2 Principal Investigator, says that Hogenesch’s “landmark discoveries of key regulators of biological clocks and approaches to maximize drug efficacy in the treatment of circadian rhythms misalignment are contributing significantly to improving human health. As one of John’s early mentors it has been gratifying to follow his academic and professional career moving from a talented research assistant to a recognized world leader in circadian biology.”

When asked if there are any additional takeaways for those planning to attend his June 1 seminar, Hogenesch offered a simple and direct piece of advice based on his years of research: “Turn your phone off before bed and keep it off.”

The CTSI Distinguished Speaker Seminar Series is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 to the University at Buffalo.

For questions about the series, contact scholar1@buffalo.edu or (716) 829-4718.