Researchers Puzzling Over The Body’s Rhythmicity
By Deborah Borfitz
March 24, 2020 | Circadian medicine gained newfound attention in 2017 when three scientists were awarded the Nobel Prize in Physiology and Medicine for their discovery of the molecular mechanisms controlling how time is measured in biological systems. But the backstory on the field goes back decades, including the 1997 discovery and cloning of the first circadian clock gene in mammals.
Essentially all cells in the body have their own autonomous peripheral clock governed by feeding patterns and rest-activity cycles as well as light, the primary regulator of rhythmicity for the body’s “master pacemaker”—the suprachiasmatic nucleus (SCN) in the hypothalamus of the brain, says Charna Dibner, Ph.D., principal investigator in the departments of medicine, cell physiology and metabolism, the Diabetes Centre at the University of Geneva faculty of medicine, and at University Hospitals of Geneva. Hormones, nerve impulses, and temperature cycles also play supporting roles.
“But we’re far from understanding how all of those signals are coming together to synchronize each organ and each type of cell,” Dibner adds. In some organs, including the liver, feeding seems to be calling most of the shots. In other peripheral organs, additional neural or hormonal synchronizing cues—called Zeitgebers—are more predominant than feeding.
The SCN has been considered the master circadian pacemaker since 1972, says Erik Herzog, a neuroscientist and professor at Washington University as well as president of the president of Society for Research on Biological Rhythms (SRBR). He compares it to the atomic clock in Boulder that keeps Apple watches and computers synchronized to central time. “It’s extraordinary in its ability to coordinate all these other clocks in the brain, the liver and in the heart, and for that reason… many labs are studying the role of the master clock in those other cell types.”
Circadian Intervention For Diabetes?
As she published several years ago in Genes & Development, pancreatic islet cellular clocks have been shown to coordinate the secretion of insulin and glucagon in a daytime-dependent manner, highlighting the role of the oscillator system in anticipating changes related to traditional rest-activity and feeding-fasting cycles. Three main hormones secreted by the endocrine pancreas, including also somatostatin, have a differential effect on the clock of alpha and beta cells, says Dibner, which might be important in fine-tuning the temporal orchestration of insulin, glucagon and somatostatin secretion.
Dibner says her interest is in re-boosting circadian clocks, which were recently found to be “surprisingly disrupted” in the human pancreatic islets in association with type 2 diabetes. In the same PNAS study, the clock modulator molecule dubbed Nobiletin (extracted from citrus peel) was shown to partly repair the disrupted cellular clocks and enhance insulin secretion, she notes.
Nobiletin has been identified as one of numerous small clock modulator molecules having beneficial effects on several key aspects of metabolism, as reported in several published studies by Joseph Takahashi (Southwestern University) and his colleagues, most recently in Nature Communications.
The groundwork for Dibner’s work included a 2010 report (doi: 10.1038/nature09253) in Nature and a 2015 report in Science by Northwestern University researchers that the pancreas has its own molecular clock regulating the production of insulin and, when faulty, results in the development of overt diabetes.
Two years ago, Dibner led a research project showing disruption in these pancreatic cellular clocks interfered with insulin and glucagon secretion to promote the onset of diabetes. The team had also previously observed (doi: 10.1111/dom.12616) that the clocks of human pancreatic cells from healthy donors, when artificially perturbed in vitro, was enough to comprise the secretion of the same two key islet hormones.
The latest PNAS paper by Dibner was the first one connecting compromised circadian oscillators, islet hormone secretion, and overt type 2 diabetes in humans. Researchers will continue exploring the repair mechanism of the islet clocks and function by the clock modulators in vivo, initially in animal models, to see if clock modular molecules might be used in treating diabetes by themselves, or in combination with existing antidiabetic drugs, she says.
Recent studies enrolling patients with metabolic syndrome have suggested that adjusting the window of food consumption based on the chronotype of individuals may help them lose weight and improve their metabolic biomarkers, she says. Studies in mice have likewise suggested that exercise has more biologically healthful effects when done on a personalized schedule.
Elizabeth Klerman, M.D., Ph.D., associate professor of neurology and medicine at Harvard Medical School, joined the research staff at Massachusetts General Hospital last summer to facilitate sleep and circadian rhythm research and highlight the role of the biological clock and sleep on patient outcomes. The role potentially reaches across disciplines to clinicians in addiction research, psychiatry, psychology, women’s health, weight loss clinics, neonatal intensive care unit, oncology, cardiovascular medicine, radiology, anesthesia, surgery and clinical effectiveness.
Like multiple other researchers, Klerman’s research interests include the when and what of food consumption as it relates to health and body weight. Research by Andrew McHill (now at Oregon Health and Science University) has given credence to the hypothesis that restricting the hours people eat can be particularly beneficial, Klerman says. In a 2017 article in The American Journal of Clinical Nutrition, they drew the connection between consuming food at night and body fat composition in young adults—irrespective of how much they ate or their activity level.
Vanderbilt University researchers more recently found that to manage weight it is better to eat breakfast and not late-night snacks based on the time of day the body is best at burning calories.
Ken Wright, at the University of Boulder, years ago helped establish one physiological mechanisms by which insufficient sleep contributes to weight gain. In a more recent paper (doi: 10.1016/j.cub.2019.01.069) in Current Biology, “weekend recovery sleep” proved to be a poor strategy for preventing metabolic dysregulation.
Melatonin and Contractions
Late-term pregnant women are among the populations of current research interest to Klerman. Among her many publications is an article in the Journal of Pineal Research (doi: 10.1111/jpi.12566) showing an association between circulating melatonin concentrations and the number of uterine contractions in pregnant women during their late third trimester.
The trial was informed by reports that melatonin in vitro can cause contractions of the uterine tissue and that melatonin receptors only appear on the uterus late in pregnancy, say Klerman. The timing of melatonin secretion could explain why more women—at least until recently—went into labor and gave birth at night, which is when more of the hormone is released.
The study with late-term pregnant women involved a pair of protocols, the first of which exposed participants to either blue light (which suppresses melatonin) or red light (which does not), says Klerman. In the second protocol, all women were exposed to red light on night one and then randomized to either the red or blue light on night two to gain insights on night-to-night variability in uterine contractions and light effects among the two groups.
What initiates labor in humans remains unknown, says Klerman, but the correlation between melatonin and contractions has “huge implications for healthcare. First, were midwives correct that women should give birth in dark room?”
It is also hypothesized that “a certain number” of contractions are required for delivery to happen, “and it turns out labor has gotten longer over the past 50 years,” she continues. Shortening the process might mean less stress on the mother and baby, fewer cesarean sections, and lower expenditure of limited healthcare resources. The cause of pre-term labor might be connected to melatonin receptors showing up too early, Klerman ponders.
Neither of the pilot studies were sufficiently powered to show that lighting levels can affect the number of contractions, she says. Follow-up work is planned.
A few years ago, Klerman teamed up with neurologist Aleksandar Videnovic, M.D., at Mass General Hospital to show that appropriately timed light exposure can decrease non-motor symptoms of patients with Parkinson’s disease. As detailed in a JAMA Neurology paper, properly timed blue lights were used to strengthen the circadian system to improve sleep and daytime alertness.
In the next few months, Klerman says, a larger version of that study will get underway at about two dozen sites. The intervention and control—desktop-sized blue and red lights—are inexpensive relative to typical drugs and devices in clinical trials and potential side effects are not a major concern. Participants will be screened for eye disorders, she adds, but will be exposed to less light than if they were standing outside at dawn or dusk.
The issue of “sundowning”—a symptom of Alzheimer’s disease that causes pacing or wandering in the late afternoon and evening—has been another topic of interest for Klerman. “It’s usually what drives families to put someone in assisted living,” she says. “The question is, if we can restore the sleep-wake rhythm so people don’t wander the halls [or outside] at night, can they stay at home longer?”
Moving forward, her research endeavors include a collaboration with Frank Doyle, dean of Harvard’s school of engineering and applied sciences, to devise control theory approaches for effecting circadian rhythms using drugs instead of light, says Klerman. Most people prefer taking a pill to sitting in front of a light for several hours, she adds.
The objective is to identify “the best timing and dose [of a drug] to produce the desired effect,” she says. Most experiments, in contrast, take an educated guess on those parameters and then measure the outcomes. “We’re not at the point of doing clinical trials yet, but that’s the goal.”
Klerman previously developed a mathematical model of circadian rhythm, she says. The model has been used in a study showing astronauts took more sleeping medications on nights their sleeping was predicted to be out of phase, based on what was known about their sleep-wake cycles. It could be used as part of decision-making to help plan mission-critical tasks in space based on objective rather than subjective measures of their alertness, which often do not coincide.
The model also explained an apparent discrepancy in some of the original experiments on the human circadian rhythm that suggested the internal clock's "day" was closer to 25 than 24 hours, Klerman says. Neither protocol was wrong, but they were different, and therefore produced two different results.