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Scaling Up W ITH THEIR PILOT STUDY having proved the feasibility of describing the human chronobiome in a real-world setting, researchers at Perelman School of Medicine at the University of Pennsylvania will seek to build on their fi ndings in a mixed-sex group of 200 healthy volunteers of varying age. The team plans to follow the cohort for a year to understand the effects of seasonality on participants' chronobiomes. As part of the study, researchers will subject participants' chronobiomes to controlled challenges to simulate characteristics of disease. One example is inducing an infl ammatory response via a safe, bacteria-wall injection, according to Carsten Skarke, MD, Research Assistant Professor of Medicine at the Institute for Translational Medicine and Therapeutics at the Perelman School. "We want to use the stimulus to defi ne how the human chronobiome changes or reacts to an infl ammatory stimulus," he says. "The idea behind that is that initiating an infl ammatory reaction in healthy volunteers simulates the infl ammatory conditions associated with many diseases, like cardiovascular disease." Therapeutics at Perelman School of Medicine at the University of Pennsylvania. Those procedures are appropriate only for small groups of patients and yield an incomplete picture of the biological clock because they do not take environmental cues into account, Dr. Skarke says. He and his team of researchers at Penn needed to solve the problems of scale and setting if they were to characterize the human chronobiome. "In order to scale up easily, we would need to be able to study a large number of patients more easily," Dr. Skarke says. "The easiest way to study is if we don't really have to ask patients to come for frequent visits to the hospital, but just observe them while they go about their daily lives." So, for four months, researchers used wearable devices and smartphone apps to collect physiological data from six healthy young men who went about their normal routines. Those tech- nologies yielded information about activity, sleep patterns, nutrition, light exposure and communication. Additionally, the participants visited the Center for Human Phenomic Science at Penn for two 48-hour periods during the study so the researchers could collect plasma, serum and saliva, as well as oral and rectal samples. The researchers collected approximately 2.2 million data points. "We observed, collected a lot of data and asked, 'Are we able, in these healthy volunteers, despite the fact that they each follow individual daily schedules of activity, food intake, etc., to discern rhythmic signals?'" Dr. Skarke says. "[O]nly if we are able to cut through the noise of daily life and ... see these rhythmic signals, only then would we be able to detect disruption of these rhythmic signals in patients who have crossed over from this healthy phenotype and readout to a signal that associates with some sort of pathological change, underlying change, that leads to disease." THE CHRONOBIOME IN FOCUS Sixty-two percent of the study's sensor readouts showed time- specifi c variability, including, crucially, results that validated the researchers' expectations, according to fi ndings that appeared in Scientifi c Reports. Cortisol levels, for example, were higher in the morning than in the evening, and blood pressure was higher during the day than at night. Those data proved the validity of the team's methodology — critical for their ability to conduct larger studies of the human chronobiome (see "Scaling Up"). Other fi ndings were surprising, including the extent to which certain genera of bacteria in the microbiome were more abundant in the evening and less so in the morning, according to Dr. Skarke. Hughes, who was not involved with the study, fi nds its results exciting and thinks the fi rst implications will be felt in personal- ized pharmacology. "[C]an we predict which drugs and humans will benefi t most from timed administration?" he asks. "Related to this, clinical studies will hopefully be better designed from here onward, with more care given to the time of administration, and time itself being treated as a variable in all statistical modeling." Dr. Skarke sees great potential for the human chronobiome in the development of precision medicine, and he thinks his team's pilot study could provide a model for the fi eld of how to integrate multidimensional data sets. Wearable devices, he says, could fi ll informational gaps for clinicians between patient visits, provided there are ways to identify and act on anomalies. "If there's an actionable fi nding, who's taking care of that?" Dr. Skarke asks. "Is the physician reviewing all of that data? Probably not, so we need to have smart algorithms in place to fl ag actionable clinical signals and transmit them to a physician to take action." ■ M D N E W S . C O M /// M D N E W S C L E V E L A N D /A K R O N / C A N T O N ■ J U LY/A U G U S T 2 018 0 7