Foundations of circadian medicine

Achim Kramer, Tanja Lange, Claudia Spies, Anna-Marie Finger, Daniela Berg, Henrik Oster, Achim Kramer, Tanja Lange, Claudia Spies, Anna-Marie Finger, Daniela Berg, Henrik Oster

Abstract

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock-disease interaction for clinical diagnosis, treatment, and prevention. In this Essay, we outline the principle approaches of circadian medicine, highlight the development of the field in selected areas, and point out open questions and challenges. Circadian medicine has unambiguous health benefits over standard care but is rarely utilized. It is time for clock biology to become an integrated part of translational research.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: AK’s institution has issued patents (PCT/EP2018/066771) and is preparing patents related to biomarkers for detecting the clock. This intellectual property has been licensed by BodyClock GmbH, in which AK is a shareholder. AK receives editor’s honoraria from Springer Verlag and Georg Thieme Verlag. AK is a paid consultant to Circadian Therapeutics, and Stanford University. AK is member of the Editorial Board of PLoS Biology. In addition, he and his research program have received financial, material and travel support from a range of federal, industrial, legal and philanthropic organizations in the past and present. CS reports grants from Deutsche Forschungsgemeinschaft / German Research Society, grants from Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR) /German Aerospace Center, grants from Einstein Stiftung Berlin/ Einstein Foundation Berlin, grants from Gemeinsamer Bundesausschuss / Federal Joint Committee (G-BA), grants from Inneruniversitäre Forschungsförderung / Inner University Grants, grants from Projektträger im DLR / Project Management Agency, grants from Stifterverband/Non-Profit Society Promoting Science and Education, grants from European Society of Anaesthesiology and Intensive Care, grants from Baxter Deutschland GmbH, grants from Cytosorbents Europe GmbH, grants from Edwards Lifesciences Germany GmbH, grants from Fresenius Medical Care, grants from Grünenthal GmbH, grants from Masimo Europe Ltd., grants from Pfizer Pharma PFE GmbH, personal fees from Georg Thieme Verlag, grants from Dr. F. Köhler Chemie GmbH, grants from Sintetica GmbH, grants from Stifterverband für die deutsche Wissenschaft e.V. / Philips grants from Stiftung Charité, grants from AGUETTANT Deutschland GmbH, grants from AbbVie Deutschland GmbH & Co. KG, grants from Amomed Pharma GmbH, grants from InTouch Health, grants from Copra System GmbH, grants from Correvio GmbH, grants from Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., grants from Deutsche Gesellschaft für Anästhesiologie & Intensivmedizin (DGAI, grants from Stifterverband für die deutsche Wissenschaft Þ.V. / Metronic, grants from Philips ElectronicsNederland BV, grants from BMG, grants from BMBF, grants from BMBF, grants from Drägerwerk AG & Co. KGaA, outside the submitted work; In addition, CS has a patent 10 2014 215 211.9 licensed, a patent 10 2018 114 364.8 licensed, a patent 10 2018 110 275.5 licensed, a patent 50 2015 010 534.8 licensed, a patent 50 2015 010 347.7 licensed, and a patent 10 2014 215 212.7 licensed.

Figures

Fig 1. Circadian misalignment and disruption are…
Fig 1. Circadian misalignment and disruption are associated with disease.
Circadian rhythms are present at the level of the individual cell, tissue, and system and contribute to the optimal temporal coordination of physiological organ functions with environmental entrainment signals (left). It is therefore not surprising that misalignment of endogenous circadian and exogenous environmental cycles, as well as disruption of endogenous circadian rhythmicity is associated with or increases the risk for many diseases (right). Moreover, by contributing to circadian disruption or by altering behavioral rhythms, disease may in turn aggravate pathologies related to dysfunction of the circadian system (created with biorender.com).
Fig 2. The future of circadian medicine.
Fig 2. The future of circadian medicine.
Our vision for the future of circadian medicine is to firmly integrate it into medical guidelines so that, for each patient, the circadian aspect is always taken into consideration and incorporated into the treatment plan as appropriate. Circadian medicine has many facets and to sustain its development, they all need to be advanced. They include treatment and diagnosis at the right time of day (exploiting), realigning and strengthening the circadian system (targeting), and diagnosing the patient’s circadian characteristics to develop personalized treatment plans (detecting). To achieve this goal, more evidence, especially on overarching principles of circadian medicine, needs to be gathered. To do this, on the one hand, we need a transdisciplinary approach to research, but we also need to train a new generation of physicians and communicate our findings more to the public and decision makers. TRE, time-restricted eating.
Fig 3. Circadian medicine in ICUs.
Fig 3. Circadian medicine in ICUs.
Critically ill patients frequently exhibit disturbed or absent diurnal rhythms. This is likely to be a result of their illness and sedative measures but could also be related to the often-arrhythmic environment of an ICU (inadequate light exposure, parenteral nutrition, etc.). At the same time, they are arguably the best monitored patients, and vast amounts of routine clinical data are available with time courses for a variety of physiological parameters. We propose evaluating this treasure trove of information much more systematically with data science methods to detect the clock and improving light settings in the ICUs to target the clock. The analysis of clinical source data will help to characterize patients in the ICU in terms of their circadian rhythms, to identify predictors of circadian disruption as well as therapy-based improvements, and to associate circadian rhythms with clinical parameters (for example, delirium). In addition, since current ICUs do not provide adequate light settings, we have implemented a novel concept at Charité –Universitätsmedizin Berlin, consisting of a light ceiling for each experimental ICU bed that extends from the head above the patient to the patient’s feet [67]. Each light ceiling consists of multiple layers of light-emitting diodes designed to target the patient’s circadian clock. ICU, intensive care unit. Photos can be used with kind permission of GRAFT; photo credit is given to Tobias Hein.

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