The circadian clock ticks in virtually every body cell

ZEIT - Die Chemotherapie der Zukunft: Patient*innen-Empowerment durch die innere Uhr für optimierte Behandlungen

ZEIT - The chemotherapy of the future: patient empowerment through the internal clock for optimised treatments.

Background:

The biological clock, also known as the circadian clock, regulates the timing of many cellular and molecular mechanisms and plays a vital role in maintaining human health. Disruption of your circadian rhythm is associated with diseases like sleep disorders, depression, diabetes, neurodegenerative diseases, obesity and cancer. A dysregulated circadian clock can impair both physical and cognitive performance.

We all have our own circadian rhythm

Circadian rhythms and thus the timing of molecular processes differ from person to person. Knowing your personal circadian rhythm and adjusting activities such as sleep, exercise, daylight or medicine intake according to your internal timing can improve health and reduce recovery or therapy time in patients.

TimeTeller® profiles your unique circadian rhythm

We have developed a non-invasive method to profile the personal circadian rhythm based on saliva samples. Sampling is easy, risk-free and can be carried out at home, you send your samples to TimeTeller® for analysis and receive back a report with personalized recommendations for lifestyle adjustments.

TimeTeller® profiles your circadian clock using molecular analysis of saliva samples and computational modelling to provide toxicity profiles for optimization of treatment timing.

TimeTeller® in health and performance

The human circadian clock regulates a number of cellular and molecular mechanisms and plays a vital role in maintaining human health. Around 50% of human genes are rhythmically expressed in at least one tissue. Disruption of circadian rhythms is associated with diseases including sleep disorders, depression, diabetes, neurodegenerative diseases, obesity and cancer. Clock disruption may be caused by conflicting external (environmental) or internal (feeding/resting) signals that are not in synchrony with the personal circadian time.

A well-functioning circadian clock, in synchrony with an individual's behavioural habits, can improve general health and wellbeing. The circadian clock influences and times important functions in our bodies, such as:

  • Hormone release
  • Eating habits and digestion
  • Body temperature
  • Sleep

Synchrony of circadian rhythms is important to keep these functions working properly. Sleep behaviour is one of the factors that might affect circadian rhythms.

The TimeTeller® analysis produces a detailed description of your own circadian rhythm. lt also provides predictions of optimal timing for your daily activities.

ZEIT - Die Chemotherapie der Zukunft: Patient*innen-Empowerment durch die innere Uhr für optimierte Behandlungen

Project Summary: Chemotherapy has massive side effects and extreme long-term consequences. Since many biological processes, including drug metabolism, are controlled by our internal clock, adjusting the timing of treatment can minimise side effects and improve efficacy. Our approach: ZEIT supports patients by characterising their internal clock and providing personalised recommendations to maintain the rhythmicity of the clock, as well as determining personalised optimal times of day for treatment. With this project, we are pursuing three goals: 1. to improve the quality of life of patients, 2. to increase the effectiveness of therapy and 3. to reduce costs per patient and relieve the burden to healthcare system.
Challenges of Cancer Treatment: Cancer is a complex and multifaceted disease that affects people of all genders and ages. According to the International Cancer Genome Consortium, the number of cancer-related deaths is expected to reach 35 million by 2050.

Patients suffer from the toxicity of chemotherapy. This can lead to life-saving therapies having to be discontinued without an equivalent alternative being available. The current solution is to treat the side effects with medication, which is associated with polypharmaceutical therapy and often prolonged hospitalisation for patients. In addition to the suffering for patients and their families, cancer is associated with massive costs for the healthcare system: 19.9 billion euros in direct medical costs, which corresponds to 6.3 % of total healthcare costs in Germany.

ZEIT for value-based Healthcare in Cancer Treatment: There is one factor that can improve therapy: ZEIT. Cancer cells have an altered internal clock compared to healthy cells. Treatment can therefore be optimised by choosing a time when the treatment is less toxic for healthy cells than for tumour cells. - This allows drugs to be administered that would otherwise be intolerable due to their toxicity. In Phase III clinical trials, chronotherapy (e.g. taking drugs in the morning vs. evening) was tested in comparison to conventional treatment regimens and showed up to 5x better tolerability and up to 2x increase in efficacy (patient dependent). In addition, chemotherapies can also disrupt the internal clock, so the use of measures to improve these rhythms (e.g. light therapy, the timing of meals or physical exercise) can help patients to better tolerate the therapy. In order to exploit the full potential of chronotherapy, personalisation is necessary, in which the timing of medication administration is adapted to the internal clock of individual patients. To do this, the patient's internal clock must be measured. This is what we do in the project: ZEIT.

Clinical Insights from ZEIT: Our results indicate a significant correlation between dysregulated CR and the frequency and severity of side effects in cancer patients. Added medical benefit: The results of the project have significant medical value for oncology. By identifying the relationship between CR and treatment side effects, healthcare providers can personalise treatment plans to the patient's internal clock. This personalised approach has the potential to reduce the severity and frequency of side effects and thus improve the quality of life of cancer patients. In addition, optimising treatment plans based on CR can increase the effectiveness of treatment.

Perspective: By introducing personalised chronotherapy planning based on CR, healthcare providers can improve treatment outcomes, enhance patients' quality of life and optimise the use of resources in cancer care. Results from ZEIT underline the importance of considering CR in oncological practice and demonstrate the potential for more efficient and effective cancer treatment strategies.

TimeTeller® in cancer care

Adjusting the timing of medical treatment to the circadian rhythm of the individual patient can optimize efficacy and diminish unwanted side effects, leading to improved life quality for patients and reduced healthcare costs.

40-50% of new drugs compounds fail due to lack of clinical efficacy, and another 30% due to uncontrollable toxicity. These numbers can be significantly improved by administering the drug at a specific time of day (chronotherapy). The circadian clock coordinates the timing of cellular processes (e.g. cell cycle and metabolism) and thus have an impact on the side effects and efficacy of drugs. Accordingly, the biological clock is of crucial importance for the development of new therapeutics, to overcome the current high failure rates. TimeTeller® exploits the circadian rhythm dependencies of cellular processes to maximise efficacy and minimise side effects. Clinical trials have tested chronotherapy (e.g., taking medication in the morning versus in the evening, though no individualised recommendations) compared to conventional treatment regimens. and have shown up to five times better tolerability and an almost twofold increase in efficacy.
The Circadian Rhythm is currently not considered in drug development. This is due to the fact that no suitable instrument/IVD (non-invasive, easy to use by the user) exists to profile the individual CR of individuals.

We currently participate in clinical studies to validate and bring the benefits of our method to cancer patients in Germany and beyond.

TimeTeller®-related publications:

Cancer

Nelson, Nina et al. "Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock."  NPJ Precis Oncol (2024). doi.10.1038/s41698-024-00530-z

Ludwig, Marius, et al. "Molecular characterization of the circadian clock in paediatric leukaemia patients: a prospective study protocol." BMC pediatrics (2023). doi.org/10.1186/s12887-023-03921-6.

Hesse, Janina, et al. "An integrative mathematical model for timing treatment toxicity and Zeitgeber impact in colorectal cancer cells." npj Systems Biology and Applications (2023). doi.org/10.1038/s41540-023-00287-4.

Hesse, Janina, et al. "A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer." Computational and Structural Biotechnology Journal (2021). doi.org/10.1016/j.csbj.2021.08.051.

Hesse, Janina, et al. "An optimal time for treatment—predicting circadian time by machine learning and mathematical modelling." Cancers  (2020). doi.org/10.3390/cancers12113103.

 

Aging and Performance

Yalçin, Müge et al. "Sex and age-dependent characterization of the circadian clock as a potential biomarker for physical performance: A prospective study protocol." PLoS One (2023). doi: 10.1371/journal.pone.0293226.

Malhan, Deeksha, et al. "Circadian regulation in aging: Implications for spaceflight and life on earth." Aging Cell (2023). doi.org/10.1111/acel.13935.

Malhan, Deeksha, et al. "Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent." npj Microgravity (2023). doi: 10.1038/s41526-023-00273-4.

 

Prevention and Health Optimization

Yalçin, Müge et al. "Sex and age-dependent characterization of the circadian clock as a potential biomarker for physical performance: A prospective study protocol." Plos One (2024) doi.10.1371/journal.pone.0293226

Malhan, Deeksha et al. "A matter of timing? The influence of circadian rhythms on cardiac physiology and disease." Eur Heart J (2024) doi:10.1093/eurheartj/ehad816

Dose, Benjamin, et al. "Timing Health: The Potential of Circadian Medicine to Improve Performance, Prevent Disease and Optimize Treatment." Frontiers in Digital Health (2023). doi.org/10.3389/fdgth.2023.1157654.

Basti, Alireza, et al. "Diurnal variations in the expression of core-clock genes correlate with resting muscle properties and predict fluctuations in exercise performance across the day." BMJ open sport & exercise medicine (2021). doi.org/10.1136/bmjsem-2020-000876.

 

About the genes

A cell produces the molecules it needs by reading the genetic code written in our DNA. To do this, the heritable information in a gene, which is a sequence of DNA base pairs, is copied several times (transcription) as RNA molecules and then translated into a functional gene product, the protein. The amount of RNA molecules resulting from a single gene indicates the expression of that gene and correlates with the amount of protein produced. Proteins make many of the structures and all the enzymes in a cell or organism and are responsible for a proper cellular function.

BMAL1: This gene is a core component of the circadian clock and acts as a positive regulator of gene expression. Many other core biological processes like the cell cycle, metabolism and immune system are regulated by BMAL1. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, as well as altered sleep patterns. BMAL1 is relevant for both short and long term memory, as well as to inflammatory and stress responses, is associated with ageing, major depressive disorders, sleep deprivation and cancer. BMAL1 plays a role in physical activity due to its effect on muscle growth and action. It regulates the MyoD gene which is necessary for the maintenance of skeletal muscle phenotype and function.

PER2: This gene is a member of the Period family of genes. PER2 regulates several different biological processes like lipid metabolism and mammary gland development. PER2 plays a detrimental role in cell cycle and cell proliferation and its aberrant activity was found to be associated with cancer. Ageing leads to a change in expression of PER2 . Polymorphisms in this gene may increase the risk of developing certain cancers and have been linked to sleep disorders. Physical activity has been linked to the circadian clock and PER2 is up-regulated by strength training.