The Granada Lab (2020–2025) built a research program in quantitative oncology around one clinical question: why do patients respond so differently to the same cancer therapy? Combining live-cell imaging of cancer cells with mathematical modelling, we developed frameworks to predict treatment response and to personalize when therapies are given.
Research focus
Treatment response varies widely between patients. We traced part of this variability to individual tumor cells: how they behave, divide and respond to therapy over time.
A central line of work was treatment timing. By profiling cancer cells across the day, we predicted when drugs work best and how schedules could raise efficacy while lowering toxicity.
Our approach pairs long-term single-cell measurements with computational models. The models guide experiments, predict outcomes and reduce the need for animal testing.
Chronotherapy: timing cancer treatment
Our body’s circadian clock, which regulates various cellular processes, plays a significant role in how effective treatments can be. Disruptions to this system, such as those seen in shift workers, have been linked to an increased risk of developing certain types of cancer. Recently, there has been growing interest in leveraging circadian rhythms to optimize treatment timing, with promising but still emerging results.
Our group established a pioneering framework to harness circadian data for treatment optimization. By integrating experimental techniques with time-series analysis, we created high-resolution ‘time-of-day profiles’ to predict drug response variability across cancer cell lines. This work at Charité – Universitätsmedizin Berlin successfully demonstrated methods to personalize schedules based on individual circadian rhythms.
By comparing the profiles of tumor cells and healthy cells, we can identify the optimal times to administer treatments. This approach aims to increase the effectiveness of chemotherapy while reducing its toxicity.
Read about this work in news outlets in different languages: news coverage (Altmetric).
Why some tumor cells survive therapy
As part of the current standard treatment, most breast cancer patients receive a combination of chemotherapy and radiotherapy. Despite its success, many patients still gain little or no benefit from this treatment, as evidenced by the elevated rates of locoregional recurrence, distant metastatic spread, and cancer deaths. Unfortunately, those patients will nevertheless suffer the short- and long-term side effects of the inefficient therapy.
We developed quantitative strategies to maximize tumor damage while minimizing toxicity to healthy cells. Our research successfully mapped the signaling dynamics—including p53, cell cycle, and circadian clock interactions—that determine the heterogeneous ‘fractional response’ to chemo- and radiotherapy at the single-cell level.
After chemo- or radiotherapy a fraction of tumor cells will die, some cells will remain quiescent, while other cells will survive and continue dividing.
This characteristic response to cancer therapy is known as fractional response, where a subpopulation of cells survives the treatment. Part of our research focuses on studying the cellular events and signaling dynamics that control the heterogeneous cell fate response of individual cells in time. Specifically, we study how internal cycling factors, such as the circadian clock, the cell cycle, and the p53 protein dynamics interact with the DNA damage response pathway to determine the response to radiotherapy and chemotherapy in cancer cells.
Single-cell state space representation of three internal cellular variables
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Proliferating breast cancer cells with p53 and 53BP1 markers
Foundations: circadian biology and modelling
Earlier work, before the lab was founded, that underpins our approach to treatment timing.
Mammalian Circadian Clock — from single cells to human behaviour
For millions of years the spinning of the Earth has imposed daily, periodically recurring environmental conditions on its inhabitants. Most organisms living on our planet have adapted by evolving their own internal, about-a-day oscillator. This endogenous circadian oscillatory system controls an organism’s daily internal rhythms. In mammals, the central pacemaker responsible for generating this internal pace is the suprachiasmatic nucleus. The suprachiasmatic nucleus (SCN) is located at the base of the brain, in a region called the hypothalamus just above the optic chiasm, where the two optic nerves cross over. Many different body functions like sleep-wake cycles, body temperature and endocrine rhythms are regulated by the outputs of this nucleus.
Single-cell circadian rhythms of well-synchronized SCN neurons
Mathematical Modelling
In addition to the SCN, peripheral oscillators, such as lung tissue, exhibit damped and usually less precise oscillations, which are thought to be brought about by the lack of intercellular coupling. Both SCN and oscillators in peripheral tissues share almost identical single-cell molecular clocks, but they behave surprisingly differently upon external periodic perturbations (entrainment). Carrying out a combined theoretical and experimental study of whole tissue and single-cell circadian oscillations, my work has contributed to the understanding of the central role played by intercellular coupling in explaining the entrainment differences. In a separate theoretical study we focused on the different dynamics from hypothesized models of intercellular coupling. Our predictions clarified how coupling mechanisms affect entrainment properties.
- Abraham U*, Granada AE*, Westermark PO*, Heine M*, Kramer A, Herzel H (2010). Coupling governs entrainment range of circadian clocks. Molecular Systems Biology 6:438.
- Bordyugov G*, Granada AE*, Herzel H (2011). How coupling determines the entrainment of circadian clocks. European Physical Journal B.
- Erzberger A, Hampp G, Granada AE, Albrecht U, Herzel H (2013). Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range. Journal of the Royal Society Interface 10(84):20130221.
Entrainment & Circadian Desynchronization
Experiments elucidating SCN heterogeneity are often invasive and thus implicitly modify the SCN tissue in an unknown manner. A novel experimental protocol was proposed to non-invasively dissociate this circadian oscillatory network in vivo. Rats exposed to exotic short light-dark cycles express two stable circadian motor activity rhythms (a fast and a slow rhythm). Motivated by these exciting works that characterized SCN heterogeneity, we developed a computational model and made predictions to help elucidate the sources of the observed heterogeneity (see first publication below). In addition, when an oscillator is entrained, its endogenous period is adjusted to that of the external recurring environment. Despite its heterogeneity, the SCN has the striking ability of fast entrainment. We have identified the core oscillator properties that determine the timescales to entrainment.
- Granada AE, Cambras T, Díez-Noguera A, Herzel H (2011). Circadian desynchronization. Interface Focus 1:153–166.
- Granada AE, Herzel H (2009). How to achieve fast entrainment? The timescale to synchronization. PLoS One 4:e7057. Generic properties derived from the theory of coupled oscillators explain the observed differences in the timescales of entrainment.
Human Chronotypes and Seasonal Effects
Commonly known as “early birds” or “night owls”, a person’s chronotype is the propensity of the individual to sleep at a particular time during the day. A central question in human circadian research is to understand the interaction of the internal and environmental components that determine these chronotypes. Multiple major studies have characterized human chronotypes and studied their distributions, but little is known about the factors that determine the shape of these distributions. In a series of works we have provided a framework to explain the distributions observed in human chronotypes and how the wake-up time (phase of entrainment) depends on seasons and on additional internal circadian clock parameters such as relaxation times and intercellular coupling.
- Granada AE, Bordyugov G, Kramer A, Herzel H (2013). Human chronotypes from a theoretical perspective. PLoS One 8(3):e59464.
- Granada AE, Herzel H, Kramer A, Abraham U (2018). Information transfer in the mammalian circadian clock. In Information- and Communication Theory in Molecular Biology, Lecture Notes in Bioengineering. Springer.
Perturbation and Information Theory
Phase response curves are widely used in circadian clocks, neuroscience and heart physiology. They quantify the response of an oscillator to pulse-like perturbations. Phase response curves provide valuable information on the properties of oscillators and their synchronization. In the first publication listed below we discuss biological self-sustained oscillators (circadian clock, physiological rhythms, etc.) in the context of nonlinear dynamics theory. While direct synchronization by light is restricted to light-sensitive clock cells (e.g. in the eye), temperature cycles can be perceived by the majority of body cells, rendering them an elegant means to study environmental information transfer in mammalian clock cells. We studied the role of temperature oscillations as a zeitgeber for peripheral tissues. We combined information theory and the theory of coupled oscillators to generate a set of theoretical predictions and tested them experimentally. See the book chapter below.
- Granada AE, Hennig RM, Ronacher B, Kramer A, Herzel H (2009). Phase response curves elucidating the dynamics of coupled oscillators. Methods in Enzymology 454:1–27.
- Granada AE, Herzel H, Kramer A, Abraham U (2018). Information transfer in the mammalian circadian clock. In Information- and Communication Theory in Molecular Biology, Lecture Notes in Bioengineering. Springer.
These works were done in collaboration with the labs of Hanspeter Herzel and Achim Kramer, at Humboldt University Berlin and the Charité University Hospital, respectively.
Birdsong Production — Bifurcation Theory
The generation of a behavior involves interactions between the nervous system, the morphology of the peripheral system and the environment. The biomechanics of a peripheral system imposes constraints on the neural control, and also provides opportunities for the emergence of complexity in behavior. A rich example is birdsong, where neural instructions drive a complex respiratory system in order to activate the vocal organ. The dynamical state of the respiratory system feeds back into the nuclei in charge of expiration and inspiration, and therefore the emerging dynamics can be potentially extremely rich. As part of my master’s thesis I used bifurcation theory and simulations to inspect the respiratory patterns that can be generated as the result of the interaction of the respiratory nuclei and the respiratory peripheral system.
During this project I had the pleasure to work with Marcos Trevisan and Gabriel Mindlin at the Dynamical Systems Lab.
- Granada AE, Gabitto M, García G, Alliende J, Méndez J, Trevisan M, Mindlin GB (2006). The generation of respiratory rhythms in birds. Physica A 371:84–87.