Mathematical simulations are an important tool in physics and engineering, but its application to biology and medicine is still in its infancy. However, as our knowledge of the molecular basis of biological processes is progressing, mathematical modelling is increasingly used to understand the complexity of living organisms.
We use existing biochemical data to built dynamic models of metabolisms and dynamic molecular processes. The resulting models can be used to understand the basis of diseases and guide the development of drugs. We work in close collaboration with experimental groups, which is advantageous, as model building is always an iterative process of simulation and experimental verification of model hypothesis. It furthermore guides the developement of our models and usually defines the aim of the model.
Simulation of circadian rhythms
Most organisms employ circadian clocks to anticipate daily variations in their natural environments. Circadian clocks are self-sustained oscillators that can be entrained by external time cues like light–dark or temperature cycles to match local time. The rhythm persists in the absence of such stimuli with a period of approximately 24 h. Thus, circadian clocks are generally thought to resemble limit-cycle oscillators.
In recent years we have studied the entrainment characteristics of circadian oscillators. Most previous studies have focused on the entrainment by light-dark cycles but much less is known about the entrainment by temperature or feeding cycles. Temperature permanently influences all processes within an organism. Thus, it is difficult to study temperature regulation of circadian clocks separately by in vivo experiments. Although the clock can be entrained by temperature cycles, its free-running period is relatively constant within a broad range of physiological temperatures. This phenomenon is called temperature compensation. We unraveled the relation between temperature compensation and temperature entrainment of circadian clocks recently and have shown that temperature compensation ensures temperature entrainment at e.g. seasonal changing mean temperatures.
We have furthermore started to study the mechanisms of feeding entrainment of circadian clocks. Although it has been known for decades that the clock of peripheral tissues can be set by feeding entrainment. Recently, significant advances have been made to elucidate the molecular mechanisms behind this process. We use this data to recosntruct a dynamic model of metabolic regulation of circadian clocks.
Bioinformatic analysis and simulation of Tryptophan- and NAD-Metabolism
Tryptophan is an essential amino acid for protein biosynthesis and the precursor of serotonin, melatonin, NAD and kynurenate as well as the neurotoxins quinolinic acid (QA) and 3-hydroxy-kynurenine (3HK). Changes in tryptophan metabolism have been found in several neurodegenerative diseases such as Parkinsons’s and Huntington’s disease, in AIDS-dementia and various kinds of cancer. Furthermore, changes in serotonin levels are the basis of several gastrointestinal disorders. Serotonin is furthermore known as important regulator of the metabolism. Melatonin which is synthesized from serotonin in a light-sensitive and circadian clock regulated manner, is itself an important regulator of our sleep-wake cycle and changes in its synthesis are the basis of e.g. the delayed sleep phase syndrom.
NAD is equally important as metabolite of redox-reactions and as signaling molecule. NAD is required for DNA-damage repair and the NAD-dependent deacetylase (sirtuins) seem to play an important role in ageing and in the metabolic regulation of circadian clocks. As these enzymes consume NAD cellular NAD-pools need to be constantly replenished.