Humboldt-Universität zu Berlin - Collaborative Research Center for Theoretical Biology

1 Research programme

1.1 Summary

The central goal of the collaborative research centre is the development of theoretical concepts, mathematical models, and methods for data analysis that are used to uncover and analyse the evolutionary design of biological systems. To this end, theoreticians and experimentalists have teamed up to examine structural properties of cellular signalling pathways, regulatory and neural networks, as well as vulnerabilities of these networks to parasitic interference and exploitation. Using interdisciplinary approaches that bridge several projects, we aim to demonstrate how different systems solve the problem of robustness and adaptability, how the modularity of feedback-regulated systems is involved in this process, and what limitations exist for the evolution of robustness, adaptability, and modularity. The specific projects address different components of the nervous, immune, and reproductive systems, as well as the regulation of biological rhythms, cell differentiation, and gene expression. Some of these projects directly examine the genesis of pathological states that point out the limits of robustness in living systems. These projects address topics such as Huntington’s chorea, a degenerative disease of the nervous system, and different forms of intracellular parasitism exhibited by endosymbionts (Wolbachia and Toxoplasma gondii). Concerning data analysis, a special focus of the research centre lies on the generation of new methods for the evaluation of gene expression patterns and neuronal activity. In general, we aim to develop and highlight new ways to help biology and medicine profit from the flood of information that is currently generated in life sciences and to integrate biological knowledge by theoretical concepts and mathematical models.

The study of biological rhythms may serve as an example to illustrate our approach and its interactive development. During the first two funding periods, we investigated the problem ‘what are the intra- and intercellular network properties that enable mammalian circadian clocks to function as reliable rhythm generators’. Rigorously pursuing this research question at both the theoretical and empirical level has helped us understand important properties of the evolved ‘clockwork design’. This progress enables us in the final funding period to study the ways in which organisms actually use their clocks for creating robustness. Such research is of great importance to human health. We investigate, for example, the mechanisms through which mammalian clocks take part in tumour prevention. Is there a systemic explanation for the increased tumour rates that have been found in empirical studies of nightshift work? Intrigued by this and similar questions, several of our projects collaborate on the problem of clock use and aim at extending the theory on ‘rhythms of life’. This extension requires the merging of expert knowledge from oncology, chronobiology, and the mathematics of nonlinear systems. Our research centre offers a unique opportunity to meet these specific needs and develop an integrative theory of the clock that will be highly relevant to applied research on biological rhythms and human health. In light of our central topics – robustness, modularity, and evolutionary design – our research projects share an interest in the basic phenomena they aim to understand. The resulting topical connections manifest themselves in the multiple ways through which our projects interact. We apply tools from chronobiology, for example, to explore how the auditory system of grasshoppers processes sensory input, so that features relevant to the organism are reliably extracted in the face of fluctuating ambient temperature. The robustness of feature extraction is also addressed by several other projects that analyse neuronal systems. For instance, robust feature extraction plays a role in memory consolidation when our brains ‘replay’ behavioural sequences during slow-wave sleep and resting in order to pass information from short-term to long-term memory. Memory consolidation of a different kind is addressed in a study on longterm learning of the immune system. Furthermore, with the help of our experts in oncology, we developed a model on how parasitic nematodes perturb and outwit the immune system’s learning process to avoid inflammatory responses. Several of our projects will now explore the targets that either parasites or, in a more positive context, the medical profession can use to manipulate networks of living systems – despite the fact that these systems are protected against perturbations in manifold ways.