Browsing by Author "Eißing, Thomas"

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A systems science view on cell death signalling
(2007) Eißing, Thomas; Allgöwer, Frank (Prof. Dr.-Ing.)
This thesis provides new insight into cellular signal transduction by integrating biological knowledge into mathematical models, which are subsequently analysed using systems theoretic methods. Signal transduction has been dissected using molecular and genomic approaches providing exciting insight into the biochemistry of life. However, a detailed understanding of its dynamic properties remains elusive. The application of systems science ideas to biology is promising to put the pieces of molecular information back together, as important properties of life arise at the system level only. For example, certain signalling pathways convert graded input signals into all-or-none output signals constituting biological switches. These are implicated in cellular memory and decisions. One such decision is whether or not to undergo programmed cell death (apoptosis). Apoptosis is an important physiological process crucially involved in the development and homoeostasis of multicellular organisms. Switches, such as in apoptosis, can be represented by ordinary differential equation models showing bistable behaviour. Different biochemical mechanisms generating bistability in reaction schemes as encountered in apoptosis are presented and compared in this thesis. Bifurcation studies reveal structural and parametric requirements for bistability. In combination with reported kinetic information, inconsistencies in the literature view of apoptosis signalling in humans are revealed. An additional regulatory mechanism is proposed, which is now supported by experimental evidence. Extended robustness analyses indicate that the cell has achieved a favourable robustness-performance trade-off, imposed by network structure and evolutionary constraints. On the one hand, inhibitors of apoptosis function as noise filters and reduce variability caused by the stochastic nature of reactions. Further, qualitative properties such as bistability are comparably robust to parameter changes supporting proper decisions. On the other hand, quantitative aspects are comparably sensitive. This allows for variability in a population, as observed in experiments, and which is likely important for physiological function as recently indicated in immunological studies. The analyses further indicate that the trade-off leads to fragilities. For example, an up-regulation of inhibitors of apoptosis, as observed in certain cancers, can not only desensitise cells to apoptotic stimuli, as also suggested by experimental studies, but can contribute to cancer aggressiveness and progression through additional mechanisms. Thereby, the analyses provide insight of pharmaceutical relevance. Several results presented in this thesis are not restricted to apoptosis signalling only, but are conceptually relevant to various other signal transduction pathways.