- Mathematical modelling of cellular processes
- Spatiotemporal dynamics of signalling networks
- Network interference
Prof. Boris Kholodenko is SFI Stokes Professor of Systems Biology at Systems Biology Ireland and UCD Conway Institute. He is also Adjunct Professor at Thomas Jefferson University, Philadelphia, USA. Kholodenko is the author of more than 220 publications on spatio-temporal dynamics and control analysis of cellular signalling and metabolic networks, and is a founding chairman of the International Consortium on Systems Biology of Receptor Tyrosine Kinase Regulatory Networks. He is widely recognised as a leader in the field of Systems Biology and predictive models of cellular functions and his work is been highly influential in shaping the field of systems biology as it is known today.
Kholodenko graduated with a Ph.D. in Biophysics from the Moscow Institute of Physics and Technology, Russia. He was then invited to work in the laboratory of Anatol M. Zhabotinsky, known for his studies of the Belousov-Zhabotinsky reaction. Afterwards, Kholodenko worked at the Moscow State University, where he has made crucial contributions to metabolic control analysis, such as the development of the control analysis of cellular systems involving direct enzyme-enzyme interactions, restricted diffusion and information transfer. Because of his unique combination of expertise in biochemistry, physical chemistry and mathematics, Kholodenko was invited to the Free University of Amsterdam, the Netherlands, by Hans Westerhoff. In 1997, Kholodenko joined the faculty of Thomas Jefferson University, where his group along with Dr. Jan Hoek and others developed the first systems biology model of the Epidermal Growth Factor Receptor signalling pathway. In 2009, he moved to Dublin to organise together with Prof Kolch, Systems Biology Ireland at UCD.
Getting Insights into Cell Biology by Modelling of Cellular Networks
Boris N. Kholodenko Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland
The advancements in “omics” (proteomics, genomics, and metabolomics) technologies have yielded large inventories of genes, transcripts, proteins, and metabolites. The challenge is to find out how these entities work together to regulate cellular responses to external and internal cues. Computational models provide insight into the intricate relationships between stimuli and responses, revealing mechanisms that enable networks to amplify signals and reduce noise and generate discontinuous bistable dynamics or oscillations. In this talk, I review experimental and theoretical progress towards better understanding of how the cellular functions are encoded by the dynamics of signalling and gene networks and how the design features of networks specify biological decisions(1,2). I focus on (i) how graded, analogue signals from growth factor receptors can be converted into diverse patterns of mitogenic and survival signalling, (3,4,5) and (ii) bistability at the signalling network level results in a bistable behaviour of the actin dynamics and cell migration6. Finally, I show that drug resistance resulting from dimerization of kinases, such as BRAF/CRAF, JAK2 and others can be explained by allosteric inhibitor effects and the emergence of different drug affinities between free kinase monomers versus dimers(7). This analysis extends to kinase homo- and heterodimers, allows for their symmetric and asymmetric conformations and predicts how thermodynamic factors influence dose-response dependencies. I show how two inhibitors ineffective on their own when combined can abolish drug resistance at lower doses than either inhibitor applied alone(7).
1. Kolch, W., Halasz, M., Granovskaya, M. & Kholodenko, B.N. The dynamic control of signal transduction networks in cancer cells. Nature Reviews Cancer 15, 515-527 (2015).
2. Kholodenko, B. N. Cell-signalling dynamics in time and space, Nat Rev Mol Cell Biol. 7, 165-176 (2006). 3. Nakakuki et al. Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics, Cell. 141, 884-896 (2010).
4. Kholodenko, B., Yaffe, M. B. & Kolch, W. Computational approaches for analyzing information flow in biological networks. Science signaling 5, re1, doi:10.1126/scisignal.2002961 (2012).
5. Ryu et al. Frequency modulation of ERK activation dynamics rewires cell fate. Molecular systems biology 11, 838 (2015).
6. Byrne et al. Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches. Cell Systems, 2, 38–48 (2016).
7. Kholodenko, B. N. Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects. Cell reports 12, 1939-1949, (2015).
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