Institute for Frontier Life and Medical Sciences, Kyoto University

Theoretical Biology Seminar

Date: June. 14, 2019 16:00~17:00
Room: Seminar Room104, 1st Floor, Bldg. #2 of Institute for Frontier Life and Medical Sciences, Kyoto University
Speaker: Prof. Boris N. Kholodenko Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland
Department of Pharmacology, Yale University School of Medicine, New Haven, USA
Title: Can physics-based dynamic models help us understand biology?

Abstract

In this talk, I first show how topological design principles determine the spatiotemporal dynamics of the RhoGTPase family signalling networks. Then, I demonstrate computational and experimental results supporting a novel hypothesis of how spatially-distributed Rho-Rac interactions can coordinate cell migration. In the second part of the talk, I will demonstrate applications of fundamental thermodynamics relationships and show that drug resistance resulting from dimerization of kinases (including, tyrosine kinase receptors, BRAF/CRAF, JAK2, etc) can be explained by allosteric inhibitor effects and the emergence of different drug affinities between free kinase monomers versus dimers. Finally, I overview an exciting and counterintuitive discovery made using a new type of mathematical modelling, which combines aspects of protein structure, posttranslational modifications, thermodynamics, and dynamic reaction mechanisms. We used model predictions to block oncogenic RAS signalling in metastatic melanoma cells. RAS is mutated in 30% of all human cancers, and RAS mutated cancers are clinically considered to be undruggable and resistant to current treatments. Our approach identified non-intuitive drug combinations that synergise to block critical RAS effector pathways.