Design Principles | David Rand

David Rand

Warwick Mathematics Institute & Zeeman Institute

CURRENT RESEARCH INTERESTS

Design principles of regulatory and signalling systems

One of the systems I work on is the NF-κB signalling system. NF-κB controls inflammation and in different contexts has varying effects on cell death and division. It is activated by various stress stimuli, including inflammatory cytokines such as TNFα and IL-1β and is regarded as one of the most important stress response pathways in the mammalian cell. In a variety of conditions it displays oscillatory dynamics when stimulated, with the transcription factor entering the nucleus in a pulsatile fashion with a period of roughly 100 minutes. The figure on the left summarises some of the interactions involved in passing information to the genes from the cell's external environment. In this case it is sensing the amount of the TNFα to assess the inflammatory state of the tissue.

Gene regulatory networks have an important role in every process of life, including cell differentiation, metabolism, cell replication and signal transduction. They work by encoding a stochastic dynamical system that, usually interacting with other such systems, carries out the various task that the cell needs to undertake. Thus, for example, the cell needs to time schedule its processes so they they coordinated correctly and share resources appropriately. To do this it employs the circadian clock, a complex oscillator involving a set of genes that directly interact with other genes to produce oscillations that can be used for timing.

They have an important role in every process of life, including cell differentiation, metabolism, cell replication and signal transduction. They work by encoding a stochastic dynamical system that, usually interacting with other such systems, carries out the various task that the cell needs to undertake. Thus, for example, the cell needs to time schedule its processes so they they coordinated correctly and share resources appropriately. To do this it employs the circadian clock, a complex oscillator involving a set of genes that directly interact with other genes to produce oscillations that can be used for timing.

Much of my research is concerned with understanding the design principles behind such regulatory systems. I use mathematical analysis and modelling to try and how they work and why evolution has fashioned them as they are. I try to create mathematical tools to help with this. Deep involvement with experimentalists and experimental data is key to success in this endeavour. Moreover, biological data is rapidly improving with new technologies that enable deeper observation of the cell arising continually. Therefore, a key part of my work involves the development of statistical tools to facilitate the analysis of such data.

Collaborations.

Mike White (Manchester), George Minas (St Andrews), Pawel Pascak (Manchester), Julian Davis (Manchester), Claire Harper (Mnachester)

Recent papers in this area.

Multiplexing information flow through dynamic signalling systems. G. Minas, D. J. Woodcock, L. Ashall, C. V. Harper, M. R. H. White, D. A. Rand, Preprint biorxiv. https://doi.org/10.1101/863159

Parameter sensitivity analysis for biochemical reaction networks. Giorgos Minas, David A Rand, Mathematical Biosciences and Engineering, 2019, 16(5): 3965-3987. doi: 10.3934/mbe.2019196.

Long-time analytic approximation of large stochastic oscillators: simulation, analysis and inference. Giorgos Minas, David A Rand. PLoS Computational Biology (2017) 13(7):e1005676 doi.org/10.1371/journal.pcbi.1005676.

Temperature regulates NF-κB dynamics and function through timing of A20 transcription. C. V. Harper, D. J. Woodcock, C. Lam, M. Garcia-Albornoz, A. Adamson, L. Ashall, W. Rowe, P. Downton, L. Schmidt, S. West, D. G. Spiller, D. A. Rand* and M. R. H. White*. Proceedings of the National Academy of Sciences. 2018, DOI: 10.1073/pnas.1803609115, PMID: 29760065 *Communicating author.