Shearwin Laboratory

Our research integrates biochemistry, genetics and mathematical modelling to characterise fundamental mechanisms of gene control and how these elements are combined to create gene regulatory circuits with complex functions.

We have a strong focus on using and developing mathematical modelling as a tool to advance understanding of gene regulatory mechanisms and systems, a tool that will be essential for the new ‘systems biology’ as molecular biology tries to move from characterizing the parts of cells and their simple interactions to understanding how these interactions combine to generate complex functions.  We find that the process of attempting to construct a mathematical model of a biological system is valuable in itself - helping to clarify ideas, define assumptions and identify missing information. Once a model is made, comparison of the model with available experimental data can reveal shortcomings in either, leading to changes to the model or to improved data collection or interpretation. A consistent mathematical description is a powerful tool, providing precise predictions to aid further experimental tests, and allowing rapid exploration of the range of properties of the system to generate insights into design features.

Our primary experimental systems are two E. coli bacteriophages, lambda and 186. These temperate phages can replicate their genomes using alternative developmental pathways, lysis and lysogeny, and are some of the simplest organisms to make developmental decisions. Despite their relative simplicity, the phage systems combine a wide range of gene control mechanisms in complex ways and have many lessons to teach us. Bacteriophage lambda continues to be a key model system for many molecular biological processes; phage 186 is less well characterised but provides a powerful comparison with lambda, as it achieves similar outcomes using different regulatory circuits. The fundamental biochemistry shared by all living things means that the study of any organism, from phages to humans, continues to illuminate universal principles that apply to all organisms.

Given the marked molecular genetic advantages of E. coli, one can readily study the operation of the phage circuits at all levels, from the thermodynamic properties and structure-function relationships of the individual components, through the operation of isolated circuit ‘modules’, to the integration of these modules into the genomic network and their function in the lifecycle of the whole organism. Together with the wealth of data available for all aspects of gene expression in E. coli, a deep understanding of whole organism behaviour becomes a feasible goal, one much desired but not yet achievable for more complex organisms.

Our research program and our strong links with the Center for Models of Life at the Niels Bohr Institute for Theoretical Physics in Copenhagen (http://cmol.nbi.dk/), including student exchanges, provide an exceptional environment for researchers and students to experience and contribute to applying mathematical thinking to gene regulation and to the collection of experimental data that is amenable to this kind of analysis.

Research projects

Our research comprises a number of inter-related projects:

• Gene regulatory circuits in phages 186 and lambda

• Synthetic regulatory circuits using well-defined components

• Use and control of DNA looping interactions between regulatory proteins

• ‘DNA traffic’ - interactions between elongating RNA polymerases and residents of DNA

click here for a Java based interactive model of DNA traffic

• Models of cell memory and gene regulation by nucleosome modification circuits

click here for a Java based  interactive model of a nucleosome modification circuit