Sir William Dunn School of Pathology

T cells are important white blood cells that continually circulate in the body in search of the molecular signatures ('antigens') of infection and cancer. We (and many other labs) are trying to construct models of the T cell signalling network that can be used to predict how ligand binding (at the surface of the cell) controls gene express (in the nucleus). To do this, we stimulate T cells with various ligands (input) and measure products of gene expression (output) and then try to determine which model must be invoked to explain the data. The challenge that we face is finding 1) unique models and 2) scaling the method to many different input and outputs.

We aim to determine how cells faithfully complete genome replication. Accurate and complete genome replication is essential for all life. A single DNA replication error in a single cell division can give rise to a genomic disorder. However, almost all experimental data are ensemble; collected from millions of cells. We used a combination of high-resolution, genomic-wide DNA replication data, mathematical modelling and single cell experiments to demonstrate that ensemble data mask the significant heterogeneity present within a cell population; see [1-4]. Therefore, the pattern of replication origin usage and dynamics of genome replication in individual cells remains largely unknown. We are now developing cutting-edge single molecule methods and allied mathematical models to determine the dynamics of genome replication at the DNA sequence level in normal and perturbed human cells.

[1] de Moura et al., 2010, Nucleic Acids Research, 38: 5623-5633

[2] Retkute et al, 2011, PRL, 107:068103

[3] Retkute et al, 2012, PRE, 86:031916

[4] Hawkins et al., 2013, Cell Reports, 5:1132-41