Research Interests

Research in the group focuses on spatiotemporal and/or stochastic dynamics in cell and developmental biology. Recent topics have included:

Epigenetic Dynamics

Understanding the mechanistic basis of epigenetic memory is a central question in molecular biology. A key hypothesis is that covalent modifications, such as trimethylation, added to specific locations on histone proteins are one important epigenetic memory element. Although much is known about the proteins involved in histone modification dynamics, our overall mechanistic understanding is still limited. Recently, my group has been working closely with Caroline Dean's in an effort to more fully understand these issues in the context of the floral regulator gene FLC. FLC is repressed by cold, such that in a subsequent warm period, the level of repression is quantitatively dependent on the prior cold period. In effect the length of the cold period is epigenetically remembered by the plant, a memory that is crucial in the timing of flowering and therefore of reproductive success. We have shown that this quantitative epigenetic memory is encoded by the plant in an all or nothing fashion in each cell (where FLC is either fully repressed or not), with the fraction of repressed cells increasing with an increasing period of cold. We have developed a simple mathematical model that can explain this quantitative FLC silencing in terms of the highly dynamic behaviour of the histone mark H3K27me3. Although based on the FLC system, the high levels of conservation of epigenetic elements, means that the model's conclusions (recently published in Nature) are very widely applicable in biology.

Spatiotemporal Protein Dynamics inside Bacteria

Similar to eukaryotic cells, bacteria also localise proteins to specific locations in space and time, so as to organise and coordinate development. Past work in the group has involved the spatiotemporal oscillations of the MinCDE proteins that regulate cell division positioning in E. coli. This work clearly demonstrated that intricate patterns and localisation can be generated from very simple protein interactions and diffusion. My group also pioneered the study of low copy number fluctuations in spatiotemporal protein dynamics, as applied to both the MinCDE system in E. coli and the Spo0J/Soj system in B. subtilis. Currently, we are investigating the spatiotemporal dynamics of the ParABC system regulating low copy number plasmid segregation in E. coli (movie available here; Warning! File size=2.5MB), and the dynamics of hyphal branching in Streptomyces.

Cell Division in Fission Yeast

Cell division positioning in bacteria is already quite well understood, at least in some model systems such as E. coli (see above). However, our understanding of the same question in eukaryotes is at a lower level. As an intermediate between bacteria and metazoan cells, we have been investigating cell division positioning in fission yeast. Mathematical modelling and experimental results from the group of Fred Chang (Columbia) have revealed a combination of repressive cues from the cell poles together with activating signals from the centrally placed nucleus act together to determine cell division positioning.

Flucutations in Morphogen Gradients

Many biological systems require precise positional information to function correctly. This positional information is often encoded in a concentration (or morphogen) gradient. By switching on a signal only where the local concentration is above a certain threshold, a gradient can provide positional information. However, fluctuations in the concentration profile will lead to fluctuations in the identified position. We have therefore investigated the impact of fluctuations on positional precision. Interestingly we have found that the profile of a concentration gradient can be optimised to provide maximally precise positional information. Applications have been made to both cell and developmental biology, including yeast cell division and the developing Drosophila embryo. The latter work has been carried out in collaboration with the lab of Jun Ma (Cincinnati). The role of spatial, as well as temporal, averaging has been closely investigated. We have also examined pre-steady-state read out of mophogen gradients and found that, contrary to earlier claims, such decoding is generally not more precise than in steady-state.

Models of Signal Transduction/Amplification

The question of how a signal emanating from a small structure inside a cell can be amplified and propagated to the entire cell is fundamental to cell biology. An excellent example is provided by the Spindle Assembly Checkpoint (SAC). This checkpoint permits cell cycle progression to anaphase only if all the chromosomes are properly attached to spindle microtubules. We have developed a new model for the SAC in metazoan cells with open mitosis involving diffusible cell cycle inhibitors. The model incorporates a novel form of signal amplification that nevertheless allows for rapid signal switch off after complete microtubule-kinetochore attachment.

Modelling the Dynamics of Cell Polarity

The question of how cells acquire polarity is fundamental to cell biology and development. An excellent system in which to study these questions is the development of anterior-posterior polarity in the one cell C. elegans embryo. This process involves the PAR proteins, which form complementary anterior and posterior domains in a dynamic process driven by cytoskeletal rearrangement. We have developed a mathematical model of this polarity establishment process, in which we take a novel approach to combine reaction-diffusion dynamics of the PAR proteins coupled to a simple model of actomyosin contraction. We showed that the known interactions between the PAR proteins are sufficient to explain many aspects of the observed cortical PAR dynamics in both wild-type and mutant embryos. However, cytoplasmic PAR protein polarity, which is vital for generating daughter cells with distinct molecular components, cannot be properly explained within such a framework.

Spatiotemporal Dynamics of the early stages of Phagocytosis

Phagocytosis is the process by which cells internalize particulate material, and is of central importance to immunity, homeostasis and development. In collaboration with the group of Emmanuelle Caron (Imperial), we studied the internalization of particles in cells transfected with Fcγ receptors (FcγRs) through the formation of an enveloping phagocytic cup. Surprisingly, we found that phagocytic cups growing around identical spherical particles showed great variability even within a single cell and exhibited two eventual fates: a cup either stalled before forming a half-cup or it proceeded until the particle was fully enveloped. We explained these observations in terms of a mechanical bottleneck using a simple mathematical model of the overall process of cup growth.