Our goal is to understand how the immune system is activated to effectively eliminate infected or cancer cells. We focus on dendritic cells, which have a unique ability to initiate immune responses and mobilize cytotoxic killer cells. Indeed, patients (or animals) lacking dendritic cells fail to control infections, malignancies, and auto-immune diseases. Dendritic reside in all tissues and survey the environment for signals associated with infection or cancer. In response to such signals, they sample surrounding cells and migrate to the nearby lymph nodes. In the lymph nodes, they present fragments of pathogen- or cancer-derived proteins on the cell surface in order to specifically activate only the relevant T cells. Activated T cells migrate to the inflamed tissues and rapidly kill the target cells. The molecular mechanisms involved in tissue sampling and processing of proteins for presentation to T cells remain elusive. We also have very limited understanding of how cancer-derived signals enhance or inhibit dendritic cell functions. Here, we approach these two questions using genetics, proteomics, and transcriptomics-based techniques. Better understanding of the molecular mechanisms involved in initiation of immune responses by dendritic cells is a stepping stone for rational design of more effective vaccines and anticancer therapies.

Stem cells have the unique capability of generating daughter cells that acquire different fates (e.g. muscle, bone or skin). This is important during embryo development, when hundreds of different cell types are generated in an organized manner to form a baby with a final shape and function; and during adult regeneration, when stem cells provide cellular progeny to replace damaged tissues. Our main objective is to understand how the spatial organization of stem cells in embryos and adult tissues modulates their fate. To achieve this goal we use a novel technology to culture and study early mouse and human embryos in the laboratory. We focus on the behaviour of the stem cells as the embryo undergoes changes in shape. In the case of the human embryo these studies are limited to the first 14 days of development. We also use stem cells as building blocks to recreate specific embryonic and adult tissues in the laboratory. This is a very powerful approach to understand the basic mechanisms that regulate stem cell fate decisions, and design future strategies to improve the efficiency of human embryo development, and to promote tissue regeneration in situations of damage.

All living cells require a constant source of energy to drive the many reactions and other processes that are essential for the cell's survival. A significant part of this energy is stored in molecules of adenosine triphosphate (ATP), which is synthesised by the complex multi-component protein ATP synthase. Intriguingly, one component of this enzyme has been shown to operate as a nanoscale molecular rotary motor. Our studies are aimed at determining the three dimensional atomic structure of ATP synthase using X-ray crystallography to provide a detailed understanding of how it functions. G-protein coupled receptors are proteins that control communication between cells in the body. They are the targets for drugs used in the treatment of a wide variety of conditions including cardiac conditions (beta-blockers), mood disorders and asthma. Knowledge of the three dimensional structure of these proteins will help our understanding of how they work and help direct the discovery of improved, more selective, drugs that have fewer side effects. X-ray crystallography of biological molecules requires the collection and processing of large amounts of X-ray diffraction data, typically collected using the intense X-ray beams available at synchrotrons. We are developing software to help automate the collection and processing of this data.

Microtubules are essential components of the self-assembling machinery that enables cells to move, grow and divide. The aim of this work is to look in detail at the nuts and bolts of this machinery using electron microscopy and X-ray diffraction. The microtubules themselves are made up of self-associating globular protein subunits but as soon as they assemble, the structure becomes unstable, ready to be broken down and rebuilt elsewhere. Minor components that bind all along the microtubules or only at their ends control their assembly and disassembly at different stages in the cycle of cell growth and division. We want to see how these components interact with and control the globular subunits. Other molecules called motor proteins move along the outside surface of the tubes, carrying things to different parts of the cell. We try to see how these motor molecules change shape in order to move without losing contact with the microtubule surface.

Large organisms, like animals and plants, are made from enormous numbers of cells that work together. Under the microscope, one is struck by the extraordinary beauty and complexity of each individual “eukaryotic” cell in the collective. My team is fascinated by ability of these cells to rapidly reshape themselves to give rise to new structures, especially during division, as one cell becomes two. We are also interested in the origins of complex cells. Remarkably, eukaryotes first arose ~1 billion years ago as the result of a merger between a relatively simple archaeal cell and a bacterial cell. While it is not known precisely how this happened, we recently proposed that eukaryotic cell architecture evolved in a step-wise manner, from the ‘inside-out”, as an archaeal host cell elaborated protrusions that it used to share resources with its free-living bacterial partner. If true, features once thought to be unique to eukaryotic cells may have their origins in archaea. This is a hypothesis we now aim to test. Finally, by studying cell division in archaea and eukaryotes, we also expect this work to reveal new fundamental aspects of the cell division process that can be used to aid our understanding of human cancer.