Almost all bacteria rely on a molecular machine called FtsZ to divide and multiply. We are trying to find small chemical molecules which recognise FtsZ and stop it from working normally. If we can interfere with FtsZ we should be able to use these molecules as drugs to kill the bacteria which cause disease.

Protein secretion is an essential process that is conserved across all eukaryotes and is initiated by COPII-coated vesicles that bud from the endoplasmic reticulum (ER) carrying nascent secretory and membrane proteins. COPII vesicles are formed by five conserved "coat" proteins that self-assemble to simultaneously select cargo proteins and sculpt the membrane into a vesicle carrier. To achieve this, the coat must fulfil several seemingly contradictory principles: it must be (1) sufficiently robust to exert significant force to bend the membrane; (2) intrinsically unstable to permit uncoating, which drives fusion with the Golgi membrane and protein/lipid delivery; and (3) be architecturally adaptable, such that the morphology of transport carriers can encompass small vesicles (60-80 nm) as well as larger structures that carry cargos like pro-collagen (300nm rods) or lipoprotein particles (300nm spheres). Understanding how the COPII coat assembly pathway is initiated, regulated, and modified to generate transport intermediates with diverse morphologies is the focus of my project. I propose to investigate how the COPII assembly pathway proceeds in the context of dynamic protein-protein and protein-lipid interactions, and aim to bring new methodologies to solve the problem of how coat assembly is modulated to adapt to specific physiological needs. I will develop a real-time imaging assay that visualizes coat assembly on supported bilayers. Such reconstitution will allow analysis of the dynamics of the coat in the context of physiologically relevant states, including nucleotide (GTP), cargo, and accessory proteins. Moreover, capitalizing on the library of specific coat mutants available in the Miller lab will further reveal mechanisms that govern coat assembly and adaptivity.

The Wnt/beta-catenin signalling pathway is highly conserved and controls the normal development and tissue homeostasis of animals. This pathway is also a major cancer pathway. In particular, most bowel cancers are initiated by hyperactive Wnt signalling activity in the intestinal epithelium, caused by mutations in the Adenomatous Polyposis Coli (APC) tumour suppressor or in beta-catenin itself. Our aim is to understand the molecular mechanisms governing Wnt signalling in normal and malignant cells. In focus are the molecular functions of pathway components that have potential as drug targets. These include Dishevelled, an ancient Wnt signalling component assembling dynamic Wnt signalosomes to relay the Wnt signal from the cell surface to the cell nucleus. Our approach is to combine biochemical, biophysical and structural analysis with functional tests in human cell lines and in whole-organism models such as fruit flies and plants to gain insight into how dynamic protein assemblies are formed. Our work could pave the way towards the discovery of Wnt pathway inhibitors for therapeutic intervention in cancer.

The information stored in the DNA is essential to every form of life. It is therefore crucial that the information is copied accurately, without the introduction of any mistakes. The process of copying DNA, called DNA replication, is a complicated process that requires many different proteins to work together. How this is achieved is not well understood. We therefore study DNA replication in the model organism E. coli. For this we use structural methods such cryo-electron microscopy and protein crystallography to determine how the different proteins interact with one another. We also use biochemical and single molecule methods to determine how the sequential steps of DNA replication are organized in time. We also study DNA replication in the bacterium Mycobacterium tuberculosis (Mtb). Mtb causes tuberculosis that kills an estimated 1.5 million people world-wide each year, making Mtb the deadliest pathogen, even before HIV. We study DNA replication in Mycobacterium tuberculosis to find new targets that can be used to develop new antibiotics for the treatment of TB. New antibiotics are urgently needed as resistance to antibiotics is increasing at an alarming rate in Mtb, but also other pathogenic bacteria. We have already found a new target and are currently screening for chemical inhibitors that will be further developed into novel antibiotics.

Animals interact with the world by combining inputs from their senses of vision, hearing, smell, taste, touch and multiple others, with memories of past experiences, to then select a single, appropriate motor response that we observe as behavior. The study of each individual module of the brain revealed how signals are processed locally within. But the output of one module (e.g retinas) are the inputs of another (e.g. motor centres). To study how the brain chooses a specific behavioral response over any other, we must study both the internal circuits of a module and the signals that modules exchange with each other. In other words, we must observe the activity of all brain neurons on the basis of knowing the wiring diagram of the whole brain. In the lab, we are ma Dinq and anal zing the wirina diaaram of the whole