About me:

I chose a career in science primarily because I like solving puzzles, but what motivates me to solve them is the knowledge that whatever I find will have an impact on one of the most significant medical health challenges we face today.

I received my PhD in Biophysics from Harvard University in 2005 where I used cryo-electron microscopy to investigate the cell entry mechanism of poliovirus.  As an EMBO postdoctoral fellow and Cancer Research Institute Fellow at the University of Oxford, I continued to explore the structures of membrane proteins, focusing on the complement immune pathway. I am currently a lecturer in Structural Biology within the Department of Life Sciences and recipient of a Cancer Research UK Career Establishment Award.  Funding from CRUK has enabled me to realize my goal of leading an internationally competitive research team committed to understanding how the immune system can be targeted to fight cancer.

What is this project about?

Complement is an important component of the immune system that kills cells by making pores in cell membranes. Our research uses structural biology to visualize pore-forming proteins with immune receptors in model membranes. Our research addresses biological questions relevant to understanding a mechanism of immunity and provides a strong foundation for the development of future antibiotics and cancer therapeutics.

Host cells are protected from complement attack by receptors such as CD59 that block pore assembly and prevent membrane insertion. Some bacteria secrete pore-forming toxins that hijack these immune receptors to promote their own pore formation and contribute to their pathogenicity. Cancer cells also manipulate this protection mechanism to evade the complement response during antibody-based immunotherapy treatments. Work in the lab integrates biochemical and biophysical experiments with structural techniques to understand the role of CD59 and cholesterol in pore-formation. 

How does this project align with the rest of our research?

The complement membrane attack complex (MAC) is one of the first lines of defense against bacterial infection and is essential for fighting Neisseria meningitidis. MAC pores drill holes in lipid bilayers and cause lysis of pathogens or host cells, if not properly controlled. MAC lesions were first identified in 1964, yet half a century later details of its structure and assembly mechanism remain undiscovered. We aim to understand how individual complement proteins come together to form the pore and the role the membrane plays in that process. To achieve this we use electron cryo-microscopy to visualize the human MAC and its assembly precursors in model membrane systems. Recent work in the laboratory has shown for the first time the molecular architecture of the MAC and reveals that the MAC is in several ways different from other closely related pore-forming proteins.