Engineering cell-type specificity in a naturally occurring protein nanosyringe for intracellular protein delivery

This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

Project:
The use of biologically active proteins for biomedical applications is becoming increasingly important as they can exhibit highly specific and potent activities. Good examples include antibody and cytokine-based therapies. It should be noted, however, that the majority of current successful polypeptide-based therapies, such as these, act externally to host cells or require endocytic processing. A major hurdle remains in getting active polypeptides across biological membranes to target them to specific compartments within target cells. As such there is an unmet need to develop more sophisticated tools for intracellular nanomedicines. Nature has evolved highly diverse and efficient molecular mechanisms for the translocation of biologically active polypeptides across biological membranes. In particular, secreted bacterial toxins are self-contained and highly adapted molecular devices that can delivery active polypeptides into host cells. Advanced synthetic biology techniques now afford the opportunity to re-engineer toxin systems in order to adapt them for biomedical benefit. Notably, the insect pathogenic bacterium, Photorhabdus, deploys a nanoscale protein syringes to deliver toxins into host cells. In this project we will build upon significant recent progress in re-engineering these nanoscale syringes into viable intracellular protein drug delivery tools. These tools will ultimately be valuable for addressing a huge range of human diseases such as cancer, immunology disorders and enzyme deficiencies. The student will gain experience in synthetic biology, high resolution microscopy, tissue culture/cell biology techniques and advanced analytical chemistry methodologies.