We seek an enthusiastic PhD student, from the physical or life sciences, excited about uniting advanced biophysics and cell biology to study how microbial toxins work.
Protein toxins serve as weapons in evolutionary conflicts across biological systems. A number of toxins in the “A/B family” (e.g. tetanus, cholera, anthrax, shiga and diphtheria toxins) cause millions of deaths annually. An example is budding yeast K28 ‘killer’ toxin which is a useful model of clinically relevant A/B toxins. However, the mechanisms of A/B toxin sensitivity and how cells defend against toxin is poorly understood. To investigate these mechanisms, you will develop novel single-molecule bioimaging tools using biophysics in the group of Mark Leake (https://sites.google.com/a/york.ac.uk/mark-leake-group/home) applied to yeast cell strains you will help develop in the MacDonald group (https://www.york.ac.uk/biology/research/developmental-biology/chris-macdonald/) which recently discovered the K28 defence factor, Ktd1 (Andreev et al., PNAS 2023). You will help to explore the hypothesis that endosomally localised Ktd1 works to sequester K28 toxin as it enters cells and directs toxin to the lysosome for degradation.
You will:
1 – learn how to develop new cell strains to characterize vacuolar dynamics in the presence and absence of Killer toxin K28, using a range of fluorescence microscopy in combination with a new pH based reporter for the vacuole (https://doi.org/10.1038/s42255-023-00872-1).
2 learn how to use live cell single-molecule “Slimfield” microscopy (https://pubmed.ncbi.nlm.nih.gov/20023777/) and associated analysis to define membrane organization of Ktd1 in living cells and its oligomeric state, in combination with biochemical approaches.
3 – establish how the biophysical of the vacuole are influenced by the functional activity of the toxin and associated cellular physicochemisty (including molecular crowding, ionic strength, pH, hydrophobicity and local ATP levels) (https://pubmed.ncbi.nlm.nih.gov/34862033/) by developing bespoke 3D spectral imaging and 3D imaging for live cells.
The Departments of Biology and Chemistry both hold an Athena SWAN Gold Award. We are committed to supporting equality and diversity and strive to provide a positive working environment for all staff and students.
The WR DTP and the University of York are committed to recruiting future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and we have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.
Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with any biological, chemical, and/or physical science backgrounds, or students with mathematical background who are interested in using their skills in addressing biological questions.
Programme: PhD in Mechanistic Biology (4 years)
Start Date: 1st October 2024
Shortlisted candidates will be interviewed by the WR DTP panel in February 2024 on a date to be confirmed.
Funding Notes
tax-free annual UKRI stipend (£18,622 for 2023/24 academic year), tuition fees and
Research Support and Training Charges (RSTC). International students will need to have sufficient funds to cover the costs of their student visa, NHS health surcharge, travel insurance and transport to the UK as these are excluded from UKRI funding.
