Cryo-EM for understanding molecular processes in health and disease

Knowledge of the molecular structure of proteins and nucleic acids that are the building blocks of life has had unparalleled impact on our understanding of human health and disease. Almost 90% of the structures determined to date have been solved by crystallography, using diffraction of X-rays. Electrons are, however, 1000 times less damaging to biological molecules than X-rays, in terms of energy deposited per useful scattering event. This makes it possible to use electron cryomicroscopy (cryo-EM) to record images of single macromolecules embedded in a layer of vitreous ice at cryogenic temperatures. It is expected that this technique, for which Jacques Dubochet, Joachim Frank and Richard Henderson were awarded the 2017 Nobel Prize, will be used to determine an ever increasing proportion of structures of macromolecules in the future.

Aligning images of smaller macromolecules with sufficient accuracy to obtain a high resolution cryo-EM reconstruction becomes increasingly challenging as the molecules get smaller. An alternative approach involves rotating an arrangement of aligned molecules (i.e. a crystal) in a beam of electrons to enable structure determination from sub-micron sized crystals (nanocrystals) by electron diffraction. Electron diffraction has been used to determine structures from nanocrystals of standard test specimens (such as lysozyme) and also novel structures from ‘invisible’ crystals of short peptides. Studies suggest that attempts to crystallise macromolecules often result in nanocrystals that would in principle be suitable for electron diffraction, but are too small for X-ray crystallography.

This PhD project is at the interface of biochemistry, physics and structural biology; it will involve both the development of novel methods and structure determination by cryo-EM, in particular by electron diffraction, for several macromolecules that are important for human health. The co-supervisors laboratories have a wealth of expertise in using structural biology to study nucleic acid-processing machines involved in virus biogenesis (Prof Fred Antson) and proteins involved in host:pathogen interactions (Prof Jennifer Potts).

This PhD will provide a unique opportunity to be actively involved in the establishment of cryo-EM and particularly the electron diffraction technique at the world-renowned York Structural Biology Laboratory in the Department of Chemistry at the University of York. The project is suitable for students who have a strong interest in development and application of cutting-edge techniques to determine the structures of biological molecules. Applicants would be expected to have a background in chemistry, biochemistry or physics.

All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.

Training will also be provided in Structural Biology techniques specific to this project. The PhD student will be based in York Structural Biology Laboratory, which is a major research grouping at the University of York. YSBL research focuses on macromolecular crystallography, and will expand into Cryo-EM from 2018. The project is of strategic importance for the University, as it fits the University’s research theme on "Health and Wellbeing" and its drive to tackle the "globe’s most pressing health, environmental and social challenges". The project would help in the establishment of cryo-EM studies at York and would kick-start studies on electron diffraction. There will be opportunities to attend international workshops and conferences with a possibility of collaboration with research laboratories at the national facility at Diamond (Oxford).

The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel. Chemistry at York was the first academic department in the UK to receive the Athena SWAN Gold award, first attained in 2007 and then renewed in October 2010 and in April 2015. This PhD project is available to study full-time or part-time (50%).

Shortlisted candidates will be invited to a panel interview at the University of York (date TBC)