Developing new computational tools for the next generation of structural imaging with single molecule and super resolution microscopy

Background:

Super Resolution Microscopy (SRM) is a broad class of microscopy techniques collectively aimed at breaking the fundamental limit imposed on fluorescence imaging due to the diffractive nature of light. Recent advances in SRMs have enabled nanometre and sub-nanometre resolution imaging of protein complexes in their native cellular environments. However, these methods remain severely limited in the size and number of complexes they can image; hence, improved methods are needed to image the widely sized intracellular protein complexes at a structural and ultra-structural level.

Aim:

As part of this PhD project, you will develop a range of instrument automation, processing, and analysis tools to image structurally heterogeneous and disease-implicated protein complexes at molecular resolution with the aim of mapping the ultra-structural diversity of misfolded protein aggregates in mice and human brain samples of neurodegeneration. This opportunity will allow you to develop expertise in super resolution imaging, computer vision, and deep learning tools for biological imaging. As part of your training, you will be extensively exposed to the expansive fields of neurodegeneration and ultra-sensitive immunological assaying. Towards the end of the PhD, you will develop an all-rounded skill set that is in high demand across academia and industry.

Importance:

Intrinsically Disordered Proteins (IDPs) regulate a wide range of biological processes by assembling into flexible complexes that escape (ultra) structural imaging using existing methods, such as Cryogenic Electron Microscopy (CryoEM), being heterogeneous. SRM can image single protein complexes but at a lower resolution. By pushing the resolution of SRM towards molecular scales, the (ultra) structure of flexible protein assemblies can be resolved at a single assembly level, allowing the structural basis of many biological processes and diseases to be studied.

Our lab:

The Danial Lab, situated at the School of Physics and Astronomy within the University of St Andrews, pioneers technical advancements aimed at advancing single-molecule fluorescence microscopy for ex vivo and in situ structural imaging. Within this pursuit, the lab wishes to accommodate researchers boasting diverse expertise, spanning from optical engineering and software development to biochemistry and assay development. Together, they would collaborate to unravel the structural and molecular foundations of human brain disorders. Accessible resources include cutting-edge single molecule microscopes that are fit-for-purpose as well as powerful workstations hosting the most advanced GPUs.

Your profile:

We are looking for a talented individual with strong and demonstrated expertise in Python programming (front-to-back end) as well as instrument automation applied to fluorescence imaging. The ideal candidate should demonstrate a strong enthusiasm for acquiring new skills at the forefront of biophotonics and neurodegeneration and the stamina to develop major software with wide impact.

Enquiries:

For enquiries, please send an email (including a CV and an open-source repository of prior work) to Dr John S H Danial (jshd1@st-andrews.ac.uk).