PhD Opportunities

Our research group has selected several PhD projects, listed below, which have priority for funding. Please contact the supervisor(s) of the PhD project that you are most interested in directly via email for more information. Applying is relatively straightforward and can be done electronically.

The entire list of projects offered by our group (on many topics across biophysics) can be found here. These can be funded from various other funding opportunities, including scholarship schemes offered by the University and by external agencies. More information about these scholarships (for UK, EU and international students) can be found here.

 

Seeing photosynthesis at the nanoscale: mapping the properties of light-harvesting membranes by video-speed atomic force and fluorescence microscopy

Supervisors: Dr Peter Adams, Dr George Heath and Prof. Steve Evans

Project description. Understanding photosynthesis could provide valuable clues for future solar technology and help our understanding of food crops. Photons of sunlight are absorbed by biomembranes found within chloroplasts, where large numbers of Light-Harvesting Complex (LHC) proteins act as a satellite dish for channelling energy to Photosystem (PS) proteins. The LHC and PS proteins contain chlorophyll and carotenoid pigments which act as the light-absorbing, energy-transferring cofactors. Much is known about the structure and function of main proteins within this system, however, we need a better understanding of the structural dynamics of each protein and the energy transfers processes taking place across the membrane system. We can map the protein structure and arrangement to nanoscale resolution using a technique called Atomic Force Microscopy (AFM). Recent developments in AFM allow video-speed imaging and measurements of the protein dynamics at the millisecond to microsecond timescale. Fluorescence microscopy (FM) can be used to locate these pigment-protein complexes and fluorescence spectroscopy can quantify the energy transfer processes which occur between pigments.

In this project, you will quantify the nanoscale structural dynamics and energy transfer processes of these proteins using high speed AFM and fluorescence techniques. Firstly, you will study how the so-called supercomplexes of PS/LHC proteins can assemble and disassemble in real time with AFM and FM imaging. You will systematically assess the effect of membrane composition and the effect of temperature. This will reveal the interaction strength and remodelling capabilities of these critically important Photosystem clusters. Secondly, you will quantify the flexibility and rearrangement of single LHC proteins with a newly developed ultra-fast height spectroscopy mode of AFM. Here, you will assess the effect of pH, which is thought to trigger changes to these proteins. Finally, you will quantify energy transfer processes of different configurations of proteins using advanced fluorescence spectroscopy. Characterizing the structural arrangement and biophysical properties of these membrane proteins will greatly advance our understanding photosynthesis.

 

Polymeric Micro- & Nano- Bubbles for Tackling Antimicrobial Resistance

Supervisors: Prof Steve Evans and Dr Zhan Yuin Ong

Project description. Staphylococcus aureus (S. aureus) is a bloodstream infection that has mortality rates of 17-46% and is a daily occurrence, with over 12,700 cases in England per year. It is a significant cause of hospital-acquired infection and leads to extended hospitalisation, at an estimated cost per patient of £8k pa. S. aureus forms biofilms, a complex mixture of biopolymers and bacterial cells, on internal organ surfaces, implants, and vasculature. The biofilm structure shields most bacteria from any antibiotics leading to poor efficacy in the treatment of infection whilst having adverse effects on the microbiome. This poor localised delivery coupled with the emergence of antimicrobial resistance means that new approaches are needed to continue treating such infections.

In Leeds, we have used ultrasound (US) waves to burst tiny bubbles coated with drugs, to treat tumours effectively.

1 We have also developed some novel drugs, antimicrobial peptides (AMPs), that are selective at killing bacteria whilst leaving human cells intact.

2 However, these drugs often get broken down by enzymes in the bloodstream before reaching the infection site reducing their efficacy.

In the project outlined here, we propose to protect the AMPs by hiding them in a polymeric shell surrounding the bubbles. Ultrasound will then be used to trigger the release of the drug are the site of infection by bursting the bubbles. Further, in addition to the localised delivery of drugs, we will investigate the additional benefit of physically disrupting the biofilms using US to enhance drug delivery deeper into the biofilms and for the treatment of released ‘planktonic’ bacterium.

 

Novel nanoparticle-loaded formulations to enhance the locoregional delivery of anticancer drugs to brain tumours

Supervisors: Dr Zhan Yuin Ong

Project description. Glioblastoma (GBM) is the deadliest form of primary brain tumour with an extremely poor survival duration of less than 15 months. The treatment of GBM involves surgical debulking of the tumour mass, followed by radio/chemotherapy. However, residual cancer cells remain in the so-called margin zone and are responsible for the inevitable recurrence and resistance to treatment. We have recently developed a simple and versatile synthetic method to produce highly uniform porous silica nanoparticles with intrinsic cancer targeting and pH responsive drug release properties. This project aims to develop a novel formulation comprised of the organic-inorganic hybrid nanoparticles that can enhance the penetration and delivery of anticancer drugs following local administration in the brain. The student will first prepare and characterise the release of anticancer drug loaded nanoparticles from the formulation. Subsequently, the effect of surface chemistry and particle size on the penetration and cellular accumulation of the nanoparticles will be studied in 2D and 3D patient-derived GBM cell models using high resolution electron microscopy and fluorescence microscopy techniques. The degradation profiles of the novel nanoparticle-loaded formulation will be evaluated under physiologically relevant conditions. Biocompatibility of the novel formulation will be studied using various patient-derived brain relevant cell types.

This project is well-suited to highly motivated student with a keen interest in the interdisciplinary area of Nanotechnology for biomedical applications. Students are expected to possess a minimum of an upper second-class degree (or equivalent) in a relevant Pharmacy, Biomedical Science, Chemistry, Physics or Engineering background. The successful candidate will be trained in a wide range of highly desirable skills in the field of Nanomedicine, Drug delivery, and Biomaterials such as nanoparticle fabrication, use of electron microscopes (TEM/SEM) and confocal microscopes, drug loading and release, in vitro 2D and 3D cell culture and/or animal work. The student will benefit from working in a vibrant and multidisciplinary environment in the Bragg Centre for Materials Research as well as with staff and students from the Schools of Physics and Medicine at the University of Leeds.

 

Developing the next generation of biomaterial structural characterisation

Supervisors: Prof. Lorna Dougan and Dr Arwen Tyler

Project description. Folded protein hydrogels are an exciting new class of biomaterial which possess specific biological functionality, enabling dynamic changes in mechanical and structural properties in response to biomolecular cues. At Leeds we use a unique cross length scale approach to translate knowledge of the nanoscale biophysics of folded proteins to the mesoscale architecture and function of the biomaterial. This new project will involve the development of a suite of new experimental tools for measuring the structure and mechanics of hydrogels during network formation. The student will join a multi-disciplinary team of researchers at Leeds and at the Diamond Light Source. Using a Small angle x-ray scattering instrument at Leeds we will investigate the biomaterials structural design space. Using our state of the art off-line SAXS/WAXS Leeds/ Diamond instrument as well as large scale facilities we will measure the dynamic structural transformation of the protein solution into a cross-linked protein network. Finally, to explore the potential of the protein hydrogels for targeted drug delivery we will measure the structure of hydrogels containing microbubbles and determine the impact of their bursting due to ultrasound.

Full description
Folded protein-based hydrogels are a novel class of biomaterials which combine the useful viscoelastic and functional properties of proteins together with the prospect of rational design principles [1]. At Leeds we are developing tools to deliver a cross length scale understanding, providing exciting new opportunities towards new applications. Our arsenal of tools allows measurement of the mechanics, structure and function, from single proteins to biomaterial. Professor Lorna Dougan’s group (LD) has shown the hierarchical emergence of worm-like chain behaviour from biopolymer chains1, translation of mechanical properties from nanoscale to macroscale,[2] developed equipment to control the reaction rate which governs the viscoelasticity and nanostructure of folded protein hydrogels [3] and developed a modelling platform, BioNet, to measure network growth and structure of hydrogels [4]. Intriguingly, our latest work has shown that in situ protein unfolding defines the network architecture and mechanics of the hydrogel [5].

However, missing from our tools is insight into the formation mechanisms of these biomaterials. Such insight would deliver the bespoke hydrogels for specified applications.

The project will involve the development of a suite of new experimental tools for measuring the structure of hydrogels during network formation. The project will be in 3 parts (i) Using Dr Arwen Tylers’s group lab based SAXS instrument at Leeds we will investigate the biomaterials structural design space by tuning the protein volume fraction, cross-link density and location. (ii) Using our state of the art off-line SAXS/WAXS Leeds/ Diamond instrument and large scale facilities we will measure the dynamic structural transformation of the protein solution into a cross-linked protein network. (iii) To explore the potential of the protein hydrogels for targeted drug delivery we will measure the structure of hydrogels containing microbubbles and determine the impact of their bursting due to ultrasound.

Our research groups are proud to create inclusive student, research, and working cultures that are supportive and welcoming to those from all backgrounds, genders, ages, disabilities, religions, and other protected groups. We are committed to providing a postgraduate program that not only equips you with the technical and professional skills you will need in your career, but which is also enjoyable, supportive, diverse, and inclusive.

1.B.S.Hanson et al., Soft Matter, 15, 8778 (2019)
2. M.Hughes et al., Soft Matter, 16, 6389 (2020)
3. A. Aufderhorst et al., Biomacromolecules, 21, 4253 (2020)
4.B.S.Hanson, L.Dougan, Macromolecules, 53, 7335 (2020)
5. M. Hughes et al, ACS Nano, 15, 11296 (2021)

 

Multiscale mechanics: folded globular proteins as hydrogel Lego bricks

Supervisors: Prof. Lorna Dougan

Project description. Proteins are bionanomachines. These workhorses of the cell are responsible for a vast array of biological functions. Acting in isolation or as part of larger, often complex machinery, they perform their function through structural and mechanical changes. Mechanical properties are an essential property of biological scaffolds, where cell behaviour can be controlled by designing material scaffolds that incorporate specific structural and mechanical cues.

Proteins are semi-flexible polymer and biopolymer networks formed by semi-flexible polymers have emerged as a new class of biological soft matter systems with remarkable material properties, motivating many theoretical developments. Such theories include the mechanics and dynamics of individual semiflexible polymers, bundles and entangled solutions and non-affine approaches for disordered polymer networks.

You will join a multidisciplinary team to understand the physics of the building block (the folded protein) and its connectivity (the protein network). This will be achieved through a cross length scale, physics based approach which will translate knowledge of the nanoscale biophysics of folded proteins to the mesoscale architecture and function of novel folded protein hydrogels. Experimental techniques will include single molecule force spectroscopy, rheology and scattering.

 

 

IOP Bell Burnell Graduate Scholarship Fund:

The IOP Bell Burnell Graduate Scholarship Fund is for full or part-time graduates wishing to study towards a doctorate in physics and from groups that are currently under-represented in physics. We have an internal deadline of 8th December 2021. You need to be interviewed and sent an offer letter by this date.

If you would like to talk to us about this scholarship then please email m.e.ries@leeds.ac.uk

To find out more information go here:
https://www.iop.org/about/support-grants/bell-burnell-fund

Watch this YouTube video from Jocelyn Bell Burnell herself, talking about this funding: https://www.youtube.com/watch?v=EigAPYgJo0M

 

Inclusivity:

“Our department is proud to create inclusive student, research, and working cultures that are supportive and welcoming to those from all backgrounds, genders, ages, disabilities, religions, and other protected groups. We are committed to providing a postgraduate program that not only equips you with the technical and professional skills you will need in your career, but which is also enjoyable, supportive, diverse, and inclusive. We welcome all applications, but especially those from the under-represented groups in physics. Everybody’s needs will be supported, but if you do have any concerns, you can contact us, in confidence, to discuss how we can support your particular needs during a research degree at the University of Leeds.”

 

 

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