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Prof David Brockwell Prof Sheena Radford No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Leeds United Kingdom Artificial Intelligence Biochemistry Bioinformatics Biotechnology Data Science Machine Learning Molecular Biology Neuroscience Structural Biology

MRC DiMeN Doctoral Training Partnership, University of Leeds

About the Project

Neurodegenerative diseases of ageing such as Alzheimer’s and Parkinson’s diseases (AD and PD) have a huge societal and financial impact yet cost-effective therapies to delay or cure these diseases are lacking. Traditional methods for studying the mechanisms of aggregation of the culprit proteins (Ab42 in AD and a-synuclein (AS) in PD) are complex, requiring the purification and characterisation of experimentally challenging proteins. How and why sequence modifications affect disease remain obscure, especially given the emerging importance of the synergistic co-aggregation of two or more proteins in AD and PD (AS and Ab42) and in Amyotrophic Lateral Sclerosis (AS and TDP-43). This complexity can be deciphered using machine learning (ML) and artificial intelligence (AI) but this requires large amounts of data linking the genotype to the observed phenotype. We have integrated an in vivo screen for protein aggregation [1][2] into a deep mutational scanning (DMS) platform[3]. Using this method, we have shown that the aggregation potential of every single-residue variant of Ab42 (~800 proteins) can be quantified in just a few days, opening the door to generating transformative understanding of amyloid formation.

You will build on our exciting new approach by applying the screen to AS and TDP-43 when expressed separately and together. You will then use these datasets and AI/ML to generate predictive models for amyloidogenecity focussing on the unmet need of synergistic co-aggregation in neurodegeneration.

This will be achieved by using molecular biological, biochemical, structural and data science methods: variant libraries will be created using error-prone PCR and fitness scores calculated via next generation sequencing using lab. protocols. ML/AI will be trained on these data to generate predictive models for amyloid formation and validated using biochemical, amyloid growth kinetics and structural analysis (cryoEM) of selected variants.

The project will be supervised by Professor David Brockwell and Professor Sheena Radford FRS. These groups (RadfordLab – X.com) share an integrated laboratory space with weekly science progress meetings, journal clubs and to annual research retreats. Expertise available across the groups is exceptional spanning cell biology, microbiology, biophysics, biochemistry and molecular biology and a range of structural techniques including NMR, MS and EM provided a rich training environment.

David Brockwell: https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/38/professor-david-brockwell

Sheena Radford: https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/127/professor-sheena-radford

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/applications ;

Studentships commence: 1st October 2025

Good luck!

References

[1] Ebo J, Saunders J, Devine P, Gordon A, Warwick A, Schiffrin B, Chin S, England E, Button J, Lloyd C, Bond N, Ashcroft A, Radford S, Lowe D and Brockwell D (2020). An in vivo platform to select and evolve aggregation-resistant proteins. Nature Communications. 11:1816.
[2] Saunders J, Young L, Mahood R, Jackson M, Revill C, Foster R, Smith D, Ashcroft A, Brockwell D and Radford S (2016). An in vivo platform for identifying inhibitors of protein aggregation. Nature Chemical Biology. 12:94-101.
[3] Mclure R, Radford S and Brockwell D (2022). High-throughput directed evolution: a golden era for protein science. Trends in Chemistry. 4:378-391.

Where will I study?

University of Leeds

The University of Leeds is one of the largest research-intensive universities in the UK, offering a range of research degrees from Masters to PhDs (full-time or split-site), as well as professional doctorates. Our postgraduate researchers are a fundamental part of our vibrant research culture.

Career overview

Professor David Brockwell is a Professor of Biochemistry and Molecular Biology at the University of Leeds, where he has been a faculty member since 2004. He completed his BSc in Pharmacy at the University of Manchester, followed by a pre-registration year at St Bartholomew''s Hospital in London, qualifying as a pharmacist in 1993. He returned to the University of Manchester for his PhD research, supervised by Dr Jill Barber, focusing on the biophysical effects of protein perdeuteriation. After a brief postdoctoral position at the same laboratory, he worked as a postdoc at the University of Leeds in Professor Sheena Radford''s lab for six years, where he began investigating force-induced unfolding and remodelling of proteins. In 2004, he was appointed to a joint URF/Lecturer position at Leeds and became an Associate Professor in 2012. With over 15 years of experience, Professor Brockwell''s research primarily investigates the effects of force on proteins and their aggregation, resulting in more than 45 publications in the field. His expertise encompasses protein (un)folding, force in biology, outer membrane protein biogenesis, biopharmaceutical aggregation and engineering, and protein hydrogels.

Research interests

Professor Brockwell''s research focuses on several key areas within biochemistry and molecular biology. His work investigates the effects of mechanical force on proteins and their complexes, utilising atomic force microscopy (AFM) to measure the mechanical properties of single protein molecules. He has explored how proteins with similar stability to chemical denaturants can exhibit different behaviours when subjected to force, and has studied the mechanical gating of outer membrane transporters. In the realm of membrane protein folding, Professor Brockwell examines the folding and insertion processes of bacterial outer membrane proteins (OMPs), collaborating with other researchers to understand how periplasmic chaperones and the b-barrel assembly machinery facilitate these processes. His research also addresses the challenges in biopharmaceutical manufacture, particularly how environmental changes can lead to unwanted protein unfolding and aggregation, which is critical in the biopharmaceutical industry. He collaborates with colleagues to investigate flow-induced aggregation and the manufacturability of biopharmaceuticals. Additionally, Professor Brockwell''s interests extend to protein hydrogels, which have applications in tissue engineering and drug delivery. He is working on developing hydrogels from folded globular proteins to exploit their full functional spectrum, including catalysis and ligand binding.

Biochemistry Molecular Biology Protein Folding Protein Unfolding Force in Biology Outer Membrane Protein Biogenesis Biopharmaceutical Aggregation Protein Engineering Protein Hydrogels Mechanical Properties of Proteins Membrane Protein Folding Biopharmaceutical Manufacture Hydrodynamic Forces Protein Aggregation Tissue Engineering Stimulus-Responsive Hydrogels Ligand-Triggered Actuators Drug Delivery Periplasmic Chaperones Bacterial Outer Membrane Proteins AFM (Atomic Force Microscopy) Protein Stability Protein Dynamics.

View Professor David Brockwell's profile

Career overview

Professor Sheena Radford joined the University of Leeds in 1995 as a Lecturer in the School of Biochemistry and Molecular Biology, progressing to Reader in 1998 and Professor in 2000. In 2009, she became the Deputy Director of the Astbury Centre for Structural Molecular Biology, and served as its Director from 2012 to 2021. She was appointed Astbury Professor of Biophysics in 2014 and became a Royal Society Research Professor in 2021. Professor Radford graduated with a BSc in Biochemistry from the University of Birmingham and completed her PhD in Biochemistry at the University of Cambridge under the supervision of Professor R.N. Perham, FRS. She has held various postdoctoral positions and a Royal Society University Research Fellowship at the Oxford Centre for Molecular Sciences. Throughout her career, Professor Radford has supervised around 25 PhD students and postdoctoral researchers in her laboratory, with over 160 individuals successfully progressing from her lab into various careers in academic research, industry, and technical editing. She has published more than 360 peer-reviewed papers and book chapters and has delivered over 475 invited lectures at national and international conferences across numerous countries. In the last five years, she has served on five major research funding panels and 20 Scientific Advisory Boards for prestigious institutions and companies. Additionally, she has been involved with editorial boards for several journals and currently serves as an Associate Editor for the Journal of Molecular Biology. She is also a Trustee and Council member of the Dementia Research Institute, UK, and the Regional Champion for the Academy of Medical Sciences. Professor Radford has received multiple awards, including the Biochemical Society Colworth Medal in 1996, the Royal Society of Chemistry AstraZeneca Prize in 2005, the Hites Award from the American Society for Mass Spectrometry in 2009, the Protein Society Carl Branden Award in 2013, and the Rita and John Cornforth Award of the Royal Society of Chemistry in 2015. She was elected a member of EMBO in 2007, a member of Academia Europaea in 2020, and has been recognised as a Fellow of the Academy of Medical Sciences (2010), the Royal Society (2014), and the Royal Society of Biology (2021). She was made an honorary member of the British Biophysical Society in 2014 and a Fellow of the Biophysical Society in 2018. In 2022, she received an honorary doctorate from the University of Liège, and in 2024, she became an International Member of the National Academy of Sciences (USA).

Research interests

Professor Radford''s research focuses on fundamental structural molecular biology, specifically the measurement of the conformational dynamics of proteins and the elucidation of the role that these motions play in protein folding and misfolding of both water-soluble and membrane proteins. Their research employs a wide range of biophysical methods, combining techniques from protein chemistry, molecular biology, chemical biology, and structural biology. Over the last 35 years, they have concentrated on delineating the mechanisms by which proteins fold or misfold, how dynamic excursions enable proteins to self-associate into amyloid fibrils—which are complex macromolecular assemblies associated with some of the deadliest human diseases—and how proteins fold into the bacterial outer membranes of Gram-negative organisms. Current major projects include: Mechanism(s) of protein misfolding and assembly into amyloid, Outer Membrane Protein (OMP) folding – The role of chaperones & BAM, Stabilising proteins of therapeutic interest against aggregation, Method development (MS, NMR, single molecule, biophysical methods).

Protein Folding Protein Misfolding Protein Aggregation Amyloid Membrane Protein Folding Biopharmaceuticals Structural Molecular Biology Biophysical Methods Protein Chemistry Chemical Biology Cell Biology Conformational Dynamics Mechanisms of Protein Folding Therapeutic Proteins Dynamic Excursions Self-Association Gram-Negative Bacteria Chaperones Method Development Mass Spectrometry NMR Single Molecule Techniques.

View Professor Sheena Radford's profile

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About the Project

Funding Notes

References