Professor David Brockwell

Profile

Professor (Leeds) 2020-present

BSc (Manchester) PhD (Manchester)

Postdoc (Manchester) 1997-1998

Postdoc (Leeds) 1998-2004

URF/Lecturer (Leeds) 2004-2012

Associate Professor (Leeds) 2012 - 2020

After studying Pharmacy at the University of Manchester, I undertook a pre-registration year at St Bartholomew's hospital in London and qualified as a pharmacist in 1993. I returned to Manchester for my PhD research supervised by Dr Jill Barber, investigating thebiophysical effects of protein perdeuteriation.  After a short post-doc in the same laboroatory I worked as a post-doc at the University of Leeds in Professor Sheena Radford's lab for 6 years where I started studies into force-induced unfolding and remodelling of proteins.

I was appointed to a joint URF/Lecturer position in 2004 and became an Associate Professor in 2012.  I have >15 years’ experience of investigating the effects of force on proteins and protein folding and aggregation. He has published >45 papers on the biophysical analysis of proteins broadly in four areas: the effects of mechanical force on proteins and their complexes; membrane protein folding and folding factors; biopharmaceutical manufacture and protein hydrogels

Responsibilities

• Biochemistry Programme Leader

Research interests

Currently research in the group is following four themes which are described below. If you are interested in joining the lab to study for a PhD find studentship and eligibility details here.

The effects of force on proteins and their complexes.

In vitro many proteins are required to resist or respond to mechanical stimuli. Over the last decade the development of atomic force microscope (AFM) instruments with high force sensitivity and sub-nanometre distance resolution has allowed the mechanical properties of single protein molecules to be measured and the effects of force on protein complexes to be assessed. This work has revealed that proteins with similar stability to chemical denaturants can behave very differently when unfolded by the AFM (Sadler et al. (2009) J. Mol. Biol.), that some extremely thermodynamically stable complexes are exquisitely sensitive to force (Farrance et al. (2013) PLoS Biol.)  while others are strong enough to mechanically gate outer membrane transporters (Hickman et al. (2017) Nature Commun.)

Membrane protein folding and folding factors

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. Despite their ubiquity and importance as cellular gatekeepers, progress in understanding how OMPs fold into the narrow ensemble of structures required for their function is slow. In a collaboration with Professor Sheena Radford we are examining the folding and insertion of bacterial outer membrane proteins (Huysmans et al. (2010) Proc. Natl. Acad. Sci. USA, Huysmans et al. (2012) J Mol Biol.) and how periplasmic chaperones (McMorran et al. (2013) J. Mol. Biol.; Schiffrin et al. (2016) Nature Struct. Mol. Biol.) and the essential b-barrel assembly machiney (BAM) complex facilitate this process (Schiffrin et al. (2017) J. Mol. Biol.).

Biopharmaceutical manufacture

The abiliy of proteins to respond to environmental changes is functionally important but can also trigger unwanted unfolding and aberrant self-assembly. Such deleterious behaviour is highly problematic in the ~£200bn biopharmaceutical industry where hydrodynamic forces are exerted on proteinaceious drugs such as antibodies during their large-scale manufacture.  These forces can induce the exposure of new protein surfaces with greater self-affinity, leading to aggregation, loss of efficacy of the protein drug and even immune responses upon administration.

While generating highly avid candidate therapeutics is relatively straightforward, identifying which of these are robust to stresses encountered during manufacture is difficult. In a collaboration with Professors Nik Kapur (School of Mechanical Engineering) and Sheena Radford, we are investigating the mechanism of flow-induced aggregation (Dobson et al. 2017) Proc. Natl. Acad. Sci. USA), the utility of bench-top hydrodynamic flow devices to assess manufacturability and process optimisation (Willis et al. (2018) Biotech Bioeng) and the use of an in vivo screen to assess and modulate the ‘manufacturability’ of candidate biopharmaceuticals (Saunders et al. (2016) Nature Chem. Biol.)

Protein hydrogels

Protein hydrogels are macroscopic three dimensional, hydrated, highly porous, percolating networks that have found applications in tissue engineering, such as vascular grafts and neural tissue regeneration, as well as scaffolds for controlling cell behaviour and stimulus-responsive protein hydrogels have been explored as ligand-triggered actuators for biosensors and for controlled release for drug delivery.  The biomaterials industry is rapidly expanding and is projected to be worth over £70bn by 2020.

Currently as most protein-based hydrogels are obtained from unstructured peptides or through aggregation of unfolded globular proteins, the full spectrum of protein function (e.g., catalysis, signalling, and ligand binding) has not yet been exploited. In a collaboration with Dr Lorna Dougan (School of Physics and Astronomy) we are building hydrogels from tandem arrayed, folded globular proteins with known mechanical properties assessed using AFM and investigating the emergent macroscopic rheological properties (da Silva et al. (2017) Biomacromol.).

• Does functional 'misfolding' of TonB drive import across the outer membrane?
• EMBeDs: Ensuring Manufacturability of next-generation Biopharmaceuticals by Design

Qualifications

• BSc, PhD 1997, Manchester.

Student education

Faculty Graduate School

FindaPhD Project details:

• Project 5843
• Project 44845

Academic roles:

• UG Programme Leader - Biochemistry programmes

Committees:

• Member of Undergraduate School Taught Student Education Committee

Research groups and institutes

• Structural Biology
• Biotechnology

Current postgraduate researchers

• Jim Horne
• Samantha Marie Lawrence
• James Whitehouse

Projects

<li><a href="//phd.leeds.ac.uk/project/1925-engineering-developable-biopharmaceuticals">Engineering Developable Biopharmaceuticals</a></li>