Atomic Force Microscopy

The group's primary tool is the atomic force microscope (AFM). We develop the technique and use it to study living systems and soft matter. Instrument developments include Torsional Tapping AFM (TTAFM), Torsional Resonance AFM in liquid, VideoAFM, large area high speed AFM, and STORMforce. Jamie co-founded Infinitesima Ltd. and collaborates with them to develop tools for the semiconductor market.

Biological Physics

Many of the most exciting unanswered questions in Science lie in the area traditionally covered by the Life Sciences. Similarly, some of the greatest challenges facing our society, such as sustainability of food and energy supply, the threat of non-communicable diseases (e.g. cancer), and the emergence of antibiotic resistant pathogens (e.g. MRSA), will be solved through a better understanding of living systems. My group is part of the Physics of Life network, Imagine project, and the Florey Institute, working closely with biological and medical scientists to gain a better understanding of the dynamical behaviour, physical properties, and structural complexity of living systems.

The figure shows intact chromatophore vesicles from Rhodabacter sphaeroides, taken with conventional AFM (scale bar 20 nm).

Current Projects

The bacterial cell wall in life and death

Funder: Wellcome

This is a joint programme of work between myself and Prof Simon Foster in The School of Biosciences, UoS. Here is the summary from the application:

The bacterial cell wall is essential for viability. The synthesis of its major structural polymer, peptidoglycan, is the target of crucial antibiotics such as penicillin and vancomycin. The wall also forms the interface between pathogenic bacteria and their host. Despite this importance, we do not understand how the wall is able to maintain life and yet be dynamic to permit growth and division, how the wall allows appropriate interaction with the environment or even how antibiotics kill bacteria. We will address these fundamentally important areas, focusing on the human pathogen Staphylococcus aureus as our primary target organism. We aim to:

1. Determine the molecular architecture and dynamics of the wall in the living cell by developing and applying our world leading microscopy approaches and novel chemical probes.

2. Understand how the structure of the wall is maintained and how it acts as the interface with the environment.

3. Examine the simple underlying principles that govern bacterial growth and how this is perturbed by antibiotics, explaining why some antibiotics are bactericidal and others bacteriostatic.

The figure shows the extracted cell wall of Staphylococcus aureus imaged in buffer.

The Physics of Antimicrobial resistance

Funder: UKRI Strategic Priorities Fund

This "Physics of Life" funded interdisciplinary programme of work is a joint project led by myself and Prof Simon Foster (School of Biosciences, UoS) in collaboration with Prof Pietro Cicuta (University of Cambridge), Prof Rosalind Allen (University of Edinburgh and University of Jena, Germany), Profs Waldemar Vollmer and Nikolay Zenkin (University of Newcastle).

The development by bacteria of resistance to antibiotics (antimicrobial resistance, AMR) is a global challenge that threatens to undermine many of the advances of modern medicine, with consequential massive human and financial costs. AMR is a multi-faceted problem in which processes occurring over many different length and timescales interact, leading to the emergence of resistant bacteria. To obtain a predictive understanding of this complexity we will take an interdisciplinary approach, bringing together quantitative experimental and mathematical physics with cutting-edge microbiology, biochemistry and infectious disease biology. Bacteria become resistant through genetic mutation and gene acquisition which inevitably leads to physiological changes, including the obvious sustained growth when under antibiotic stress. By better understanding the physical nature of these changes we aim to reveal exploitable fitness costs associated with AMR, i.e. ways in which the bacteria become more vulnerable as the price they pay for becoming resistant to particular antibiotics.

The figure shows the interdisciplinary project plan and living cells of S. aureus imaged with AFM.

CsxA protein crystal from Clostridium sporogenes spores. Obtained with conventional Tapping Mode AFM in buffer.

Next generation AFM for solving problems in biomedicine

Funder: Wellcome

This technology development project is jointly led by myself and Dr Nic Mullin. Below is the summary of the project:

Advances in microscopy can change how we see the natural world and have repeatedly led to breakthroughs in biomedicine. Atomic force microscopy provides unique capabilities, being able to image living samples with molecular resolution, in liquid, at room temperature with minimal preparation. However, for biomedical applications it has failed to live up to its potential, arguably because instruments truly optimised for biology have not been developed. We will push each aspect of the microscope towards its theoretical limit to develop a new instrument that can image biomolecules with resolution comparable to structural biology approaches, but in context, under native conditions. These same advances will also allow us to measure the tiny forces that drive living processes. We will use the instrument to help understand pressing biomedical questions including: how bacteria live and how they die through antibiotic attack; how genetic code is read and regulated; how intercellular forces control embryo development.

The mechanobiology of the bone metastatic niche in breast cancer

Funder: CRUK and EPSRC

This project was jointly led by Profs Nicola Brown, Ingunn Holen and myself, and brought together a cross-disciplinary team to better understand breast cancer metastasis to bone. The funded round of the project has now finished and the work published, but we are looking to extend the project.

To determine the unique mechanobiological features of the bone metastasis microenvironment in breast cancer using biological, mechanical and theoretical physics modelling approaches. The hypothesis of this proposal is that pharmacological interventions modify the biomechanics of the bone metastasis niche and reduce breast tumour colonisation and growth. By utilising recently available biophysical methods in addition to developing new technology where appropriate, direct testing of this hypothesis is only now becoming possible. This is of key relevance to cancer research, as a large proportion of patients diagnosed with primary breast cancer already have single or small foci of disseminated cells, circulating, or dormant in the skeleton, representing a sub-population of patients with high risk of metastatic disease. There are 12,000 deaths/annum in the UK, with patients with metastatic breast cancer, equating to 40,000 deaths over the lifetime of this proposal. The ability to modify the bone microenvironment of these patients may reduce bone metastasis resulting in a significant impact in disease progression and thereby extend life. Importantly, these findings will be applicable to prostate cancer and myeloma, where bone colonisation by tumour cells occurs in the majority of patients.

The figure shows the variation in modulus across fresh tissue in native bone. The graph shows how modulus varies between the tumour, the surrounding bone microenvironment, and the same cancer cell line grown in a dish.