Translational cell biophysics
Collinson L and Larijani B - The Francis Crick Institute and University of Bath
These are linked with the four research themes summarised below. Our endeavour is to demonstrate how we utilise novel advanced imaging with specific artificial intelligence tools (AI-ART doctoral training programme) and biomechanical-engineering to address mechanistic disease questions. To this end we will set up various platforms within our Centre with the already established precision medicine networks in Glasgow, Oxford and Cardiff (such as the National Consortium of Intelligent Medical Imaging (NCIM) and Radiomics in Oxford and Cardiff respectively) this would contribute to answering our biomechanistic questions with cutting edge tools. It is by utilising advanced spectroscopy, both light and electron microscopy quantitative imaging, as well as medical imaging that we can create a quantifiable spatio-temporal landscape related to underpinning the mechanisms in the dysregulation of molecular signalling.
CTI currently consists of four research themes that collectively refer to as the science, engineering and translational unit (SET) (opposite scheme). The main objective is for the SET Unit to pursue interdisciplinary research addressing the main questions in Inflammation, autoimmune, immunoncology pathologies and rare/unmet diseases with common signal transduction pathways. The questions will be addressed by exploiting advances in quantitative imaging, omics platforms, drug delivery and nanotechnology devices.
In time, the objective is to create an Innovation Unit that will have a dual role. Firstly, it will comprise industrial partners that would be involved in the research in SET, by funding post-doctoral researchers to perform research at the interface of academia and research. Secondly, it would be to work with the Corporate Engagement Team (CET) and SETsquared (https://bath-setsquared.co.uk/) to setup the necessary tools for transfer technology implementation, innovation and strategies for incubator space. This role is an important one for setting up correctly the transfer technology that may result from the interdisciplinary work in the SET Unit.
Our Diagnostic and Prognostics Unit will, be integrated into the interdisciplinary academic and innovation unites focusing on developing novel medical devices and imaging platforms for quantitative prognostics. The aim is to be a unique Diagnostics Unit whereby world-wide hospitals can utilise for early detection of disease and the analysis of patient outcomes. The main objective is to create tools for this unit that have been commercialised by the CTI via our Innovation Unit.
Collinson L and Larijani B - The Francis Crick Institute and University of Bath
Structure-function of proteins controlled by immune related lipid signalling events, affected by membrane morphology
The main objective of this theme is to investigate the structure-function of various proteins involved in inflammation and immune cell activation pathways, particularly those controlled by lipid signalling events and how they are affected by membrane morphology. This will be in relation to localised intervention of small molecules and/or macromolecules with the aim of transforming the activation states of the proteins involved for application in pharmaceutics.
The implementation of membrane biophysics is essential to the functional targeting of therapeutics to subcellular compartments in models of immuno-oncology and immune pathology. The functional targeting is dependent on physical properties of the membranes to which proteins interact with/bind, such as membrane curvature and localised molecular order, which themselves are primarily determined by lipid composition. Thus, it is imperative to characterise these physical properties non-invasively in the living cells; this is where advances in the underlying physics/biophysics techniques will make a critical difference. The relationship between membrane structure alterations, via lipid synthesis pathways will be interrogated. High throughput image recognition, pathway analysis of global patterns resulting from the functional proteomics and lipidomics will be utilised in this research theme. It will also include the determination of structural activity-relationships of possible new medicines designed to target the sites of dysregulation in the signalling network of inflammation, oncology, and immune pathologies.
Tosh D and Ward SG- The University of Bath
Understanding molecular pathways responsible for physiological processes, how their dysregulation leads to disease, how they can be repaired, or regenerated.
The focus is to understand the molecular pathways responsible for physiological processes, how their dysregulation leads to disease and how they can be repaired or regenerated. The theme seeks to develop new therapeutics that include traditional small molecule chemical entities but better harness the new field of “biologic” medicines that span vaccines, monoclonal antibodies (and their variants) and cell-based therapeutics such as stem cells. We use interdisciplinary pharmacological, biochemical, chemical biology as well as cellular, molecular and genetic approaches to better understand, interrogate and manipulate these processes. Our approaches span in vitro/vivo models through to identification of biomarkers in groups of patients with a distinct disease phenotype or response to a therapeutic strategy. Clinical variability is likely to result from an interplay of genetic factors with environmental and lifestyle differences. We are entering the era of ‘precision medicine’ where drug development is moving away from the traditional one-size-fits-all therapeutic approach. Ultimately, linking a molecular pathway or biomarker to a patient group and new sensing techniques will transform our therapeutic approach and the effectiveness of new and emerging medicines. We have a breadth of expertise in several areas of immune regulation and inflammation including autoimmune and inflammatory disease, cardiovascular disease, obesity and cancer. This area is both interdisciplinary and strongly collaborative with clinical, pharmaceutical and biotech partners.
Medicines design, development of biologics and delivery, with the aim to attain the precise target sites.
This theme comprises experts in the broad fields of drug design and delivery with an overall aim to facilitate the creation of better medicines. The specific goals are: (1) to generate new chemical entities as potential therapeutics and as molecular probes to aid in fundamental research, and (2) to improve formulations in order to increase the rate and extent of drug absorption at its site of administration (the so-called bioavailability of the drug) and (3) improve delivery and development of so-called “biologics” such as proteins, vaccines, antibodies and antibody-drug conjugates). The molecular events taking place at the interface between the formulation delivering the drug, and the mechanism by which it is absorbed and then interacts with its biological target, are complex and depend on many factors. Indeed, the development of biologics as medicines presents a different set of biological and biophysical problems to overcome compared to small chemical entities.
Presently, there are few reliable, simple, experimental or theoretical tools that can predict how well a medicine might work. As a result, the pharmaceutical industry is often obliged to undertake expensive and lengthy animal or clinical studies to answer this question. Our research addresses these challenges by developing a suite of experimental methods and predictive models to direct the efficient and rational design and optimisation of high-performance drugs and drug products. In essence, therefore, this drug development initiative complements the focus of the CTI strategy by enabling new drug discovery and its eventual translation into novel and effective therapies for patient benefit.
Gill R. University of Bath
Interfacing life scientists, engineers and healthcare professionals, to develop leading-edge medical technology and devices, and advanced imaging systems.
The aim of the Advanced Bioimaging & Medical Devices theme is to bring together physical scientists and engineers with healthcare professionals and life scientists in the development of leading-edge advanced imaging systems, medical technology and devices . The scope of this theme spans fundamental discovery through to clinical treatment and life-long care. Our vision is to foster creation of novel methods and devices that cover this whole pathway, creating a unique pipeline for therapeutic innovation. Within CTI this theme has three functions: i) creating novel imaging/sensing for discovery & clinical pathways, ii) provide integrated support platforms for the other three themes, iii) translate research findings by creating delivery vehicles and personalised therapies. This Research Theme will be closely collaborating with a newly created Centre for Biosensors Bioelectronics and Biodevices (C3Bio), which brings together a critical mass of researchers working on different aspects of:
- biosensors (sensing elements and techniques)
- bioelectronics (electrophysiology and bioelectronic circuits)
- biodevices (device co-design and integration).
Furthermore, C3Bio closely collaborates with companies such as Abbott Diabetes Care, Oxford Instruments, Airbus, NeuDrive and The Technology Partnership (TTP). In turn this will enhance our interactions with industry to seek for funding and carry out our mobilities.
Members of this theme are encouraged to maintain a focus on the clinical translation and regulatory pathways throughout to ensure their research has a genuine impact on the quality of patient care. The collective regulatory experience gained by CTI members through forming spinouts and partnerships with medical technology sector companies will greatly aid the translation of the Centre’s work.
My laboratory is specialised in the design and evaluation of smart molecules for sensing and adjustment of iron with potential application as diagnostics/prognostics or photo-protectants/ therapeutics for a growing number of iron-related oxidative conditions and pathologies. With this unique expertise and several collaborative studies at the biology-chemistry interface, we have showcased multiple pioneering works based on the design and evaluation of ‘light-activatable caged-iron chelators’ and ‘mitochondria-targeted iron chelators’ for skin photoprotection against the ultraviolet A component of sunlight. My laboratory has also had strong collaborative links with Estee Lauder, Garnier/L’Oreal and Croda Europe, all interested in our light-activatable iron chelators. The mitochondria-targeted iron chelators designed by us have also demonstrated great promise for the therapy of neurodegenerative disorders such as Parkinson’s disease and Friedreich’s ataxia. We have also provided proof of concept for the high sensitivity and selectivity of two generations of novel mitochondrial iron sensors which may be used as diagnostic/prognostic markers for the mitochondrial iron-overload diseases such as Friedreich’s ataxia, Wolfram Syndrome and Parkinson’s disease. My major multidisciplinary grants awarded to date have all been related to the design and evaluation of smart molecules with iron chelation and/or antioxidant capacity (Welcome Trust Showcase Award, EPSRC, European Marie Curie Network FP7 People, BBSRC, British Skin Foundation/Garnier, BBSRC NIBB and Parkinson’s UK). In 2017, I launched the successful Skin@Bath Network comprised of prestigious national and international academics and clinicians, all interested in the skin damage and the therapy of skin-related disorders. The network members meet every two years in Bath (UK) as part of a two days Symposium.
Pedro Estrela is an Associate Professor at the Department of Electronic & Electrical Engineering and Director of the Centre for Biosensors, Bioelectronics and Biodevices (C3Bio). His work focuses on the development of molecular electrochemical biosensors and point-of-care biodevices for medical diagnosis, prognosis, surveillance and therapeutic monitoring.
Miniaturizable and multiplexable sensors have been developed for the detection of ions, small molecules, oligonucleotides, proteins, bacteria and cells in complex media such as blood and urine. These sensors, coupled with microfluidics and on-chip electronics can simultaneously detected a range of molecular biomarkers and therapeutic drugs in a lab-on-chip approach. A particular focus has been on cancer diagnosis and management, particularly prostate cancer. Dr Estrela was the Coordinator of the Marie Curie Initial Training Network PROSENSE devoted to prostate cancer diagnosis. Another particular interest is on disease management systems / companion diagnostics for infectious diseases, looking at point-of-care devices that can diagnose, monitor disease progression, detect co-infection with other infections and assess therapeutic interventions for a personalised medicine approach.
The Pudney lab develops new analytical approaches for health-care applications. The approaches we develop are based on translating fundamental findings from molecular biophysics studies on enzymes, disease associated proteins, and bio-active small molecules. Specifically, we combine spectroscopy, kinetics, numerical modelling, machine learning and molecular dynamics simulation to achieve insight into protein thermodynamics and biomolecular detection. Our work has led to advances in (i) predicting biopharmaceutical stability, (ii) detecting early stage pathological protein aggregation and (iii) point-of-care diagnostics for drug detection.
BLOC Laboratories Ltd is a spin-out from the Pudney lab, which commercialises the QUBES platform for biopharmaceutical stability assessment. This technology enables the rapid assessment and prediction of protein stability, without requiring labelling, surface attachment or the addition of exogenous chemicals. The major applications are in the development of biopharmaceuticals, decreasing the time and cost to achieve a stable candidate and for consistent QC across the life course of development. See www.bloclaboratories.com for more information.
We are currently developing a point-of-care detection approach for synthetic cannabinoid receptor agonists, otherwise called synthetic cannabis or Spice. Spice use is epidemic in homeless groups and prison populations in the UK and other countries around the world, despite the severe side-effects of use. Our approach is based on spectral fingerprinting, combined with numerical modelling, enabling the detection of the range of different Spice-like molecules. The approach has applications in harm-reduction, supporting vulnerable users and in decreasing the flow of drugs into prisons.
Research in the Masuyer lab focuses on the structure and function of bacterial toxins, particularly the mechanisms by which they interact with their host receptors, and the development of toxin-based therapeutics.
Previous projects include the study of botulinum neurotoxins interaction with their human receptors using a biophysical approach, including X-ray crystallography. This led to the design of new molecules with improved receptor-recognition and enhanced clinical properties for the treatment of neuromuscular disorders.
Current projects centre on ADP-ribosyltransferase exotoxins, a group of potent bacterial virulence factors that include Pseudomonas exotoxin A and Cholix. They target essential intracellular pathways of their eukaryotic host by modifying key proteins through addition of ADP-ribose, leading to protein synthesis inhibition and cell death. These toxins are able to cross epithelial barriers of the lung or intestine, to reach their target cells. Their modular architecture makes them ideal molecules for protein engineering to retarget specific toxin functions into beneficial uses, such as immunotoxins or biological drug transporters.
Our structural studies help us understand the molecular mechanisms underpinning the natural functions of this family of bacterial toxins in order to develop a new generation of toxin-based therapeutics, and design more efficient and safer molecules that will address current clinical concerns.
My group is interested in understanding how cells sense and respond to their physical environment. Normal development, wound healing, cancer, and aging are intimately associated with changes in tissue mechanics. We use high content microscopy, as well as molecular and cell biological techniques, to study the signalling pathways that couple physical forces with cell behaviours such as gene expression, migration, and proliferation. We are also interested in exploring how cells interact with synthetic materials, such as nanoparticles, and how engineered materials impact cell fate. Our goals are to figure out how cells organise themselves into tissues, how these processes can go wrong in diseases, and how nanoscale biomaterials can be used to treat cancer and repair damaged tissues.
Biological images provide a wealth of information, but we are still in the process of inventing the tools that we need to make sense of the information we can derive. We use computer algorithms to automatically identify cells from microscope images and extract of measurements of features from cell shape and cell-cell contact to intracellular structures and protein localisation. The resulting datasets, comprised of millions of cells with hundreds of features are heterogeneous, and highly complex. We are working with mathematicians and computer scientists to develop models that can help us interpret single-cell imaging data and the map signalling networks that underlie human disease and tissue regeneration.