Dr Hannah Britt

Introduction

Understanding the intricate and interwoven landscape of dynamic biological molecules which form the molecular basis of life is a fascinating but challenging puzzle. Unpicking this world in miniature holds the key to tackling some of the greatest challenges of our time, from ensuring food sustainability to improving human health. One innovative approach to understanding this fundamental biology is to study the molecular mechanisms of life using chemical approaches. Mass spectrometry (MS) is a powerful analytical technique capable of achieving this goal. When applied to biological systems, MS can unravel protein-effector interactions, protein dynamics, and post-translational modifications, building up a comprehensive molecular picture of biological pathways. Like many existing techniques, however, MS is currently limited in its ability to capture the full complexity of biological systems on physiologically relevant millisecond timescales.

Imagine if it were possible not only to watch molecular mechanisms play out in real time in their native environment, but to simultaneously unpick the therapeutic strategies which modulate them.

My group develop and apply structural MS approaches, particularly native and top-down MS, to achieve this vision. By studying dynamic molecular mechanisms in this way, we aim to revolutionise disease diagnosis and treatment. Our focus is on unpicking biochemical pathways directly from human tissues and biofluids, maintaining the complexity of their native environment into the mass spectrometer. We are also interested in how these molecular pathways are altered and modulated, particularly in disease states or by pharmaceuticals.

Current major projects

• Developing mass spectrometry methods to study the rules of life.
• Bringing the physiological environment into the mass spectrometer.
• Unravelling protein signalling in healthy and disease states.
• Uncovering the molecular details of protein-glycan interactions.

Detailed research programme

Bringing the physiological environment into the mass spectrometer

To fully understand the molecular rules of life we need methods that enable us to study biological molecules within their complex biological milieu. Our goal is to achieve this by bringing the physiological environment into the mass spectrometer. By pairing new sample preparation methodologies with advanced instrumentation, we are moving towards making truly native MS a reality.

Unravelling protein signalling in healthy and disease states

One of the major challenges in drug discovery is the relatively high failure rate of therapeutic candidates. Many of these failures are attributed to poor understanding of the underlying disease mechanisms for which the drug is designed. By unravelling these biochemical pathways, we greatly improve our chances of successful disease diagnosis and treatment. Using parallel targeted and discovery approaches, we unpick molecular behaviour directly from human tissues, biofluids, and extracellular vesicles. By comparing healthy and disease systems, this enables us to better understand both intrinsic human heterogeneity and dynamic disease mechanisms. We are also interested in how these molecular pathways are modulated by therapeutics, hoping that better understanding will improve patient treatment and drive the field of personalised medicine.

Uncovering the molecular details of protein-glycan interactions

Glycans are intricate sugar molecules which decorate the outside of every cell. Interactions between glycans and proteins are responsible for translating glycan structures into biological function. These interactions therefore underpin a range of normal and pathological processes, including pathogen recognition, plant stress responses, and human immunity. To harness the potential of these interactions, uncovering their molecular details is imperative. We use our mass spectrometry approach to study these dynamic interactions in detail, and on a physiologically relevant timescale. Whilst our approach is applicable to studying glycan-protein interactions across a wide biological remit, we are particularly interested in understanding (auto)immunity, therefore our work focuses on dendritic cell lectins.