Professor David J Beech

Profile

After Pharmacology undergraduate studies at the University of Manchester and PhD studies at St George’s University London, I trained in biophysics at the University of Washington, Seattle, before returning to the UK as a Wellcome Career Development Fellow. Since 2000 I have been Professor at the University of Leeds. My primary research aims have been to advance understanding of calcium-permeable cation channels and mechanical force sensing mechanisms in cardiovascular and metabolic biology. So far, I published 190 articles, filed 2 patents and delivered 170 invited research lectures worldwide on this and related topics. My group’s 2014 Nature article was the first to demonstrate PIEZO (PIEZO1) channels as sensors of physiological mechanical force (shear stress), a discovery that helped to justify PIEZOs as one of two topics of the Nobel Prize in Physiology or Medicine in 2021. With partners I led on developing pharmacology for these and other channels, discovering important tool compounds and motivating investment in therapeutic drug discovery. I fostered the careers of over 50 scientists in the field in both academic and industrial sectors and assembled basic and clinician scientist teams for translation to patient benefit. I am Fellow of the Academy of Medical Sciences and investigator on a portfolio of research grants that include a Wellcome Investigator Award and British Heart Foundation (BHF) Programme Grant, supporting a team of 10-15 postdoctoral, postgraduate and technical researchers. I lead major cross-faculty university activities, particularly in research and postgraduate research education. I spent 8 years as Head of School, Department and Institute. I founded and still direct the pan-Leeds cross-faculty Multidisciplinary Cardiovascular Research Centre (MCRC) that achieved an approximate doubling of cardiovascular research activity and an institutional strategic priority of cardiovascular disease and diabetes research. I co-founded and directed for almost 4 years the Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), comprising over 200 staff and 100 PhD students. I founded and direct our Doctoral Training Programme in Cardiovascular Disease and Diabetes Research (BHF-funded since 2017 and the only programme with such a focus in the UK). In 2021 I brought prominence to the breadth and quality of mechanobiology research at Leeds (https://www.leeds.ac.uk/mechanobiology-mechanotechnology) and plan next to advance this and other key areas of research.

Responsibilities

• MCRC Director
• BHF 4-Year PhD Programme Director
• Academy of Medical Sciences Regional Champion

Research interests

In my PhD and postdoctoral studies I discovered multiple voltage-gated potassium channel subtypes and nucleotide diphosphate-dependent potassium channels in vascular smooth muscle cells as well as kinetically distinct calcium channel regulatory pathways in sympathetic neurones. I then turned to the problem of non-voltage-gated non-selective cationic and calcium-entry pathways in the vasculature and other parts of the body. My group revealed Transient Receptor Potential Canonical 1 (TRPC1) as a component of constitutive and agonist-regulated calcium and sodium influx channels in vascular smooth muscle cells. We went on to find partner channel subunits, related channels and associated regulatory systems in smooth muscle, endothelium and other cell systems. We discovered lipid and redox regulators of the channels and ion channel switching as a response to vascular injury and its relevance to human disease through inhibitor antibody design and collaboration with surgeons. We found downstream signalling mechanisms, including a previously unrecognised calcium-regulated G protein, Rab46. We identified potent and selective pharmacology for TRPC1/4/5 and ORAI1 channels, which now motivates translational investments, patent filing and partnership with the Max Planck-founded Lead Discovery Centre. Despite these successes, there remained the major unsolved problem of how mechanical force is sensed in cardiovascular biology; it was central to my aims because calcium-permeable channels had been suspected as pivotal players but their molecular identity was unknown. TRPCs were candidates but I questioned this idea, leading the cardiovascular field to a different type of ion channel, called PIEZO1. We discovered PIEZO1 as a critical sensor of shear stress force caused by blood flow and showed how it integrates physiological force with vascular architecture. We were pioneers in revealing PIEZO1’s essential non-inactivating property in physiology and how its intrinsic inactivation gate is disabled. We found how red blood cells profoundly slow the gating kinetics of PIEZO1 and revealed failure of PIEZO1 deactivation as a mechanism of hereditary anaemia. We discovered important downstream signalling pathways, including calpain, endothelial nitric oxide synthase, ADAM10 and Notch1, and physical interaction with cell adhesion molecules. We developed computational models to first suggest how PIEZO1 channel opens in response to force and responds to lipids. We showed how PIEZO1 enables elevated blood pressure in exercise and began testing the case for PIEZO1 as the pivotal general force sensor of cardiovascular and metabolic biology.

Qualifications

• BSc Hons
• PhD

Professional memberships

• Fellow of the Academy of Medical Sciences
• Member of the Physiological Society

Student education

Director and teacher on the British Heart Foundation 4-Year PhD Programme in Cardiovascular Disease and Diabetes at Leeds

Research groups and institutes

• Leeds Institute of Cardiovascular and Metabolic Medicine
• Discovery and Translational Science
• British Heart Foundation - Cardiovascular research
• Multidisciplinary Cardiovascular Research Centre
• LICAMM - international PhD academy

Current postgraduate researchers

• Kath Norman
• Emily Woodhouse