Professor David J Beech

Professor David J Beech

Profile

After a Bachelor of Science at Manchester University and PhD at St George’s University London I moved to the University of Washington for postdoctoral research in biophysics before returning to London and then Leeds as a Wellcome Trust Career Development Fellow. Since 2000 I have been Professor at the University of Leeds with the primary aim of understanding cellular cation entry and mechanical force sensing in cardiovascular and metabolic biology and, in this field, to generate new pharmacology to enable therapeutic drug discovery, cultivate interdisciplinary science including basic science and clinical teams for translational impact and support the development of new productive academic careers. I am a Wellcome Investigator who also holds a British Heart Foundation (BHF) Programme Grant and portfolio of other research grants supporting a group of 12-15 investigators. I have many years’ experience as a university leader including 8 years as Head of School/ Department. In 2008 I founded the pan-Leeds cross-faculty Multidisciplinary Cardiovascular Research Centre (MCRC) that led to an approximate doubling of cardiovascular research activity at Leeds, a cardiometabolic focus, the Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) of over 200 staff and 100 PhD students and the UK’s first Doctoral Training Programme in Cardiovascular Disease and Diabetes, which has been BHF-funded since 2017 and was renewed in 2020 until 2028. I was director of LICAMM until 2020 and continue to direct both the MCRC and PhD programme. Recent efforts include a cross-faculty Mechanobiology initiative (https://www.leeds.ac.uk/mechanobiology-mechanotechnology). I published 190 articles, delivered 170 invited lectures worldwide and fostered the careers of over 30 scientists in my field across the academic and industrial sectors. In 2021 I am founding a spinout company for therapeutic innovation in calcium-permeable channels with partners at Leeds, the Lead Discovery Centre Dortmund and Max Planck Dortmund.

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

Current postgraduate researchers

<h4>Postgraduate research opportunities</h4> <p>We welcome enquiries from motivated and qualified applicants from all around the world who are interested in PhD study. Our <a href="https://phd.leeds.ac.uk">research opportunities</a> allow you to search for projects and scholarships.</p>
Projects
    <li><a href="//phd.leeds.ac.uk/project/231-endothelial-piezo1-channels-of-human-placenta-and-their-physiological-roles">Endothelial Piezo1 channels of human placenta and their physiological roles</a></li>