Personal profile

Biography

Current post:

Professor of Biochemistry, University of Manchester, UK.

Director, Wellcome Trust Centre for Cell-Matrix Research

Director, Cellular & Developmental Systems Domain, Faculty of Biology, Medicine and Health, University of Manchester

Research interests

Most tissues are supported by a fibrous scaffold of collagen fibrils that accounts for 30% of total body mass. As a postdoc in the USA, I developed an in vitro system of assembling collagen fibrils in vitro by cleavage of procollagen with the procollagen N- and C-proteinases.  With this system, I discovered the tip-mediated nucleation-propagation mechanism of collagen fibril assembly.  I went on to discover how mutations in collagen genes that cause osteogenesis imperfecta (‘brittle bone disease’) and the Ehlers-Danlos syndrome (flexible joints and hyperextensible skin) alter procollagen structure, procollagen cleavage, fibril structure, and fibril assembly. This was the first demonstration that disease-causing mutations in collagens can change the structure and function of collagen molecules. On returning to the UK as a Wellcome Trust Senior Research Fellow, my own laboratory was the first to use serial block face-scanning electron microscopy (SBF-SEM) in the UK, and we developed methods that are now widely used to study tissues architecture.  Using our SBF-SEM approach, we discovered that the collagen fibrils that are the majority of the mass of adult connective tissues are generated during embryogenesis and adolescence and remain unchanged during adulthood.  Using SBF-SEM, we discovered that collagen fibrils assemble in vivo at the plasma membrane in structures we called fibripositors.  My lab was the first to show that fibripositors are actin-based mechanosensors via which fibroblasts generate oscillatory tension on the extracellular matrix.  The persistence of collagen fibrils throughout life implies the existence of a robust protection mechanism but none have been found.  However, we have recently shown that the circadian clock regulates trafficking of procollagen through the secretory pathway to generate a rhythmic pulse of collagen that is generated and degraded each day to protect the permanent collagen from loss and damage.

Methodological knowledge

We use a multidisciplinary approach to address our research questions including molecular biology (e.g. CRISPR/Cas9), protein biochemistry (e.g. mass spectrometry), light microscopy (e.g. confocal) and cell culture (e.g. 3D fibrous tissue).  Historically we are known for our electron microscopy approaches to studying collagen fibril assembly, especially serial block face-scanning electron microscopy (SBF-SEM) using an FEI Quanta 250 environmental scanning electron microscope fitted with a Gatan 3View in-microscope ultamicrotome. 

Further information

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

PhD Medical Biophysics, The University of Manchester

Award Date: 1 Jun 1984

BSc (Hons) Biochemistry, The University of Salford

Award Date: 1 Jun 1980

External positions

ARUK - Disease Committee

1 Oct 2016 → …

Areas of expertise

  • Q Science (General)
  • Extracellular Matrix
  • Electron Microscopy

Research Beacons, Institutes and Platforms

  • Manchester Regenerative Medicine Network
  • Cancer

Keywords

  • Extracellular matrix
  • Circadian
  • fibrosis
  • Tango1
  • Collagen
  • HSP47
  • VPS33B
  • MMP14
  • PDE4D
  • secretory pathway
  • Tendon
  • Osteogenesis imperfecta
  • Ehlers-Danlos syndrome

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Collaborations and top research areas from the last five years

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  • Fell-Muir Prize

    Kadler, Karl (Recipient), 4 Apr 2016

    Prize: Prize (including medals and awards)