Biography

• D.Sc.  Physiology, London University 1991 
• B.A. Mathematics. Class: First, The Open University 1981-1986 
• Ph.D. Physiology, Leicester University, 1971-1974 
• B.Sc. Biological Sciences.  Class: Upper Second, Leicester University 1968-1971  

Research Interests

The cell physiology of cardiac and smooth muscle, in particular the study of those factors that determine the contractility and excitability of these tissues.  This has developed into investigations that seek to explain the pathophysiology of muscle dysfunction associated with organ disease.  The two major organ systems I study are the heart and the smooth muscles of the lower urinary tract.  Although these are two different organ systems, the fundamental cellular physiological control systems and derangements of function that occur in disease are not dissimilar so that valuable conclusions drawn from one tissue may be applied to another. 

The experimental approach is to use electrophysiological and real-time fluorescence imaging techniques to record from isolated cells and multicellular preparations, coupled to immuno-histochemical analyses, tension measurements and molecular techniques.  My laboratory has pioneered the use of human biopsy material (cardiac and lower urinary tract tissues) from patients with well-defined clinical conditions, to investigate the pathophysiology of these conditions.

Lower urinary tract cell physiology

1. The cell physiology of sub-urothelial myofibroblasts and urothelial epithelium. 
The aim of the work is to understand the cellular basis of the sensations of bladder filling and pain.  A heightened sense of bladder filling, termed bladder urgency, is an extremely prevalent condition, resulting in urinary incontinence in a proportion of patients; it is also related to other sensory disorders such as painful bladder syndrome.  We study the role of urothelial cells and sub-urothelial myofibroblasts in initiating and modulating these sensations by their ability to release neurotransmitters that activate afferent nerve fibres.
 
2. The regulation of function in lower urinary tract smooth muscle. 
This is concerned with identifying and characterising the cellular actions of neurotransmitters, identifying the importance of spontaneous activity in these tissues, and identifying the intracellular signalling pathways that mediate the action of extracellular modulators. Examples include: i) the role of purinergic signalling in determining normal and abnormal lower urinary tract function  ii) the quantal subcellular release of intracellular Ca2+ in regulating spontaneous activity and iii) the role of intercellular coupling in determining normal and abnormal contractile function. 

3. The development of functional activity in the fetal and neonatal lower urinary tract and the effect of congenital abnormalities on such development.
Human tissue from Great Ormond St has enabled my laboratory to investigate the effect that development abnormalities, such as bladder exstrophy and posterior urethral valves, have on lower urinary tract function. In concert we have developed animal (sheep) models of analogous anomalies to study in a more controlled environment not just the effects of these lesions, but also the extent of functional recovery when the anomalies are corrected.  The aim is to develop optimal strategies to guide the timing of surgical intervention that correct these abnormalities to maximise the recovery of normal lower urinary tract function in later life.

Previous research highlights in lower urinary tract cell physiology

• Initial characterisation of a novel cell type in the bladder wall (myofibroblasts) and its potential role in bladder sensation, and pathologies such as urinary urgency and bladder pain.
• Demonstration that detrusor from fetal and neonatal human and animal bladders subjected to congenital or experimental abnormalities underlies bladder dysfunction
• Demonstration of the mechanisms whereby ATP acts as an additional parasympathetic neurotransmitter in human detrusor from patients with bladder disorders
• First description of the ionic basis of electrical activity in bladder (detrusor) smooth muscle and of the regulation of the intracellular [Ca2+] during contractile activation
• Development of techniques to use human biopsies of lower and upper urinary tract tissues for physiological measurements.

Cardiac muscle cell physiology

1. The role of gap junction remodelling in generating arrhythmias.
This uses hearts in failure, with compensated ventricular hypertrophy, with regional ventricular ischaemia or with atrial fibrillation and utilises electrophysiological mapping techniques, biophysical characterisation of the tissue and immunohistochemical analysis of the tissue. Tissue is derived from a number of animal models and human biopsy tissue. In particular we are investigating the role of intracellular kinases and phosphatases that regulate gap junction function.

2. The cellular basis of contractile and conduction failure in human myocardium from patients with cardiomyopathies. 
Genetic analysis has identified specific genetic defects and the laboratory work aims to find how this leads to functional abnormalities.

3. Identification of failed intracellular ion regulation in hearts with left ventricular hypertrophy
The rise of the intracellular [Na+] is the primary change that leads to electrophysiological and contractile disorders in these hearts.  We aim to study the cause of this defect. The translational interest in this work is being extended to patients at the cardiac centres have end-stage heart failure. It is hypothesised that pharmacological regimes that aim to modulate the intracellular [Na+] will salvage myocardial function.

Previous research highlights in cardiac muscle cell physiology

• Demonstration of the central role of the intracellular [Na+] in determining electrophysiological and contractile dysfunction in left ventricular hypertrophy
• Measurement of the electrical properties of gap junctions in intact myocardium and their central role in generating conduction abnormalities in hypertrophied and failed myocardium.
• Demonstration that mitochondria play a crucial dynamic role in intracellular Ca2+ regulation in myocardium
• Development of multidimensional biophysical models of electrical current flow in myocardium.
• Original proposal of the concept of Ca2+-dependent outward currents in myocardium and its role in controlling action potential duration.

Publications

Affiliations

Honorary contracts
Imperial College London, Professor of Cardiac Electrophysiology; National Heart and Lung Institute
University College London, Professor of Physiology; Department of Neuroscience, Physiology and Pharmacology

External Examiner Posts
Cambridge University, Tripos (medicine and veterinary sciences) examinations
Bristol University,  BSc physiology programme
Royal College of Surgeons, Court of examiners for MRCS.

Journal Editorial Posts
Neurourology and Urodynamics, section editor biochemistry and physiology
Surgery, basic science editor

Professional affiliations
Physiological Society; American Physiological Society; International Continence Society; British Cardiovascular Society

Advisory Boards
Pfizer, Astellas (lower urinary tract disorders)

Tri-services ethical review panel member, Ministry of Defence