Virgilio Lew

Research in my laboratory is concerned with cellular homeostasis.

What is cellular homeostasis? 

Behind the immense complexity and diversity of living cells, there is an ancient and universal subset of basic processes that maintain cell integrity throughout all dynamic and reproductive cell changes.  These processes, usually referred to as cellular homeostasis, control membrane potentials and the balance in the transport of water and solutes across the plasma membrane of the cells; they are distinct from those controlling membrane traffic by endo- and exocytosis. Cellular homeostasis processes follow a consistent and extremely versatile strategy, enabling extensive adaptive variations for different cell types. 

The key feature of this strategy is that it organizes membrane transport in two fundamentally different hierarchical categories according to energy source. Primary transport is mediated by a restricted set of ionic pumps fuelled by ATP.  Secondary transport is mediated by a large variety of transporters operating like pores, channels and carriers.  These use the ionic gradients generated and sustained by the primary pumps as energy sources.  The mechanism by which this two-tier organization has enabled successful diversification rests on the fact that secondary transporters, freed from direct metabolic constraints, could evolve in nature and numbers to operate at rates required for functional optimizations, regardless of the extent of ionic gradient dissipation.  Delayed restoration of the ionic gradients by the primary pumps could then proceed at rates compatible with the overall ATP metabolism of the cells. 

Modelling cellular homeostasis

Even in the simplest of cells, the subset of processes involved in cellular homeostasis is so complex and interconnected that predicting normal or altered cell responses from the integrated operation of these processes has proven time and again to be beyond intuitive grasp. A modelling approach became necessary to address this level of complexity. 

Our models, based on the biophysical principles underlying the two-tier strategy, proved their value in predicting novel, unexpected and often counterintuitive cell behaviours that upon experimental validation helped solve key issues of major physiological and pathophysiological relevance: on the mechanism of vectorial transport in epithelia, on the physiology of healthy and diseased human red blood cells and erythroid cell precursors, on the mechanisms of sickle cell dehydration in particular, on the homeostasis of malaria-infected red blood cells, and on the control of guard cell volume, turgor pressure and stomatal dynamics.  The approach that enabled this unusual level of predictive power in biology was based on a modelling design that minimized indetermination in the handling of the parameter space and on the creative bespoke fitting of key phenomenological expressions for complex subsets of cell processes. 

 

Current research projectsA web-based version of the original red blood cell model is nearing completion

This was developed in collaboration with Dr Simon Rogers from Glasgow University.  It is hoped that web availability will help spread the use of this model as a research and teaching tool for hematologists, biologists, physiologists, and biophysicists.

Modelling the guard cell mechanisms involved in the control of stomatal dynamics

In collaboration with plant physiologists led by Professor Michael Blatt from Glasgow University, we are currently investigating the mechanisms behind the biphasic response of stomata to changes in environmental humidity, and those involved in the rate-control of stomatal opening.  Model extensions incorporating the new findings will be applied to explore ways of increasing the water use efficiency of plants and crops.

The pre-invasion stage in falciparum malaria 

The mechanism of apical alignment by which merozoites become poised with their apex irreversibly attached to the red cell surface remains the least understood step of the malaria invasion process.  In collaboration with colleagues from The Physiological Laboratory, from The Cavendish Laboratory, and from the The Sanger Institute, University of Cambridge, we are attempting to elucidate the biology of this process, alert to the possibility that this knowledge may help expose new targets for prevention or treatments of this endemic disease.   

 

Collaborators

Teresa Tiffert
Pietro Cicuta
Michael Blatt
Adrian Hills
Simon Rogers