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Virgilio Leon Lew MD

I specialise in membrane transport and cellular biophysics.
Virgilio Leon Lew, MD

Emeritus Reader in Cell Biophysics (retired, active)

Visiting Professor of Medicine (1980-2007), Albert Einstein College of Medicine, New York


Office Phone: +44 (0) 1223 333746

Research Interests

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 projects

A 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

Dr Teresa Tiffert

Teaching

Introductory course on the cell physiology of calcium to third year PDN (PII) students

Key Publications

Minguet-Parramona, C, Wang, Y, Hills, A, Vialet-Chabrand, S, Griffiths, H, Rogers, S, Lawson, T, Lew, VL, and Blatt, MR (2016)  An optimal frequency in Ca2+ oscillations for stomatal closure is an emergent property of ion transport in guard cells. Plant Physiology, 170, 33–42

Lew, VL and Tiffert, T (2015)  Volume control in Plasmodium falciparum infected red blood cells  Encyclopedia of Malaria (Springer), DOI 10, 1007/978-1-4614-8757-9_27-1

Tiffert,T and  Lew, VL (2014)  Dynamic morphology and cytoskeletal protein changes during spontaneous inside-out vesiculation of red blood cell membranes  Pflugers Arch - Eur J Physiol DOI 101007/s00424-014-1483-5

Crick, AJ, Theron, M, Tiffert, T, Lew, VL, Cicuta, P and Rayner, JC (2014) Quantitation of malaria parasite-erythrocyte cell-cell interactions using optical tweezers Biophys J 107:846-853

Crick, AJ, Tiffert, T, Shah, SM, Kotar, J, Lew, VL and Cicuta, P (2013)  An automated live imaging platform for studying merozoite egress-invasion in malaria cultures  Biophys J, 104, 997-1005

Hills, A, Chen, Z, Amtmann, A, Blatt, MR and Lew, VL (2012) OnGuard, a computational platform for quantitative kinetic modelling of guard cell physiology Plant Physiology, 159(3), 1026-1042

Tiffert, T and Lew, VL (2011)  Elevated intracellular Ca2+ reveals functional membrane nucleotide pool in intact human red blood cells  J Gen Physiol, 138(4), 381–391

Mauritz, JMA, R Seear, A Esposito, CF Kaminski, JN Skepper, A Warley, VL Lew and T Tiffert (2011) X-ray microanalysis investigation of the stage-related changes in Na, K and hemoglobin concentration in Plasmodium falciparum-infected red blood cells  Biophys J, 100, 1438-1445

Lew, VL (2011) Malaria: surprising mechanism of merozoite egress revealed Current Biology, 21, R314-R316

Swietach, P, T Tiffert, JMA Mauritz, R Seear, A Esposito, CF Kaminski, VL Lew and RD Vaughan-Jones (2010) Hydrogen ion dynamics in human red blood cells J Physiol 58824 (2010) pp 4995–5014

Mauritz, JMA, Esposito, A, Ginsburg, H, Kaminski, CF, Tiffert, T and Lew, VL (2009)  The homeostasis of Plasmodium falciparum-infected red blood cells PLoS Computational Biology, 5, e1000339

Tiffert, T, Lew, VL, Ginsburg, H, Krugliak, M, Croisille, L, and Mohandas, N (2005)  The hydration state of human red blood cells and their susceptibility to invasion by Plasmodium falciparum  Blood, 105, 4853-4860

Lew, VL and Bookchin, RB (2005) Ion transport pathology in the mechanism of sickle cell dehydration  Physiol Rev 85, 179-200

Lew, V L, Daw, N, Perdomo, D, Etzion, Z, Bookchin, R M and Tiffert, T (2003) Distribution of plasma membrane Ca2+ pump activity in normal human red blood cells  Blood, 102, 4206-4213

Lew, VL, Tiffert, T and Ginsburg, H (2003)  Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells  Blood, 101,4189-4194

Bookchin, RM, Etzion, Z, Sorette, M, Mohandas, N, Skepper, JN, and Lew, VL (2000)  Identification and characterization of a novel population of high-Na+, low-K+, low density sickle and normal red cells Proc  Nat  Acad  Sci (PNAS), 97, 8045-8050

Tiffert, T, Ginsburg, H, Krugliak, M, Elford, B and Lew, VL (2000) Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum  Proc Nat  Acad  Sci (PNAS), 97, 331-336

Bookchin, RM, Balazs, T,  Wang, Z, Josephs, R and Lew, VL (1999)  Polymer Structure and Solubility of Deoxyhemoglobin S in the Presence of High Concentrations of Volume-excluding 70 kDa Dextran  Effects of Non-S Hemoglobins and Inhibitors  J Biol Chem, 274, 6689-6697

Tiffert, T and Lew, VL (1997) Cytoplasmic Ca2+ buffers of intact human red cells J Physiol, 5001, 139-153

Lew, VL, Ortiz-Carranza, OE and Bookchin, RM (1997)  Stochastic nature and red cell population distribution of the sickling-induced Ca2+ permeability  Journal of Clinical Investigation, 99, 2727-2735

Lew,VL, Raftos, JE, Sorette, M Bookchin, RM and Mohandas, N (1995)  Generation of normal human red cell volume, hemoglobin content and membrane area distributions, by "birth" or regulation?  Blood, 86, 334-341

Lew, VL,Freeman, CJ, Ortiz, OE and Bookchin, RM (1991) A Mathematical Model on the Volume, pH and Ion Content Regulation in Reticulocytes Application to the Pathophysiology of Sickle Cell Dehydration Journal of Clinical Investigation, 87, 100-112

Lew, VL, and Bookchin, RM (1991) The osmotic effects of protein polymerization Analysis of volume changes in sickle cell anemia red cells following deoxy-hemoglobin S polymerization Journal of Membrane Biology, 122, 55-67

Garcia Sancho, J, & Lew, VL (1988)  Detection and separation of red cells with different Ca contents following uniform calcium permeabilization  Journal of Physiology, 407, 505-522

Lew, VL, Hockaday, A, Freeman, CJ, and Bookchin, RM (1988) Mechanism of inside-out vesiculation of red cell membranes Journal of Cell Biology, 106, 1893-1901

Lew, VL & Bookchin, RM (1986)  Volume pH and ion content regulation in human red cells: analysis of transient behaviour using an integrated mathematical model  Journal of Membrane Biology 92, 57 74

Lew,  VL, Hockaday, A, Sepulveda, MI, Somlyo, AP, Somlyo, AV, Ortiz, OE & Bookchin, RM (1985)  Compartmentalization of sickle cell calcium in endocytic inside out vesicles  Nature 315, 586 589

Lew, VL, Tsien, RY, Miner, C & Bookchin, RM (1982) Physiological [Ca2+]i level and pump leak turnover in intact red cells measured using an incorporated Ca chelator  Nature 298, 478 481

Lew, VL, Muallem, S & Seymour, CA (1982)  Properties of the Ca2+ activated K+ channel in one step inside out vesicles from human red cell membranes  Nature 296, 742 744

Lew, VL, Ferreira, HG & Moura, T (1979)  The behaviour of transporting epithelial cells  I  Computer analysis of a basic model  Proc R Soc Lond B 206, 53 83

Flatman, PW & Lew, VL (1977)  Use of ionophore A23187 to measure and to control free and bound cytoplasmic Mg in intact red cells  Nature 267, 360 362

Ferreira, HG & Lew, VL (1976)  Use of ionophore A23187 to measure cytoplasmic Ca buffering and activation of the Ca pump by internal Ca  Nature 259, 47 49

Lew, VL (1971)  On the ATP dependence of the Ca induced increase in K permeability observed in human red cells  Biochim Biophys Acta 233, 827 830

Lew, VL, Glynn, IM & Ellory, JC (1970)  Net synthesis of ATP by reversal of the sodium pump  Nature 225, 865 866

Above: Components that participate in a basic formulation of a model of human red blood cell homeostasis (J. Membrane Biol. 1986, 92, 57-74; J. Clin. Invest. 1991, 87, 100-112; Physiol. Rev. 2005, 85, 179-200; PLoS Computational Biology. 2009, 5, e1000339)

Above: Comparison between the dynamic morphology changes of human red blood cell membranes during merozoite release from Plasmodium falciparum-infected red blood cells and during the process of spontaneous inside-out vesiculation (Current Biology. 2011, 21, R314-R316)