Modelling and Simulation in Biomedical Research   

Chairperson: Ferran Sanz
GRIB, IMIM/Universitat Pompeu Fabra
Barcelona, Spain

Alex Frangi
Universitat Pompeu Fabra
Barcelona, Spain
"An Integrative Approach to Cerebral Aneurysms Disease Management: The @neurIST Project"
When considered separately from other cardiovascular diseases, stroke ranks third among all causes of death, after heart disease and cancer. Hemorrhagic stroke occurs when a blood vessel, typically an aneurysm, ruptures inside the brain. This often leads to severe disability or death. Despite considerable advances in treatment, rupture is associated with exceptionally high levels of morbidity and mortality. Currently, invasive or minimally invasive treatment is offered to almost all patients because there is insufficient evidence to support a decision of non-intervention.
It is the primary thesis of @neurIST that the process of cerebral aneurysm diagnosis, treatment planning and treatment development is significantly compromised by the fragmentation of relevant data. To address this issue, @neurIST is developing a complete IT infrastructure for the management and processing of heterogeneous data associated with the diagnosis and treatment of cerebral aneurysm and subarachnoid haemorrhage. It will provide seamless access to data spanning the range of scales, from molecular, through cellular, tissue, organ, and patient level, to population level. @neurIST will transform the management of cerebral aneurysm by providing new insight, personalised risk assessment and methods for the design of improved medical devices and treatment protocols.

Peter J. Bond
University of Oxford
Oxford, United Kingdom
"Coarse-Grained Molecular Dynamics Simulations of Membrane Proteins"
Membrane proteins play key roles in a wide range of processes in cells, representing ~25% of genes and ~50% of drug targets. Molecular dynamics (MD) simulations provide an opportunity to study membrane proteins under approximately physiological conditions, but are limited to timescales of ~100 ns. Coarse-grained (CG) MD, in which small groups of atoms are treated as single particles, enable extended (~ms) timescales to be addressed. We have developed a CG-MD model and used it to simulate the insertion and oligomerization of a number of membrane proteins, ranging from simple TM a-helix and b-barrel test-cases, to biomedically important viral peptides and membrane transporters, such as LacY and CFTR. For one particular protein, the Glycophorin A a-helical bundle, CG-MD simulations demonstrate that a dynamic equilibrium exists between the monomer and dimer which can be affected by a single point mutation. Finally, we show that deformation of the bilayer may be important in the mechanism of insertion of non-canonical membrane proteins, via multi-ms simulations of fragments of the highly-charged, but paradoxically TM, voltage-gated potassium channels. Building on these test-cases, we are also constructing a database containing CG-MD membrane-inserted models of all high resolution membrane proteins (http://sbcb.bioch.ox.ac.uk/cgdb).

Amin Rostami-Hodjegan
University of Sheffield
Sheffield, United Kingdom
"Modelling ADME in Drug Development and Linking in vitro Data to in vivo Outcome: Integrating Known-knowns to Assess Impact of Known-unknowns"
The rising cost of drug development has initiated a surge of intrest in the application of in silico (Modelling & Simulation - M&S) approaches with potential (1) to improve candidate slection, (2) to deterimine the right studies to be done at the right time, (3) to help with optimal design of studies, and (4) to avoid unnecessary clinical studies. One of the most attractive features of M&S, namely the possibility of extrapolating observations from in vitro systems to the in vivo behavior of new compounds (IVIVE), has received far less attention that the emphasis put on the value of M&S in discovery stages or its implicatuions later during the analysis of data from clinical studies.
The interpretation and value of IVIVE efforts remain the subject of debate as the vital distinction between a useful "simulation" and a precise "prediction" is often not appreciated (Rostami-Hodjegan & Tucker 2004). However, as the applications of the models grow, many cases are identified where detailed knowledge on some biological parameters of relevance to IVIVE are missing ('known-unknowns' of systems biology applied to IVIVE). The presentation will focus on assessing the propagation of genetic differences in drug metabolizing enzymes in different populations as well as evaluating potential drug-drug interactions. This will highlit that the full advantages of simulations can be realized only if they are used as a framework for integrating discrete pieces of information and a concerted effort by many stakeholders [based on our experience within the Simcyp Consortium (www.simcyp.com)).

James Sharpe
Centre de Regulació Genòmica
Barcelona, Spain
"Towards a 4D Computer Simulation of Vertebrate Limb Development"
A full understanding of complex biological systems will require multi-scale computer models. While much work has been done on abstract mathematical models, simulations which use quantitative empirical data from real multicellular systems are rare. As part of our goal to create a 4D model of limb development we are developing new quantitative techniques for measuring the dynamics of vertebrate limb development. This includes a 3D map of cell cycle times, an accurate morphometric staging system and 4D whole-organ imaging of limb buds in culture using time-lapse OPT (optical projection tomography).

Gianni de Fabritiis
GRIB, IMIM/Universitat Pompeu Fabra
Barcelona, Spain
"PS3GRID.NET: A Distributed Computing Environment for Molecular Simulations on the PlayStation3"
The new Cell processor of the PlayStation3 is capable of improving performances of computing intensive applications by twenty times, as recently demonstrated by the full-atom CellMD program for molecular dynamics (MD) applications to bio-molecules. We have used CellMD to exploit such computational power using distributed computing over the Internet provided by the computational infrastructure behind SETI@home, the Berkeley Open Infrastructure for Network Computing (BOINC). In PS3GRID, we target explicitly the Cell processors available in Sony Playstation3 game consoles to compute ion permeability for the trans-membrane Gramicidin A by distributed steered molecular dynamics simulations. The availability of PlayStation3 game consoles and the steered molecular dynamics protocol allow us to perform novel computational molecular experiments on biomolecules by harnessing enourmous computational resources.

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