BioSim
BioSim is a project funded by the European Community under the 6th Framework program and was initiated on December 1, 2004. The main objective of the Network is to demonstrate how the use of modern simulation technique through a deeper and more qualitative understanding of the underlying biological, pathological and pharmacological processes can lead to a more rational [...] development process, improved treatment procedures, and a reduction in the needs for animal experiments.
Introduction
Bio-simulation represents the application of advanced mathematical modelling to create a coherent picture of the functioning of living systems at the genetic, cellular and macrophysiological levels. The term advanced is associated with the fact that living systems are many times more complex than anything we know from the inanimate world. This complexity arises from the many mutually interacting feedback controls, from the vast ranges of time and space scales over which the processes take place, and from the instabilities that are at the heart of all forms of life. The idea is to generate a closed loop structure in which models are used to plan new experiments and interpret the results in order to gradually assimilate the obtained information into a consistent framework that can be used to predict the outcome of experiments that have never previously been performed. The BioSim Network has unusually strong expertise in this area with several partners having worked in mathematical modelling of living systems since the mid 1970’s.
The Network aims to promote the field of Systems Biology by demonstrating how the modelling approach can help establish new and better treatments for patients with various chronic progressive disorders and how mathematical modelling can be applied in the pharmaceutical industry to reduce development costs and at the same time reduce the need for animal experiments. To this aim the Network organizes conferences and workshops in collaboration with both industry and regulatory agencies. At the same time, we try to maintain a balanced communication with the general public in order to explain both the perspectives that Systems Biology provides and the challenges it faces. The use of models generally calls for new types of experiments to be performed. Successful work in this area must therefore involve the development of new tools for non-invasive studies of living systems.
During the past year (the fourth BioSim year) we have pursued all of these objectives with significant success. The Network participants have completed around 240 papers in international scientific journals or approximately 9 papers per academic partner. Novo Nordisk and several of BioSim’s SME partners have also contributed to this publication figure. The Network has completed a total of 152 deliverables, and in several areas we have obtained results which go well beyond the defined goals. The following section provides an overview of the attained results, while the Activity Reports, which come after that, present the results work package by work package.
Research Highlights
New techniques for non-invasive studies of intra-cellular processes
Laser interference microscopy represents a technique for non-invasive studies of live cells, which has been developed in collaboration between the Department of Biophysics at Moscow State University and the BioSim Group at The Technical University of Denmark (partner 1). With this technique one measures the phase shift of a laser beam that passes through the cell. The phase shift depends on the intrinsic optical properties along the beam and thus reflects variations in membrane potential and fluidity, motion of membrane-bound proteins, changes in intracellular calcium concentrations, displacements of organelles and transport of vesicles, as well as any other process that influences the local refractive index. A particular asset of the laser interference approach is that the different cellular processes are detected simultaneously. On one hand, this allows us to study the interactions among the various processes, but on the other hand it complicates the interpretation of the measured phase shifts significantly, and one has to combine measurements performed under a number of different conditions with advanced statistical methods to unravel the various contributions. We have previously applied the technique to study changes in red blood cells, but have now succeeded in performing a detailed study on nerve cells and nerve fibres.
Advanced modelling of inter-cellular communication in smooth muscles
The BioSim Group at the University of Copenhagen (partner 14) has developed a detailed model that can describe the role of cellular heterogeneity and weak coupling in explaining the experimentally observed gradual synchronization characteristics for smooth muscle cells in vascular resistance vessels. Fluorescent microscopy studies show that such cells at low muscular activation display asynchroneous wave-like fluctuations in their cytoplasmic calcium concentrations. As the muscles are further activated, an increasing number of cells are recruited into a synchronized oscillatory state, and this is the transition that gives birth to the rhythmic contractions of the vessel known as vasomotion. The model considers a system of 20 cells arranged in a two-dimensional lattice and coupled via gap junctions. Cellular heterogeneity is represented through a statistical distribution of volume fractions of sarcoplasmic reticulum that can exchange calcium with the cytoplasm. The group is presently engaged on an extension of the model to describe the interaction between the smooth muscle cells and the endothelial cells.
New effective techniques for target localization in deep brain stimulation
High frequency test stimulation is a standard procedure for target localization in deep brain stimulation treatments of patients with tremor. However, this method does not work in cases where the tremor disappears under global anaesthesia as used during insertion of an electrode. To avoid this problem the BioSim Group at the Jülich Research Centre (partner 9) has developed a new stimulation technique that evokes tremor in a well-defined manner even when the patient is under anaesthesia. This technique uses patterned low-frequency stimulation in the form of brief high-frequency pulse trains applied at pulse rates similar to typical neuronal burst frequencies. This makes it possible to attain higher charge densities in the target area without violating safety criteria. Numerical simulations of a network of interacting neurons have demonstrated that patterned low- frequency stimulation can synchronize the cells in a mode that is phase-locked to the stimulation pulse. When subsequently applying this approach to patients with pronounced tremor, the results were found to be in accordance with the mathematical calculations, and the target selection was confirmed by excellent postoperative tremor suppression.
Model-based and personalized treatment of cancer
The potential benefits of a chrono-therapeutical approach to the treatment of cancer derive from the close relationship that exists between the circadian rhythm and both the cell proliferation cycle and the variation in toxicity and efficacy of many anti-cancer drugs. In previous work, Lévi et al. (partner 26) have demonstrated that an 8-hour shift in dosing time in experimental models may account for an eightfold increase in tolerability for more than 30 anti-cancer drugs. In order to establish an optimal basis for the use of chronotherapy in the treatment of colorectal cancer, the BioSim Groups in Paris (partner 26) and Brussels (partner 12) have developed both a cell cycle automaton model that can be synchronized by the circadian clock and a deterministic model of anti-cancer [...] chrono- pharmacodynamics. Simulations with these models reveal the key role played by the degree of circadian entrainment and, hence, by the variability in the cell cycle phase durations. However, the simulations have also revealed new and optimal circadian schedules for anti-cancer [...] administration, depending on the therapeutic strategy adopted for the individual patient.
Investigation of new types of anti-cancer drugs
The work performed by the BioSim Group in Budapest focuses on examining the effects of KAR-2, a potent anti-mitotic component, and TPPP/p25 a new brain specific, intrinsically unstructured protein, on the functional and structural characteristics of the microtubular system. This system is consistently restructured during the cell cycle and plays an important role in the actual cell division process. Whereas KAR-2 directly targets mitotic spindels resulting in the arrest of the cell division in the M-phase of the cell cycle, the mechanisms underlying the observed anti-mitotic effects of TPPP/p25 are less clear. It appears that this protein can also be expressed in tissue outside of the central nervous system and that upregulation of its expression leads to cell differentiation and to prolonged phases of quiescent and neuron-like behaviour. This indicates that the protein could represent a new family of anti- cancer drugs. Other important conclusions of the study are that KAR-2 demonstrates unique bioavailability properties. The data obtained for this compound suggest that it has a better absorption profile, a broader tissue distribution and a more effective penetration to cancer cells than its mother [...], vinblastine.
Communication with the public
In connection with the 4th BioSim Conference in Budapest, Erik Mosekilde, Anne Marie Clemensen and Judit Ovádi were interviewed on the aims of the EU-sponsored BioSim project in connection with the development of new effective drugs, better treatment procedures in hospitals and rational data utilization in biomedical research. The interview, which was broadcast by Duna Television and published in both the newspaper Nepszava and the weekly magazine Elet es Tudomany, also focused on the contributions to BioSim made by the Institute of Enzymology, Hungarian Academy of Sciences. Articles on ‘biosimulation’ were published (in Danish) by Bente Steffansen and Louise Gram (partner 14b) in Lægemiddelforskning and Dansk Kemi. Bente Steffansen has also written a commentary to Pharmadanmark (distributed with the Danish newspaper ''Politiken‘‘) on how gender issues and race differences can give rise to variations in [...] bioavailability and how biosimulation can be used to explain such variations.
Martin Bertau (partner 19) contributed an article on ‘Mit einer Tasse Kaffee zu neuen Wirkstoffen – Chirale pharmazeutische Intermediate in Hoeherer Stereoisomerenreinheit’ to Bioforum 2008. Hanspeter Herzel (partner 22) gave an interview on ‘chronotypes and cancer’ to Hamburger Abendblatt. Francis Lévi (partner 26) was interviewed on his work on ‘chronotherapy of cancer’ by New Scientist (August 2008), Radio Suisse Romandi (September 2008) and Radio J (November 2008). Mats Jirstrand (partner 34) was interviewed by the national Swedish public television broadcaster SVT Rapport in connection with the 9th International Conference on Systems Biology in Gothenburg. Novo Nordisk (partner 37) discussed the benefits of mechanism-based modelling and the role of the BioSim Network in the company’s Bioethics Report entitled ‘Animals in Pharmaceutical Research and Development’ (2008).
Tue Søeborg (partner 41) wrote an article on ‘International research collaboration and the role of BioSim’ in the annual report of the Danish Medicines Agency. In a subsequent article in the agency’s internal newspaper he explains some of the results that can be gained from a biosimulation study. Erik Mosekilde (partner 1), Søren Brunak (partner 1a) and Mads Krogsgaard (partner 37) have given a couple of joint interviews to the Danish media on the challenges and difficulties in realizing the creation of a virtual human for [...] testing.
Conclusion
The BioSim Network has now reached the end of its 4th year, and the issue of sustainability, i.e. the possibility of continuing our activities, naturally comes to the forefront. All BioSim partners have expressed a clear and unconditional wish to continue the collaboration. Together with representatives from other networks of excellence in the Health area BioSim has participated in a meeting on ‘The Sustainability of Networks’ with representatives from the EU Research Directorate in Brussels. It appears that many national representatives have provided feedback to the Research Directorate that focuses on the administrative difficulties of running such a large research collaboration. On the other hand, the broad range of different specialities required to establish the new field of systems biology and demonstrate its results must involve contributions from many different partners.
During a workshop in Malmö and Governing Board and Steering Group meetings in Oxford and The Hague, our discussions have focused primarily on projects offered by the Innovative Medicines Initiative (IMI). We have, unfortunately concluded, however, that this initiative does not allow for such broad and generic research in the development of predictive and mechanism-based models and, in particular, it does not include research projects that would allow a major part of BioSim to continue the already established collaboration.