Systems Biology Insight into Human Disease and Treatment   

Chairperson: Jordi Villà-Freixa
GRIB, IMIM/Universitat Pompeu Fabra
Barcelona, Spain

Marta Cascante
Dep. Bioquímica i Biol. Mol.
Universitat de Barcelona
Barcelona, Spain
"Fragilities in a Robustly Specialized Metabolism Could Become New Targets for Novel Designed Therapies"
Several techniques as DNA sequencing, expression arrays, and proteomic and metabolomic experiments have provided us a large amount of new information that cannot be easily interpreted. The integration of all these in vivo information in models is likely to be the most interesting tool to understand and to complete an overview picture of the cellular processes. Metabolic profile is the end point of the signaling events, where changes caused by diseases may be reflected. Using data from the different –omics, incubation with 13C labeled substrates and isotopomer analysis in selected metabolite pools, and appropriate software developed in our laboratory to estimate dynamic flux distribution among the metabolic network we are able to identify the main steps that control a metabolic pathway, which may be used as new therapeutical targets. We are applying this approach to understand metabolic adaptations accompanying different multifactorial diseases as cancer, diabetes and chronic obstructive pulmonary disease (COPD).Applying these strategies we identify the maintenance of pentose phosphate cycle oxidative and nonoxidative unbalance to be critical for cancer cell survival and vulnerable to chemotherapeutic intervention. Additionally, we used Metabolic Control Analysis (MCA) to identify the main enzymes controlling ribose-5-P synthesis and to plan combined target strategies. Finally, we validated the obtained strategies using specific inhibitors. This strategy results of great interest in imminent applications for the study of other multifactorial diseases. In particular, we are applying this strategy to achieve a better understanding of glucose hepatic metabolic network to design interventions at a metabolic level in diabetes and COPD. This new principle for rational drug design originates from the integrative, systems biology approach of understanding cell function and opens new ways to develop novel treatments for diseases as diabetes or COPD.

Ricard V. Solé
GRIB, IMIM/Universitat Pompeu Fabra
Barcelona, Spain
"Cancer Dynamics: from Stem Cells to Error Catastrophes"
Cancer is a complex disease, involving different levels of organization and displaying Darwinian dynamics. Such microevolutionary dynamics is complicated by two different ingredients. The first is genetic instability, creating high levels of internal disorder. The second is the presence of a stable component, namely cancer stem cells. The two components are important in understanding tumor progression. Mathematical and computational models predict that such unstable tumors would self-organize close to a threshold of instability, being cancer stem cells the engine of tumor development.

Fernando Martín
Instituto de Salud Carlos III
Madrid, Spain
"Biomedical Informatics and Convergent Technologies (NBIC): Interactions in Pursuit of Better Healthcare"
The term convergent technologies refers to the synergistic combination of nanotechnology, biotechnology, information technology, and cognitive sciences (NBIC). Interactions with the field of Biomedical Informatics are expected to occur in the coming years, bringing about potential improvements in science and engineering and in the development of new diagnostic and therapeutic solutions. New opportunities for biomedical informatics, from an integrative and system level approach, are identified. They arise from the new trends in biomedicine (Nano, personalised, regenerative). Examples of new systems in this context are presented: –next generation of biochips, -intelligent devices at the point-of-care, and -integrated biosensors. The final part of the presentation describes the requirements that these new services could impose on the healthcare system.

Kevin Robertson
University of Edinburgh
Edinburgh, Scotland, United Kingdom
"Transforming Pathway Biology into Pathway Medicine"
Systems approaches with demonstrable clinical benefits are beginning to emerge. For example, over the past 10 years gene expression signatures defined by whole genome screens have been applied to the diagnostic classification of cancer patients. Despite these successes, much work is still required in the definition of theoretical and applied frameworks applicable to the development of tractable clinical treatment strategies. Over the past 6 years, the Division of Pathway Medicine has established an integrated structure in an attempt to overcome barriers between reductionist medical practice and an evolving systems view of medicine. In this presentation, examples of our pathway-centric systems approach to the study of infectious disease and the acquisition of clinically relevant information will be presented. To conclude, medical and informatics challenges and issues in this area will be discussed.

Baldo Oliva
GRIB, IMIM/Universitat Pompeu Fabra
Barcelona, Spain
"Protein-Protein Interactions Reveal Molecular Details of Proteins and Provide Biological Insights"
While genome-scale methods are available for detecting interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). We have developed a method for identifying the interacting motifs and we show that the number of inferred interacting motifs per yeast hub is highly correlated with its essentiality for cell survival. We have also used structural similarities between domains of known interacting proteins and conservation of sequence patches in protein-protein interfaces to predict putative protein interaction pairs and we have used structural information to validate protein-protein docked interfaces. Finally, we have designed a tool for creating and analyzing protein-protein interaction networks that includes our predictions and we have used it to identify phenotypes selected by Bcl-xL in breast cancer cells that in vivo enhance the ubiquity of clinical metastases.

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