Taking into account the dual dependence of GRIB and the IMIM focus of the present report, only its research groups leaded by IMIM staff are described in detail in the following sections.
Mar Albà joined the GRIB as a UPF Ramón y Cajal researcher beginning of 2002, and in October 2005 was appointed ICREA Research Professor at IMIM. She is one of the senior scientists of the research lab on Computational Genomics. Within it, she is leading the research group on Evolutionary Genomics (genomics.imim.es/htdocs_eg), which is focused in the use of comparative genomics to learn about the evolution of genes, to identify new functional elements in genomes, and to gain insights into the molecular biology underlying human disease processes. In the period 2002-2007 the group has published 18 articles in ISI-indexed journals and 1 book chapter. Currently, the group includes 5 PhD students.
Its main current research lines are:
The repertoire of human genes is a mosaic of genes of very ancient origin, present in all eukaryotes, and other genes that have a more recent origin. The group has dated the appearance of the genes in the human genome across the eukaryotic phylogeny, demonstrating that the more recent genes show accelerated evolutionary rates, and have thus a greater potential to play important roles in adaptative processes. The group also performs studies on the evolution and functional implications of amino acid repeat expansions. Among these there are a number of poly-alanine and poly-glutamine repeats whose uncontrolled expansion causes developmental or neurological human diseases, respectively. The studies in the group have shown that whereas disease-associated poly-alanine repeats are remarkably well conserved across mammals, suggesting that they play important ancient roles, poly-glutamine repeats are highly variable across species and show high polymorphism in humans. These properties can help identify putative novel disease loci.
Gene upstream regions are rich in motifs involved in the regulation of transcription. The Evolutionary Genomics Group has developed different methods to predict regulatory motifs (PROMO, PEAKS), using pathway information and the conservation of motif arrangements across many different human and mouse genes. In addition, using large-scale human and mouse gene expression data the group has recently shown that housekeeping genes show less conserved promoters than genes with tissue-specific expression, which indicates that genes with constitutive expression require shorter functional promoters. In these studies, we have also identified subsets of regulatory motifs that are specifically over-represented in housekeeping or tissue-specific promoters. These studies enhance our understanding of gene regulatory networks and provide the scientific community with tools for the analysis of gene regulatory sequences.
The group performs studies on the evolution of virus gene families and the identification of horizontal gene transfer between virus and host genomes, specially related to the herpesvirus family, including human and rodent cytomegalovirus. The group has developed new protocols using protein-domain based searches to increase the sensitivity of detection of remote homology between virus and host genes, leading to the identification of new putative viral genes that interact with the immune response. Compilation of virus protein families in the Virus Database VIDA serves as a basis for these bioinformatics studies. The group has recently established a number of collaborations with experimental groups, with the aim to combine bioinformatics and wet lab studies to improve our understanding of virus immune evasion pathways.
Chemogenomics (Jordi Mestres)
The Chemogenomics Laboratory was established in September 2003 with the incorporation of Dr. Jordi Mestres at the GRIB after a 7-year experience in pharmaceutical industry (1 year at Pharmacia&Upjohn in USA and 6 years at Organon in the Netherlands and UK). Today, apart from its head, the lab is composed of one post-doctoral researcher and 5 PhD students, with a current vacancy for a second post-doctoral researcher. In terms of scientific production, within the period 2004-2007, the lab has published 17 articles in ISI journals and 2 book chapters. Research in the lab is done at the interface between chemistry, biology, and informatics, which requires a multidisciplinary team of skilled individuals in different fields. The ultimate aim is to develop and apply novel integrative biochemoinformatics tools for the systematic annotation of molecules to entire target families of therapeutic relevance. This information can then be used either upstream to identify chemical probes for target validation or downstream to identify novel hits for lead generation in the drug discovery process.
Main Research Lines
The Chemogenomics Lab has two main methodological research lines, namely, research on the Chemome and the research on the Proteome. In addition to these methodological lines, we have recently initiated four therapeutic research lines directed to the disease areas of cardiovascular, obesity, pain, and oncology. A brief description of each line is provided next:
Therapeutic Research Lines
References to individual protein targets and bioactive small molecules associated to multifactorial diseases can be found scattered in multiple bibliographic sources over the years. Mining these sources, we are collecting lists of targets associated to four therapeutic areas, namely, cardiovascular, obesity, pain, and oncology, and organising them using functional classification schemes in the four main protein families of therapeutic relevance, namely, enzymes, G protein-coupled receptors, ion channels, and nuclear receptors. Each disease-associated target space is then taken to interrogate an annotated chemical library and extract the bioactive chemical space connected to the corresponding target space. Some of these bioactive ligands were also found to have affinity for targets not directly linked to its respective diseases, thus constituting a valuable indirect source to infer the potential disease-associated off-target space. Compilation, classification, and integration of this prior knowledge provide a comprehensive perspective of the pharmacological space relevant to modern global drug discovery.
Integrative Biomedical Informatics (Ferran Sanz)
This particular research group constitutes the specific platform for the direct research activity carried out by the GRIB Director, Ferran Sanz, as well as for the promotion of large-scale initiatives aiming to take advantage of synergic contributions of several GRIB labs. A post-doctoral scientist and two PhD students are directly assigned to this group.
A clear example of such large-scale initiatives has been the EU-funded INFOBIOMED Network of Excellence (www.infobiomed.org). This network of excellence has been active in the 2004-2007 period with the general objective of structuring European Biomedical Informatics in order to Support Individualised Healthcare. It has been led by Ferran Sanz and had an active participation of the GRIB research groups led by M. Albà, B. Oliva and J. Mestres.
A similar case is the GRIB participation in the @neurIST EU-funded integrated project (www.cilab.upf.edu/aneurist1), a European initiative to integrate biomedical informatics in the management of cerebral aneurisms. In this case the GRIB group leaders with active participation are B. Oliva, J. Villà, M. Pastor and F. Sanz.
CancerGRID (www.cancergrid.eu) is another case of EU-funded project with the participation of scientists from different GRIB labs (J. Mestres, I. Zamora and F. Sanz). The aim of this project is to develop and refine methods for the enrichment of molecular libraries in order to facilitate the discovery of potential anti-cancer agents.
The same strategy is being followed in proposals submitted to the first calls of the EU 7th Framework Programme. A clear example of it is the ALERT project for the early detection of adverse drug events by integrative mining of clinical records and biomedical knowledge, which has been selected for funding in the first call and will start by the beginning of 2008. The GRIB contribution in ALERT will be mainly carried out by the groups led by J. Mestres and F. Sanz and will be focused on the automatic generation of scientifically and mechanistically sound explanations for the signals obtained from the mining of clinical records by means of a combination of analyses of biomedical literature and databases, in silico predictions and pathway mapping.
At the Spanish level, the same integrative philosophy inspired GRIB participation in the INBIOMED thematic network funded by the ISCIII (www.inbiomed.retics.net), which lasted from 2003 to 2006. A new thematic network proposal (COMBIOMED) has been submitted to the 2007 call of the ISCIII.
The participation of the GRIB in the Spanish National Institute of Bioinformatics is another example of the joint participation of several GRIB labs in strategic initiatives.
On the other hand, F. Sanz is particularly interested in the application of biomedical informatics in the pharmaceutical domain. I this field, he is currently interested in the integrative knowledge management and exploitation. His participation in the European (www.imi-europe.org) and Spanish (www.medicamentos-innovadores.org) Technology Platforms on Innovative Medicines are key activities in such a domain. In particular, he is acting as expert by invitation of the European Commission and EFPIA, and he is coordinating the Spanish Platform.
Another collaborative initiative in the pharmaceutical field that is being promoted is the ChemBioBank, a joint initiative of the Barcelona Scientific Park, the Pharmacological Screening Platform of the University of Santiago de Compostela and the GRIB (Jordi Mestres and Ferran Sanz). The aim is the collection, in vitro and in silico annotation, and the dissemination and exploitation of the publicly-generated Spanish chemical diversity.