Institute for Systems Biology

About: Institute for Systems Biology is a nonprofit organization based out in Seattle, Washington, United States. It is known for research contribution in the topics: Population & Proteomics. The organization has 1277 authors who have published 2777 publications receiving 353165 citations.

Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells

Abstract: Genetic instability is invoked in explaining the cell phenotype changes that take place during cancer progression. However, the coexistence of a vast diversity of distinct clones, most prominently visible in the form of non-clonal chromosomal aberrations, suggests that Darwinian selection of mutant cells is not operating at maximal efficacy. Conversely, non-genetic instability of cancer cells must also be considered. Such mutation-independent instability of cell states is most prosaically manifest in the phenotypic heterogeneity within clonal cell populations or in the reversible switching between immature “cancer stem cell-like” and more differentiated states. How are genetic and non-genetic instability related to each other? Here, we review basic theoretical foundations and offer a dynamical systems perspective in which cancer is the inevitable pathological manifestation of modes of malfunction that are immanent to the complex gene regulatory network of the genome. We explain in an accessible, qualitative, and permissively simplified manner the mathematical basis for the “epigenetic landscape” and how the latter relates to the better known “fitness landscape.” We show that these two classical metaphors have a formal basis. By combining these two landscape concepts, we unite development and somatic evolution as the drivers of the relentless increase in malignancy. Herein, the cancer cells are pushed toward cancer attractors in the evolutionarily unused regions of the epigenetic landscape that encode more and more “dedifferentiated” states as a consequence of both genetic (mutagenic) and non-genetic (regulatory) perturbations—including therapy. This would explain why for the cancer cell, the principle of “What does not kill me makes me stronger” is as much a driving force in tumor progression and development of drug resistance as the simple principle of “survival of the fittest.”

The Gaggle: An open-source software system for integrating bioinformatics software and data sources

Abstract: Systems biologists work with many kinds of data, from many different sources, using a variety of software tools. Each of these tools typically excels at one type of analysis, such as of microarrays, of metabolic networks and of predicted protein structure. A crucial challenge is to combine the capabilities of these (and other forthcoming) data resources and tools to create a data exploration and analysis environment that does justice to the variety and complexity of systems biology data sets. A solution to this problem should recognize that data types, formats and software in this high throughput age of biology are constantly changing. In this paper we describe the Gaggle -a simple, open-source Java software environment that helps to solve the problem of software and database integration. Guided by the classic software engineering strategy of separation of concerns and a policy of semantic flexibility, it integrates existing popular programs and web resources into a user-friendly, easily-extended environment. We demonstrate that four simple data types (names, matrices, networks, and associative arrays) are sufficient to bring together diverse databases and software. We highlight some capabilities of the Gaggle with an exploration of Helicobacter pylori pathogenesis genes, in which we identify a putative ricin-like protein -a discovery made possible by simultaneous data exploration using a wide range of publicly available data and a variety of popular bioinformatics software tools. We have integrated diverse databases (for example, KEGG, BioCyc, String) and software (Cytoscape, DataMatrixViewer, R statistical environment, and TIGR Microarray Expression Viewer). Through this loose coupling of diverse software and databases the Gaggle enables simultaneous exploration of experimental data (mRNA and protein abundance, protein-protein and protein-DNA interactions), functional associations (operon, chromosomal proximity, phylogenetic pattern), metabolic pathways (KEGG) and Pubmed abstracts (STRING web resource), creating an exploratory environment useful to 'web browser and spreadsheet biologists', to statistically savvy computational biologists, and those in between. The Gaggle uses Java RMI and Java Web Start technologies and can be found at http://gaggle.systemsbiology.net .

Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis.

Abstract: Inflammatory bowel diseases and infectious gastroenteritis likely occur when the integrity of intestinal barriers is disrupted allowing luminal bacterial products to cross into the intestinal mucosa, stimulating immune cells and triggering inflammation. While specific Toll-like receptors (TLR) are involved in the generation of inflammatory responses against enteric bacteria, their contributions to the maintenance of intestinal mucosal integrity are less clear. These studies investigated the role of TLR2 in a model of murine colitis induced by the bacterial pathogen Citrobacter rodentium. C. rodentium supernatants specifically activated TLR2 in vitro while infected TLR2-/- mice suffered a lethal colitis coincident with colonic mucosal ulcerations, bleeding and increased cell death but not increased pathogen burden. TLR2-/- mice suffered impaired epithelial barrier function mediated via zonula occludens (ZO)-1 in naive mice and claudin-3 in infected mice, suggesting this could underlie their susceptibility. TLR2 deficiency was also associated with impaired production of IL-6 by bone marrow-derived macrophages and infected colons cultured ex vivo. As IL-6 has antiapoptotic and epithelial repair capabilities, its reduced expression could contribute to the impaired mucosal integrity. These studies report for the first time that TLR2 plays a critical role in maintaining intestinal mucosal integrity during infection by a bacterial pathogen.

Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Abstract: The immunogenetic factors that influence susceptibility to pneumonia are poorly understood. Recent studies suggest an association of toll-like receptor 4 (TLR4) polymorphisms with increased susceptibility to some infections. Here, we examined whether polymorphisms in TLR4 influence susceptibility to Legionnaires' disease (LD) by using a case-control study to compare the allele frequencies of two SNPs (A896G and C1196T). Cases (n = 108) were obtained from a LD outbreak in The Netherlands in 1999. Controls were exposed at the same outbreak, did not develop pneumonia, and were either unmatched (n = 421) or matched (n = 89) to patients for age, sex, and geographic residence. Allele 896G was associated with LD susceptibility with a frequency of 6.5% in the combined control group (matched and unmatched) vs. 2.5% in patients [odds ratio (OR) of 0.36, 95% confidence interval (C.I.) 0.14–0.91, P = 0.025]. In the matched control group comparison, allele 896G also showed a protective association with an OR of 0.27 (95% C.I. 0.09–0.75, P = 0.008). An analysis of genotype frequencies (896 AA vs. AG and GG) demonstrated similar protective associations (patient vs. combined control group comparison, OR = 0.35, 95% C.I. 0.14–0.89, P = 0.02; matched control group comparison, OR = 0.25, 95% C.I. 0.09–0.71, P = 0.006). Allele 1196T cosegregated with allele 896G and, thus, had identical associations. Although previous studies suggest that these TLR4 SNPs are associated with an increased risk of infection, this study demonstrates an association with resistance. This protective association illustrates that an innate immune receptor can mediate either beneficial or deleterious inflammatory responses and that these outcomes vary with different pathogens.