Computational Systems Biology

Summary of research activities

Development of new methodologies and workflows for rational design of industrial enzymes Kal Subramanian MSc, prof dr G Vriend, dr PJ Schaap.

Nearly all industrially used enzymes are the result of directed evolutionary approaches that invariably were guided with rational (in silico) studies. For development of new enzymes the industry aims to increase the use of the rational approaches because those have the potential to produce new or better enzymes with less wet-lab experimental efforts.

The aim of this project is to develop validated methodologies and workflows that predict mutations that improve enzyme properties ranging from shelf-life to specificity. These newly developed methodologies are based on a unique combination of statistical analyses of large structure based superfamily alignments and a series of existing and novel sequence- and structure-based computational approaches. New generation gene synthesis technologies will be used to efficiently produce the controlled sets of mutations with altered properties needed to validate formulated methodologies.

Systems biology of Mycobacterium tuberculosis RA Rienksma MSc, dr PJ Schaap, Prof dr VAP Martins dos Santos

An estimated one-third of the world’s population is infected with tuberculosis (TB), but only 5-10% become sick or infectious during some point in their lives (World Health Organization, 2010). In the remaining 90-95% of the individuals, it is thought that Mycobacterium tuberculosis persists in a dormant state (latent infection). This persistency presents a major challenge in disease control

Scope of the project
The SysteMTb project aims at providing a rational framework to understand mycobacterial physiology during infection and to identify essential nodes that are optimal for effective therapeutic interventions (www.systemtb.org, 2011). By integrating the various (relevant) omics-data into a constraint based metabolic model of Mycobacterium tuberculosis, new hypotheses can be generated. These can be experimentally tested, leading to an expansion of the model. The new model in turn will lead to new hypotheses etc. The goal of this project is to extend/optimize the model to such a degree that it can be used to generate novel strategies to treat and prevent tuberculosis

BSc or MSc thesis?
If you are looking for a BSc or MSc thesis project (without wetlab work) and like metabolic modelling, do not hesitate to contact me.

Reverse engineering of regulation in prokaryotes Dr María Suárez Diez, dr PJ Schaap, Prof dr VAP Martins dos Santos

Systems Biology advocates for a system-wide perspective in which molecules and molecular interactions in the cell are no longer regarded as operating in isolation but are accounted for in their cellular embedding. In prokaryotes, a substantial part of regulatory events proceed through transcriptional regulation. A solid knowledge of both the gene co-expression network and the transcriptional regulatory network (TRN) is therefore crucial for our understanding of the states of living organisms, their interactions with hosts and their reactions to environmental changes.

In this project, we aim to develop new methods for accurate, automatic reconstruction of TRN by combining successful methods developed in the past. We will develop a pipeline for integration thereof and we will apply our workflow to the specific examples of Mycobacterium tuberculosis and Mycoplasma pneumoniae in the context of infection. In addition we will develop a method to search for the master regulators of the network. Furthermore, we will combine the TRN-inference techniques herein proposed with methods for inference of non-transcriptional regulation, including those mediated by small RNAs. This will allow for a more complete picture of regulation in these micro-organisms. We will subsequently integrate the regulatory information hereby derived into the genome-scale metabolic modelling frameworks previous developed for these specific microbes. Owing to the non-specific nature of the methods proposed, it is expected these will be of great value for application to prokaryotes in general.

BSc or MSc thesis?
If you are looking for a BSc or MSc thesis project on computational systems biology and if you are interested in gene expression regulation, do not hesitate to contact me .

Constrained based metabolic modeling of the gut microbiota (NCSB/TIFN Project) M. Davids MSc, Dr P.J. Schaap, Prof.dr.ir V.A.P. Martins dos Santos.

The overall project will address the formation of short chain fatty acids (SCFA) by the gut microbiota and the subsequent metabolism of these biologically active compounds in gut epithelial cells and the liver.

At systems and synthetic biology we aim at the construction of (meta) genome-scale metabolic models of the gut microbiota, focusing on SCFA metabolism. In close collaboration with the molecular ecology group of the microbiology department meta-transcriptome data of mice-microbiota will be analyzed and different activity profiles on various diets will be identified.

Furthermore, a synthetic microbial community, representing the main players of the intestinal tract, will be analyzed in silico with use of genome scale metabolic model. The activity profiles and models will shed light on how the microbiota interacts and how it might be manipulated to alter its SCFA production.

BSc or MSc thesis?
If you are looking for a BSc or MSc thesis project on computational systems biology and if you are interested in gene expression regulation, do not hesitate to contact me .