NETSENSOR: Design and Engineeringof gene networks to respond to and correct alterations in signal transduction pathways

Duration: 36 months

Coordinator: European Molecular Biology Laboratory (Germany)

Websitenetsensor.crg.es

Contact Person:

Prof. Luis Serrano
System Biology
CRG – Centre de Regulatió Genòmica
Dr. Aiguader 88
08003 Barcelona
email: luis.serrano(at)crg.es
Tel: +34-933160247
Fax: +34-933969983

 

Partners:

  • Celletis (France)
  • Medical School Hannover (Germany)
  • Centro Nacional de Investigaciones Oncológicas (Spain)

 

Project Description:

Recent progress in constructing small artificial gene networks has allowed the engineering of predictable logical switches, or system behaviours, by harnessing feedback loops (Becskei, A. & Serrano, L. Nature 405, 590-3 (2000)). It should be possible to apply our growing knowledge of such networks to construct multi-component sensors and effectors to react to particular metabolic states in a cell, especially the aberrant states associated with disease. In this project, we aim to design modular gene networks of increasing complexity, that will sense errors at multiple levels in cellular pathways and will respond to repair the affected genes selectively. As a primary target, we have selected the p53 pathway; p53 itself is altered in ~50% of all cancers, while the other 50% of tumors carry alterations either in direct regulators of p53 (such as MDM2, p14ARF, E6 from HPV), or in pathways activating the p53 checkpoint (such as ATM, ATR, Brca1). Therefore we can consider that the p53 pathway is altered in virtually every cancer. The global idea of the project involves designing a network that will detect 3 or more steps in the pathway, identify the step that is not working properly and then selectively respond, either by killing the cell or by repairing the affected gene through double-strand induced recombination. Thus, we aim to combine expertise from a systems biology and protein design group (Serrano), a cell biology group with experience in p53 pathways (Carnero), a company specialising in meganuclease-induced recombination (Cellectis) and a group specialising in viral vector delivery to cells and cancer therapeutics (Kühnel). By integrating the experience of these different groups, we expect to develop robust cancer sensors with therapeutic potential. Furthermore, by exploring which network topologies and effector systems function best, we intend to provide a generally applicable framework to build synthetic networks to react to aberrant cellular pathways.

(source: Cordis Nest Pathfinder projects 2003-2006)