Vol 8, No 3 - Drug Discovery and Proof of Concept
Past issues Contributors How to publish Contributions and comments Home
 
ecent reports have highlighted the imbalance between rising costs in drug discovery and the produc- tion of new molecular entities for the market,1,2 leading to a long-term loss of efficiency. Remarkably, this decline in productivity has occurred despite the fact that bio- medical research benefits from large governmental and private  investments, and  despite  the  comprehensive improvements in our knowledge of human genes result- ing from large sequencing projects. The tremendous efforts that have to be invested for drug target identification, follow-up validation studies, and clinical trials, in combination with the high failure rate as a consequence of individual response to drugs, has imposed high costs on the development of drugs. Understanding  individual  response  to  a  drug, what determines its efficacy and tolerability in the patient’s body, is the major bottleneck in drug development and S t a t e  o f  t h e  a r t R Copyright © 2006 LLS SAS.  All rights reserved www.dialogues-cns.org Expression profiling of drug response— from genes to pathways Ralf Herwig, PhD; Hans Lehrach, PhD Keywords: drug discovery; functional genomics; microarray; bioinformatics; data integration; database; systems biology Author affiliations: Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany Address for correspondence: Dr Ralf Herwig, Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Ihnestr. 73, D-14195 Berlin, Germany (e-mail: herwig@molgen.mpg.de) Understanding individual response to a drug—what determines its efficacy and tolerability—is the major bottleneck in current drug development and clinical trials. Intracellular response and metabolism, for example through cytochrome P- 450 enzymes, may either enhance or decrease the effect of different drugs, dependent on the genetic variant. Microarrays offer the potential to screen the genetic composition of the individual patient. However, experiments are “noisy” and must be accompanied by solid and robust data analysis. Furthermore, recent research aims at the combination of high- throughput data with methods of mathematical modeling, enabling problem-oriented assistance in the drug discovery process. This article will discuss state-of-the-art DNA array technology platforms and the basic elements of data analysis and bioinformatics research in drug discovery. Enhancing single-gene analysis, we will present a new method for inter- preting gene expression changes in the context of entire pathways. Furthermore, we will introduce the concept of sys- tems biology as a new paradigm for drug development and highlight our recent research—the development of a mod- eling and simulation platform for biomedical applications. We discuss the potentials of systems biology for modeling the drug response of the individual patient.   © 2006, LLS SAS Dialogues Clin Neurosci. 2006;8:283-293.