1359-6446/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(03)02600-X ▼ Systems biology uses an integrated ap- proach to study and understand the function of biological systems, and how perturbations of such systems, for example the adminis- tration of a therapeutic drug, affect their func- tion. The biological system can be at the level of a subcellular organelle, cell, organ, tissue or organism. The approach requires the simulta- neous static and/or temporal measurement of genomic, proteomic and metabolomic para- meters. Furthermore, it can only be success- fully applied with a seamlessly integrated bioanalytical and computational biology capability in place. Here, we outline general approaches to the study of biological com- plexity through systems biology, and provide examples of successful application of this discipline in the understanding of disease. Until recently, drug discovery has primarily been a linear process based on the sequential approaches of biology and chemistry. This has led to the separation of scientific disciplines into ‘functional silos’, with relatively limited cross-talk within the discovery process. As a consequence, the primary approach in the drug discovery process typically involves screening vast, randomized chemical libraries against a small number of pharmacologically relevant, and in some instances poorly de- fined, biological targets [1]. Although this approach has provided some success, the impact of HTS, ultra-HTS and high-speed combinatorial chemistry technologies has been less than the initially projected ‘several- fold’ increase in drug discovery productivity [2]. This is best reflected in the relationship between the estimated number of HTS assays per target versus the number of new chemi- cal entities (NCEs) reaching the market. In the past decade, this ‘numbers game’ indi- cated a trend of diminishing returns where assays per target have increased exponen- tially from several thousand to hundreds of millions. At the same time, the number of resultant NCEs remained stagnant [3,4]. Nevertheless, several specific molecular tar- gets have been identified and exploited for the treatment of a broad range of patho- genic conditions, including: β-adrenoceptor antagonists and angiotensin-converting enzyme inhibitors for cardiac arrhythmias; HMG-CoA reductase inhibitors (statins) for hyperlipidemia; and cyclooxygenase-2 (COX-2) inhibitors for arthritis and general inflammation. However, in multifactorial diseases, where multiple targets or pathways have to be affected for successful treatment outcomes, linking structurally and function- ally characterized targets with the disease still remains a challenge. A new knowledge-based approach has emerged that is a more comprehensive, sys- tems biology-based approach to biological function, cellular processes and disease- mediated processes, and that increases the probability of success in the drug discovery process. The emphasis is on the integration of analytical technologies and information, and includes the incorporation of structural Advancing drug discovery through systems biology Eugene J. Davidov, Joanne M. Holland, Edward W. Marple and Stephen Naylor Eugene Davidov* Joanne M. Holland Edward W. Marple Stephen Naylor Beyond Genomics 40 Bear Hill Road Waltham, MA 02451, USA tel: +1 781 434 0225 fax: +1 781 895 1119 *e-mail: edavidov@ beyondgenomics.com reviews research focus 175 DDT Vol. 8, No. 4 February 2003 Pharmaceutical companies are facing an urgent need to both increase their lead compound and clinical candidate portfolios and satisfy market demands for continued innovation and revenue growth. Here, we outline an emerging approach that attempts to facilitate and alleviate many of the current drug discovery issues and problems. This is, in part, achieved through the systematic integration of technologies, which results in a superior output of data and information, thereby enhancing our understanding of biological function, chemico–biological interactions and, ultimately, drug discovery. Systems biology is one new discipline that is positioned to significantly impact this process. www.drugdiscoverytoday.com