The impact of systems approaches on biological problems in drug discovery

The production of new molecular entities (NMEs) endowed with salutary medicinal properties provides a key metric by which the effectiveness of the pharmaceutical industry may be judged. Nearly a decade ago, Juergen Drews noted that the combined output of NMEs by all major pharmaceutical companies at the time was insufficient to support the healthy growth of the group. Indeed, a recent analysis documents a 30-year decline in pharmaceutical R&D productivity. This decline in productivity has occurred despite accelerating investment in biomedical research on the part of both industry and governments, with compound annual growth rates in research expenditures approaching 13%. Approvals aside, the number of late-stage clinical trials supported by the pharmaceutical industry has also declined during the past decade, auguring poorly for future triumphs in disease interdiction. Despite several notable discoveries, the emergence of major biotech companies has done little to improve the yield of new disease-ameliorating molecules. How is it that extraordinary advances in biomedical research over the past decade have exerted so little positive effect on drug discovery? We argue here that an inability to visualize the complexity of biological systems has impeded the identification of novel therapies. In the future, application of systems approaches to drug discovery promises to have a profound impact on medical practice, permitting a comprehensive evaluation of underlying predisposition to disease, disease diagnosis and disease progression. In the near term, systems biology will provide powerful means for validating new drug targets, improving the success with which pharmaceuticals are identified. Farther into the future, the same approaches will drive the development of early diagnostics, enabling disease stratification, individualized therapy and ultimately preventive drugs, based on both genetic and environmental considerations. Although systems biology as currently envisioned does not have a direct impact on the chemistry of identifying drugs or pharmacological challenges of drug metabolism, it may provide rapid and useful assays for these in the future.