The promise and challenge of personalized medicine: aging populations, complex diseases, and unmet medical need.

The concept of personalized medicine is not new. It is being discussed with increasing interest in the medical, scientific, and general media because of the availability of advanced scientific and computational technologies, and the promise of the potential to improve the targeting and delivery of novel medicines. It is also being seen as one approach that may have a beneficial impact on reducing health care budgets. But what are the challenges that need to be addressed in its implementation in the clinic? This article poses some provocative questions and suggests some things that need to be considered.

The virtual liver: a multidisciplinary, multilevel challenge for systems biology.

The liver is the central metabolic organ in human physiology, with functions that are fundamentally important to the detoxification of xenobiotics (drugs), the maintenance of homeostasis of numerous blood metabolites, and the production of mediators of the acute phase response. Liver toxicity, whether actual or implied is the reason for the failure of a significant proportion of many promising novel medicines that consequently never reach the market, and diseases such as atherosclerosis, diabetes, and fatty liver diseases, that are a major burden on current health resources, are directly linked to functional and structural disorders of the liver. This article presents the concepts and approaches underpinning one of the most exciting and ambitious modeling projects in the field of systems biology and systems medicine. This major multidisciplinary research program is aimed at developing a whole-organ model of the human liver, representing its central physiological functions under normal and pathological conditions The model will be composed of a larger battery of interconnected submodels representing liver anatomy and physiology, integrating processes across hierarchical levels in space, time, and structural organization. In this article, we outline the general architecture of the liver model and present first step taken to reach this ambitious goal.

Systems Biology: a new hope for drug discovery?

The rapid expansion of biomedical information following the mapping of the human genome has contributed to significant advances in acquiring a highly detailed picture of disease mechanisms at the molecular level. This revolution in biomedical science has also generated hope and expectation for the delivery of novel treatments for serious illnesses. However, the reality is that despite this detailed information the return in terms of delivery of new medicines has been relatively modest.

Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor.

Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.