Pathways of Toxicity.

Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. To this end, a workshop was organized to explore one key aspect of this transformation - the development of Pathways of Toxicity as a key tool for hazard identification based on systems biology. Several issues were discussed in depth in the workshop: The first was the challenge of formally defining the concept of a Pathway of Toxicity (PoT), as distinct from, but complementary to, other toxicological pathway concepts such as mode of action (MoA). The workshop came up with a preliminary definition of PoT as "A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants". It is further recognized that normal physiological pathways exist that maintain homeostasis and these, sufficiently perturbed, can become PoT. Second, the workshop sought to define the adequate public and commercial resources for PoT information, including data, visualization, analyses, tools, and use-cases, as well as the kinds of efforts that will be necessary to enable the creation of such a resource. Third, the workshop explored ways in which systems biology approaches could inform pathway annotation, and which resources are needed and available that can provide relevant PoT information to the diverse user communities.

The Virtual Liver Network: systems understanding from bench to bedside.

Adriano Henney speaks to Hannah Coaker, Commissioning Editor. After achieving a PhD in medicine and spending many years in academic research in the field of cardiovascular disease, Adriano Henney was recruited by Zeneca Pharmaceuticals from a British Heart Foundation Senior Fellowship, where he led the exploration of new therapeutic approaches in atherosclerosis, specifically focusing on his research interests in vascular biology. Following the merger with Astra to form AstraZeneca, Henney became responsible for exploring strategic improvements to the company's approaches to pharmaceutical target identification and the reduction of attrition in early development, directing projects across research sites and across functional project teams in the USA, Sweden and the UK. This resulted in the creation of a new multidisciplinary department that focused on pathway mapping, modeling and simulation and supporting projects across research and development, which evolved into the establishment of the practice of systems biology within the company. Here, projects prototyped the application of mechanistic disease-modeling approaches in order to support the discovery of innovative new medicines, such as Iressa®. Since leaving AstraZeneca, Henney has continued his interest in systems biology, synthetic biology and systems medicine through his company, Obsidian Biomedical Consulting Ltd. He now directs a major €50 million German national flagship program ­ the Virtual Liver Network ­ which is currently the largest systems biology program in Europe.

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.

Report on EU-USA workshop: how systems biology can advance cancer research (27 October 2008).

The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include: Systems biology and computational approaches can make important contributions to research and development in key clinical aspects of cancer and of cancer treatment, and should be developed for understanding and application to diagnosis, biomarkers, cancer progression, drug development and treatment strategies. Development of new measurement technologies is central to successful systems approaches, and should be strongly encouraged. The systems view of disease combined with these new technologies and novel computational tools will over the next 5-20 years lead to medicine that is predictive, personalized, preventive and participatory (P4 medicine).Major initiatives are in progress to gather extremely wide ranges of data for both somatic and germ-line genetic variations, as well as gene, transcript, protein and metabolite expression profiles that are cancer-relevant. Electronic databases and repositories play a central role to store and analyze these data. These resources need to be developed and sustained. Understanding cellular pathways is crucial in cancer research, and these pathways need to be considered in the context of the progression of cancer at various stages. At all stages of cancer progression, major areas require modelling via systems and developmental biology methods including immune system reactions, angiogenesis and tumour progression.A number of mathematical models of an analytical or computational nature have been developed that can give detailed insights into the dynamics of cancer-relevant systems. These models should be further integrated across multiple levels of biological organization in conjunction with analysis of laboratory and clinical data.Biomarkers represent major tools in determining the presence of cancer, its progression and the responses to treatments. There is a need for sets of high-quality annotated clinical samples, enabling comparisons across different diseases and the quantitative simulation of major pathways leading to biomarker development and analysis of drug effects.Education is recognized as a key component in the success of any systems biology programme, especially for applications to cancer research. It is recognized that a balance needs to be found between the need to be interdisciplinary and the necessity of having extensive specialist knowledge in particular areas.A proposal from this workshop is to explore one or more types of cancer over the full scale of their progression, for example glioblastoma or colon cancer. Such an exemplar project would require all the experimental and computational tools available for the generation and analysis of quantitative data over the entire hierarchy of biological information. These tools and approaches could be mobilized to understand, detect and treat cancerous processes and establish methods applicable across a wide range of cancers.

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.