Patient‐Specific Modelling in Drug Design, Development and Selection Including its Role in Clinical Decision‐Making

Abstract

Genomics has made enormous progress in the twelve years since the publication of the first draft human genome sequence, but it has not yet been translated into the clinic. Despite spiralling development costs, the number of new drug registrations is not increasing. One reason for this lies in the genetic complexity of disease. Most diseases involve dysregulation in pathways that involve many genes, and many (including most cancers) are themselves genetically heterogeneous. Systems biology involves the multi-level simulation of physiology, cell biology and biochemistry using complex computational techniques. We show here using case studies in cancer and HIV how such computational models, and particularly models based on individual patient data, can be used for drug design and development, and in the selection of the appropriate treatment for a given patient in the face of resistance mutations. If these techniques are to be adopted in routine clinical practice, clinicians will need better training in modern approaches to the integrated analysis of large-scale heterogeneous data and multi-scale models, while developers will need to provide much more usable tools. Investment in computational infrastructure is needed so that results can be returned on clinically relevant timescales and data warehouses designed with data protection as well as accessibility in mind.

Applying systems biology methods to the study of human physiology in extreme environments

“…Yet, we are not alone in emphasising the central role of computation in systems biology [6-8]. Therefore, we propose defining systems biology (for the purposes of this review) as ‘an iterative process of computational model building and experimental model revision with the aim of understanding or simulating complex biological systems’ (Figure 1).…”

“…Although there is currently a shortage of systems biology studies (as defined here and elsewhere [4,8]) on human environmental physiology, excellent work has been conducted in the areas of high-altitude genetics and proteomics. Several studies have shown convincingly that human populations at high altitude have experienced a degree of genetic divergence.…”

A vision and strategy for the virtual physiological human: 2012 update

“…This, together with the development of plans for dissemination, training and outreach to the communities of researchers, physicians, patients, students, industry and the public in general, was the primary focus for the first year of the NoE. Direct engagement with the other VPH projects and clear examples of how standard-based models, software tools and Web-based services can be used to facilitate clinical outcomes have now become the top priority targets [3]. These goals are discussed below, along with proposals for the identification and use of additional resources and engagement needed to establish digital, personalized, and predictive medicine in Europe.…”

“…The biomedical genetics community is now facing serious challenges concerning the overall applicability of the genome wide association study (GWAS) approach when it comes to drug development and personalized medicine. The VPH initiative may be of substantial help by providing mechanistic model descriptions of the phenotypic effects originating from genomic network variation [3]. Such causally cohesive genotype -phenotype models are very advanced multiscale physiological models with an explicit link to molecular information and with the capacity to describe, for example, how genetic variation manifests in phenotypic variation at various systemic levels up to the tissue, organ and whole-organism level.…”

Beyond the Hundred Dollar Genome – Drug Discovery Futures

“…Systems biology seeks to develop mathematical models of systems and even ambitiously, as Shublaq et al. (2) describe, for individual patients. Personalized medicine may be considered a step along this road by targeting specific genetic abnormalities driving a cancer.…”