Dynamics of biological systems: role of systems biology in medical research

Assmus, Heike E.; Herwig, Ralf; Cho, Kwang-Hyun; Wolkenhauer, Olaf

doi:10.1586/14737159.6.6.891

Cited by 52 publications

(33 citation statements)

References 101 publications

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“…Kitano suggested that understanding of critical questions in biology required the integration of experimental and computational research [1]. Assmus et al and others maintained that analysis of the dynamics of human relevant networks using predictive computer models and high-throughput data generation would play an increasingly important role in medical research and the elucidation of disease mechanisms [2,3]. However, parametric and structural uncertainty remains an open challenge to mechanistic modeling in medicine.…”

Section: Introductionmentioning

confidence: 99%

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

2007

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The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein–protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa) activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of fragility of human relevant cascades could be used as a rational basis for target selection despite model uncertainty.

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Section: Introductionmentioning

confidence: 99%

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

2007

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“…He suggests that more efforts are needed to promote thorough validation of chemical-specific biomarkers of exposure, the development of reliable and highthroughput phenotypic assays of biomarkers of susceptibility and the formulation of a systems biology approach to the analysis of the modulation of biomarkers by environmental and genetic factors. The latter utilizes mathematical models to describe the structure and behaviour of the biological system (Assmus et al 2006, Hornberg et al 2006. Major systems biology efforts have been applied to cancer in order to understand disease mechanisms and the ability to devise effective therapeutics (Celis et al 2005, Khalil & Hill 2005, Chen et al 2006, Wang et al 2007).…”

Section: Resultsmentioning

confidence: 99%

Carcinogen DNA adducts and the risk of colon cancer: case–control study

et al. 2008

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Colorectal cancer represents 8.5% of all tumours at the King Faisal Specialist Hospital & Research Centre. Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) have long been suspected to play a prominent role in colon cancer aetiology. We designed a caseÁcontrol study to test the hypothesis of whether or not the presence of DNA adducts can play a role in the aetiology of colon cancer. DNA adducts were measured in 24 cancerous and 20 non-cancerous tissue samples of newly diagnosed colon cancer patients by 32 P-post-labelling technique. Normal tissue from 19 hospital patients served as controls. The mean levels of adducts per 10 10 nucleotides in cancerous and non-cancerous tissue were 151.759217.27 and 114.819186.10, respectively; however, only adducts in cancerous tissue were significantly higher than controls (32.78957.51 per 10 10 nucleotides) with p-values of 0.017. No BPDE-DNA adducts were found. No relationship was found between urinary cotinine as a marker of tobacco smoke and 1-hydroxypyrene as an indicator of an individual's internal dose of PAHs and DNA adducts. In a logistic regression model, only adducts in cancerous tissue were associated with the subsequent risk of colon cancer, with an odds ratio of 3.587 (95% confidence interval 0.833Á15.448) after adjustment for age and the duration of living in the current region, but of a borderline significance (p 00.086). Although it is difficult to arrive at a definite conclusion from a small dataset, our preliminary results suggest the potential role of DNA adducts in the colon carcinogenesis process. Additional studies with larger sample sizes are needed to confirm our preliminary finding. It is also important to identify the structural characterization of these unknown DNA adducts in order to have a better understanding of whether or not environmental carcinogens play a role in the aetiology of colon cancer.

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“…Despite a surge in the perspectives of using mechanistic mathematical modelling in clinical development [60][61][62][63], parametric uncertainty remains a challenge to mechanistic approaches in medicine [13]. However, contrary to the scarcity of kinetic data, the comprehensive quantification of all concentrations and fluxes within a metabolic system is, at least in principle, experimentally feasible.…”

Section: Discussionmentioning

confidence: 99%

A probabilistic approach to identify putative drug targets in biochemical networks

Murabito

Smallbone

Swinton

et al. 2010

J. R. Soc. Interface.

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Network-based drug design holds great promise in clinical research as a way to overcome the limitations of traditional approaches in the development of drugs with high efficacy and low toxicity. This novel strategy aims to study how a biochemical network as a whole, rather than its individual components, responds to specific perturbations in different physiological conditions. Proteins exerting little control over normal cells and larger control over altered cells may be considered as good candidates for drug targets. The application of network-based drug design would greatly benefit from using an explicit computational model describing the dynamics of the system under investigation. However, creating a fully characterized kinetic model is not an easy task, even for relatively small networks, as it is still significantly hampered by the lack of data about kinetic mechanisms and parameters values. Here, we propose a Monte Carlo approach to identify the differences between flux control profiles of a metabolic network in different physiological states, when information about the kinetics of the system is partially or totally missing. Based on experimentally accessible information on metabolic phenotypes, we develop a novel method to determine probabilistic differences in the flux control coefficients between the two observable phenotypes. Knowledge of how differences in flux control are distributed among the different enzymatic steps is exploited to identify points of fragility in one of the phenotypes. Using a prototypical cancerous phenotype as an example, we demonstrate how our approach can assist researchers in developing compounds with high efficacy and low toxicity.

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Dynamics of biological systems: role of systems biology in medical research

Cited by 52 publications

References 101 publications

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

Computationally Derived Points of Fragility of a Human Cascade Are Consistent with Current Therapeutic Strategies

Carcinogen DNA adducts and the risk of colon cancer: case–control study

A probabilistic approach to identify putative drug targets in biochemical networks

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