Login

Multiscale Mathematical Modeling to Support Drug Development

DAVID A. NORDSLETTEN, BERACAH YANKAMA, RENATO UMETON, V. A. SHIVA AYYADURAI, AND C. FORBES DEWEY, JR.

IEEE Transactions On Biomedical Engineering, Vol. 58, No. 12, December 2011
DOI: 10.1109/TBME.2011.2173245

Abstract:

It is widely recognized that major improvements are required in the methods currently being used to develop new therapeutic drugs. The time frominitial target identification to commercialization can be 10–14 years and incur a cost in the hundreds of millions of dollars. Even after substantial investment, only 30–40% of the candidate compounds entering clinical trials are successful. We propose that multiscale mathematical pathway modeling can be used to decrease time required to bring candidate drugs to clinical trial and increase the probability that they will be successful in humans. The requirements for multiple time scales and spatial scales are discussed, and new computational paradigms are identified to address the increased complexity of modeling.

Pericytes of the neurovascular unit: key functions and signaling pathways

MELANIE D SWEENEY, SHIVA AYYADURAI & BERISLAV V ZLOKOVIC

nature neuroscience VOLUME 19 | NUMBER 6 | JUNE 2016 © Nature America, Inc.
DOI:10.1038/nn.4288

Abstract:

Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood–brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer’s disease and brain tumors. Finally, we discuss directions for future studies.

Combinatorial drug therapy for cancer in the post-genomic era

BISSAN AL-LAZIKANI, UDAI BANERJI & PAUL WORKMAN

nature biotechnology VOLUME 30 NUMBER 7 JULY 2012 © Nature America, Inc.
DOI:10.1038/nbt.2284

Abstract:

Over the past decade, whole genome sequencing and other ‘omics’ technologies have defined pathogenic driver mutations to which tumor cells are addicted. Such addictions, synthetic lethalities and other tumor vulnerabilities have yielded novel targets for a new generation of cancer drugs to treat discrete, genetically defined patient subgroups. This personalized cancer medicine strategy could eventually replace the conventional one-size-fits-all cytotoxic chemotherapy approach. However, the extraordinary intratumor genetic heterogeneity in cancers revealed by deep sequencing explains why de novo and acquired resistance arise with molecularly targeted drugs and cytotoxic chemotherapy, limiting their utility. One solution to the enduring challenge of polygenic cancer drug resistance is rational combinatorial targeted therapy.

In Silico Modeling of Shear-Stress-Induced Nitric Oxide Production in Endothelial Cells through Systems Biology

ANDREW KOO, DAVID NORDSLETTEN, RENATO UMETON, BERACAH YANKAMA, SHIVA AYYADURAI, GUILLERMO GARCIA-CARDENA, AND C. FORBES DEWEY, JR.

Biophysical Journal Volume 104 May 2013 2295–2306 © 2013 by the Biophysical Society
DOI: 0006-3495/13/05/2295/12

Abstract:

Nitric oxide (NO) produced by vascular endothelial cells is a potent vasodilator and an antiinflammatory mediator. Regulating production of endothelial-derived NO is a complex undertaking, involving multiple signaling and genetic pathways that are activated by diverse humoral and biomechanical stimuli. To gain a thorough understanding of the rich diversity of responses observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously. In this article, we have assembled four quantitative molecular pathways previously proposed for shear-stress-induced NO production. In these pathways, endothelial NO synthase is activated 1), via calcium release, 2), via phosphorylation reactions, and 3), via enhanced protein expression. To these activation pathways, we have added a fourth, a pathway describing actual NO production from endothelial NO synthase and its various protein partners. These pathways were combined and simulated using CytoSolve, a computational environment for combining independent pathway calculations. The integrated model is able to describe the experimentally observed change in NO production with time after the application of fluid shear stress. This model can also be used to predict the specific effects on the system after interventional pharmacological or genetic changes. Importantly, this model reflects the up-to-date understanding of the NO system, providing a platform upon which information can be aggregated in an additive way.

Services-Based Systems Architecture for Modeling the Whole Cell: A Distributed Collaborative Engineering Systems Approach

V. A. S. AYYADURAI

Abstract:

Modeling the whole cell is a goal of modern systems biology. Current approaches are neither scalable nor flexible to model complex cellular functions. They do not support collaborative development, are monolithic and, take a primarily manual approach of combining each biological pathway model’s software source code to build one large monolithic model that executes on a single computer. What is needed is a distributed collaborative engineering systems approach that offers massive scalability and flexibility, treating each part as a services-based component, potentially delivered by multiple suppliers, that can be dynamically integrated in real-time. A requirements specification for such a services-based architecture is presented. This specification is used to develop CytoSolve, a working prototype that implements the services-based architecture enabling dynamic and collaborative integration of an ensemble of biological pathway models, that may be developed and maintained by teams distributed globally. This architecture computes solutions in a parallel manner while offering ease of maintenance of the integrated model. The individual biological pathway models can be represented in SBML, CellML or in any number of formats. The EGFR model of Kholodenko with known solutions is first tested within the CytoSolve framework to prove it viability. Success of the EGFR test is followed with the development of an integrative model of interferon (IFN) response to virus infection using the CytoSolve platform. The resulting integrated model of IFN yields accurate results based on comparison with previously published in vitro and in vivo studies. A open web-based environment for collaborative testing and continued development is now underway and available on www.cytosolve.com. As more biological pathway models develop in a disparate and decentralized manner, this architecture offers a unique platform for collaborative systems biology, to build large-scale integrative models of cellular function, and eventually one day model the whole cell.

CytoSolve: A Scalable Computational Method for Dynamic Integration of Multiple Molecular Pathway Models

V. A. SHIVA AYYADURAI and C. FORBES DEWEY JR

Abstract:

A grand challenge of computational systems biology is to create a molecular pathway model of the whole cell. Current approaches involve merging smaller molecular pathway models’ source codes to create a large monolithic model (computer program) that runs on a single computer. Such a larger model is difficult, if not impossible, to maintain given ongoing updates to the source codes of the smaller models. This paper describes a new system called CytoSolve that dynamically integrates computations of smaller models that can run in parallel across different machines without the need to merge the source codes of the individual models. This approach is demonstrated on the classic Epidermal Growth Factor Receptor (EGFR) model of Kholodenko. The EGFR model is split into four smaller models and each smaller model is distributed on a different machine. Results from four smaller models are dynamically integrated to generate identical results to the monolithic EGFR model running on a single machine. The overhead for parallel and dynamic computation is approximately twice that of a monolithic model running on a single machine. The CytoSolve approach provides a scalable method since smaller models may reside on any computer worldwide, where the source code of each model can be independently maintained and updated.