Date of Award

Spring 2012

Degree Type

Thesis

Degree Name

Doctor of Philosophy (Medical Science)

Department

Medical Sciences (Molecular Virology and Immunology Program)

Supervisor

Manel Jordana

Co-Supervisor

Miroslav Lovric

Language

English

Committee Member

Del Harnish

Abstract

Regardless of their origin or pathology, many, if not all, diseases have long been regarded as complex. Yet, despite the progression in the understanding of complexity and the development of systems biology, the majority of biomedical research has been derived from qualitative principles. In comparison to the ethical, temporal and logistical limitations of human experimentation, in vivo animal models have served to provide a more advantageous means to elucidate the underlying disease mechanisms. However, given the additional limitations presented by such models, in silico models have emerged as an effective complement, and, in some cases, a replacement for in vivo experimentation. The in silico models presented in this thesis were developed using mathematical and computational methods to investigate the evolution of two complex, diverse diseases from a systems biology perspective: allergic asthma and cancer.

We generated two novel in silico models of allergic asthma aimed at clarifying some dynamic aspects of allergic responses. Experimentally, we utilized an in vivo murine model of chronic exposure to the most pervasive aeroallergen worldwide, house dust mite (HDM), for up to 20 weeks, equivalent to at least 20 human years. Using a range of HDM concentrations, experimental data were collected to study local and systemic effects. The first model applied empirical mathematical techniques to establish equations for airway inflammation and HDM-specific immunoglobulins using an iterative approach of experimentation and validation. Using the equations generated, we showed that the model was able to accurately predict and simulate data. The model also demonstrated the non-linear relationship between HDM exposure and both airway inflammation and allergic sensitization and identified system thresholds.

The second model used mechanistic mathematical techniques to investigate the trafficking of eosinophils as they migrated from bone marrow to the blood and, ultimately, to the lungs. Making use of a limited data set, the model determined the effect of individual processes on the system. We identified eosinophil production, survival and death as having the greatest impacts, while migration played a relatively minor role. Furthermore, the model was used to simulate knockout models and the use of antibodies in silico.

In the context of cancer growth and metastasis, we developed a theoretical model demonstrating the spatio-temporal development of a tumour in two-dimensions. The model was encoded to create a computer graphic simulation program, which simulated the effects of various parameters on the size and shape of a tumour. Through simulations, we demonstrated the importance of the diffusion process in cancer growth and metastasis.

Ultimately, we believe the greatest benefit of each in silico model is the ability to provide an understanding of each respective disease recognized as dynamic and formally complex, but predominantly studied in reductionist, static or un-integrated approaches.

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