Colorectal Cancer Through Simulation and Experiment

Colorectal cancer has continued to generate a huge amount of research interest over several decades, forming a canonical example of tumourigenesis since its use in Fearon and Vogelstein’s linear model of genetic mutation. Over time, the field has witnessed a transition from solely experimental work to the inclusion of mathematical biology and computer-based modelling. The fusion of these disciplines has the potential to provide valuable insights into oncologic processes, but also presents the challenge of uniting many diverse perspectives. Furthermore, the cancer cell phenotype defined by the ‘Hallmarks of Cancer’ has been extended in recent times and provides an excellent basis for future research. We present a timely summary of the literature relating to colorectal cancer, addressing the traditional experimental findings, summarising the key mathematical and computational approaches, and emphasising the role of the Hallmarks in current and future developments. We conclude with a discussion of interdisciplinary work, outlining areas of experimental interest which would benefit from the insight that mathematical and computational modelling can provide

Hierarchical Bayesian inference for ion channel screening dose-response data

Dose-response (or 'concentration-effect') relationships commonly occur in biological and pharmacological systems and are well characterised by Hill curves. These curves are described by an equation with two parameters: the inhibitory concentration 50% (IC50); and the Hill coefficient. Typically just the 'best fit' parameter values are reported in the literature. Here we introduce a Python-based software tool, PyHillFit , and describe the underlying Bayesian inference methods that it uses, to infer probability distributions for these parameters as well as the level of experimental observation noise. The tool also allows for hierarchical fitting, characterising the effect of inter-experiment variability. We demonstrate the use of the tool on a recently published dataset on multiple ion channel inhibition by multiple drug compounds. We compare the maximum likelihood, Bayesian and hierarchical Bayesian approaches. We then show how uncertainty in dose-response inputs can be characterised and propagated into a cardiac action potential simulation to give a probability distribution on model outputs

Validity of the Cauchy-Born rule applied to discrete cellular-scale models of biological tissues

The development of new models of biological tissues that consider cells in a discrete manner is becoming increasingly popular as an alternative to PDE-based continuum methods, although formal relationships between the discrete and continuum frameworks remain to be established. For crystal mechanics, the discrete-to-continuum bridge is often made by assuming that local atom displacements can be mapped homogeneously from the mesoscale deformation gradient, an assumption known as the Cauchy-Born rule (CBR). Although the CBR does not hold exactly for non-crystalline materials, it may still be used as a first order approximation for analytic calculations of effective stresses or strain energies. In this work, our goal is to investigate numerically the applicability of the CBR to 2-D cellular-scale models by assessing the mechanical behaviour of model biological tissues, including crystalline (honeycomb) and non-crystalline reference states. The numerical procedure consists in precribing an affine deformation on the boundary cells and computing the position of internal cells. The position of internal cells is then compared with the prediction of the CBR and an average deviation is calculated in the strain domain. For centre-based models, we show that the CBR holds exactly when the deformation gradient is relatively small and the reference stress-free configuration is defined by a honeycomb lattice. We show further that the CBR may be used approximately when the reference state is perturbed from the honeycomb configuration. By contrast, for vertex-based models, a similar analysis reveals that the CBR does not provide a good representation of the tissue mechanics, even when the reference configuration is defined by a honeycomb lattice. The paper concludes with a discussion of the implications of these results for concurrent discrete/continuous modelling, adaptation of atom-to-continuum (AtC) techniques to biological tissues and model classification

Challenges of ultra large scale integration of biomedical computing systems

The NCRI Informatics Initiative is overseeing the implementation of an informatics framework for the UK cancer research community. The framework advocates an integrated multidisciplinary method of working between scientific and medical communities. Key to this process is community adoption of high quality acquisition, storage, sharing and integration of diverse data elements to improve knowledge of the causes, prevention and treatment of cancer. The integration of the complex data and meta-data used by these multiple communities is a significant challenge and there are technical, resource-based and sociological issues to be addressed. In this paper we review progress aimed at establishing the framework and outline key challenges in ultra large scale integration of biomedical computing systems

Solute transport within porous biofilms: diffusion or dispersion?

Many microorganisms live within surface-associated consortia, termed biofilms, that can form intricate porous structures interspersed with a network of fluid channels. In such systems, transport phenomena, including flow and advection, regulate various aspects of cell behaviour by controllling nutrient supply, evacuation of waste products and permeation of antimicrobial agents. This study presents multiscale analysis of solute transport in these porous biofilms. We start our analysis with a channel-scale description of mass transport and use the method of volume averaging to derive a set of homogenized equations at the biofilmscale. We show that solute transport may be described via two coupled partial differential equations for the averaged concentrations, or telegrapher’s equations. These models are particularly relevant for chemical species, such as some antimicrobial agents, that penetrate cell clusters very slowly. In most cases, especially for nutrients, solute penetration is faster, and transport can be described via an advection-dispersion equation. In this simpler case, the effective diffusion is characterised by a second-order tensor whose components depend on: (1) the topology of the channels’ network; (2) the solute’s diffusion coefficients in the fluid and the cell clusters; (3) hydrodynamic dispersion effects; and (4) an additional dispersion term intrinsic to the two-phase configuration. Although solute transport in biofilms is commonly thought to be diffusion-dominated, this analysis shows that dispersion effects may significantly contribute to transport

Evaluation of a portable image overlay projector for the visualisation of surgical navigation data: phantom studies

Introduction: Presenting visual feedback for image-guided surgery on a monitor requires the surgeon to perform time-consuming comparisons and diversion of sight and attention away from the patient. Deficiencies in previously developed augmented reality systems for image-guided surgery have, however, prevented the general acceptance of any one technique as a viable alternative to monitor displays. This work presents an evaluation of the feasibility and versatility of a novel augmented reality approach for the visualisation of surgical planning and navigation data. The approach, which utilises a portable image overlay device, was evaluated during integration into existing surgical navigation systems and during application within simulated navigated surgery scenarios. Methods: A range of anatomical models, surgical planning data and guidance information taken from liver surgery, cranio-maxillofacial surgery, orthopaedic surgery and biopsy were displayed on patient-specific phantoms, directly on to the patient's skin and on to cadaver tissue. The feasibility of employing the proposed augmented reality visualisation approach in each of the four tested clinical applications was qualitatively assessed for usability, visibility, workspace, line of sight and obtrusiveness. Results: The visualisation approach was found to assist in spatial understanding and reduced the need for sight diversion throughout the simulated surgical procedures. The approach enabled structures to be identified and targeted quickly and intuitively. All validated augmented reality scenes were easily visible and were implemented with minimal overhead. The device showed sufficient workspace for each of the presented applications, and the approach was minimally intrusiveness to the surgical scene. Conclusion: The presented visualisation approach proved to be versatile and applicable to a range of image-guided surgery applications, overcoming many of the deficiencies of previously described AR approaches. The approach presents an initial step towards a widely accepted alternative to monitor displays for the visualisation of surgical navigation dat

Hydrodynamic dispersion within porous biofilms

Many microorganisms live within surface-associated consortia, termed biofilms, that can form intricate porous structures interspersed with a network of fluid channels. In such systems, transport phenomena, including flow and advection, regulate various aspects of cell behavior by controlling nutrient supply, evacuation of waste products, and permeation of antimicrobial agents. This study presents multiscale analysis of solute transport in these porous biofilms. We start our analysis with a channel-scale description of mass transport and use the method of volume averaging to derive a set of homogenized equations at the biofilm-scale in the case where the width of the channels is significantly smaller than the thickness of the biofilm. We show that solute transport may be described via two coupled partial differential equations or telegrapher's equations for the averaged concentrations. These models are particularly relevant for chemicals, such as some antimicrobial agents, that penetrate cell clusters very slowly. In most cases, especially for nutrients, solute penetration is faster, and transport can be described via an advection-dispersion equation. In this simpler case, the effective diffusion is characterized by a second-order tensor whose components depend on (1) the topology of the channels' network; (2) the solute's diffusion coefficients in the fluid and the cell clusters; (3) hydrodynamic dispersion effects; and (4) an additional dispersion term intrinsic to the two-phase configuration. Although solute transport in biofilms is commonly thought to be diffusion dominated, this analysis shows that hydrodynamic dispersion effects may significantly contribute to transport

Quiescience as a mechanism for cyclical hypoxia and acidosis

Tumour tissue characteristically experiences fluctuations in substrate supply. This unstable microenvironment drives constitutive metabolic changes within cellular populations and, ultimately, leads to a more aggressive phenotype. Previously, variations in substrate levels were assumed to occur through oscillations in the hæmodynamics of nearby and distant blood vessels. In this paper we examine an alternative hypothesis, that cycles of metabolite concentrations are also driven by cycles of cellular quiescence and proliferation. Using a mathematical modelling approach, we show that the interdependence between cell cycle and the microenvironment will induce typical cycles with the period of order hours in tumour acidity and oxygenation. As a corollary, this means that the standard assumption of metabolites entering diffusive equilibrium around the tumour is not valid; instead temporal dynamics must be considered

Chaste: a test-driven approach to software development for biological modelling

Chaste (‘Cancer, heart and soft-tissue environment’) is a software library and a set of test suites for computational simulations in the domain of biology. Current functionality has arisen from modelling in the fields of cancer, cardiac physiology and soft-tissue mechanics. It is released under the LGPL 2.1 licence.\ud \ud Chaste has been developed using agile programming methods. The project began in 2005 when it was reasoned that the modelling of a variety of physiological phenomena required both a generic mathematical modelling framework, and a generic computational/simulation framework. The Chaste project evolved from the Integrative Biology (IB) e-Science Project, an inter-institutional project aimed at developing a suitable IT infrastructure to support physiome-level computational modelling, with a primary focus on cardiac and cancer modelling

An integrative computational model for intestinal tissue renewal

Objectives\ud \ud The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation.\ud \ud Methods\ud \ud At the subcellular level, deterministic models characterise molecular networks, such as cell-cycle control and Wnt signalling. The output of these models determines the behaviour of each epithelial cell in response to intra-, inter- and extracellular cues. The modular nature of the model enables us to easily modify individual assumptions and analyse their effects on the system as a whole.\ud \ud Results\ud \ud We perform virtual microdissection and labelling-index experiments, evaluate the impact of various model extensions, obtain new insight into clonal expansion in the crypt, and compare our predictions with recent mitochondrial DNA mutation data. \ud \ud Conclusions\ud \ud We demonstrate that relaxing the assumption that stem-cell positions are fixed enables clonal expansion and niche succession to occur. We also predict that the presence of extracellular factors near the base of the crypt alone suffices to explain the observed spatial variation in nuclear beta-catenin levels along the crypt axis