Boundary-driven instability

We analyse a reaction-diffusion system and show that complex spatial patterns can be generated by imposing Dirichlet boundary conditions on one or more of the reactant concentrations. This pattern persists even when the homogeneous steady state with Neumann conditions is stable

Multiscale modelling of intestinal crypt organization and carcinogenesis

Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial scales, from mutations that cause inappropriate intracellular responses to changes at the cell/tissue level, such as uncontrolled proliferation and altered motility and adhesion. Multiscale mathematical modelling can provide insight into the spatiotemporal organisation of such a complex, highly regulated and dynamic system. Moreover, the aforementioned challenges are inherent to the multiscale modelling of biological tissue more generally. In this review we describe the mathematical approaches that have been applied to investigate multiscale aspects of crypt behavior, highlighting a number of model predictions that have since been validated experimentally. We also discuss some of the key mathematical and computational challenges associated with the multiscale modelling approach. We conclude by discussing recent efforts to derive coarse-grained descriptions of such models, which may offer one way of reducing the computational cost of simulation by leveraging well-established tools of mathematical analysis to address key problems in multiscale modelling

Size dependent symmetry breaking in models for morphogenesis

A general property of dynamical systems is the appearance of spatial and temporal patterns due to a change of stability of a homogeneous steady state. Such spontaneous symmetry breaking is observed very frequently in all kinds of real systems, including the development of shape in living organisms. Many nonlinear dynamical systems present a wide variety of patterns with different shapes and symmetries. This fact restricts the applicability of these models to morphogenesis, since one often finds a surprisingly small variation in the shapes of living organisms. For instance, all individuals in the Phylum Echinodermata share a persistent radial fivefold symmetry. In this paper, we investigate in detail the symmetry-breaking properties of a Turing reaction–diffusion system confined in a small disk in two dimensions. It is shown that the symmetry of the resulting pattern depends only on the size of the disk, regardless of the boundary conditions and of the differences in the parameters that differentiate the interior of the domain from the outer space. This study suggests that additional regulatory mechanisms to control the size of the system are of crucial importance in morphogenesis

Estimation of effective vaccination rate for pertussis in New Zealand as a case study

In some cases vaccination is unreliable. For example vaccination against pertussis has comparatively high level of primary and secondary failures. To evaluate efficiency of vaccination we introduce the idea of effective vaccination rate and suggest an approach to estimate it. We consider pertussis in New Zealand as a case study. The results indicate that the level of immunity failure for pertussis is considerably higher than was anticipated

Tracking bifurcating solutions of a model biological pattern generator

We study heterogeneous steady-state solutions of a cell-chemotaxis model for generating biological spatial patterns in two-dimensional domains with zero flux boundary conditions. We use the finite-element package ENTWIFE to investigate bifurcation from the uniform solution as the chemotactic parameter varies and as the domain scale and geometry change. We show that this simple cell-chemotaxis model can produce a remarkably wide and surprising range of complex spatial patterns

Inferring tumour proliferative organisation from phylogenetic tree measures in a computational model

We use a computational modelling approach to explore whether it is possible to infer a solid tumour’s cellular proliferative hierarchy under the assumptions of the cancer stem cell hypothesis and neutral evolution. We focus on inferring the symmetric division probability for cancer stem cells, since this is believed to be a key driver of progression and therapeutic response. Motivated by the advent of multi-region sampling and resulting opportunities to infer tumour evolutionary history, we focus on a suite of statistical measures of the phylogenetic trees resulting from the tumour’s evolution in different regions of parameter space and through time. We find strikingly different patterns in these measures for changing symmetric division probability which hinge on the inclusion of spatial constraints. These results give us a starting point to begin stratifying tumours by this biological parameter and also generate a number of actionable clinical and biological hypotheses including changes during therapy, and through tumour evolution

Analysis of tumor as an inverse problem provides a novel theoretical framework for understanding tumor biology and therapy

We use a novel “inverse problem” technique to construct a basic mathematical model of the interacting populations at the tumor-host interface. This approach assumes that invasive cancer is a solution to the set of state equations that govern the interactions of transformed and normal cells. By considering the invading tumor edge as a traveling wave, the general form of the state equations can be inferred. The stability of this traveling wave solution imposes constraints on key biological quantities which appear as parameters in the model equations. Based on these constraints, we demonstrate the limitations of traditional therapeutic strategies in clinical oncology that focus solely on killing tumor cells or reducing their rate of proliferation. The results provide insights into fundamental mechanisms that may prevent these approaches from successfully eradicating most common cancers despite several decades of research. Alternative therapies directed at modifying the key parameters in the state equations to destabilize the propagating solution are proposed

Spatial Metrics of Tumour Vascular Organisation Predict Radiation Efficacy in a Computational Model

Intratumoural heterogeneity is known to contribute to poor therapeutic response. Variations in oxygen tension in particular have been correlated with changes in radiation response in vitro and at the clinical scale with overall survival. Heterogeneity at the microscopic scale in tumour blood vessel architecture has been described, and is one source of the underlying variations in oxygen tension. We seek to determine whether histologic scale measures of the erratic distribution of blood vessels within a tumour can be used to predict differing radiation response. Using a two-dimensional hybrid cellular automaton model of tumour growth, we evaluate the effect of vessel distribution on cell survival outcomes of simulated radiation therapy. Using the standard equations for the oxygen enhancement ratio for cell survival probability under differing oxygen tensions, we calculate average radiation effect over a range of different vessel densities and organisations. We go on to quantify the vessel distribution heterogeneity and measure spatial organization using Ripley's L function, a measure designed to detect deviations from complete spatial randomness. We find that under differing regimes of vessel density the correlation coefficient between the measure of spatial organization and radiation effect changes sign. This provides not only a useful way to understand the differences seen in radiation effect for tissues based on vessel architecture, but also an alternate explanation for the vessel normalization hypothesis

Inferring tumour proliferative organisation from phylogenetic tree measures in a computational model

We use a computational modelling approach to explore whether it is possible to infer a tumour's cell proliferative hierarchy, under the assumptions of the cancer stem cell hypothesis and neutral evolution. We focus on inferring the symmetric division probability for cancer stem cells in our model, as this is believed to be a key driving parameter of tumour progression and therapeutic response. Given the advent of multi-region sampling, and the opportunities offered by them to understand tumour evolutionary history, we focus on a suite of statistical measures of the phylogenetic trees resulting from the tumour's evolution in different regions of parameter space and through time. We find strikingly different patterns in these measures for changing symmetric division probability which hinge on the inclusion of spatial constraints. These results give us a starting point to begin stratifying tumours by this biological parameter and also generate a number of actionable clinical and biological hypotheses including changes during therapy, and through tumour evolution

A simple mechanistic model of sprout spacing in tumour-associated angiogenesis

This paper develops a simple mathematical model of the siting of capillary sprouts on an existing blood vessel during the initiation of tumour-induced angiogenesis. The model represents an inceptive attempt to address the question of how unchecked sprouting of the parent vessel is avoided at the initiation of angiogenesis, based on the idea that feedback regulation processes play the dominant role. No chemical interaction between the proangiogenic and antiangiogenic factors is assumed. The model is based on corneal pocket experiments, and provides a mathematical analysis of the initial spacing of angiogenic sprouts