Nicholas Geard

A Gene Network Model for Developing Cell Lineages

Biological development is a remarkably complex process. A single cell, in an appropriate environment, contains sufficient information to generate a variety of differentiated cell types, whose spatial and temporal dynamics interact to form detailed morphological patterns. While several different physical and chemical processes play an important role in the development of an organism, the locus of control is the cells gene regulatory network. We designed a dynamic recurrent gene network (DRGN) model and evaluated its ability to control the developmental trajectories of cells during embryogenesis. Three tasks were developed to evaluate the model, inspired by cell lineage specification in C. elegans, describing the variation in gene activity required for early cell diversification, combinatorial control of cell lineages, and cell lineage termination. Three corresponding sets of simulations compared performance on the tasks for different gene network sizes, demonstrating the ability of DRGNs to perform the tasks with minimal external input. The model and task definition represent a new means of linking the fundamental properties of genetic networks with the topology of the cell lineages whose development they control.

Synthetic Population Dynamics: A Model of Household Demography

Computer-simulated synthetic populations are used by researchers and policy makers to help understand and predict the aggregate behaviour of large numbers of individuals. Research aims include explaining the structural and dynamic characteristics of populations, and the implications of these characteristics for dynamic processes such as the spread of disease, opinions and social norms. Policy makers planning for the future economic, healthcare or infrastructure needs of a population want to be able to evaluate the possible effects of their policies. In both cases, it is desirable that the structure and dynamic behaviour of synthetic populations be statistically congruent to that of real populations. Here, we present a parsimonious individual-based model for generating synthetic population dynamics that focuses on the effects that demographic change have on the structure and composition of households.

Maximally rugged NK landscapes contain the highest peaks

NK models provide a family of tunably rugged fitness landscapes used in a wide range of evolutionary computation studies. It is well known that the average height of local optima regresses to the mean of the landscape with increasing epistasis, k. This fact has been confirmed using both theoretical studies of landscape structure and empirical studies of evolutionary search. We show that the global optimum behaves quite differently: the expected value of the global maximum is highest in the maximally rugged case. Furthermore, we demonstrate that this expected value increases with K, despite the fact that the average fitness of the local optima decreases. That is, the highest peaks are found in the most rugged landscapes, scattered amongst masses of low-lying peaks. We find the asymptotic value of the global optimum as N approaches infinity for both the smooth and maximally rugged cases. In evolutionary search, the optima that are found reflect the local optima that exist in the landscape, the size of these optima -- which corresponds to the size of their basins of attraction, and the effort expended in the search process. Increasing the level of epistasis in an NK landscape stochastically introduces higher peaks, but renders them exponentially more difficult to find.

Stability in flux: community structure in dynamic networks.

The structure of many biological, social and technological systems can usefully be described in terms of complex networks. Although often portrayed as fixed in time, such networks are inherently dynamic, as the edges that join nodes are cut and rewired, and nodes themselves update their states. Understanding the structure of these networks requires us to understand the dynamic processes that create, maintain and modify them. Here, we build upon existing models of coevolving networks to characterize how dynamic behaviour at the level of individual nodes generates stable aggregate behaviours. We focus particularly on the dynamics of groups of nodes formed endogenously by nodes that share similar properties (represented as node state) and demonstrate that, under certain conditions, network modularity based on state compares well with network modularity based on topology. We show that if nodes rewire their edges based on fixed node states, the network modularity reaches a stable equilibrium which we quantify analytically. Furthermore, if node state is not fixed, but can be adopted from neighbouring nodes, the distribution of group sizes reaches a dynamic equilibrium, which remains stable even as the composition and identity of the groups change. These results show that dynamic networks can maintain the stable community structure that has been observed in many social and biological systems.

Dynamical approaches to modeling developmental gene regulatory networks

The network of interacting regulatory signals within a cell comprises one of the most complex and powerful computational systems in biology. Gene regulatory networks (GRNs) play a key role in transforming the information encoded in a genome into morphological form. To achieve this feat, GRNs must respond to and integrate environmental signals with their internal dynamics in a robust and coordinated fashion. The highly dynamic nature of this process lends itself to interpretation and analysis in the language of dynamical models. Modeling provides a means of systematically untangling the complicated structure of GRNs, a framework within which to simulate the behavior of reconstructed systems and, in some cases, suites of analytic tools for exploring that behavior and its implications. This review provides a general background to the idea of treating a regulatory network as a dynamical system, and describes a variety of different approaches that have been taken to the dynamical modeling of GRNs.

The effects of demographic change on disease transmission and vaccine impact in a household structured population.

The demographic structure of populations in both more developed and less developed countries is changing: increases in life expectancy and declining fertility have led to older populations and smaller households. The implications of these demographic changes for the spread and control of infectious diseases are not fully understood. Here we use an individual based model with realistic and dynamic age and household structure to demonstrate the marked effect that demographic change has on disease transmission at the population and household level. The decline in fertility is associated with a decrease in disease incidence and an increase in the age of first infection, even in the absence of vaccination or other control measures. Although large households become rarer as fertility decreases, we show that there is a proportionate increase in incidence of disease in these households as the accumulation of susceptible clusters increases the potential for explosive outbreaks. By modelling vaccination, we provide a direct comparison of the relative importance of demographic change and vaccination on incidence of disease. We highlight the increased risks associated with unvaccinated households in a low fertility setting if vaccine behaviour is correlated with household membership. We suggest that models that do not account for future demographic change, and especially its effect on household structure, may potentially overestimate the impact of vaccination.

Structure and dynamics of a gene network model incorporating small RNAs

As advances in molecular biology continue to reveal additional layers of complexity in gene regulation, computational models need to incorporate additional features to explore the implications of new theories and hypotheses. It has recently been suggested that eukaryotic organisms owe their phenotypic complexity and diversity to the exploitation of small RNAs as signalling molecules. Previous models of genetic systems are, for several reasons, inadequate to investigate this theory. In this study, we present an artificial genome model of genetic regulatory networks based upon previous work by Torsten Reil, and demonstrate how this model generates networks with biologically plausible structural and dynamic properties. We also extend the model to explore the implications of incorporating regulation by small RNA molecules in a gene network. We demonstrate how, using these signals, highly connected networks can display dynamics that are more stable than expected given their level of connectivity.

A generative bias towards average complexity in artificial cell lineages

The evolution of life on earth has been characterized by generalized long-term increases in phenotypic complexity. Although natural selection is a plausible cause for these trends, one alternative hypothesis—generative bias—has been proposed repeatedly based on theoretical considerations. Here, we introduce a computational model of a developmental system and use it to test the hypothesis that long-term increasing trends in phenotypic complexity are caused by a generative bias towards greater complexity. We use our model to generate random organisms with different levels of phenotypic complexity and analyse the distributions of mutational effects on complexity. We show that highly complex organisms are easy to generate but there are trade-offs between different measures of complexity. We also find that only the simplest possible phenotypes show a generative bias towards higher complexity, whereas phenotypes with high complexity display a generative bias towards lower complexity. These results suggest that generative biases alone are not sufficient to explain long-term evolutionary increases in phenotypic complexity. Rather, our finding of a generative bias towards average complexity argues for a critical role of selective biases in driving increases in phenotypic complexity and in maintaining high complexity once it has evolved.

Vaccination Programs for Endemic Infections: Modelling Real versus Apparent Impacts of Vaccine and Infection Characteristics.

Vaccine effect, as measured in clinical trials, may not accurately reflect population-level impact. Furthermore, little is known about how sensitive apparent or real vaccine impacts are to factors such as the risk of re-infection or the mechanism of protection. We present a dynamic compartmental model to simulate vaccination for endemic infections. Several measures of effectiveness are calculated to compare the real and apparent impact of vaccination, and assess the effect of a range of infection and vaccine characteristics on these measures. Although broadly correlated, measures of real and apparent vaccine effectiveness can differ widely. Vaccine impact is markedly underestimated when primary infection provides partial natural immunity, when coverage is high and when post-vaccination infectiousness is reduced. Despite equivalent efficacy, ‘all or nothing’ vaccines are more effective than ‘leaky’ vaccines, particularly in settings with high risk of re-infection and transmissibility. Latent periods result in greater real impacts when risk of re-infection is high, but this effect diminishes if partial natural immunity is assumed. Assessments of population-level vaccine effects against endemic infections from clinical trials may be significantly biased, and vaccine and infection characteristics should be considered when modelling outcomes of vaccination programs, as their impact may be dramatic.

COMPETITION AND THE DYNAMICS OF GROUP AFFILIATION

How can we understand the interaction between the social network topology of a population and the patterns of group affiliation in that population? Each aspect influences the other: social networks provide the conduits via which groups recruit new members and groups provide the context in which new social ties are formed. Given that the resources of individuals are finite, groups can be considered to compete with one another for the time and energy of their members. Such competition is likely to have an impact on the way in which social structure and group affiliation co-evolve. While many social simulation models exhibit group formation as a part of their behaviour (e.g., opinion clusters or converged cultures), models that explicitly focus on group affiliation are less common. We describe and explore the behaviour of a model in which, distinct from most current models, individual nodes can belong to multiple groups simultaneously. By varying the capacity of individuals to belong to groups, and the costs associated with group membership, we explore the effect of different levels of competition on population structure and group dynamics.