A Multiscale Approach to Genes Growth and Geometry

Many complex systems, such as biological organisms, the internet or the economy, involve integrated parallel processes operating at many different scales. Organisms for example, exhibit massively parallel organisation, with units interacting at levels ranging from molecules to ecosystems. A key challenge is to understand how such parallel multiscale interactions work. In the case of biological systems, a major focus in recent years has been on the molecular to cellular scale. However, advances in developmental biology and imaging, in particular the ability to isolate and study genes affecting the development of organisms in 3D, raises the possibility of a systems approach at a larger scale, from the subcellular to organism levels. The key link between these scales is growth, as it is through growth that molecular changes lead to modifications in cell size, shape and division, eventually leading to production of multicellular tissues and organisms. Growing structures can be divided into those that reach a steady state, such as the growing tips of plants, and those in which shape continually changes, such as developing insect wings or plant leaves. The latter cases present the particular challenge of capturing multiple interactions as a structure undergoes changes in shape and size over several orders of magnitude. Studying this problem requires growth, shape, patterning and gene action to be analysed and integrated at many levels. Moreover formal languages and modelling frameworks need to be developed to allow the dynamics and interactions to be captured. By pursuing these approaches at many scales in parallel, key experimental and conceptual links should emerge that would not be evident from studying each scale in isolation. Recent advances in both experimental and computational science now make this feasible. The aim of this project is to provide a platform for such an approach by studying the mechanism by which leaves acquire their characteristic shapes and patterns. The project will involve a combination experimental analysis, image-processing, computer modelling and integration at four different scales. (1) At the subcellular level, we will track the way components of the cytoskeleton are synthesised and change in parallel over time in 3D. Models will then be constructed to account for this behaviour and tested through further rounds of experimentation. These models will also be related to cellular properties. (2) At the cellular level, the pattern of cell growth and division will be determined for multiple regions of a growing leaf by live 3D imaging. Computer languages will be developed for modelling this behaviour based on local interactions between growing cells. Models will be tested by modifying gene activity at particular places and times during leaf development. These models will also be related to properties at the whole organ level. (3) At the organ level, the growth of the leaf in 3D will be tracked using a variety of imaging methods. A modelling framework will be developed that allows the observed cellular and tissue properties to be integrated with gene action. Models will be tested by analysing how experimental manipulation of local gene activity modifies growth. This will be aided by developing a system for measuring the 3D shapes of a diverse collection of mutants that affect leaf shape at various stages of development. (4) At the whole plant level, leaf growth will be incorporated into a virtual plant in which local interactions between modules account for the dynamics of growth and architecture. By interfacing the various models, an integrated multiscale view of plant development should emerge. The project will also train a new cohort of scientists familiar with disciplines ranging from molecular genetics, developmental biology, bio-imaging, image-processing to computer modelling.

To understand the dynamics and genetic control underlying shape, we will use a combination experimental analysis, image-processing, computer modelling to study and integrate leaf growth at multiple scales. (1) At the subcellular level, the dynamics of microtubule synthesis in growing leaf cells at various stages and locations will be tracked in 3D. The observed behaviour will be modelled and tested through analysis of mutants or plants treated with cytoskeletal inhibitors. (2) At the cellular level, the pattern of cell growth and division will be determined for multiple regions of a growing leaf by live 3D imaging. Suitable computer languages will be developed for modelling this behaviour based on local interactions between multiple units growing in parallel. The models will be tested by analysing the effects of modifying gene activity at particular places and times on leaf growth. (3) At the organ level, leaf growth in 3D will be tracked using Optical Projection Tomography, Confocal microscopy and fluorescent marking. A modelling framework will be developed that allows the observed cellular and tissue properties to be integrated with the action of genes. Models will be tested by experimental perturbation of local gene activity. This will be aided by developing a system for quantifying the 3D shapes of a diverse collection of mutants that affect leaf shape and size at various stages of development. (4) At the whole plant level, leaf growth will be incorporated into a virtual plant in which local interactions between modules account for the dynamics of growth and architecture. By interfacing the models at different scales, an integrated view of plant development should emerge. The project will also train a new cohort of interdisciplinary scientists familiar with concepts and methods that range from molecular genetics, developmental biology, bio-imaging, image-processing to computer modelling.