A Multiscale Approach to Genes Growth and Geometry

许多复杂的系统，如生物有机体、互联网或经济，都涉及在许多不同规模上运行的综合并行过程。例如，生物体表现出大规模的平行组织，单位在从分子到生态系统的各个层面上相互作用。一个关键的挑战是了解这种并行的多尺度互动是如何工作的。就生物系统而言，近年来的一个主要焦点一直是从分子到细胞的尺度。然而，发育生物学和成像的进步，特别是在3D中分离和研究影响生物体发育的基因的能力，增加了从亚细胞到生物体层面在更大范围内采用系统方法的可能性。这些尺度之间的关键环节是生长，因为正是通过生长，分子变化导致细胞大小、形状和分裂的改变，最终导致多细胞组织和生物体的生产。生长结构可分为达到稳定状态的结构，如植物的生长尖端，以及形状不断变化的结构，如发育中的昆虫翅膀或植物叶片。后一种情况提出了捕捉多个相互作用的特殊挑战，因为结构在几个数量级上经历了形状和大小的变化。研究这一问题需要在多个层面上分析和整合生长、形状、图案和基因作用。此外，需要开发正式的语言和建模框架，以便能够捕捉动态和相互作用。通过在许多尺度上并行地追求这些方法，关键的实验和概念联系应该会出现，而这些联系不会从孤立地研究每个尺度中明显地显现出来。最近在实验和计算科学方面的进步使这一点成为可能。这个项目的目的是通过研究树叶获得其特有形状和图案的机制，为这种方法提供一个平台。该项目将涉及四个不同尺度的综合实验分析、图像处理、计算机建模和综合。(1)在亚细胞水平，我们将跟踪细胞骨架成分的合成方式，并在3D中并行变化。然后将构建模型来解释这种行为，并通过进一步的实验进行测试。这些模型还将与细胞属性相关。(2)在细胞水平上，将通过实时3D成像来确定正在生长的叶片的多个区域的细胞生长和分裂模式。将开发计算机语言，以基于生长细胞之间的局部相互作用来模拟这种行为。模型将通过修改叶片发育期间特定地点和时间的基因活动来进行测试。这些模型还将与整个器官水平的属性相关。(3)在器官层面，将使用各种成像方法跟踪3D叶片的生长。将开发一个模型框架，允许观察到的细胞和组织属性与基因作用相结合。模型将通过分析对局部基因活动的实验性操纵如何改变生长来进行测试。这将有助于开发一种系统，用于测量在不同发育阶段影响叶片形状的不同突变体集合的3D形状。(4)在整个植物水平上，叶片生长将被合并到一个虚拟植物中，其中模块之间的局部相互作用考虑了生长和结构的动态。通过将各种模型连接起来，应该会出现一个关于植物发展的综合的多尺度观点。该项目还将培训一批熟悉分子遗传学、发育生物学、生物成像、图像处理和计算机建模等学科的新科学家。

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.