CAREER: Artificial Pattern Formation with Synthetic Gene Networks

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Biological pattern formation is an elaborate process that requires spatiotemporal coordination of cellular activities. To-date, research has focused on studying naturally occurring patterns either by devising abstract models that explain the formation of these patterns or by characterizing relevant genetic circuits and biochemical interactions. The knowledge gained from understanding how cells form patterns has practical applications in tissue engineering, biosensing, and biomaterial fabrication. However, to fully realize the potential of these applications one must be able to form arbitrary patterns, e.g. tissues with new arrangements of cells. Existing efforts to coerce cells to form particular patterns have largely focused on setting up scaffolds and appropriate environmental conditions, but such efforts are limited because they rely on the cells' existing genetic circuitry. The approach in this project is fundamentally different: the focus is to engineer de novo patterns by building synthetic gene networks and in the process gain a greater understanding of pattern formation. The project strives to create a new engineering discipline for generating user-specified artificial differentiation patterns. The main component of this discipline is the tight integration of modeling tools with experimental work. Based on these models, novel genetic circuits will be built and validated experimentally. These circuits will direct cells to form stable and dynamic spatiotemporal gene expression patterns - lines, standing waves, Turing Patterns, Conway's Game of Life, and branched structures. Results from the project will serve as the basis for a pattern formation toolkit that will be used to engineer more complex patterns, enable future applications, and elucidate the underlying principles governing natural pattern formation. The research outlined here will have a broad impact both in academia and industry. This project will advance knowledge in a number of important areas in systems biology including the understanding of robust gene networks, noise in gene expression, gene regulation, cell-cell communications, in addition to providing mathematical models for intracellular and intercellular systems. Research in multicellular pattern formation is not only fundamental to understanding organism development and coordinated cell behavior, but also has practical applications. For example, micro-pattern formation will benefit nanotechnology where such patterns could be used for bacterial nano-fabrication. Also, the ability to construct synthetic patterns will contribute to the field of tissue engineering, where such patterns could be utilized to differentiate stem cells into tissues and organs. In the long term, knowledge gained from this research into the coordination of cell behaviors will be applicable to areas outside of biology, including the design of robust multi-agent systems such as computer networks. Perhaps the most important contribution will be through the multidisciplinary education of students and future leaders in the field. This will be accomplished through various activities including the Burroughs Wellcome Fund and the Synthetic Biology Summer Program, where the focus is on recruiting and providing specific funding for underrepresented minorities and women.