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Young Innovator Speaker Series

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Lingchong You, an assistant professor in the Department of Biomedical Engineering at Duke University, speaks on "Biology by Design: Reduction and Synthesis of Cellular Networks."Abstract: Research in our group aims to decode "design principles" of cellular networks by analyzing naturally existing networks and by creating artificial ones. In this talk, I will present two examples to illustrate these efforts. I will first discuss the analysis of signaling dynamics involved in mammalian cell cycle entry. By integrating single-cell measurements and modeling, we have demonstrated that the cell cycle entry is mediated by a bistable Myc/Rb/E2F switch: Once turned-on, as characterized by the activation of E2F, this switch can trigger cell cycle entry in an "all-or-none" manner; it will then stay on to drive cells through the proliferation cycle even after growth stimuli are removed. This bistability provides an intuitive explanation for the concept of restriction point. Further analysis, by taking advantage of viral-mediated noisy gene expression, indicates that this network has the ability to generate biphasic E2F response upon strong Myc stimulation. This property defines a safeguard mechanism to limit cell proliferation in the presence of aberrant growth stimulation; its dysregulation may have implications in tumor development. As another example, I will discuss a synthetic gene circuit that was initially inspired by the cell-cycle study. This circuit consists of a mutant T7 RNA polymerase (T7 RNAP*) that activates its own expression in bacterium Escherichia coli. Although activation by the T7 RNAP* is non-cooperative, the circuit caused bistable gene expression. This counterintuitive observation can be explained by growth retardation caused by circuit activation, which resulted in nonlinear dilution of T7 RNAP* in individual bacteria. Predictions made by models accounting for such effects were verified by further experimental measurements. Our results reveal a novel mechanism to generate bistability and underscore the need to account for host physiology modulation when engineering gene circuits.

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  • Workflow Status: Published
  • Created By: Michael Hagearty
  • Created: 02/24/2010
  • Modified By: Fletcher Moore
  • Modified: 10/07/2016

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