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Integrating Models and Experiments: Synthetic Ecosystems and Molecular Switches

GRADUATE SEMINARIntegrating Models and Experiments: Synthetic Ecosystems and Molecular SwitchesDr. Xiaoxia (Nina) Lin
Harvard Medical SchoolABSTRACTIn this talk, I will focus on two of my current projects that aim to advance our understanding of important biological processes through a systems biology and synthetic biology approach.
1. Construction and evolution of synthetic microbial symbiotic systems. Mutualistic symbiosis exists widely in nature. It is of fundamental importance to understand its origin, evolution, and the principles of its working. A synthetic system would be ideal for such study, as it would allow us to focus on relevant features by simplifying the system and make precise measurements that are difficult for much more complicated natural mutualistic ecosystems. We engineered a microbial symbiotic system that consists of two cross-feeding E. coli amino acid auxotrophs and investigated its evolutionary adaptation in minimal medium in serial batch cultures. We observed that different lineages all showed an overall trend of improving fitness. Interestingly, the growth rate did decrease occasionally. To identify the genetic basis for the observed mutualistic adaptation, we utilized new polony based whole-genome sequencing technology to analyze an isolated clone of one of the auxotrophs after 40 rounds of passaging in the evolution and pindowned a number of relevant mutations. We also developed an ordinary differential equation (ODE) model to investigate the dynamics of the system, which has provided important insights into the interactions between the two auxotrophs.
2. Mechanisms of biological switching through multi-site modifications of single molecules. A widespread feature of biological systems is their switch-like response to external or internal signals, also termed ultrasensitivity, which is crucial for the regulation of numerous biological processes. Multi-site modifications of single molecules have been known to contribute to ultrasensitivity. However, the underlying mechanism has largely remained unclear. We proposed a new mathematical model that describes how ultrasensitivity can emerge at a system level through multi-site modifications of a single protein. The fundamental features include: i) a chain of different phosphorylation states of the substrate protein caused by not-fully processive kinase/phosphatase; and ii) change of substrate protein activities along the phosphorylation chain. We have further quantitatively characterized how the degree of ultrasensitivity is affected by various properties of a multi-site system. The proposed model is capable of explaining mechanistically the switch-like behavior of many biological systems and the revealed mechanism may constitute a major paradigm for achieving biological switching.
Finally, I will discuss my future research plan. The directions in which I would like to continue and expand my current research include: 1) mechanisms of multi-site based ultrasensitivity; 2) engineering of genetic circuits; and 3) system-level modeling and engineering of micro-organisms.Wednesday, March 1, 2006
12 noon – SGM 101
The Scientific Community is Cordially Invited

Location: Seeley G. Mudd Building (SGM) - 101

Audiences: Everyone Is Invited

Contact: Petra Pearce