Synthetic biology will fundamentally change the nature of molecular medicine, as human engineers learn how to build and program cells. These forward engineering efforts will help us understand developmental processes and use that understanding for tissue engineering, biofabrication, biosensing, and more. The reality, however, is currently less exciting than the dream: programming cell behavior poses huge technical and conceptual challenges. The proposed research is designed to take important first steps towards engineering intercellular communications pathways and coordinating gene expression and behavior across cell populations. These synthetic communications systems utilize natural components from bacterial 'quorum-sensing' systems, but assemble them in new ways to allow human control over how a population develops and eventually what it does. The coordinated activity of many cells is often required for complex biological behaviors, including development, biofilm formation, or swarm behaviors. Each cell interacts with its neighbors according to simple local rules, and collectively these interactions yield the desired global spatiotemporal actions. The ultimate aim of the proposed work is to build a synthetic bacterial system that exhibits such a capability, entirely programmed in a synthetic circuit. Towards this goal, the research will also build the framework for engineering intercellular communications networks, including appropriate mathematical descriptions of signal diffusion and cellular responses, as well as novel components that will allow cells to sense and respond to multiple chemical signals. Specific communications components and sub-circuits developed in this research are anticipated to be transferable to other organisms, including mammalian cells. This collaborative project is unique in combining 'rational' design principles gleaned from decades of computer engineering and biological research with laboratory evolution, which can fine-tune rough human designs and make smoothly-functioning synthetic communications networks. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM074712-01A1
Application #
7099950
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Anderson, James J
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$461,572
Indirect Cost
Name
Princeton University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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Tracewell, Cara A; Arnold, Frances H (2009) Directed enzyme evolution: climbing fitness peaks one amino acid at a time. Curr Opin Chem Biol 13:3-9
Brenner, Katie; Karig, David K; Weiss, Ron et al. (2007) Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proc Natl Acad Sci U S A 104:17300-4
Collins, Cynthia H; Leadbetter, Jared R; Arnold, Frances H (2006) Dual selection enhances the signaling specificity of a variant of the quorum-sensing transcriptional activator LuxR. Nat Biotechnol 24:708-12