Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 330 (6008): 1251-1255

Copyright © 2010 by the American Association for the Advancement of Science

Reprogramming Cellular Behavior with RNA Controllers Responsive to Endogenous Proteins

Stephanie J. Culler,1 Kevin G. Hoff,1 Christina D. Smolke1,2,*

Abstract: Synthetic genetic devices that interface with native cellular pathways can be used to change natural networks to implement new forms of control and behavior. The engineering of gene networks has been limited by an inability to interface with native components. We describe a class of RNA control devices that overcome these limitations by coupling increased abundance of particular proteins to targeted gene expression events through the regulation of alternative RNA splicing. We engineered RNA devices that detect signaling through the nuclear factor {kappa}B and Wnt signaling pathways in human cells and rewire these pathways to produce new behaviors, thereby linking disease markers to noninvasive sensing and reprogrammed cellular fates. Our work provides a genetic platform that can build programmable sensing-actuation devices enabling autonomous control over cellular behavior.

1 Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, MC 210-41, California Institute of Technology, Pasadena, CA 91125, USA.
2 Department of Bioengineering, 473 Via Ortega, MC 4201, Stanford University, Stanford, CA 94305, USA.

* To whom correspondence should be addressed. E-mail: csmolke{at}

Biomedically relevant circuit-design strategies in mammalian synthetic biology.
W. Bacchus, D. Aubel, and M. Fussenegger (2014)
Mol Syst Biol 9, 691
   Abstract »    Full Text »    PDF »
Dynamically Reshaping Signaling Networks to Program Cell Fate via Genetic Controllers.
K. E. Galloway, E. Franco, and C. D. Smolke (2013)
Science 341, 1235005
   Abstract »    Full Text »    PDF »
Quantitative and simultaneous translational control of distinct mammalian mRNAs.
K. Endo, J. A. Stapleton, K. Hayashi, H. Saito, and T. Inoue (2013)
Nucleic Acids Res. 41, e135
   Abstract »    Full Text »    PDF »
Concise Review: New Paradigms for Down Syndrome Research Using Induced Pluripotent Stem Cells: Tackling Complex Human Genetic Disease.
J. A. Briggs, E. A. Mason, D. A. Ovchinnikov, C. A. Wells, and E. J. Wolvetang (2013)
Stem Cells Trans Med 2, 175-184
   Abstract »    Full Text »    PDF »
Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome.
H. Ye, G. Charpin-El Hamri, K. Zwicky, M. Christen, M. Folcher, and M. Fussenegger (2013)
PNAS 110, 141-146
   Abstract »    Full Text »    PDF »
A high-throughput, quantitative cell-based screen for efficient tailoring of RNA device activity.
J. C. Liang, A. L. Chang, A. B. Kennedy, and C. D. Smolke (2012)
Nucleic Acids Res. 40, e154
   Abstract »    Full Text »    PDF »
A global sampling approach to designing and reengineering RNA secondary structures.
A. Levin, M. Lis, Y. Ponty, C. W. O'Donnell, S. Devadas, B. Berger, and J. Waldispuhl (2012)
Nucleic Acids Res. 40, 10041-10052
   Abstract »    Full Text »    PDF »
Three-dimensionally designed protein-responsive RNA devices for cell signaling regulation.
S. Kashida, T. Inoue, and H. Saito (2012)
Nucleic Acids Res. 40, 9369-9378
   Abstract »    Full Text »    PDF »
De novo automated design of small RNA circuits for engineering synthetic riboregulation in living cells.
G. Rodrigo, T. E. Landrain, and A. Jaramillo (2012)
PNAS 109, 15271-15276
   Abstract »    Full Text »    PDF »
A mechanical Turing machine: blueprint for a biomolecular computer.
E. Shapiro (2012)
Interface Focus 2, 497-503
   Abstract »    Full Text »    PDF »
Engineering naturally occurring trans-acting non-coding RNAs to sense molecular signals.
L. Qi, J. B. Lucks, C. C. Liu, V. K. Mutalik, and A. P. Arkin (2012)
Nucleic Acids Res. 40, 5775-5786
   Abstract »    Full Text »    PDF »
Transgene regulation in plants by alternative splicing of a suicide exon.
S. F. Hickey, M. Sridhar, A. J. Westermann, Q. Qin, P. Vijayendra, G. Liou, and M. C. Hammond (2012)
Nucleic Acids Res. 40, 4701-4710
   Abstract »    Full Text »    PDF »
Rational design of a small molecule-responsive intramer controlling transgene expression in mammalian cells.
D. Auslander, M. Wieland, S. Auslander, M. Tigges, and M. Fussenegger (2011)
Nucleic Acids Res. 39, e155
   Abstract »    Full Text »    PDF »
From DNA to Targeted Therapeutics: Bringing Synthetic Biology to the Clinic.
Y. Y. Chen and C. D. Smolke (2011)
Science Translational Medicine 3, 106ps42
   Full Text »    PDF »
Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells.
Z. Xie, L. Wroblewska, L. Prochazka, R. Weiss, and Y. Benenson (2011)
Science 333, 1307-1311
   Abstract »    Full Text »    PDF »
Bringing It Together with RNA.
K. Thodey and C. D. Smolke (2011)
Science 333, 412-413
   Abstract »    Full Text »    PDF »
Engineering ligand-responsive RNA controllers in yeast through the assembly of RNase III tuning modules.
A. H. Babiskin and C. D. Smolke (2011)
Nucleic Acids Res. 39, 5299-5311
   Abstract »    Full Text »    PDF »
A Synthetic Optogenetic Transcription Device Enhances Blood-Glucose Homeostasis in Mice.
H. Ye, M. D.-E. Baba, R.-W. Peng, and M. Fussenegger (2011)
Science 332, 1565-1568
   Abstract »    Full Text »    PDF »
A New Approach to an Old Problem: Synthetic Biology Tools for Human Disease and Metabolism.
D. R. Burrill, P. M. Boyle, and P. A. Silver (2011)
Cold Spring Harb Symp Quant Biol 76, 145-154
   Abstract »    Full Text »    PDF »
The Case for RNA.
C. C. Liu and A. P. Arkin (2010)
Science 330, 1185-1186
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882