Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
skip to main content
research-article

Fluigi: Microfluidic Device Synthesis for Synthetic Biology

Published: 30 December 2014 Publication History

Abstract

One goal of synthetic biology is to design and build genetic circuits in living cells for a range of applications. Our incomplete knowledge of the effects of metabolic load and biological “crosstalk” on the host cell make it difficult to construct multilevel genetic logic circuits in a single cell, limiting the scalability of engineered biological systems. Microfluidic technologies provide reliable and scalable construction of synthetic biological systems by allowing compartmentalization of cells encoding simple genetic circuits and the spatiotemporal control of communication among these cells. This control is achieved via valves on the microfluidics chip which restrict fluid flow when activated. We describe a Computer Aided Design (CAD) framework called “Fluigi” for optimizing the layout of genetic circuits on a microfluidic chip, generating the control sequence of the associated signaling fluid valves, and simulating the behavior of the configured biological circuits. We demonstrate the capabilities of Fluigi on a set of Boolean algebraic benchmark circuits found in both synthetic biology and electrical engineering and a set of assay-based benchmark circuits. The integration of microfluidics and synthetic biology has the capability to increase the scale of engineered biological systems for applications in DNA assembly, biosensors, and screening assays for novel orthogonal genetic parts.

References

[1]
Nada Amin, William Thies, and Saman Amarasinghe. 2009. Computer-aided design for microfluidic chips based on multilayer soft lithography. In Proceedings of the IEEE International Conference on Computer Design (ICCD'09). IEEE, 2--9.
[2]
Ernesto Andrianantoandro, Subhayu Basu, David K. Karig, and Ron Weiss. 2006. Synthetic biology: New engineering rules for an emerging discipline. Molec. Syst. Biol. 2, 1.
[3]
Frederick K. Balagaddé, Lingchong You, Carl L. Hansen, Frances H. Arnold, and Stephen R. Quake. 2005. Long-term monitoring of bacteria undergoing programmed population control in a microchemostat. Science 309, 5731, 137--140.
[4]
Subhayu Basu, Yoram Gerchman, Cynthia H. Collins, Frances H. Arnold, and Ron Weiss. 2005. A synthetic multicellular system for programmed pattern formation. Nature 434, 7037, 1130--1134.
[5]
Jacob Beal, Ting Lu, and Ron Weiss. 2011. Automatic compilation from high-level biologically-oriented programming language to genetic regulatory networks. PLoS One 6, 8, e22490.
[6]
Jacob Beal, Ron Weiss, Douglas Densmore, Aaron Adler, Evan Appleton, Jonathan Babb, Swapnil Bhatia, Noah Davidsohn, Traci Haddock, Joseph Loyall, et al. 2012. An end-to-end workflow for engineering of biological networks from high-level specifications. ACS Synthet. Biol. 1, 8, 317--331.
[7]
Vaughn Betz and Jonathan Rose. 1997. VPR: A new packing, placement, and routing tool for FPGA research. In Proceedings of the International Workshop on Field Programmable Logic and Appliation.
[8]
Jerome Bonnet, Pakpoom Subsoontorn, and Drew Endy. 2012. Rewritable digital data storage in live cells via engineered control of recombination directionality. Proc. Natl. Acad. Sci. 109, 23, 8884--8889.
[9]
Jennifer A. N. Brophy and Christopher A. Voigt. 2014. Principles of genetic circuit design. Nat. Meth. 11, 5, 508--520.
[10]
Yizhi Cai, Mandy L. Wilson, and Jean Peccoud. 2010. GenoCAD for iGEM: A grammatical approach to the design of standard-compliant constructs. Nucl. Acids Res. 38, 8, 2637--2644.
[11]
Barry Canton, Anna Labno, and Drew Endy. 2008. Refinement and standardization of synthetic biological parts and devices. Nat. Biotechnol. 26, 7, 787--793.
[12]
Krishnendu Chakrabarty. 2010. Design automation and test solutions for digital microfluidic biochips. IEEE Trans. Circ. Syst. I (Regular Papers), 57, 1. 4--17.
[13]
Krishnendu Chakrabarty and Jun Zeng. 2005. Design automation for microfluidics-based biochips. ACM J. Emerg. Technol. Comput. Syst. 1, 3, 186--223.
[14]
Deepak Chandran, Frank T. Bergmann, Herbert M. Sauro, et al. 2009. TinkerCell: Modular CAD tool for synthetic biology. J. Biol. Eng. 3, 1, 19.
[15]
Ramiz Daniel, Jacob R. Rubens, Rahul Sarpeshkar, and Timothy K. Lu. 2013. Synthetic analog computation in living cells. Nature 497, 619--623.
[16]
Tal Danino, Octavio Mondragón-Palomino, Lev Tsimring, and Jeff Hasty. 2010. A synchronized quorum of genetic clocks. Nature 463, 7279, 326--330.
[17]
Giovanni De Micheli. 1994. Synthesis and Optimization of Digital Circuits. McGraw-Hill Higher Education.
[18]
Stephan K. W. Dertinger, Daniel T. Chiu, Noo Li Jeon, and George M. Whitesides. 2001. Generation of gradients having complex shapes using microfluidic networks. Anal. Chem. 73, 6, 1240--1246.
[19]
David C. Duffy, J. Cooper McDonald, Olivier J. A. Schueller, and George M. Whitesides. 1998. Rapid prototyping of microfluidic systems in poly (dimethylsiloxane). Anal. Chem. 70, 23, 4974--4984.
[20]
Carl Ebeling, Larry McMurchie, Scott A. Hauck, and Steven Burns. 1995. Placement and routing tools for the triptych FPGA. IEEE Trans. VLSI 473--482.
[21]
Michael B. Elowitz and Stanislas Leibler. 2000. A synthetic oscillatory network of transcriptional regulators. Nature 403, 6767, 335--338.
[22]
Drew Endy. 2005. Foundations for engineering biology. Nature 438, 7067, 449--453.
[23]
M. S. Ferry, I. A. Razinkov, and J. Hasty. 2011. Microfluidics for synthetic biology from design to execution. Meth. Enzymol. 497 (2011), 295.
[24]
Ashish Gehani and John Reif. 1999. Micro flow bio-molecular computation. Biosystems 52, 1, 197--216.
[25]
S. Hassoun and T. Sasao. 2002. Logic Synthesis and Verification. Springer US. http://books.google.com/books?id=qfIFQu4o0AMC.
[26]
J. P. Hayes. 1993. Digital Logic Design. Addison-Wescley.
[27]
Haiyao Huang and Douglas Densmore. 2014. Integration of microfluidics into the synthetic biology design flow. Lab on a Chip.
[28]
Ahmad S. Khalil, Timothy K. Lu, Caleb J. Bashor, Cherie L. Ramirez, Nora C. Pyenson, J. Keith Joung, and James J. Collins. 2012. A synthetic biology framework for programming eukaryotic transcription functions. Cell 150, 3, 647--658.
[29]
Stefan Klumpp, Zhongge Zhang, and Terence Hwa. 2009. Growth rate-dependent global effects on gene expression in bacteria. Cell 139, 7, 1366--1375.
[30]
Benjamin Lin and Andre Levchenko. 2012. Microfluidic technologies for studying synthetic circuits. Curr. Opin. Chem. Biol. 16, 3, 307--317.
[31]
Wenming Liu, Li Li, Xuming Wang, Li Ren, Xueqin Wang, Jianchun Wang, Qin Tu, Xiaowen Huang, and Jinyi Wang. 2010. An integrated microfluidic system for studying cell-microenvironmental interactions versatilely and dynamically. Lab on a Chip 10, 13, 1717--1724.
[32]
Michael S. Livstone, Ron Weiss, and Laura F. Landweber. 2006. Automated design and programming of a microfluidic DNA computer. Nat. Comput. 5, 1, 1--13.
[33]
James C. W. Locke and Michael B. Elowitz. 2009. Using movies to analyse gene circuit dynamics in single cells. Nat. Rev. Microbiol. 7, 5, 383--392.
[34]
Timothy K. Lu. 2010. Engineering scalable biological systems. Bioeng. Bugs 1, 6, 378--384.
[35]
Javier Macía, Francesc Posas, and Ricard V. Solé. 2012. Distributed computation: the new wave of synthetic biology devices. Trends Biotechnol. 30, 6, 342--349.
[36]
Daniel Mark, Stefan Haeberle, Günter Roth, Felix von Stetten, and Roland Zengerle. 2010. Microfluidic lab-on-a-chip platforms: Requirements, characteristics and applications. Chem. Soc. Rev. 39, 3, 1153--1182.
[37]
Wajid Hassan Minhass, Paul Pop, Jan Madsen, and Felician Stefan Blaga. 2012. Architectural synthesis of flow-based microfluidic large-scale integration biochips. In Proceedings of the International Conference on Compilers, Architectures and Synthesis for Embedded Systems. ACM, 181--190.
[38]
Wajid Hassan Minhass, Paul Pop, Jan Madsen, and Tsung-Yi Ho. 2013. Control synthesis for the flow-based microfluidic large-scale integration biochips. In Proceedings of the 18th Asia and South Pacific Design Automation Conference (ASP-DAC'13). 205--212.
[39]
Tae Seok Moon, Chunbo Lou, Alvin Tamsir, Brynne C. Stanton, and Christopher A. Voigt. 2012. Genetic programs constructed from layered logic gates in single cells. Nature 491, 7423, 249--253.
[40]
Lior Nissim and Roy H. Bar-Ziv. 2010. A tunable dual-promoter integrator for targeting of cancer cells. Molec. Syst. Biol. 6, 1.
[41]
Arthur Prindle, Phillip Samayoa, Ivan Razinkov, Tal Danino, Lev S. Tsimring, and Jeff Hasty. 2012. A sensing array of radically coupled genetic “biopixels”. Nature 481, 7379, 39--44.
[42]
Priscilla E. M. Purnick and Ron Weiss. 2009. The second wave of synthetic biology: from modules to systems. Nat. Rev. Molec. Cell Biol. 10, 6 (2009). 410--422.
[43]
Sergi Regot, Javier Macia, Núria Conde, Kentaro Furukawa, Jimmy Kjellén, Tom Peeters, Stefan Hohmann, Eulàlia de Nadal, Francesc Posas, and Ricard Solé. 2011. Distributed biological computation with multicellular engineered networks. Nature 469, 7329, 207--211.
[44]
Warren C. Ruder, Ting Lu, and James J. Collins. 2011. Synthetic biology moving into the clinic. Science 333, 6047, 1248--1252.
[45]
Sumitra Shankar and M. Radhakrishna Pillai. 2011. Translating cancer research by synthetic biology. Molec. BioSyst. 7, 6, 1802--1810.
[46]
Samuel K. Sia and George M. Whitesides. 2003. Microfluidic devices fabricated in poly (dimethylsiloxane) for biological studies. Electrophoresis 24, 21, 3563--3576.
[47]
Fei Su and Krishnendu Chakrabarty. 2005. Design of fault-tolerant and dynamically-reconfigurable microfluidic biochips. In Proceedings of the Symposium on Design, Automation and Test in Europe, 2005. IEEE. 1202--1207.
[48]
Fei Su, Krishnendu Chakrabarty, and Richard B. Fair. 2006. Microfluidics-based biochips: technology issues, implementation platforms, and design-automation challenges. Comput. Aid. Des. Integ. Circ. Syst. IEEE Trans. 25, 2, 211--223.
[49]
Alvin Tamsir, Jeffrey J. Tabor, and Christopher A. Voigt. 2011. Robust multicellular computing using genetically encoded NOR gates and chemical “wires”. Nature 469, 7329, 212--215.
[50]
William Thies, John Paul Urbanski, Todd Thorsen, and Saman Amarasinghe. 2008. Abstraction layers for scalable microfluidic biocomputing. Nat. Comput. 7, 2, 255--275.
[51]
William Thies, John Paul Urbanski, Todd Thorsen, and Saman Amarasinghe. 2009. Programable microfluidics. http://groups.csail.mit.edu/cag/biostream/. (Accessed: 2014-06-17.)
[52]
Todd Thorsen, Sebastian J. Maerkl, and Stephen R. Quake. 2002. Microfluidic large-scale integration. Science 298, 5593, 580--584.
[53]
Marc A. Unger, Hou-Pu Chou, Todd Thorsen, Axel Scherer, and Stephen R. Quake. 2000. Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288, 5463, 113--116.
[54]
John Paul Urbanski, William Thies, Christopher Rhodes, Saman Amarasinghe, and Todd Thorsen. 2006. Digital microfluidics using soft lithography. Lab on a Chip 6, 1, 96--104.
[55]
Christopher A. Voigt. 2006. Genetic parts to program bacteria. Curr. Opin. Biotechnol. 17, 5, 548--557.
[56]
C. Joanne Wang, Adriel Bergmann, Benjamin Lin, Kyuri Kim, and Andre Levchenko. 2012. Diverse sensitivity thresholds in dynamic signaling responses by social amoebae. Sci. Signal. 5, 213, ra17.
[57]
N. H. E. Weste and D. M. Harris. 2011. CMOS VLSI Design: A Circuits and Systems Perspective. Addison-Wesley Publishing Company, http://books.google.com/books?id=sv8OQgAACAAJ.
[58]
Bing Xia, Swapnil Bhatia, Ben Bubenheim, Maisam Dadgar, Douglas Densmore, and J. Christopher Anderson. 2011. Developers and users guide to Clotho v2. 0 A software platform for the creation of synthetic biological systems. Meth. Enzymol 498, 97--135.

Cited By

View all
  • (2024)Design automation of microfluidic single and double emulsion droplets with machine learningNature Communications10.1038/s41467-023-44068-315:1Online publication date: 2-Jan-2024
  • (2022)Hardware, Software, and Wetware Codesign Environment for Synthetic BiologyBioDesign Research10.34133/2022/97945102022Online publication date: Jan-2022
  • (2021)Machine learning enables design automation of microfluidic flow-focusing droplet generationNature Communications10.1038/s41467-020-20284-z12:1Online publication date: 4-Jan-2021
  • Show More Cited By

Index Terms

  1. Fluigi: Microfluidic Device Synthesis for Synthetic Biology

    Recommendations

    Comments

    Information & Contributors

    Information

    Published In

    cover image ACM Journal on Emerging Technologies in Computing Systems
    ACM Journal on Emerging Technologies in Computing Systems  Volume 11, Issue 3
    Special Issue on Computational Synthetic Biology and Regular Papers
    December 2014
    219 pages
    ISSN:1550-4832
    EISSN:1550-4840
    DOI:10.1145/2711453
    Issue’s Table of Contents
    Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than the author(s) must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected].

    Publisher

    Association for Computing Machinery

    New York, NY, United States

    Journal Family

    Publication History

    Published: 30 December 2014
    Accepted: 01 August 2014
    Revised: 01 June 2014
    Received: 01 January 2014
    Published in JETC Volume 11, Issue 3

    Permissions

    Request permissions for this article.

    Check for updates

    Author Tags

    1. Synthetic biology
    2. genetic circuits
    3. microfluidics

    Qualifiers

    • Research-article
    • Research
    • Refereed

    Funding Sources

    • Clare Booth Luce Graduate Fellowship

    Contributors

    Other Metrics

    Bibliometrics & Citations

    Bibliometrics

    Article Metrics

    • Downloads (Last 12 months)24
    • Downloads (Last 6 weeks)2
    Reflects downloads up to 02 Sep 2024

    Other Metrics

    Citations

    Cited By

    View all
    • (2024)Design automation of microfluidic single and double emulsion droplets with machine learningNature Communications10.1038/s41467-023-44068-315:1Online publication date: 2-Jan-2024
    • (2022)Hardware, Software, and Wetware Codesign Environment for Synthetic BiologyBioDesign Research10.34133/2022/97945102022Online publication date: Jan-2022
    • (2021)Machine learning enables design automation of microfluidic flow-focusing droplet generationNature Communications10.1038/s41467-020-20284-z12:1Online publication date: 4-Jan-2021
    • (2020)Computer-Aided Design of Microfluidic CircuitsAnnual Review of Biomedical Engineering10.1146/annurev-bioeng-082219-03335822:1(285-307)Online publication date: 4-Jun-2020
    • (2020)Domain-Specific Programming Languages for Computational Nucleic Acid SystemsACS Synthetic Biology10.1021/acssynbio.0c000509:7(1499-1513)Online publication date: 26-Jun-2020
    • (2019)3DμF - Interactive Design Environment for Continuous Flow Microfluidic DevicesScientific Reports10.1038/s41598-019-45623-z9:1Online publication date: 24-Jun-2019
    • (2018)Computer-aided design of resistance micro-fluidic circuits for 3D printingComputer-Aided Design10.1016/j.cad.2017.12.00498:C(12-23)Online publication date: 1-May-2018
    • (2017)Scheduling and optimization of genetic logic circuits on flow-based microfluidic biochipsProceedings of the Conference on Design, Automation & Test in Europe10.5555/3130379.3130799(1809-1814)Online publication date: 27-Mar-2017
    • (2017)Scheduling and optimization of genetic logic circuits on flow-based microfluidic biochipsDesign, Automation & Test in Europe Conference & Exhibition (DATE), 201710.23919/DATE.2017.7927285(1805-1810)Online publication date: Mar-2017
    • (2017)Design Automation in Synthetic BiologyCold Spring Harbor Perspectives in Biology10.1101/cshperspect.a0239789:4(a023978)Online publication date: 28-Feb-2017

    View Options

    Get Access

    Login options

    Full Access

    View options

    PDF

    View or Download as a PDF file.

    PDF

    eReader

    View online with eReader.

    eReader

    Media

    Figures

    Other

    Tables

    Share

    Share

    Share this Publication link

    Share on social media