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ArticlesTowards programming languages for genetic engineering of living cells
Published:15 April 2009https://doi.org/10.1098/rsif.2008.0516.focus
Abstract
Synthetic biology aims at producing novel biological systems to carry out some desired and well-defined functions. An ultimate dream is to design these systems at a high level of abstraction using engineering-based tools and programming languages, press a button, and have the design translated to DNA sequences that can be synthesized and put to work in living cells. We introduce such a programming language, which allows logical interactions between potentially undetermined proteins and genes to be expressed in a modular manner. Programs can be translated by a compiler into sequences of standard biological parts, a process that relies on logic programming and prototype databases that contain known biological parts and protein interactions. Programs can also be translated to reactions, allowing simulations to be carried out. While current limitations on available data prevent full use of the language in practical applications, the language can be used to develop formal models of synthetic systems, which are otherwise often presented by informal notations. The language can also serve as a concrete proposal on which future language designs can be discussed, and can help to guide the emerging standard of biological parts which so far has focused on biological, rather than logical, properties of parts.
References
Afif H., Allali N., Couturier M.& Van Melderen L. . 2001The ratio between ccda and ccdb modulates the transcriptional repression of the ccd poison-antidote system. Mol. Microbiol. 41, 73–82. (doi:10.1046/j.1365-2958.2001.02492.x). Crossref, PubMed, ISI, Google ScholarAndrianantoandro E., Basu S., Karig D.& Weiss R. . 2006Synthetic biology: new engineering rules for an emerging discipline. Mol. Syst. Biol. 2, 2006.0028. (doi:10.1038/msb4100073). Crossref, PubMed, ISI, Google ScholarApt K. R.& Wallace M. G. . 2007Constraint logic programming using ECLiPSe. Cambridge, UK: Cambridge University Press. Google ScholarBalagaddé F., Song H., Ozaki J., Collins C., Barnet M., Arnold F., Quake S.& You L. . 2008A synthetic Escherichia coli predator–prey ecosystem. Mol. Syst. Biol. 4, 187. (doi:10.1038/msb.2008.24). Crossref, PubMed, ISI, Google ScholarBergmann F. T.& Sauro H. M. . 2006SBW—a modular framework for systems biology.WSC '06: Proc. 38th Conf. on Winter Simulation , pp. 1637–1645. Crossref, Google ScholarBlossey R., Cardelli L.& Phillips A. . 2008Compositionality, stochasticity and cooperativity in dynamic models of gene regulation. HFSP J. 2, 17–28. (doi:10.2976/1.2804749). Crossref, PubMed, Google ScholarBornstein B. J., Keating S. M., Jouraku A.& Hucka M. . 2008LibSBML: an API library for SBML. Bioinformatics. 24, 880–881. (doi:10.1093/bioinformatics/btn051). Crossref, PubMed, ISI, Google ScholarBuchler N. E., Gerland U.& Hwa T. . 2003On schemes of combinatorial transcription logic. Proc. Natl Acad. Sci. USA. 100, 5136–5141. (doi:10.1073/pnas.0930314100). Crossref, PubMed, ISI, Google ScholarCai Y., Hartnett B., Gustafsson C.& Peccoud J. . 2007A syntactic model to design and verify synthetic genetic constructs derived from standard biological parts. Bioinformatics. 23, 2760–2767. (doi:10.1093/bioinformatics/btm446). Crossref, PubMed, ISI, Google ScholarChabrier-Rivier N., Fages F.& Soliman S. . 2004The biochemical abstract machine BIOCHAM.Proc. CMSB , vol. 3082 (eds, Danos V.& Schächter V. ). Lecture Notes in Computer Science, pp. 172–191. Berlin, Germany: Springer. Google ScholarCiocchetta F.& Hillston J. . 2008Bio-pepa: an extension of the process algebra pepa for biochemical networks. Electron. Notes Theor. Comput. Sci. 194, 103–117. (doi:10.1016/j.entcs.2007.12.008). Crossref, Google ScholarCox R. S., Surette M. G.& Elowitz M. B. . 2007Programming gene expression with combinatorial promoters. Mol. Syst. Biol. 3, 145> (doi:10.1038/msb4100187). Crossref, PubMed, ISI, Google ScholarDanos V., Feret J., Fontana W., Harmer R.& Krivine J. . 2007Rule-based modelling of cellular signalling. CONCUR, vol. 4703 (eds, Caires L.& Vasconcelos V. T. ). Lecture Notes in Computer Science, pp. 17–41. Berlin, Germany: Springer. Tutorial paper. Google ScholarElowitz M. B.& Leibler S. . 2000A synthetic oscillatory network of transcriptional regulators. Nature. 403, 335–338. (doi:10.1038/35002125). Crossref, PubMed, ISI, Google ScholarEndy D. . 2005Foundations for engineering biology. Nature. 438, 449–453. (doi:10.1038/nature04342). Crossref, PubMed, ISI, Google ScholarFisher J.& Henzinger T. . 2007Executable cell biology. Nat. Biotechnol. 25, 1239–1249. (doi:10.1038/nbt1356). Crossref, PubMed, ISI, Google ScholarGarfinkel D. . 1968A machine-independent language for the simulation of complex chemical and biochemical systems. Comput. Biomed. Res. 2, 31–44. (doi:10.1016/0010-4809(68)90006-2). Crossref, PubMed, Google ScholarHermsen R., Tans S.& Wolde P. R. . 2006Transcriptional regulation by competing transcription factor modules. PLoS Comput. Biol. 2, 1552–1560. (doi:10.1371/journal.pcbi.0020164). Crossref, ISI, Google ScholarHucka M., 2003The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics. 19, 524–531. (doi:10.1093/bioinformatics/btg015). Crossref, PubMed, ISI, Google ScholarMallavarapu A., Thomson M., Ullian B.& Gunawardena J. . 2009Programming with models: modularity and abstraction provide powerful capabilities for systems biology. J. R. Soc. Interface. 6, 257–270. (doi:10.1098/rsif.2008.0205). Link, ISI, Google ScholarMarchisio M. A.& Stelling J. . 2008Computational design of synthetic gene circuits with composable parts. Bioinformatics. 24, 1903–1910. (doi:10.1093/bioinformatics/btn330). Crossref, PubMed, ISI, Google ScholarMarguet P., Balagadde F., Tan C.& You L. . 2007Biology by design: reduction and synthesis of cellular components and behaviour. J. R. Soc. Interface. 4, 607–623. (doi:10.1098/rsif.2006.0206). Link, ISI, Google ScholarPedersen M.& Plotkin G. . 2008A language for biochemical systems. Proc. CMSB (eds, Heiner M.& Uhrmacher A. M. ). Lecture Notes in Computer Science. Berlin, Germany: Springer. Google ScholarRegev A., Silverman W.& Shapiro E. . 2001Representation and simulation of biochemical processes using the pi-calculus process algebra. Pacific Symp. on Biocomputing, pp. 459–470. Google ScholarSauro H. . 2000Jarnac: a system for interactive metabolic analysis.Animating the cellular map: Proc. 9th Int. Meeting on BioThermoKinetics (eds, Hofmeyr J.-H., Rohwer J.& Snoep J. ), pp. 221–228. Stellenbosch, Republic of South Africa: Stellenbosch University Press. Google ScholarShrager J., Waldinger R., Stickel M.& Massar J. . 2007Deductive biocomputing. PLoS ONE. 2, e339. (doi:10.1371/journal.pone.0000339). Crossref, PubMed, ISI, Google Scholar