Systems approaches for synthetic biology: a pathway toward mammalian design
Identifieur interne : 000541 ( Pmc/Corpus ); précédent : 000540; suivant : 000542Systems approaches for synthetic biology: a pathway toward mammalian design
Auteurs : Rahul Rekhi ; Amina A. QutubSource :
- Frontiers in Physiology [ 1664-042X ] ; 2013.
Abstract
We review methods of understanding cellular interactions through computation in order to guide the synthetic design of mammalian cells for translational applications, such as regenerative medicine and cancer therapies. In doing so, we argue that the challenges of engineering mammalian cells provide a prime opportunity to leverage advances in computational systems biology. We support this claim systematically, by addressing each of the principal challenges to existing synthetic bioengineering approaches—stochasticity, complexity, and scale—with specific methods and paradigms in systems biology. Moreover, we characterize a key set of diverse computational techniques, including agent-based modeling, Bayesian network analysis, graph theory, and Gillespie simulations, with specific utility toward synthetic biology. Lastly, we examine the mammalian applications of synthetic biology for medicine and health, and how computational systems biology can aid in the continued development of these applications.
Url:
DOI: 10.3389/fphys.2013.00285
PubMed: 24130532
PubMed Central: 3793170
Links to Exploration step
PMC:3793170Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Systems approaches for synthetic biology: a pathway toward mammalian design</title><author><name sortKey="Rekhi, Rahul" sort="Rekhi, Rahul" uniqKey="Rekhi R" first="Rahul" last="Rekhi">Rahul Rekhi</name></author><author><name sortKey="Qutub, Amina A" sort="Qutub, Amina A" uniqKey="Qutub A" first="Amina A." last="Qutub">Amina A. Qutub</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24130532</idno><idno type="pmc">3793170</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793170</idno><idno type="RBID">PMC:3793170</idno><idno type="doi">10.3389/fphys.2013.00285</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000541</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Systems approaches for synthetic biology: a pathway toward mammalian design</title><author><name sortKey="Rekhi, Rahul" sort="Rekhi, Rahul" uniqKey="Rekhi R" first="Rahul" last="Rekhi">Rahul Rekhi</name></author><author><name sortKey="Qutub, Amina A" sort="Qutub, Amina A" uniqKey="Qutub A" first="Amina A." last="Qutub">Amina A. Qutub</name></author></analytic><series><title level="j">Frontiers in Physiology</title><idno type="eISSN">1664-042X</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We review methods of understanding cellular interactions through computation in order to guide the synthetic design of mammalian cells for translational applications, such as regenerative medicine and cancer therapies. In doing so, we argue that the challenges of engineering mammalian cells provide a prime opportunity to leverage advances in computational systems biology. We support this claim systematically, by addressing each of the principal challenges to existing synthetic bioengineering approaches—stochasticity, complexity, and scale—with specific methods and paradigms in systems biology. Moreover, we characterize a key set of diverse computational techniques, including agent-based modeling, Bayesian network analysis, graph theory, and Gillespie simulations, with specific utility toward synthetic biology. Lastly, we examine the mammalian applications of synthetic biology for medicine and health, and how computational systems biology can aid in the continued development of these applications.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Agapakis, C M" uniqKey="Agapakis C">C. M. Agapakis</name></author><author><name sortKey="Boyle, P M" uniqKey="Boyle P">P. M. Boyle</name></author><author><name sortKey="Silver, P A" uniqKey="Silver P">P. A. Silver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alon, U" uniqKey="Alon U">U. Alon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alterovitz, G" uniqKey="Alterovitz G">G. Alterovitz</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J. Liu</name></author><author><name sortKey="Afkhami, E" uniqKey="Afkhami E">E. Afkhami</name></author><author><name sortKey="Ramoni, M F" uniqKey="Ramoni M">M. F. Ramoni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="An, G" uniqKey="An G">G. An</name></author><author><name sortKey="Mi, Q" uniqKey="Mi Q">Q. Mi</name></author><author><name sortKey="Dutta Oscato, J" uniqKey="Dutta Oscato J">J. Dutta−Moscato</name></author><author><name sortKey="Vodovotz, Y" uniqKey="Vodovotz Y">Y. Vodovotz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anderson, J C" uniqKey="Anderson J">J. C. Anderson</name></author><author><name sortKey="Clarke, E J" uniqKey="Clarke E">E. J. Clarke</name></author><author><name sortKey="Arkin, A P" uniqKey="Arkin A">A. P. Arkin</name></author><author><name sortKey="Voigt, C A" uniqKey="Voigt C">C. A. Voigt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andrianantoandro, E" uniqKey="Andrianantoandro E">E. Andrianantoandro</name></author><author><name sortKey="Basu, S" uniqKey="Basu S">S. Basu</name></author><author><name sortKey="Karig, D K" uniqKey="Karig D">D. K. Karig</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Appel, B" uniqKey="Appel B">B. Appel</name></author><author><name sortKey="Givan, L A" uniqKey="Givan L">L. A. Givan</name></author><author><name sortKey="Eisen, J" uniqKey="Eisen J">J. Eisen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arkin, A" uniqKey="Arkin A">A. Arkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Athale, C" uniqKey="Athale C">C. Athale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bailey, A M" uniqKey="Bailey A">A. M. Bailey</name></author><author><name sortKey="Thorne, B C" uniqKey="Thorne B">B. C. Thorne</name></author><author><name sortKey="Peirce, S M" uniqKey="Peirce S">S. M. Peirce</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barnes, C P" uniqKey="Barnes C">C. P. Barnes</name></author><author><name sortKey="Silk, D" uniqKey="Silk D">D. Silk</name></author><author><name sortKey="Sheng, X" uniqKey="Sheng X">X. Sheng</name></author><author><name sortKey="Stumpf, M P H" uniqKey="Stumpf M">M. P. H. Stumpf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Basanta, D" uniqKey="Basanta D">D. Basanta</name></author><author><name sortKey="Gatenby, R A" uniqKey="Gatenby R">R. A. Gatenby</name></author><author><name sortKey="Anderson, A R A" uniqKey="Anderson A">A. R. A. Anderson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Basu, S" uniqKey="Basu S">S. Basu</name></author><author><name sortKey="Gerchman, Y" uniqKey="Gerchman Y">Y. Gerchman</name></author><author><name sortKey="Collins, C H" uniqKey="Collins C">C. H. Collins</name></author><author><name sortKey="Arnold, F H" uniqKey="Arnold F">F. H. Arnold</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Basu, S" uniqKey="Basu S">S. Basu</name></author><author><name sortKey="Mehreja, R" uniqKey="Mehreja R">R. Mehreja</name></author><author><name sortKey="Thiberge, S" uniqKey="Thiberge S">S. Thiberge</name></author><author><name sortKey="Chen, M T" uniqKey="Chen M">M.-T. Chen</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beisel, C L" uniqKey="Beisel C">C. L. Beisel</name></author><author><name sortKey="Bayer, T S" uniqKey="Bayer T">T. S. Bayer</name></author><author><name sortKey="Hoff, K G" uniqKey="Hoff K">K. G. Hoff</name></author><author><name sortKey="Smolke, C D" uniqKey="Smolke C">C. D. Smolke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Benner, S A" uniqKey="Benner S">S. A. Benner</name></author><author><name sortKey="Sismour, A M" uniqKey="Sismour A">A. M. Sismour</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ben Ze Ev, A" uniqKey="Ben Ze Ev A">A. Ben-Ze'ev</name></author><author><name sortKey="Robinson, G S" uniqKey="Robinson G">G. S. Robinson</name></author><author><name sortKey="Bucher, N L" uniqKey="Bucher N">N. L. Bucher</name></author><author><name sortKey="Farmer, S R" uniqKey="Farmer S">S. R. Farmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bianchini, M" uniqKey="Bianchini M">M. Bianchini</name></author><author><name sortKey="Gori, M" uniqKey="Gori M">M. Gori</name></author><author><name sortKey="Sarti, L" uniqKey="Sarti L">L. Sarti</name></author><author><name sortKey="Scarselli, F" uniqKey="Scarselli F">F. Scarselli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blake, W J" uniqKey="Blake W">W. J. Blake</name></author><author><name sortKey="Kaern, M" uniqKey="Kaern M">M. KAErn</name></author><author><name sortKey="Cantor, C R" uniqKey="Cantor C">C. R. Cantor</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bleris, L" uniqKey="Bleris L">L. Bleris</name></author><author><name sortKey="Xie, Z" uniqKey="Xie Z">Z. Xie</name></author><author><name sortKey="Glass, D" uniqKey="Glass D">D. Glass</name></author><author><name sortKey="Adadey, A" uniqKey="Adadey A">A. Adadey</name></author><author><name sortKey="Sontag, E" uniqKey="Sontag E">E. Sontag</name></author><author><name sortKey="Benenson, Y" uniqKey="Benenson Y">Y. Benenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bloom, J D" uniqKey="Bloom J">J. D. Bloom</name></author><author><name sortKey="Arnold, F H" uniqKey="Arnold F">F. H. Arnold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bonnet, E" uniqKey="Bonnet E">E. Bonnet</name></author><author><name sortKey="Calzone, L" uniqKey="Calzone L">L. Calzone</name></author><author><name sortKey="Rovera, D" uniqKey="Rovera D">D. Rovera</name></author><author><name sortKey="Stoll, G" uniqKey="Stoll G">G. Stoll</name></author><author><name sortKey="Barillot, E" uniqKey="Barillot E">E. Barillot</name></author><author><name sortKey="Zinovyev, A" uniqKey="Zinovyev A">A. Zinovyev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bowsher, C G" uniqKey="Bowsher C">C. G. Bowsher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Buetow, K H" uniqKey="Buetow K">K. H. Buetow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Canton, B" uniqKey="Canton B">B. Canton</name></author><author><name sortKey="Labno, A" uniqKey="Labno A">A. Labno</name></author><author><name sortKey="Endy, D" uniqKey="Endy D">D. Endy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carothers, J M" uniqKey="Carothers J">J. M. Carothers</name></author><author><name sortKey="Goler, J A" uniqKey="Goler J">J. A. Goler</name></author><author><name sortKey="Juminaga, D" uniqKey="Juminaga D">D. Juminaga</name></author><author><name sortKey="Keasling, J D" uniqKey="Keasling J">J. D. Keasling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chandran, D" uniqKey="Chandran D">D. Chandran</name></author><author><name sortKey="Copeland, W B" uniqKey="Copeland W">W. B. Copeland</name></author><author><name sortKey="Sleight, S C" uniqKey="Sleight S">S. C. Sleight</name></author><author><name sortKey="Sauro, H M" uniqKey="Sauro H">H. M. Sauro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, B S" uniqKey="Chen B">B.-S. Chen</name></author><author><name sortKey="Hsu, C Y" uniqKey="Hsu C">C.-Y. Hsu</name></author><author><name sortKey="Liou, J J" uniqKey="Liou J">J.-J. Liou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, T" uniqKey="Cheng T">T. Cheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chopra, P" uniqKey="Chopra P">P. Chopra</name></author><author><name sortKey="Kamma, A" uniqKey="Kamma A">A. Kamma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chung, K" uniqKey="Chung K">K. Chung</name></author><author><name sortKey="Crane, M M" uniqKey="Crane M">M. M. Crane</name></author><author><name sortKey="Lu, H" uniqKey="Lu H">H. Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ellis, T" uniqKey="Ellis T">T. Ellis</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Elowitz, M B" uniqKey="Elowitz M">M. B. Elowitz</name></author><author><name sortKey="Leibler, S" uniqKey="Leibler S">S. Leibler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Elowitz, M B" uniqKey="Elowitz M">M. B. Elowitz</name></author><author><name sortKey="Levine, A J" uniqKey="Levine A">A. J. Levine</name></author><author><name sortKey="Siggia, E D" uniqKey="Siggia E">E. D. Siggia</name></author><author><name sortKey="Swain, P S" uniqKey="Swain P">P. S. Swain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Endler, L" uniqKey="Endler L">L. Endler</name></author><author><name sortKey="Rodriguez, N" uniqKey="Rodriguez N">N. Rodriguez</name></author><author><name sortKey="Juty, N" uniqKey="Juty N">N. Juty</name></author><author><name sortKey="Chelliah, V" uniqKey="Chelliah V">V. Chelliah</name></author><author><name sortKey="Laibe, C" uniqKey="Laibe C">C. Laibe</name></author><author><name sortKey="Li, C" uniqKey="Li C">C. Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Endy, D" uniqKey="Endy D">D. Endy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feret, J" uniqKey="Feret J">J. Feret</name></author><author><name sortKey="Danos, V" uniqKey="Danos V">V. Danos</name></author><author><name sortKey="Krivine, J" uniqKey="Krivine J">J. Krivine</name></author><author><name sortKey="Harmer, R" uniqKey="Harmer R">R. Harmer</name></author><author><name sortKey="Fontana, W" uniqKey="Fontana W">W. Fontana</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gahan, P B" uniqKey="Gahan P">P. B. Gahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gardner, T S" uniqKey="Gardner T">T. S. Gardner</name></author><author><name sortKey="Cantor, C R" uniqKey="Cantor C">C. R. Cantor</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gersbach, C A" uniqKey="Gersbach C">C. A. Gersbach</name></author><author><name sortKey="Phillips, J E" uniqKey="Phillips J">J. E. Phillips</name></author><author><name sortKey="Garcia, A J" uniqKey="Garcia A">A. J. García</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gibson, D G" uniqKey="Gibson D">D. G. Gibson</name></author><author><name sortKey="Glass, J I" uniqKey="Glass J">J. I. Glass</name></author><author><name sortKey="Lartigue, C" uniqKey="Lartigue C">C. Lartigue</name></author><author><name sortKey="Noskov, V N" uniqKey="Noskov V">V. N. Noskov</name></author><author><name sortKey="Chuang, R Y" uniqKey="Chuang R">R.-Y. Chuang</name></author><author><name sortKey="Algire, M A" uniqKey="Algire M">M. A. Algire</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gillespie, D T" uniqKey="Gillespie D">D. T. Gillespie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haeuptle, M T" uniqKey="Haeuptle M">M. T. Haeuptle</name></author><author><name sortKey="Suard, Y L" uniqKey="Suard Y">Y. L. Suard</name></author><author><name sortKey="Bogenmann, E" uniqKey="Bogenmann E">E. Bogenmann</name></author><author><name sortKey="Reggio, H" uniqKey="Reggio H">H. Reggio</name></author><author><name sortKey="Racine, L" uniqKey="Racine L">L. Racine</name></author><author><name sortKey="Kraehenbuhl, J P" uniqKey="Kraehenbuhl J">J. P. Kraehenbuhl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hallinan, J S" uniqKey="Hallinan J">J. S. Hallinan</name></author><author><name sortKey="Misirli, G" uniqKey="Misirli G">G. Misirli</name></author><author><name sortKey="Wipat, A" uniqKey="Wipat A">A. Wipat</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harold, F M" uniqKey="Harold F">F. M. Harold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hooshangi, S" uniqKey="Hooshangi S">S. Hooshangi</name></author><author><name sortKey="Thiberge, S" uniqKey="Thiberge S">S. Thiberge</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hornung, G" uniqKey="Hornung G">G. Hornung</name></author><author><name sortKey="Barkai, N" uniqKey="Barkai N">N. Barkai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, S" uniqKey="Huang S">S. Huang</name></author><author><name sortKey="Sultan, C" uniqKey="Sultan C">C. Sultan</name></author><author><name sortKey="Ingber, D" uniqKey="Ingber D">D. Ingber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeong, H" uniqKey="Jeong H">H. Jeong</name></author><author><name sortKey="Mason, S P" uniqKey="Mason S">S. P. Mason</name></author><author><name sortKey="Barabasi, A L" uniqKey="Barabasi A">A.-L. Barabási</name></author><author><name sortKey="Oltvai, Z N" uniqKey="Oltvai Z">Z. N. Oltvai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeong, H" uniqKey="Jeong H">H. Jeong</name></author><author><name sortKey="Tombor, B" uniqKey="Tombor B">B. Tombor</name></author><author><name sortKey="Albert, R" uniqKey="Albert R">R. Albert</name></author><author><name sortKey="Oltvai, Z N" uniqKey="Oltvai Z">Z. N. Oltvai</name></author><author><name sortKey="Barabasi, A L" uniqKey="Barabasi A">A.-L. Barabási</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kardas, D" uniqKey="Kardas D">D. Kardas</name></author><author><name sortKey="Nackenhorst, U" uniqKey="Nackenhorst U">U. Nackenhorst</name></author><author><name sortKey="Balzani, D" uniqKey="Balzani D">D. Balzani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karr, J R" uniqKey="Karr J">J. R. Karr</name></author><author><name sortKey="Sanghvi, J C" uniqKey="Sanghvi J">J. C. Sanghvi</name></author><author><name sortKey="Macklin, D N" uniqKey="Macklin D">D. N. Macklin</name></author><author><name sortKey="Gutschow, M V" uniqKey="Gutschow M">M. V. Gutschow</name></author><author><name sortKey="Jacobs, J M" uniqKey="Jacobs J">J. M. Jacobs</name></author><author><name sortKey="Bolival, B" uniqKey="Bolival B">B. Bolival</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kestler, H A" uniqKey="Kestler H">H. A. Kestler</name></author><author><name sortKey="Kuhl, M" uniqKey="Kuhl M">M. Kühl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khalil, A S" uniqKey="Khalil A">A. S. Khalil</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kitano, H" uniqKey="Kitano H">H. Kitano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kitano, H" uniqKey="Kitano H">H. Kitano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kitano, H" uniqKey="Kitano H">H. Kitano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klann, M" uniqKey="Klann M">M. Klann</name></author><author><name sortKey="Koeppl, H" uniqKey="Koeppl H">H. Koeppl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Araki, M" uniqKey="Araki M">M. Araki</name></author><author><name sortKey="Chung, K" uniqKey="Chung K">K. Chung</name></author><author><name sortKey="Gardner, T S" uniqKey="Gardner T">T. S. Gardner</name></author><author><name sortKey="Cantor, C R" uniqKey="Cantor C">C. R. Cantor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kramer, B P" uniqKey="Kramer B">B. P. Kramer</name></author><author><name sortKey="Viretta, A U" uniqKey="Viretta A">A. U. Viretta</name></author><author><name sortKey="Daoud El Baba, M" uniqKey="Daoud El Baba M">M. Daoud-El Baba</name></author><author><name sortKey="Aubel, D" uniqKey="Aubel D">D. Aubel</name></author><author><name sortKey="Weber, W" uniqKey="Weber W">W. Weber</name></author><author><name sortKey="Fussenegger, M" uniqKey="Fussenegger M">M. Fussenegger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kwok, R" uniqKey="Kwok R">R. Kwok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H" uniqKey="Lee H">H. Lee</name></author><author><name sortKey="Deloache, W C" uniqKey="Deloache W">W. C. DeLoache</name></author><author><name sortKey="Dueber, J E" uniqKey="Dueber J">J. E. Dueber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liou, S H" uniqKey="Liou S">S.-H. Liou</name></author><author><name sortKey="Chen, C C" uniqKey="Chen C">C.-C. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Long, B L" uniqKey="Long B">B. L. Long</name></author><author><name sortKey="Rekhi, R" uniqKey="Rekhi R">R. Rekhi</name></author><author><name sortKey="Abrego, A" uniqKey="Abrego A">A. Abrego</name></author><author><name sortKey="Jung, J" uniqKey="Jung J">J. Jung</name></author><author><name sortKey="Qutub, A A" uniqKey="Qutub A">A. A. Qutub</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, T K" uniqKey="Lu T">T. K. Lu</name></author><author><name sortKey="Khalil, A S" uniqKey="Khalil A">A. S. Khalil</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luengo Oroz, M A" uniqKey="Luengo Oroz M">M. A. Luengo-Oroz</name></author><author><name sortKey="Duloquin, L" uniqKey="Duloquin L">L. Duloquin</name></author><author><name sortKey="Castro, C" uniqKey="Castro C">C. Castro</name></author><author><name sortKey="Savy, T" uniqKey="Savy T">T. Savy</name></author><author><name sortKey="Faure, E" uniqKey="Faure E">E. Faure</name></author><author><name sortKey="Lombardot, B" uniqKey="Lombardot B">B. Lombardot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ma Ayan, A" uniqKey="Ma Ayan A">A. Ma'ayan</name></author><author><name sortKey="Blitzer, R D" uniqKey="Blitzer R">R. D. Blitzer</name></author><author><name sortKey="Iyengar, R" uniqKey="Iyengar R">R. Iyengar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marcotte, E M" uniqKey="Marcotte E">E. M. Marcotte</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michelotti, N" uniqKey="Michelotti N">N. Michelotti</name></author><author><name sortKey="Johnson Buck, A" uniqKey="Johnson Buck A">A. Johnson-Buck</name></author><author><name sortKey="Manzo, A J" uniqKey="Manzo A">A. J. Manzo</name></author><author><name sortKey="Walter, N G" uniqKey="Walter N">N. G. Walter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miller, M" uniqKey="Miller M">M. Miller</name></author><author><name sortKey="Hafner, M" uniqKey="Hafner M">M. Hafner</name></author><author><name sortKey="Sontag, E" uniqKey="Sontag E">E. Sontag</name></author><author><name sortKey="Davidsohn, N" uniqKey="Davidsohn N">N. Davidsohn</name></author><author><name sortKey="Subramanian, S" uniqKey="Subramanian S">S. Subramanian</name></author><author><name sortKey="Purnick, P E M" uniqKey="Purnick P">P. E. M. Purnick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mitchell, M" uniqKey="Mitchell M">M. Mitchell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mobashir, M" uniqKey="Mobashir M">M. Mobashir</name></author><author><name sortKey="Schraven, B" uniqKey="Schraven B">B. Schraven</name></author><author><name sortKey="Beyer, T" uniqKey="Beyer T">T. Beyer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mukherji, S" uniqKey="Mukherji S">S. Mukherji</name></author><author><name sortKey="Van Oudenaarden, A" uniqKey="Van Oudenaarden A">A. van Oudenaarden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neumann, H" uniqKey="Neumann H">H. Neumann</name></author><author><name sortKey="Neumann Staubitz, P" uniqKey="Neumann Staubitz P">P. Neumann-Staubitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nevozhay, D" uniqKey="Nevozhay D">D. Nevozhay</name></author><author><name sortKey="Zal, T" uniqKey="Zal T">T. Zal</name></author><author><name sortKey="Balazsi, G" uniqKey="Balazsi G">G. Balázsi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ozbudak, E M" uniqKey="Ozbudak E">E. M. Ozbudak</name></author><author><name sortKey="Thattai, M" uniqKey="Thattai M">M. Thattai</name></author><author><name sortKey="Kurtser, I" uniqKey="Kurtser I">I. Kurtser</name></author><author><name sortKey="Grossman, A D" uniqKey="Grossman A">A. D. Grossman</name></author><author><name sortKey="Van Oudenaarden, A" uniqKey="Van Oudenaarden A">A. van Oudenaarden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pedraza, J M" uniqKey="Pedraza J">J. M. Pedraza</name></author><author><name sortKey="Van Oudenaarden, A" uniqKey="Van Oudenaarden A">A. van Oudenaarden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pe Er, D" uniqKey="Pe Er D">D. Pe'er</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfaendtner, J" uniqKey="Pfaendtner J">J. Pfaendtner</name></author><author><name sortKey="De La Cruz, E M" uniqKey="De La Cruz E">E. M. De La Cruz</name></author><author><name sortKey="Voth, G A" uniqKey="Voth G">G. A. Voth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pothen, J J" uniqKey="Pothen J">J. J. Pothen</name></author><author><name sortKey="Poynter, M E" uniqKey="Poynter M">M. E. Poynter</name></author><author><name sortKey="Bates, J H T" uniqKey="Bates J">J. H. T. Bates</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Purnick, P E M" uniqKey="Purnick P">P. E. M. Purnick</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qutub, A A" uniqKey="Qutub A">A. A. Qutub</name></author><author><name sortKey="Mac Gabhann, F" uniqKey="Mac Gabhann F">F. Mac Gabhann</name></author><author><name sortKey="Karagiannis, E D" uniqKey="Karagiannis E">E. D. Karagiannis</name></author><author><name sortKey="Vempati, P" uniqKey="Vempati P">P. Vempati</name></author><author><name sortKey="Popel, A S" uniqKey="Popel A">A. S. Popel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rapaport, D C" uniqKey="Rapaport D">D. C. Rapaport</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ro, D K" uniqKey="Ro D">D.-K. Ro</name></author><author><name sortKey="Paradise, E M" uniqKey="Paradise E">E. M. Paradise</name></author><author><name sortKey="Ouellet, M" uniqKey="Ouellet M">M. Ouellet</name></author><author><name sortKey="Fisher, K J" uniqKey="Fisher K">K. J. Fisher</name></author><author><name sortKey="Newman, K L" uniqKey="Newman K">K. L. Newman</name></author><author><name sortKey="Ndungu, J M" uniqKey="Ndungu J">J. M. Ndungu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roze, L V" uniqKey="Roze L">L. V. Roze</name></author><author><name sortKey="Chanda, A" uniqKey="Chanda A">A. Chanda</name></author><author><name sortKey="Linz, J E" uniqKey="Linz J">J. E. Linz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruder, W C" uniqKey="Ruder W">W. C. Ruder</name></author><author><name sortKey="Lu, T" uniqKey="Lu T">T. Lu</name></author><author><name sortKey="Collins, J J" uniqKey="Collins J">J. J. Collins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ryan, D R" uniqKey="Ryan D">D. R. Ryan</name></author><author><name sortKey="Hu, J" uniqKey="Hu J">J. Hu</name></author><author><name sortKey="Long, B L" uniqKey="Long B">B. L. Long</name></author><author><name sortKey="Qutub, A A" uniqKey="Qutub A">A. A. Qutub</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scarselli, F" uniqKey="Scarselli F">F. Scarselli</name></author><author><name sortKey="Gori, M" uniqKey="Gori M">M. Gori</name></author><author><name sortKey="Tsoi, A C" uniqKey="Tsoi A">A. C. Tsoi</name></author><author><name sortKey="Hagenbuchner, M" uniqKey="Hagenbuchner M">M. Hagenbuchner</name></author><author><name sortKey="Monfardini, G" uniqKey="Monfardini G">G. Monfardini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schaller, G" uniqKey="Schaller G">G. Schaller</name></author><author><name sortKey="Meyer Hermann, M" uniqKey="Meyer Hermann M">M. Meyer-Hermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singhvi, R" uniqKey="Singhvi R">R. Singhvi</name></author><author><name sortKey="Stephanopoulos, G" uniqKey="Stephanopoulos G">G. Stephanopoulos</name></author><author><name sortKey="Wang, D I C" uniqKey="Wang D">D. I. C. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slusarczyk, A L" uniqKey="Slusarczyk A">A. L. Slusarczyk</name></author><author><name sortKey="Lin, A" uniqKey="Lin A">A. Lin</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smolke, C D" uniqKey="Smolke C">C. D. Smolke</name></author><author><name sortKey="Silver, P A" uniqKey="Silver P">P. A. Silver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, H" uniqKey="Song H">H. Song</name></author><author><name sortKey="Payne, S" uniqKey="Payne S">S. Payne</name></author><author><name sortKey="Gray, M" uniqKey="Gray M">M. Gray</name></author><author><name sortKey="You, L" uniqKey="You L">L. You</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sozzani, R" uniqKey="Sozzani R">R. Sozzani</name></author><author><name sortKey="Benfey, P N" uniqKey="Benfey P">P. N. Benfey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spicher, A" uniqKey="Spicher A">A. Spicher</name></author><author><name sortKey="Michel, O" uniqKey="Michel O">O. Michel</name></author><author><name sortKey="Giavitto, J L" uniqKey="Giavitto J">J.-L. Giavitto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stricker, J" uniqKey="Stricker J">J. Stricker</name></author><author><name sortKey="Cookson, S" uniqKey="Cookson S">S. Cookson</name></author><author><name sortKey="Bennett, M R" uniqKey="Bennett M">M. R. Bennett</name></author><author><name sortKey="Mather, W H" uniqKey="Mather W">W. H. Mather</name></author><author><name sortKey="Tsimring, L S" uniqKey="Tsimring L">L. S. Tsimring</name></author><author><name sortKey="Hasty, J" uniqKey="Hasty J">J. Hasty</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tabor, J J" uniqKey="Tabor J">J. J. Tabor</name></author><author><name sortKey="Salis, H" uniqKey="Salis H">H. Salis</name></author><author><name sortKey="Simpson, Z B" uniqKey="Simpson Z">Z. B. Simpson</name></author><author><name sortKey="Chevalier, A A" uniqKey="Chevalier A">A. A. Chevalier</name></author><author><name sortKey="Levskaya, A" uniqKey="Levskaya A">A. Levskaya</name></author><author><name sortKey="Marcotte, E M" uniqKey="Marcotte E">E. M. Marcotte</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takahashi, K" uniqKey="Takahashi K">K. Takahashi</name></author><author><name sortKey="Arjunan, S N V" uniqKey="Arjunan S">S. N. V. Arjunan</name></author><author><name sortKey="Tomita, M" uniqKey="Tomita M">M. Tomita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, H" uniqKey="Tanaka H">H. Tanaka</name></author><author><name sortKey="Yi, T M" uniqKey="Yi T">T.-M. Yi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thattai, M" uniqKey="Thattai M">M. Thattai</name></author><author><name sortKey="Van Oudenaarden, A" uniqKey="Van Oudenaarden A">A. van Oudenaarden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vendruscolo, M" uniqKey="Vendruscolo M">M. Vendruscolo</name></author><author><name sortKey="Dobson, C M" uniqKey="Dobson C">C. M. Dobson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walker, D C" uniqKey="Walker D">D. C. Walker</name></author><author><name sortKey="Southgate, J" uniqKey="Southgate J">J. Southgate</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, B" uniqKey="Wang B">B. Wang</name></author><author><name sortKey="Buck, M" uniqKey="Buck M">M. Buck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, B" uniqKey="Wang B">B. Wang</name></author><author><name sortKey="Kitney, R I" uniqKey="Kitney R">R. I. Kitney</name></author><author><name sortKey="Joly, N" uniqKey="Joly N">N. Joly</name></author><author><name sortKey="Buck, M" uniqKey="Buck M">M. Buck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Z" uniqKey="Wang Z">Z. Wang</name></author><author><name sortKey="Birch, C M" uniqKey="Birch C">C. M. Birch</name></author><author><name sortKey="Sagotsky, J" uniqKey="Sagotsky J">J. Sagotsky</name></author><author><name sortKey="Deisboeck, T S" uniqKey="Deisboeck T">T. S. Deisboeck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Win, M N" uniqKey="Win M">M. N. Win</name></author><author><name sortKey="Smolke, C D" uniqKey="Smolke C">C. D. Smolke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wodarz, D" uniqKey="Wodarz D">D. Wodarz</name></author><author><name sortKey="Hofacre, A" uniqKey="Hofacre A">A. Hofacre</name></author><author><name sortKey="Lau, J W" uniqKey="Lau J">J. W. Lau</name></author><author><name sortKey="Sun, Z" uniqKey="Sun Z">Z. Sun</name></author><author><name sortKey="Fan, H" uniqKey="Fan H">H. Fan</name></author><author><name sortKey="Komarova, N L" uniqKey="Komarova N">N. L. Komarova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xie, Z" uniqKey="Xie Z">Z. Xie</name></author><author><name sortKey="Wroblewska, L" uniqKey="Wroblewska L">L. Wroblewska</name></author><author><name sortKey="Prochazka, L" uniqKey="Prochazka L">L. Prochazka</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author><author><name sortKey="Benenson, Y" uniqKey="Benenson Y">Y. Benenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, J" uniqKey="Yang J">J. Yang</name></author><author><name sortKey="Meng, X" uniqKey="Meng X">X. Meng</name></author><author><name sortKey="Hlavacek, W S" uniqKey="Hlavacek W">W. S. Hlavacek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yeh, B J" uniqKey="Yeh B">B. J. Yeh</name></author><author><name sortKey="Rutigliano, R J" uniqKey="Rutigliano R">R. J. Rutigliano</name></author><author><name sortKey="Deb, A" uniqKey="Deb A">A. Deb</name></author><author><name sortKey="Bar Sagi, D" uniqKey="Bar Sagi D">D. Bar-Sagi</name></author><author><name sortKey="Lim, W A" uniqKey="Lim W">W. A. Lim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yingling, M" uniqKey="Yingling M">M. Yingling</name></author><author><name sortKey="O Neill, T" uniqKey="O Neill T">T. O'Neill</name></author><author><name sortKey="Skalak, T C" uniqKey="Skalak T">T. C. Skalak</name></author><author><name sortKey="Peirce Cottler, S" uniqKey="Peirce Cottler S">S. Peirce-Cottler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="You, L" uniqKey="You L">L. You</name></author><author><name sortKey="Cox, R S" uniqKey="Cox R">R. S. Cox</name></author><author><name sortKey="Weiss, R" uniqKey="Weiss R">R. Weiss</name></author><author><name sortKey="Arnold, F H" uniqKey="Arnold F">F. H. Arnold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Young, E" uniqKey="Young E">E. Young</name></author><author><name sortKey="Alper, H" uniqKey="Alper H">H. Alper</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zomaya, A Y" uniqKey="Zomaya A">A. Y. Zomaya</name></author><author><name sortKey="Kazman, R" uniqKey="Kazman R">R. Kazman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Physiol</journal-id><journal-id journal-id-type="iso-abbrev">Front Physiol</journal-id><journal-id journal-id-type="publisher-id">Front. Physiol.</journal-id><journal-title-group><journal-title>Frontiers in Physiology</journal-title></journal-title-group><issn pub-type="epub">1664-042X</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24130532</article-id><article-id pub-id-type="pmc">3793170</article-id><article-id pub-id-type="doi">10.3389/fphys.2013.00285</article-id><article-categories><subj-group subj-group-type="heading"><subject>Physiology</subject><subj-group><subject>Perspective Article</subject></subj-group></subj-group></article-categories><title-group><article-title>Systems approaches for synthetic biology: a pathway toward mammalian design</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rekhi</surname><given-names>Rahul</given-names></name></contrib><contrib contrib-type="author"><name><surname>Qutub</surname><given-names>Amina A.</given-names></name><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref></contrib></contrib-group><aff><institution>Department of Bioengineering, Rice University</institution><country>Houston, TX, USA</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: John J. Rice, Functional Genomics and Systems Biology, USA</p></fn><fn fn-type="edited-by"><p>Reviewed by: John J. Rice, Functional Genomics and Systems Biology, USA; Lingchong You, Duke University, USA</p></fn><corresp id="fn001">*Correspondence: Amina A. Qutub, Department of Bioengineering, Rice University, MS-142, 6100 Main Street, Houston TX 77005-1892, USA e-mail: <email xlink:type="simple">aminaq@rice.edu</email></corresp><fn fn-type="other" id="fn002"><p>This article was submitted to Computational Physiology and Medicine, a section of the journal Frontiers in Physiology.</p></fn></author-notes><pub-date pub-type="epub"><day>09</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="collection"><year>2013</year></pub-date><volume>4</volume><elocation-id>285</elocation-id><history><date date-type="received"><day>25</day><month>4</month><year>2013</year></date><date date-type="accepted"><day>19</day><month>9</month><year>2013</year></date></history><permissions><copyright-statement>Copyright © 2013 Rekhi and Qutub.</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>We review methods of understanding cellular interactions through computation in order to guide the synthetic design of mammalian cells for translational applications, such as regenerative medicine and cancer therapies. In doing so, we argue that the challenges of engineering mammalian cells provide a prime opportunity to leverage advances in computational systems biology. We support this claim systematically, by addressing each of the principal challenges to existing synthetic bioengineering approaches—stochasticity, complexity, and scale—with specific methods and paradigms in systems biology. Moreover, we characterize a key set of diverse computational techniques, including agent-based modeling, Bayesian network analysis, graph theory, and Gillespie simulations, with specific utility toward synthetic biology. Lastly, we examine the mammalian applications of synthetic biology for medicine and health, and how computational systems biology can aid in the continued development of these applications.</p></abstract><kwd-group><kwd>systems biology</kwd><kwd>synthetic biology</kwd><kwd>mammalian cell</kwd><kwd>computational biology</kwd><kwd>regenerative medicine</kwd><kwd>gene circuits</kwd><kwd>signaling network</kwd><kwd>multiscale modeling</kwd></kwd-group><counts><fig-count count="1"></fig-count><table-count count="1"></table-count><equation-count count="0"></equation-count><ref-count count="114"></ref-count><page-count count="8"></page-count><word-count count="7258"></word-count></counts></article-meta></front><body><sec><title>Introduction and overview</title><p>Over the past three decades, rapid advances in computational power, subcellular data resolution, and the sophistication of bioengineering design has led to cellular machinery being increasingly controlled for practical application (Buetow, <xref ref-type="bibr" rid="B24">2005</xref>; Cheng, <xref ref-type="bibr" rid="B29">2007</xref>; Vendruscolo and Dobson, <xref ref-type="bibr" rid="B101">2011</xref>). The advent of this field of “synthetic biology” has been touted as a reservoir of novel solutions for many of society's most pressing problems, including challenges in computing, health, and regenerative medicine (Gersbach et al., <xref ref-type="bibr" rid="B40">2007</xref>; Lu et al., <xref ref-type="bibr" rid="B65">2009</xref>; Ruder et al., <xref ref-type="bibr" rid="B86">2011</xref>). For instance, the creation of the first-ever genetic toggle switch and the repressilator by synthetic biologists at the turn of the century allowed for an unprecedented degree of cellular control—and, in the case of the former, a digital state that could lay the groundwork for organic computing (Elowitz and Leibler, <xref ref-type="bibr" rid="B33">2000</xref>; Gardner et al., <xref ref-type="bibr" rid="B39">2000</xref>). In subsequent years, biologists constructed oscillators (capable of biological timekeeping), pulse generators (for transcellular signal transmission), and even signaling filters (for cellular signal processing) through carefully mapped gene circuits (Basu et al., <xref ref-type="bibr" rid="B14">2004</xref>, <xref ref-type="bibr" rid="B13">2005</xref>; Stricker et al., <xref ref-type="bibr" rid="B96">2008</xref>; Khalil and Collins, <xref ref-type="bibr" rid="B54">2010</xref>).</p><p>However, while each of these individual discoveries led to numerous applications of genetic engineering in biomedicine, we still lack tools with the robustness required for transformative applications. For instance, true “plug-and-play” cellular machines remain a work in progress, in part due to the heterogeneity and adaptability of biological networks (Kobayashi et al., <xref ref-type="bibr" rid="B59">2004</xref>; Arkin, <xref ref-type="bibr" rid="B8">2008</xref>). The routine engineering of mammalian cells, too, is still a distant possibility (Khalil and Collins, <xref ref-type="bibr" rid="B54">2010</xref>). Because synthetic biology has largely been applied to microbes due to mammalian cell complexity, its impact on medicine has been limited.</p><p>Achieving these benchmarks is admittedly easier said than done. Whereas the promises and potential of the synthetic biology field lie in characterizing the cellular alphabet, the puzzle of words and sentences that define cell signaling and behavior currently present a higher order of complexity (Endy, <xref ref-type="bibr" rid="B36">2005</xref>). Moreover, the field of synthetic biology is still in its infancy, compared to the equivalent of “the Wright brothers … putting pieces of wood and paper together” (Kwok, <xref ref-type="bibr" rid="B61">2010</xref>). Some leading researchers have even suggested that “the complexity of synthetic biological systems over the past decade has reached a plateau” (Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>).</p><p>One way biologists have started to reinvigorate the field is through advances in combinatorial logic-based circuits (Lu et al., <xref ref-type="bibr" rid="B65">2009</xref>; Wang et al., <xref ref-type="bibr" rid="B104">2011</xref>; Michelotti et al., <xref ref-type="bibr" rid="B69">2012</xref>; Wang and Buck, <xref ref-type="bibr" rid="B103">2012</xref>). These formalisms possess the distinct advantages of providing a standardized framework that is adaptable across levels of abstraction as well as dynamical properties that can be estimated and combined by straightforward mathematical operations. Showing early progress, combinatorial logic-based circuits have been designed into sophisticated information processing tools in clonal mammalian cells like HeLa and MCF-7 (Xie et al., <xref ref-type="bibr" rid="B108">2011</xref>; Nevozhay et al., <xref ref-type="bibr" rid="B75">2013</xref>). However, noise, heterogeneity, complexity of structure, and time-dependent rewiring across biological scales limit the degree of control enabled by these experimental methods (Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>; Kwok, <xref ref-type="bibr" rid="B61">2010</xref>). We propose that these challenges can be tackled by capitalizing on advances in computational systems biology that are uniquely valuable for synthetic cell design. We argue that a new perspective on the role of systems modeling in synthetic biology can promote the development of new therapies for human health by enabling the complex design capability required for mammalian cell engineering.</p></sec><sec><title>Computational techniques and advances: systems biology applications</title><p>Computational methods are widely employed within synthetic biology as design tools, providing simulations of bioengineered systems in advance of their cellular assembly (Chandran et al., <xref ref-type="bibr" rid="B4">2009</xref>; Ellis et al., <xref ref-type="bibr" rid="B32">2009</xref>; Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>; Smolke and Silver, <xref ref-type="bibr" rid="B92">2011</xref>) (Figure <xref ref-type="fig" rid="F1">1</xref>). Historically, these coupled computational-experimental approaches have contributed to many of the “milestone” discoveries in the field over the past two decades (Table <xref ref-type="table" rid="T1">1</xref>). However, modeling used in synthetic biology until now has been generally limited to biocircuits and control systems, in part because the field emerged from genetic engineering where circuit representations are common (Mukherji and van Oudenaarden, <xref ref-type="bibr" rid="B73">2009</xref>). The consequence of this limited paradigm is that significant advances in human health from this field remain out of reach, as gene circuit models prove to be increasingly insufficient for characterizing mammalian cell behavior (Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>).</p><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold>(A)</bold> PUBMED references to Systems and Synthetic biology over the last four decades. <bold>(B)</bold> Recent advances in systems biology can be applied toward surmounting specific limitations to existing synthetic biology, paving the way to mammalian cell engineering.</p></caption><graphic xlink:href="fphys-04-00285-g0001"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1</label><caption><p><bold>Synthetic biology milestones employing computational methods, as well as those that were built conceptually from computational paradigms</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"><bold>Synthetic biology milestone</bold></th><th align="left" rowspan="1" colspan="1"><bold>Computational method employed</bold></th><th align="left" rowspan="1" colspan="1"><bold>Year</bold></th><th align="left" rowspan="1" colspan="1"><bold>References</bold></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Bacterial toggle switch</td><td align="left" rowspan="1" colspan="1">Receptor-ligand binding kinetics, gene circuit analysis, analog computing</td><td align="left" rowspan="1" colspan="1">2000</td><td align="left" rowspan="1" colspan="1">Kramer et al., <xref ref-type="bibr" rid="B60">2004</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Repressilator</td><td align="left" rowspan="1" colspan="1">Receptor-ligand binding kinetics, stochastic simulation, gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2000</td><td align="left" rowspan="1" colspan="1">Elowitz and Leibler, <xref ref-type="bibr" rid="B33">2000</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Stochastic gene expression</td><td align="left" rowspan="1" colspan="1">Stochastic noise modeling</td><td align="left" rowspan="1" colspan="1">2002</td><td align="left" rowspan="1" colspan="1">Elowitz et al., <xref ref-type="bibr" rid="B34">2002</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Programmed bacterial population control</td><td align="left" rowspan="1" colspan="1">Logistic ODE kinetics, gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2004</td><td align="left" rowspan="1" colspan="1">You et al., <xref ref-type="bibr" rid="B112">2004</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Mammalian transgene switch</td><td align="left" rowspan="1" colspan="1">Gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2004</td><td align="left" rowspan="1" colspan="1">Kramer et al., <xref ref-type="bibr" rid="B60">2004</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Programmed pattern formation</td><td align="left" rowspan="1" colspan="1">Logistic ODE kinetics, statistical analysis, gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2005</td><td align="left" rowspan="1" colspan="1">Basu et al., <xref ref-type="bibr" rid="B13">2005</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Engineered yeast produce artemesinin</td><td align="left" rowspan="1" colspan="1">Gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2006</td><td align="left" rowspan="1" colspan="1">Ro et al., <xref ref-type="bibr" rid="B84">2006</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Engineered bacteria target cancer by expressing invasion</td><td align="left" rowspan="1" colspan="1">Gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2006</td><td align="left" rowspan="1" colspan="1">Anderson et al., <xref ref-type="bibr" rid="B5">2006</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">RNAi logic circuits</td><td align="left" rowspan="1" colspan="1">Boolean evaluation, gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2007</td><td align="left" rowspan="1" colspan="1">Xie et al., <xref ref-type="bibr" rid="B108">2011</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Creation of logic gates</td><td align="left" rowspan="1" colspan="1">Gene circuit analysis, boolean operator models</td><td align="left" rowspan="1" colspan="1">2008</td><td align="left" rowspan="1" colspan="1">Win and Smolke, <xref ref-type="bibr" rid="B106">2008</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Bacterial edge detection</td><td align="left" rowspan="1" colspan="1">Electronic signal processing, analog computing, gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2009</td><td align="left" rowspan="1" colspan="1">Tabor et al., <xref ref-type="bibr" rid="B97">2009</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Implementation of artificial genome</td><td align="left" rowspan="1" colspan="1">Gene circuit analysis</td><td align="left" rowspan="1" colspan="1">2010</td><td align="left" rowspan="1" colspan="1">Gibson et al., <xref ref-type="bibr" rid="B41">2010</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Whole-cell computational model</td><td align="left" rowspan="1" colspan="1">Flux balance analysis, poisson processes, ODEs, receptor-ligand kinetics, stochastic simulation, boolean operators</td><td align="left" rowspan="1" colspan="1">2012</td><td align="left" rowspan="1" colspan="1">Karr et al., <xref ref-type="bibr" rid="B52">2012</xref></td></tr></tbody></table></table-wrap><p>In the aggregate, this “insufficiency” stems from a set of core properties of biological systems that current synthetic approaches do not fully capture: (1) <italic>scale</italic>, with the need to elicit controlled behavior across cell, tissue, and organ levels (Miller et al., <xref ref-type="bibr" rid="B70">2012</xref>); (2) <italic>simultaneity</italic>, as defined by the highly networked nature of cell signaling (Jeong et al., <xref ref-type="bibr" rid="B50">2000</xref>, <xref ref-type="bibr" rid="B49">2001</xref>; Marcotte, <xref ref-type="bibr" rid="B68">2001</xref>); (3) <italic>state adaptation dynamics</italic>, or the non-linear temporal fluctuations of such networks (Slusarczyk et al., <xref ref-type="bibr" rid="B91">2012</xref>); (4) <italic>shape</italic>, due to the relevance of cell morphology in defining environmental interactions (Ben-Ze'ev et al., <xref ref-type="bibr" rid="B17">1988</xref>; Singhvi et al., <xref ref-type="bibr" rid="B90">1994</xref>); (5) <italic>stochasticity</italic>, with noise and randomness being significant determinants of cellular behavior (Thattai and van Oudenaarden, <xref ref-type="bibr" rid="B100">2001</xref>; Pedraza and van Oudenaarden, <xref ref-type="bibr" rid="B77">2005</xref>; Chopra and Kamma, <xref ref-type="bibr" rid="B30">2006</xref>; Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>); and (6) <italic>spatial dependencies</italic>, both intracellular and extracellular in nature (Andrianantoandro et al., <xref ref-type="bibr" rid="B6">2006</xref>). With the present focus on microbial engineering, many of these characteristics can be safely neglected; at mammalian levels of complexity, they render the behavior of synthetic systems difficult to predict <italic>a priori</italic>.</p><p>Although these challenges are manifold, they are not insurmountable. The answers may lie in systems biology. This computational discipline seeks to shift the basic molecular biology paradigm from isolation to coordination: from characterizing individual components of cell behavior to analyzing how these components function in tandem (Kitano, <xref ref-type="bibr" rid="B56">2002a</xref>,<xref ref-type="bibr" rid="B57">b</xref>). Accordingly, systems bioengineers bring a diverse array of computational modeling techniques—drawing on mathematics, computer science, and engineering—to bear on questions of both mechanism and design at the cell and tissue levels (Kitano, <xref ref-type="bibr" rid="B55">2001</xref>; Alon, <xref ref-type="bibr" rid="B2">2007</xref>). In doing so, the field provides computational tools to characterize behavioral patterns at the cellular level that will be the building blocks of more sophisticated synthetic design. Systems biology approaches are particularly powerful in characterizing cell–cell interactions across scales, such as in capillary patterning and organ development, where the gene circuits approach in synthetic biology has proven limited in capturing adaptation, cellular heterogeneity and spatial hierarchy (Yingling et al., <xref ref-type="bibr" rid="B111">2005</xref>; Qutub et al., <xref ref-type="bibr" rid="B82">2009</xref>; Long et al., <xref ref-type="bibr" rid="B64">2013</xref>). As such, many of the challenges to applying synthetic biology toward controlling mammalian tissue can be addressed in part by methods and techniques that are well-developed in systems bioengineering. Here, we discuss each of these roadblocks categorically, with the associated tools to address them.</p><sec><title>Scale: hierarchical, agent-based modeling, and rule-based formalisms</title><p>Characterizing population-level emergent behavior and cell–cell heterogeneity has long been recognized as a principal goal and challenge in synthetic biology (Canton et al., <xref ref-type="bibr" rid="B25">2008</xref>; Neumann and Neumann-Staubitz, <xref ref-type="bibr" rid="B74">2010</xref>; Young and Alper, <xref ref-type="bibr" rid="B113">2010</xref>). Traditional synthetic designs have assumed identical expression patterns across a cell population, as the standard biocircuit framework does not permit the simulation of cell behavioral variability (Elowitz et al., <xref ref-type="bibr" rid="B34">2002</xref>; Ozbudak et al., <xref ref-type="bibr" rid="B76">2002</xref>; Blake et al., <xref ref-type="bibr" rid="B19">2003</xref>; You et al., <xref ref-type="bibr" rid="B112">2004</xref>). Moreover, the limited capacity for gene circuit models to characterize emergent behavior—defined formally as patterns that emerge from a myriad of relatively simple interactions—inhibits scale-dependent design (Benner and Sismour, <xref ref-type="bibr" rid="B16">2005</xref>). As a mammalian example, if intricate cerebral function results from the coordinated function of millions of individual neurons, any synthetic design applied to the brain must first require accurate simulations of how neural cell-level changes manifest on the cerebral tissue-level. Deriving such scale-driven causal links from observed principles is non-trivial at best.</p><p>One systems biology method to address the research challenge of emergence in biology is agent-based modeling. The approach has a simple premise: such systems exhibit emergent behavior that arises from the interactions between individual actors (or agents) and, consequently, would be impossible to know <italic>a priori</italic> (Chandran et al., <xref ref-type="bibr" rid="B4">2009</xref>). An agent is defined here as a discrete entity that has behavior, can adapt, carries “genetic codes,” holds variables and data, is governed by individual rules, and is spatially defined. Fundamentally, this class of modeling method diverges from biocircuit models, which typically characterize fluctuations in state variables governed by differential relationships. Supplanting the latter's top-down, intracellular perspective with the former's bottom-up, multi-scale viewpoint permits the simulation of heterogeneity while eliminating the need to derive inter-scale relationships beforehand (Chandran et al., <xref ref-type="bibr" rid="B4">2009</xref>).</p><p>Notably, agent-based modeling encompasses a broad range of variations in implementation, rather than any specific algorithm or rule-set. Existing libraries, such as MASON, Repast, and Swarm, allow for the construction of multi-scale agent-based models atop adaptable frameworks, facilitating their use by synthetic biologists with limited prior exposure to the technique. This methodology has been employed toward modeling brain capillary regeneration (Long et al., <xref ref-type="bibr" rid="B64">2013</xref>), immunological and inflammatory responses (Bailey et al., <xref ref-type="bibr" rid="B10">2007</xref>; Chandran et al., <xref ref-type="bibr" rid="B4">2009</xref>; Pothen et al., <xref ref-type="bibr" rid="B80">2013</xref>), and cancer progression (Wang et al., <xref ref-type="bibr" rid="B105">2009</xref>; Basanta et al., <xref ref-type="bibr" rid="B12">2012</xref>; Wodarz et al., <xref ref-type="bibr" rid="B107">2012</xref>; Walker and Southgate, <xref ref-type="bibr" rid="B102">2013</xref>), among other topics. Within synthetic biology specifically, agent-based models have also simulated tissue development, tissue formation, and microbial chemotaxis (Endler et al., <xref ref-type="bibr" rid="B35">2009</xref>).</p><p>Similarly rule-based formalisms are also being applied to coarse-grain patterns in chemical-kinetic models (Feret et al., <xref ref-type="bibr" rid="B37">2009</xref>; Yang et al., <xref ref-type="bibr" rid="B109">2010</xref>), providing scalable tools to describe complex interactions in cellular systems that begin at the molecular level.</p></sec><sec><title>Simultaneity: graph theory and network analysis</title><p>Forecasting interactions and dynamics in protein and metabolic pathways is crucial for fine-tuned control of mammalian synthetic bioengineering. Whereas traditional kinetic- and gene circuit-based methods use simplified pathways to represent these signaling dynamics, in many cases the relationships between molecules are highly non-linear (Marcotte, <xref ref-type="bibr" rid="B68">2001</xref>) and multiplex, i.e., multiple inputs combine to a single output. Signals that propagate from A->B->C at regular intervals are rare; more common are those for which such variations as A->C<->B and B->A->C->A dictate the targeted result, with time- and state-dependent transitions (Kestler and Kühl, <xref ref-type="bibr" rid="B53">2008</xref>). Common, too, are linkages between parallel molecular pathways that each simultaneously affect the output of the other (Jeong et al., <xref ref-type="bibr" rid="B50">2000</xref>, <xref ref-type="bibr" rid="B49">2001</xref>). These oscillations render more complex cell pathways intractable for traditional biocircuit methods, which are generally based on small set of ordinary differential equations (ODEs) (Kestler and Kühl, <xref ref-type="bibr" rid="B53">2008</xref>).</p><p>Several types of network models allow for better predictive simulation of these multiplex interactions. Graph methods, for example, are a class of models that represent pathway components as networked nodes, and graph-based approaches have been used to model cellular machinery including genes, proteins and other subcellular compartments (Ma'ayan et al., <xref ref-type="bibr" rid="B67">2005</xref>; Pe'er, <xref ref-type="bibr" rid="B78">2005</xref>). The interactions between components are drawn as edge connections between the relevant nodes (Ma'ayan et al., <xref ref-type="bibr" rid="B67">2005</xref>). Graph-based models vary in implementation to capture different kinds of molecular relationships (e.g., Boolean gene expression, stochastic transitions between molecular states), but are all particularly adept at identifying complex network modules, or certain structural features that “dominate” the behavior of the larger network. In mammalian cells, as an example, researchers have had early success in characterizing the dynamics of key feedforward modules and motifs, helping to enable the circuit design of adaptive gene expression (Bleris et al., <xref ref-type="bibr" rid="B20">2011</xref>).</p><p>One common type of acyclic graph method, known as Bayesian Network Analysis, is a form of directed statistical modeling designed to capture conditional dependencies between probabilistic events (Pe'er, <xref ref-type="bibr" rid="B78">2005</xref>). In a Bayesian network model, probabilities define the relationship between the current node and its predecessor or parent in a graph (Alterovitz et al., <xref ref-type="bibr" rid="B3">2007</xref>). Markov models are another network-based technique that can provide a framework to describe molecular or cellular states and the weighted probability of transitioning between them. The power of these methods lies in their ability to facilitate the reverse engineering of multiplex networks based on molecular expression, molecular activity and/or cell behavior data, serving as a precursor to synthetic modifications of existing molecular pathways (Barnes et al., <xref ref-type="bibr" rid="B11">2011</xref>). However, for gene or protein pathways with more complex topology—such as those examples offered above—cyclic graph models might be necessary, for which a variety of analytical tools and approaches are described by computational biologists in the literature (particularly from research on neural networks) (Bianchini et al., <xref ref-type="bibr" rid="B18">2006</xref>; Scarselli et al., <xref ref-type="bibr" rid="B88">2009</xref>; Bowsher, <xref ref-type="bibr" rid="B23">2010</xref>; Bonnet et al., <xref ref-type="bibr" rid="B22">2013</xref>).</p></sec><sec><title>State adaptation dynamics: evolutionary models, optimization algorithms</title><p>In parallel with the above techniques, another suite of computational methods permits not only the analysis of cellular pathways, but also directly facilitates their synthetic design. Known as evolutionary algorithms, these methods can predict state changes in the behavior of signaling pathways over time, through adaptation or random mutation, by modeling this rewiring directly (Hallinan et al., <xref ref-type="bibr" rid="B44">2010</xref>; Chen et al., <xref ref-type="bibr" rid="B28">2011</xref>; Mobashir et al., <xref ref-type="bibr" rid="B72">2012</xref>). In the same vein, these methods allow for the <italic>de novo</italic> construction and optimization of genetic networks by way of simulation (Bloom and Arnold, <xref ref-type="bibr" rid="B21">2009</xref>), “evolving” a set of viable pathway designs that meet the specified constraints (Hallinan et al., <xref ref-type="bibr" rid="B44">2010</xref>). Though these algorithms vary in construction, a subset of methods known as genetic algorithms—in which populations of potential networks “compete” against each other—are of particular utility to synthetic biologists due to their ease-of-implementation (Mitchell, <xref ref-type="bibr" rid="B71">1998</xref>). Many alternative optimization techniques exist, e.g., simulated annealing, hill climbing, and gradient descent, which can be applied to optimize synthetic network architectures and the design of synthetic constructs (Zomaya and Kazman, <xref ref-type="bibr" rid="B114">2010</xref>). In addition to these, combinatorial “tuning” strategies have been successfully applied toward model-guided, programmable control of gene expression in mammalian cells via RNAi (Beisel et al., <xref ref-type="bibr" rid="B15">2008</xref>). A unique advantage of evolutionary and optimization algorithms is their ability to (A) be applied broadly to many forms of models, including ODEs and rule-based simulations and (B) generate a diverse array of functional network topologies.</p></sec><sec><title>Shape: morphological modeling and computational cell phenotyping</title><p>Thus, far, synthetic biology research has largely omitted studies on cell shape. The few exceptions in the literature focus on morphological properties as reporters for specific signaling cascades or to control specific spatial features (Yeh et al., <xref ref-type="bibr" rid="B110">2007</xref>; Tanaka and Yi, <xref ref-type="bibr" rid="B99">2009</xref>). For instance, one recent work described controlled shape changes of synthetic yeast cells (Tanaka and Yi, <xref ref-type="bibr" rid="B99">2009</xref>). Rather than modeling how a gene circuit would induce specific cell morphology <italic>a priori</italic>, the study's authors varied α-factor pathway inputs to observe shape changes until the desired shape was achieved—in this case, one that upregulated the formation of mating projections (Tanaka and Yi, <xref ref-type="bibr" rid="B99">2009</xref>). Another study scored filopodial and lamellipodial phenotypes as indicators for successful synthetic rewiring of Rho GTPase signaling (Yeh et al., <xref ref-type="bibr" rid="B110">2007</xref>).</p><p>Despite the few studies in this area, cell morphology is often a characteristic of central importance to synthetic biology experiments. For instance, synthetic systems seeking to modulate cell–cell interactions must necessarily account for morphological and spatial-dependent interactions between cells (Ben-Ze'ev et al., <xref ref-type="bibr" rid="B17">1988</xref>; Singhvi et al., <xref ref-type="bibr" rid="B90">1994</xref>). These membrane adjacency and receptor localization are drivers of pathways like Delta-Notch signaling, in which a signaling cascade is triggered by the binding of two transmembrane proteins on adjacent cells (Appel et al., <xref ref-type="bibr" rid="B7">2001</xref>). Moreover, cell behavior—and at a higher scale, tissue functionality—is often predicated on geometry (Haeuptle et al., <xref ref-type="bibr" rid="B43">1983</xref>). For example, optimizing a synthetic cell for metabolic filtration necessitates that its membrane surface area be maximized for nutrient exchange, such as through inward folds (Gahan, <xref ref-type="bibr" rid="B38">2005</xref>). Doing so requires leveraging computational modeling to predict three-dimensional shape response to changes in genetic circuit design.</p><p>Examples of methods for geometrical-rendered modeling of cells include tensegrity models, Voronoi-based simulations, and molecular dynamics models. The concept of “tensegrity” stems from geodesic design, in which an object's shape is maintained through the joint effect of structural members in continuous tension and those in discontinuous compression (Huang et al., <xref ref-type="bibr" rid="B48">2006</xref>). Though abstract in concept, computational models of tensegrity have been demonstrated to approximate cell shape and mechanics, providing a representation for simulating cell morphology <italic>in vitro</italic> (Huang et al., <xref ref-type="bibr" rid="B48">2006</xref>). Tensegrity principles have been used to represent cytoskeletal elements, allowing for changes in these proteins induced by regulatory networks (e.g., focal adhesion kinases) to be assessed for their effects on cell shape (Kardas et al., <xref ref-type="bibr" rid="B51">2013</xref>). An alternative geometrical model is the Voronoi diagram, a mathematical concept of dividing space into distinct regions based on proximity to initial seed points. Voronoi diagrams provide a useful means of constraining complex cell shapes into adjacent spatial tessellations, a technique particularly useful to study patterning at the cell population- or tissue-level (Schaller and Meyer-Hermann, <xref ref-type="bibr" rid="B89">2005</xref>; Luengo-Oroz et al., <xref ref-type="bibr" rid="B66">2008</xref>). Lastly, molecular dynamics simulations of cell shape represent cells as collections of individual molecules in Newtonian motion, either abstractly (as particles) or concretely (as cytoskeletal elements), to model an agglomerated cellular structure at high resolution—albeit at greater computational cost (Rapaport, <xref ref-type="bibr" rid="B83">2004</xref>; Pfaendtner et al., <xref ref-type="bibr" rid="B79">2010</xref>).</p><p>Linking geometric-based models to gene network simulations offers the opportunity to guide synthetic biocircuit design <italic>in silico</italic> such that specific cell morphologies can be engineered. Previously, this method has led to a complete representation of osteocyte cytoskeleton dynamics (Kardas et al., <xref ref-type="bibr" rid="B51">2013</xref>). In conjunction, computational cell phenotyping enables changes in morphology to be quantitatively measured and tracked, such that the desired design can be achieved. Phenotyping techniques couple high-fidelity cell imaging with processing metrics to parse shape information (Chung et al., <xref ref-type="bibr" rid="B31">2008</xref>; Sozzani and Benfey, <xref ref-type="bibr" rid="B94">2011</xref>; Ryan et al., <xref ref-type="bibr" rid="B87">2013</xref>). These shape metrics can facilitate the computer-aided design of synthetic networks.</p></sec><sec><title>Stochasticity: gillespie algorithm and monte carlo methods</title><p>Perhaps the most significant research challenge in synthetic bioengineering is enabling the design of cellular systems that are robust to biological stochasticity (Chopra and Kamma, <xref ref-type="bibr" rid="B30">2006</xref>; Purnick and Weiss, <xref ref-type="bibr" rid="B81">2009</xref>). Existing gene circuit models are largely deterministic, behaving in highly reproducible ways. These models, as alluded to previously, present regulatory networks as homogeneous concentrations of molecules modulated by parameterized rate constants through coupled differential equations.</p><p>Yet there exists increasing evidence that biological networks and intracellular behavior are innately stochastic (Thattai and van Oudenaarden, <xref ref-type="bibr" rid="B100">2001</xref>). Whereas noise effects are often assumed to be negligible at the population level, noise can play a significant role at the single-cell level, e.g., where a small number of molecular interactions may trigger a cascade of downstream protein signaling (Thattai and van Oudenaarden, <xref ref-type="bibr" rid="B100">2001</xref>; Pedraza and van Oudenaarden, <xref ref-type="bibr" rid="B77">2005</xref>). Furthermore, research indicates the phenomenon of noise propagation, in which cell-level stochasticity can accrue at the population-level to create emergent behavior that deviates substantially from the desired target, a phenomena recently documented in <italic>E. Coli</italic>, leading to a loss of synchrony between cells (Hooshangi et al., <xref ref-type="bibr" rid="B46">2005</xref>; Hornung and Barkai, <xref ref-type="bibr" rid="B47">2008</xref>). Such studies suggest that complex synthetic systems cannot be engineered without first accounting for stochasticity in the circuit design.</p><p>Fortunately, there exist a wide variety of computational techniques to capture and predict this biological stochasticity at the systems level. One specific approach, known as the Gillespie Algorithm, rejects the deterministic ODE approach of modeling chemical-kinetics in favor of stochastic representations of molecular interactions (Gillespie, <xref ref-type="bibr" rid="B42">2007</xref>). This algorithm explicitly simulates each “reaction” (or interaction event) along a network, with the probability of a successful “reaction” dependent on both the rate properties and a random walk (Gillespie, <xref ref-type="bibr" rid="B42">2007</xref>). For synthetic biology applications, these reactions can be defined as discrete regulatory steps along a specific gene circuit, allowing the effects of noise along the circuit to be well-characterized.</p><p>The Gillespie algorithm belongs to a larger class of stochastic modeling techniques known as Monte Carlo methods, which can be adapted to suit the needs of a specific biocircuit design (Athale, <xref ref-type="bibr" rid="B9">2001</xref>). Monte Carlo methods, while varied in implementation, share the property of employing random simulations over many iterations to quantify properties of biological systems.</p></sec><sec><title>Spatial dependencies: particle- and lattice-based methods</title><p>Traditional synthetic biology designs are based on assumptions of biochemically homogenous cell interiors, but for gene circuit designs of higher complexity, this set of assumptions is unlikely to hold (Agapakis et al., <xref ref-type="bibr" rid="B1">2012</xref>). Often, the spatial information associated with a protein or pathway inside the cell can influence the end-behavior of a molecular network (Agapakis et al., <xref ref-type="bibr" rid="B1">2012</xref>). In addition to variations in metabolic conditions (e.g., pH levels), spatial cues can also present as receptor- or organelle- localization, intracellular polarity, and even topological sequestration (Harold, <xref ref-type="bibr" rid="B45">1991</xref>; Roze et al., <xref ref-type="bibr" rid="B85">2011</xref>; Lee et al., <xref ref-type="bibr" rid="B62">2012</xref>). Characterizing intracellular spatial dependences and molecular dynamics becomes particularly important in mammalian cells, for which fine spatial organization of regulatory pathways is commonplace.</p><p>To this end, particle- and lattice-based computational techniques can be employed to model spatial systems within a synthetic cell (Spicher et al., <xref ref-type="bibr" rid="B95">2011</xref>; Klann and Koeppl, <xref ref-type="bibr" rid="B58">2012</xref>). Rather than simulate bulk flow, particle-based models track molecules separately and in discrete quantities (Takahashi et al., <xref ref-type="bibr" rid="B98">2005</xref>), as alluded to above in the description of molecular dynamic models (see the <italic>Shape</italic> section). In systems biology, such methods have already been applied toward characterizing single-cell gradient sensing in the presence of multiple competitive ligands (Liou and Chen, <xref ref-type="bibr" rid="B63">2012</xref>). Particle models could be similarly applicable to synthetic biology in engineering mammalian cells to function as fine-tuned hypoxic or nitric oxide sensors, in an effort to minimize effects of ischemic stroke—to name just one instance.</p><p>The complexity of particle models is mitigated by the availability of open source simulators, including E-Cell and ChemCell (Klann and Koeppl, <xref ref-type="bibr" rid="B58">2012</xref>). Many of these implementations also allow particle simulations to be combined with models of other classes. As an example, a spatial derivative of the Gillespie algorithm can integrate stochastic modeling with space-dependent computation (Takahashi et al., <xref ref-type="bibr" rid="B98">2005</xref>).</p><p>Spatial modeling can also be performed using PDE models; examples include gene circuits defining chemical diffusion-mediated interactions between localized cell populations (Song et al., <xref ref-type="bibr" rid="B93">2009</xref>). In other applications to synthetic biology, these spatial techniques have been combined with mechanistic models, such as kinetic RNA folding simulations, to provide fine-tuned control of gene expression along a specific component of a regulatory pathway (Carothers et al., <xref ref-type="bibr" rid="B26">2011</xref>). PDE formalisms offer relative simplicity of construction compared to other spatiotemporal methods, with the caveat of not being well-suited to highly heterogeneous spatial environments.</p></sec></sec><sec><title>Applications for mammalian cells and human health</title><p>Until now, the overwhelming focus of research and progress in synthetic biology has been on prokaryotic cells: mostly bacteria (commonly <italic>E. Coli</italic>) and assorted microbes. This is a natural consequence of the knowledge gap described previously; prokaryotic cells are orders of magnitude simpler than eukaryotic ones—not to mention easier to manipulate. They could be said to represent the “crawling” stage of synthetic biology. However, if the ultimate goal of the discipline is to uncover novel therapeutic targets and treatments in biomedicine, such strict characterization of non-mammalian systems will restrain our ability to advance human health. In the end, we must learn to walk.</p><p>To do so means confronting the complexity that the <italic>in vivo</italic> mammalian system brings. Methods already employed in systems biology to characterize this complexity can open up the boundaries of modern medicine. As an example, it is not difficult to imagine a future where computational models enable the design of synthetic neural progenitor cells programmed to promote recovery post-ischemic stroke. To foster an era of personalized medicine, this potential could revolutionize the manner in which we approach tissue engineering: cells grown <italic>en masse</italic>, and then programmed to meet the specific needs of the patient. Moreover, such customizable cells would permit targeted regeneration to a degree that simple stem cell treatments cannot achieve. Such innovations, while distant, are attainable, but they necessitate the coupling of systems approaches with synthetic biology.</p></sec><sec><title>Concluding comments</title><p>Bringing the sister disciplines of synthetic and systems biology closer together could recast the gene circuit paradigm, and enhance our ability to engineer and program cells for applications across energy, computing and biomedicine. Leveraging a computational toolkit refined by systems biologists for the last half-century offers a unique catalyst that to help pave the future of synthetic biology.</p><sec><title>Conflict of interest statement</title><p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec></sec></body><back><ref-list><title>References</title><ref id="B1"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Agapakis</surname><given-names>C. M.</given-names></name><name><surname>Boyle</surname><given-names>P. M.</given-names></name><name><surname>Silver</surname><given-names>P. A.</given-names></name></person-group> (<year>2012</year>). <article-title>Natural strategies for the spatial optimization of metabolism in synthetic biology</article-title>. <source>Nat. Chem. Biol</source>. <volume>8</volume>, <fpage>527</fpage>–<lpage>535</lpage><pub-id pub-id-type="doi">10.1038/nchembio.975</pub-id><pub-id pub-id-type="pmid">22596204</pub-id></mixed-citation></ref><ref id="B2"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alon</surname><given-names>U.</given-names></name></person-group> (<year>2007</year>). <source>An Introduction to Systems Biology: Design Principles of Biological Circuits</source>. Chapman and Hall/CRC Press.</mixed-citation></ref><ref id="B3"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alterovitz</surname><given-names>G.</given-names></name><name><surname>Liu</surname><given-names>J.</given-names></name><name><surname>Afkhami</surname><given-names>E.</given-names></name><name><surname>Ramoni</surname><given-names>M. F.</given-names></name></person-group> (<year>2007</year>). <article-title>Bayesian methods for proteomics</article-title>. <source>Proteomics</source><volume>7</volume>, <fpage>2843</fpage>–<lpage>2855</lpage><pub-id pub-id-type="doi">10.1002/pmic.200700422</pub-id><pub-id pub-id-type="pmid">17654463</pub-id></mixed-citation></ref><ref id="B4"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>An</surname><given-names>G.</given-names></name><name><surname>Mi</surname><given-names>Q.</given-names></name><name><surname>Dutta−Moscato</surname><given-names>J.</given-names></name><name><surname>Vodovotz</surname><given-names>Y.</given-names></name></person-group> (<year>2009</year>). <article-title>Agent−based models in translational systems biology</article-title>. <source>Wiley Interdiscip. Rev. Syst. Biol. Med</source>. <volume>1</volume>, <fpage>159</fpage>–<lpage>171</lpage><pub-id pub-id-type="doi">10.1002/wsbm.45</pub-id><pub-id pub-id-type="pmid">20835989</pub-id></mixed-citation></ref><ref id="B5"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Anderson</surname><given-names>J. C.</given-names></name><name><surname>Clarke</surname><given-names>E. J.</given-names></name><name><surname>Arkin</surname><given-names>A. P.</given-names></name><name><surname>Voigt</surname><given-names>C. A.</given-names></name></person-group> (<year>2006</year>). <article-title>Environmentally controlled invasion of cancer cells by engineered bacteria</article-title>. <source>J. Mol. Biol</source>. <volume>355</volume>, <fpage>619</fpage>–<lpage>627</lpage><pub-id pub-id-type="doi">10.1016/j.jmb.2005.10.076</pub-id><pub-id pub-id-type="pmid">16330045</pub-id></mixed-citation></ref><ref id="B6"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Andrianantoandro</surname><given-names>E.</given-names></name><name><surname>Basu</surname><given-names>S.</given-names></name><name><surname>Karig</surname><given-names>D. K.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2006</year>). <article-title>Synthetic biology: new engineering rules for an emerging discipline</article-title>. <source>Mol. Syst. Biol</source>. <volume>2</volume>, <fpage>10</fpage>–<lpage>13</lpage><pub-id pub-id-type="doi">10.1038/msb4100073</pub-id><pub-id pub-id-type="pmid">16738572</pub-id></mixed-citation></ref><ref id="B7"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Appel</surname><given-names>B.</given-names></name><name><surname>Givan</surname><given-names>L. A.</given-names></name><name><surname>Eisen</surname><given-names>J.</given-names></name></person-group> (<year>2001</year>). <article-title>Delta-Notch signaling and lateral inhibition in zebrafish spinal cord development</article-title>. <source>BMC Dev. Biol</source>. <volume>1</volume>:<fpage>13</fpage><pub-id pub-id-type="doi">10.1186/1471-213X-1-13</pub-id><pub-id pub-id-type="pmid">11495630</pub-id></mixed-citation></ref><ref id="B8"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arkin</surname><given-names>A.</given-names></name></person-group> (<year>2008</year>). <article-title>Setting the standard in synthetic biology</article-title>. <source>Nat. Biotechnol</source>. <volume>26</volume>, <fpage>771</fpage>–<lpage>773</lpage><pub-id pub-id-type="doi">10.1038/nbt0708-771</pub-id><pub-id pub-id-type="pmid">18612298</pub-id></mixed-citation></ref><ref id="B9"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Athale</surname><given-names>C.</given-names></name></person-group> (<year>2001</year>). <article-title>Monte Carlo cell simulations</article-title>. <source>Genome Biol</source>. <volume>3</volume>:<fpage>reports2001</fpage><pub-id pub-id-type="doi">10.1186/gb-2001-3-1-reports2001</pub-id></mixed-citation></ref><ref id="B10"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bailey</surname><given-names>A. M.</given-names></name><name><surname>Thorne</surname><given-names>B. C.</given-names></name><name><surname>Peirce</surname><given-names>S. M.</given-names></name></person-group> (<year>2007</year>). <article-title>Multi-cell agent-based simulation of the microvasculature to study the dynamics of circulating inflammatory cell trafficking</article-title>. <source>Ann. Biomed. Eng</source>. <volume>35</volume>, <fpage>916</fpage>–<lpage>936</lpage><pub-id pub-id-type="doi">10.1007/s10439-007-9266-1</pub-id><pub-id pub-id-type="pmid">17436112</pub-id></mixed-citation></ref><ref id="B11"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barnes</surname><given-names>C. P.</given-names></name><name><surname>Silk</surname><given-names>D.</given-names></name><name><surname>Sheng</surname><given-names>X.</given-names></name><name><surname>Stumpf</surname><given-names>M. P. H.</given-names></name></person-group> (<year>2011</year>). <article-title>Bayesian design of synthetic biological systems</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>108</volume>, <fpage>8645</fpage>–<lpage>8650</lpage><pub-id pub-id-type="doi">10.1073/pnas.1017972108</pub-id><pub-id pub-id-type="pmid">21551095</pub-id></mixed-citation></ref><ref id="B12"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Basanta</surname><given-names>D.</given-names></name><name><surname>Gatenby</surname><given-names>R. A.</given-names></name><name><surname>Anderson</surname><given-names>A. R. A.</given-names></name></person-group> (<year>2012</year>). <article-title>Exploiting evolution to treat drug resistance: combination therapy and the double bind</article-title>. <source>Mol. Pharm</source>. <volume>9</volume>, <fpage>914</fpage>–<lpage>921</lpage><pub-id pub-id-type="doi">10.1021/mp200458e</pub-id><pub-id pub-id-type="pmid">22369188</pub-id></mixed-citation></ref><ref id="B13"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Basu</surname><given-names>S.</given-names></name><name><surname>Gerchman</surname><given-names>Y.</given-names></name><name><surname>Collins</surname><given-names>C. H.</given-names></name><name><surname>Arnold</surname><given-names>F. H.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2005</year>). <article-title>A synthetic multicellular system for programmed pattern formation</article-title>. <source>Nature</source><volume>434</volume>, <fpage>1130</fpage>–<lpage>1134</lpage><pub-id pub-id-type="doi">10.1038/nature03461</pub-id><pub-id pub-id-type="pmid">15858574</pub-id></mixed-citation></ref><ref id="B14"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Basu</surname><given-names>S.</given-names></name><name><surname>Mehreja</surname><given-names>R.</given-names></name><name><surname>Thiberge</surname><given-names>S.</given-names></name><name><surname>Chen</surname><given-names>M.-T.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2004</year>). <article-title>Spatiotemporal control of gene expression with pulse-generating networks</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>101</volume>, <fpage>6355</fpage>–<lpage>6360</lpage><pub-id pub-id-type="doi">10.1073/pnas.0307571101</pub-id><pub-id pub-id-type="pmid">15096621</pub-id></mixed-citation></ref><ref id="B15"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beisel</surname><given-names>C. L.</given-names></name><name><surname>Bayer</surname><given-names>T. S.</given-names></name><name><surname>Hoff</surname><given-names>K. G.</given-names></name><name><surname>Smolke</surname><given-names>C. D.</given-names></name></person-group> (<year>2008</year>). <article-title>Model-guided design of ligand-regulated RNAi for programmable control of gene expression</article-title>. <source>Mol. Syst. Biol</source>. <volume>4</volume>, <fpage>1</fpage>–<lpage>13</lpage><pub-id pub-id-type="doi">10.1038/msb.2008.62</pub-id><pub-id pub-id-type="pmid">18956013</pub-id></mixed-citation></ref><ref id="B16"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Benner</surname><given-names>S. A.</given-names></name><name><surname>Sismour</surname><given-names>A. M.</given-names></name></person-group> (<year>2005</year>). <article-title>Synthetic biology</article-title>. <source>Nat. Rev. Genet</source>. <volume>6</volume>, <fpage>533</fpage>–<lpage>543</lpage><pub-id pub-id-type="doi">10.1038/nrg1637</pub-id><pub-id pub-id-type="pmid">15995697</pub-id></mixed-citation></ref><ref id="B17"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ben-Ze'ev</surname><given-names>A.</given-names></name><name><surname>Robinson</surname><given-names>G. S.</given-names></name><name><surname>Bucher</surname><given-names>N. L.</given-names></name><name><surname>Farmer</surname><given-names>S. R.</given-names></name></person-group> (<year>1988</year>). <article-title>Cell–cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>85</volume>, <fpage>2161</fpage>–<lpage>2165</lpage><pub-id pub-id-type="doi">10.1073/pnas.85.7.2161</pub-id><pub-id pub-id-type="pmid">3353374</pub-id></mixed-citation></ref><ref id="B18"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bianchini</surname><given-names>M.</given-names></name><name><surname>Gori</surname><given-names>M.</given-names></name><name><surname>Sarti</surname><given-names>L.</given-names></name><name><surname>Scarselli</surname><given-names>F.</given-names></name></person-group> (<year>2006</year>). <article-title>Recursive processing of cyclic graphs</article-title>. <source>IEEE Trans. Neural Netw</source>. <volume>17</volume>, <fpage>10</fpage>–<lpage>18</lpage><pub-id pub-id-type="doi">10.1109/TNN.2005.860873</pub-id><pub-id pub-id-type="pmid">16526472</pub-id></mixed-citation></ref><ref id="B19"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Blake</surname><given-names>W. J.</given-names></name><name><surname>KAErn</surname><given-names>M.</given-names></name><name><surname>Cantor</surname><given-names>C. R.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2003</year>). <article-title>Noise in eukaryotic gene expression</article-title>. <source>Nature</source><volume>422</volume>, <fpage>633</fpage>–<lpage>637</lpage><pub-id pub-id-type="doi">10.1038/nature01546</pub-id><pub-id pub-id-type="pmid">12687005</pub-id></mixed-citation></ref><ref id="B20"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bleris</surname><given-names>L.</given-names></name><name><surname>Xie</surname><given-names>Z.</given-names></name><name><surname>Glass</surname><given-names>D.</given-names></name><name><surname>Adadey</surname><given-names>A.</given-names></name><name><surname>Sontag</surname><given-names>E.</given-names></name><name><surname>Benenson</surname><given-names>Y.</given-names></name></person-group> (<year>2011</year>). <article-title>Synthetic incoherent feedforward circuits show adaptation to the amount of their genetic template</article-title>. <source>Mol. Syst. Biol</source>. <volume>7</volume>, <fpage>1</fpage>–<lpage>12</lpage><pub-id pub-id-type="doi">10.1038/msb.2011.49</pub-id><pub-id pub-id-type="pmid">21811230</pub-id></mixed-citation></ref><ref id="B21"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bloom</surname><given-names>J. D.</given-names></name><name><surname>Arnold</surname><given-names>F. H.</given-names></name></person-group> (<year>2009</year>). <article-title>In the light of directed evolution: pathways of adaptive protein evolution</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>106</volume>, <fpage>9995</fpage>–<lpage>10000</lpage><pub-id pub-id-type="doi">10.1073/pnas.0901522106</pub-id><pub-id pub-id-type="pmid">19528653</pub-id></mixed-citation></ref><ref id="B22"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bonnet</surname><given-names>E.</given-names></name><name><surname>Calzone</surname><given-names>L.</given-names></name><name><surname>Rovera</surname><given-names>D.</given-names></name><name><surname>Stoll</surname><given-names>G.</given-names></name><name><surname>Barillot</surname><given-names>E.</given-names></name><name><surname>Zinovyev</surname><given-names>A.</given-names></name></person-group> (<year>2013</year>). <article-title>BiNoM 2.0, a Cytoscape plugin for accessing and analyzing pathways using standard systems biology formats</article-title>. <source>BMC Syst. Biol</source>. <volume>7</volume>:<fpage>18</fpage><pub-id pub-id-type="doi">10.1186/1752-0509-7-18</pub-id><pub-id pub-id-type="pmid">23453054</pub-id></mixed-citation></ref><ref id="B23"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bowsher</surname><given-names>C. G.</given-names></name></person-group> (<year>2010</year>). <article-title>Stochastic kinetic models: dynamic independence, modularity and graphs</article-title>. <source>Ann. Stat</source>. <volume>38</volume>, <fpage>2242</fpage>–<lpage>2281</lpage><pub-id pub-id-type="doi">10.1214/09-AOS779</pub-id><pub-id pub-id-type="pmid">21278808</pub-id></mixed-citation></ref><ref id="B24"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Buetow</surname><given-names>K. H.</given-names></name></person-group> (<year>2005</year>). <article-title>Cyberinfrastructure: empowering a “third way” in biomedical research</article-title>. <source>Science</source><volume>308</volume>, <fpage>821</fpage>–<lpage>824</lpage><pub-id pub-id-type="doi">10.1126/science.1112120</pub-id><pub-id pub-id-type="pmid">15879210</pub-id></mixed-citation></ref><ref id="B25"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Canton</surname><given-names>B.</given-names></name><name><surname>Labno</surname><given-names>A.</given-names></name><name><surname>Endy</surname><given-names>D.</given-names></name></person-group> (<year>2008</year>). <article-title>Refinement and standardization of synthetic biological parts and devices</article-title>. <source>Nat. Biotechnol</source>. <volume>26</volume>, <fpage>787</fpage>–<lpage>793</lpage><pub-id pub-id-type="doi">10.1038/nbt1413</pub-id><pub-id pub-id-type="pmid">18612302</pub-id></mixed-citation></ref><ref id="B26"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carothers</surname><given-names>J. M.</given-names></name><name><surname>Goler</surname><given-names>J. A.</given-names></name><name><surname>Juminaga</surname><given-names>D.</given-names></name><name><surname>Keasling</surname><given-names>J. D.</given-names></name></person-group> (<year>2011</year>). <article-title>Model-driven engineering of RNA devices to quantitatively program gene expression</article-title>. <source>Science</source><volume>334</volume>, <fpage>1716</fpage>–<lpage>1719</lpage><pub-id pub-id-type="doi">10.1126/science.1212209</pub-id><pub-id pub-id-type="pmid">22194579</pub-id></mixed-citation></ref><ref id="B27"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chandran</surname><given-names>D.</given-names></name><name><surname>Copeland</surname><given-names>W. B.</given-names></name><name><surname>Sleight</surname><given-names>S. C.</given-names></name><name><surname>Sauro</surname><given-names>H. M.</given-names></name></person-group> (<year>2009</year>). <article-title>Mathematical modeling and synthetic biology</article-title>. <source>Drug Discov. Today Dis. Models</source><volume>5</volume>, <fpage>299</fpage>–<lpage>309</lpage><pub-id pub-id-type="doi">10.1016/j.ddmod.2009.07.002</pub-id></mixed-citation></ref><ref id="B28"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>B.-S.</given-names></name><name><surname>Hsu</surname><given-names>C.-Y.</given-names></name><name><surname>Liou</surname><given-names>J.-J.</given-names></name></person-group> (<year>2011</year>). <article-title>Robust design of biological circuits: evolutionary systems biology approach</article-title>. <source>J. Biomed. Biotechnol</source>. <volume>2011</volume>:<fpage>304236</fpage><pub-id pub-id-type="doi">10.1155/2011/304236</pub-id><pub-id pub-id-type="pmid">22187523</pub-id></mixed-citation></ref><ref id="B29"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname><given-names>T.</given-names></name></person-group> (<year>2007</year>). <article-title>Moore's law meets the life sciences</article-title>. <source>IEEE Des. Test Comput</source>. <volume>24</volume>, <fpage>4</fpage><pub-id pub-id-type="doi">10.1109/MDT.2007.23</pub-id></mixed-citation></ref><ref id="B30"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chopra</surname><given-names>P.</given-names></name><name><surname>Kamma</surname><given-names>A.</given-names></name></person-group> (<year>2006</year>). <article-title>Engineering life through synthetic biology</article-title>. <source>In Silico Biol</source>. <volume>6</volume>, <fpage>401</fpage>–<lpage>410</lpage><pub-id pub-id-type="pmid">17274769</pub-id></mixed-citation></ref><ref id="B31"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chung</surname><given-names>K.</given-names></name><name><surname>Crane</surname><given-names>M. M.</given-names></name><name><surname>Lu</surname><given-names>H.</given-names></name></person-group> (<year>2008</year>). <article-title>Automated on-chip rapid microscopy, phenotyping and sorting of C. elegans</article-title>. <source>Nat. Methods</source><volume>5</volume>, <fpage>637</fpage>–<lpage>643</lpage><pub-id pub-id-type="doi">10.1038/nmeth.1227</pub-id><pub-id pub-id-type="pmid">18568029</pub-id></mixed-citation></ref><ref id="B32"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ellis</surname><given-names>T.</given-names></name><name><surname>Wang</surname><given-names>X.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2009</year>). <article-title>Diversity-based, model-guided construction of synthetic gene networks with predicted functions</article-title>. <source>Nat. Biotechnol</source>. <volume>27</volume>, <fpage>465</fpage>–<lpage>471</lpage><pub-id pub-id-type="doi">10.1038/nbt.1536</pub-id><pub-id pub-id-type="pmid">19377462</pub-id></mixed-citation></ref><ref id="B33"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Elowitz</surname><given-names>M. B.</given-names></name><name><surname>Leibler</surname><given-names>S.</given-names></name></person-group> (<year>2000</year>). <article-title>A synthetic oscillatory network of transcriptional regulators</article-title>. <source>Nature</source><volume>403</volume>, <fpage>335</fpage>–<lpage>338</lpage><pub-id pub-id-type="doi">10.1038/35002125</pub-id><pub-id pub-id-type="pmid">10659856</pub-id></mixed-citation></ref><ref id="B34"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Elowitz</surname><given-names>M. B.</given-names></name><name><surname>Levine</surname><given-names>A. J.</given-names></name><name><surname>Siggia</surname><given-names>E. D.</given-names></name><name><surname>Swain</surname><given-names>P. S.</given-names></name></person-group> (<year>2002</year>). <article-title>Stochastic gene expression in a single cell</article-title>. <source>Science</source><volume>297</volume>, <fpage>1183</fpage>–<lpage>1186</lpage><pub-id pub-id-type="doi">10.1126/science.1070919</pub-id><pub-id pub-id-type="pmid">12183631</pub-id></mixed-citation></ref><ref id="B35"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Endler</surname><given-names>L.</given-names></name><name><surname>Rodriguez</surname><given-names>N.</given-names></name><name><surname>Juty</surname><given-names>N.</given-names></name><name><surname>Chelliah</surname><given-names>V.</given-names></name><name><surname>Laibe</surname><given-names>C.</given-names></name><name><surname>Li</surname><given-names>C.</given-names></name></person-group> (<year>2009</year>). <article-title>Designing and encoding models for synthetic biology</article-title>. <source>J. R. Soc. Interface</source><volume>6</volume>, <fpage>S405</fpage>–<lpage>S417</lpage><pub-id pub-id-type="doi">10.1098/rsif.2009.0035.focus</pub-id><pub-id pub-id-type="pmid">19364720</pub-id></mixed-citation></ref><ref id="B36"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Endy</surname><given-names>D.</given-names></name></person-group> (<year>2005</year>). <article-title>Foundations for engineering biology</article-title>. <source>Nature</source><volume>438</volume>, <fpage>449</fpage>–<lpage>453</lpage><pub-id pub-id-type="doi">10.1038/nature04342</pub-id><pub-id pub-id-type="pmid">16306983</pub-id></mixed-citation></ref><ref id="B37"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Feret</surname><given-names>J.</given-names></name><name><surname>Danos</surname><given-names>V.</given-names></name><name><surname>Krivine</surname><given-names>J.</given-names></name><name><surname>Harmer</surname><given-names>R.</given-names></name><name><surname>Fontana</surname><given-names>W.</given-names></name></person-group> (<year>2009</year>). <article-title>Internal coarse-graining of molecular systems</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>106</volume>, <fpage>6453</fpage>–<lpage>6458</lpage><pub-id pub-id-type="doi">10.1073/pnas.0809908106</pub-id><pub-id pub-id-type="pmid">19346467</pub-id></mixed-citation></ref><ref id="B38"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gahan</surname><given-names>P. B.</given-names></name></person-group> (<year>2005</year>). <article-title>Life: the science of biology (7th edn) W. K. Purves, D. Sadava, G. H. Orians and H. C. Heller, W. H. Freeman and Co, 1121 pp., ISBN 0-7167-9856-5 (2004).</article-title><source>Cell Biochem. Funct</source>. <volume>23</volume>, <fpage>221</fpage><pub-id pub-id-type="doi">10.1002/cbf.1179</pub-id></mixed-citation></ref><ref id="B39"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gardner</surname><given-names>T. S.</given-names></name><name><surname>Cantor</surname><given-names>C. R.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2000</year>). <article-title>Construction of a genetic toggle switch in <italic>Escherichia coli</italic></article-title>. <source>Nature</source><volume>403</volume>, <fpage>339</fpage>–<lpage>342</lpage><pub-id pub-id-type="doi">10.1038/35002131</pub-id><pub-id pub-id-type="pmid">10659857</pub-id></mixed-citation></ref><ref id="B40"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gersbach</surname><given-names>C. A.</given-names></name><name><surname>Phillips</surname><given-names>J. E.</given-names></name><name><surname>García</surname><given-names>A. J.</given-names></name></person-group> (<year>2007</year>). <article-title>Genetic engineering for skeletal regenerative medicine</article-title>. <source>Annu. Rev. Biomed. Eng</source>. <volume>9</volume>, <fpage>87</fpage>–<lpage>119</lpage><pub-id pub-id-type="doi">10.1146/annurev.bioeng.9.060906.151949</pub-id><pub-id pub-id-type="pmid">17425467</pub-id></mixed-citation></ref><ref id="B41"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gibson</surname><given-names>D. G.</given-names></name><name><surname>Glass</surname><given-names>J. I.</given-names></name><name><surname>Lartigue</surname><given-names>C.</given-names></name><name><surname>Noskov</surname><given-names>V. N.</given-names></name><name><surname>Chuang</surname><given-names>R.-Y.</given-names></name><name><surname>Algire</surname><given-names>M. A.</given-names></name></person-group> (<year>2010</year>). <article-title>Creation of a bacterial cell controlled by a chemically synthesized genome</article-title>. <source>Science</source><volume>329</volume>, <fpage>52</fpage>–<lpage>56</lpage><pub-id pub-id-type="doi">10.1126/science.1190719</pub-id><pub-id pub-id-type="pmid">20488990</pub-id></mixed-citation></ref><ref id="B42"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gillespie</surname><given-names>D. T.</given-names></name></person-group> (<year>2007</year>). <article-title>Stochastic simulation of chemical kinetics</article-title>. <source>Annu. Rev. Phys. Chem</source>. <volume>58</volume>, <fpage>35</fpage>–<lpage>55</lpage><pub-id pub-id-type="doi">10.1146/annurev.physchem.58.032806.104637</pub-id><pub-id pub-id-type="pmid">17037977</pub-id></mixed-citation></ref><ref id="B43"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Haeuptle</surname><given-names>M. T.</given-names></name><name><surname>Suard</surname><given-names>Y. L.</given-names></name><name><surname>Bogenmann</surname><given-names>E.</given-names></name><name><surname>Reggio</surname><given-names>H.</given-names></name><name><surname>Racine</surname><given-names>L.</given-names></name><name><surname>Kraehenbuhl</surname><given-names>J. P.</given-names></name></person-group> (<year>1983</year>). <article-title>Effect of cell shape change on the function and differentiation of rabbit mammary cells in culture</article-title>. <source>J. Cell Biol</source>. <volume>96</volume>, <fpage>1425</fpage>–<lpage>1434</lpage><pub-id pub-id-type="doi">10.1083/jcb.96.5.1425</pub-id><pub-id pub-id-type="pmid">6841452</pub-id></mixed-citation></ref><ref id="B44"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hallinan</surname><given-names>J. S.</given-names></name><name><surname>Misirli</surname><given-names>G.</given-names></name><name><surname>Wipat</surname><given-names>A.</given-names></name></person-group> (<year>2010</year>). <article-title>Evolutionary computation for the design of a stochastic switch for synthetic genetic circuits</article-title>. <source>Conf. Proc. IEEE Eng. Med. Biol. Soc</source>. <volume>2010</volume>, <fpage>768</fpage>–<lpage>774</lpage><pub-id pub-id-type="doi">10.1109/IEMBS.2010.5626353</pub-id><pub-id pub-id-type="pmid">21095906</pub-id></mixed-citation></ref><ref id="B45"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Harold</surname><given-names>F. M.</given-names></name></person-group> (<year>1991</year>). <article-title>Biochemical topology: from vectorial metabolism to morphogenesis</article-title>. <source>Biosci. Rep</source>. <volume>11</volume>, <fpage>347</fpage>–<lpage>382</lpage> discussion: 382–385. <pub-id pub-id-type="doi">10.1007/BF01130213</pub-id><pub-id pub-id-type="pmid">1823595</pub-id></mixed-citation></ref><ref id="B46"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hooshangi</surname><given-names>S.</given-names></name><name><surname>Thiberge</surname><given-names>S.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2005</year>). <article-title>Ultrasensitivity and noise propagation in a synthetic transcriptional cascade</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>102</volume>, <fpage>3581</fpage>–<lpage>3586</lpage><pub-id pub-id-type="doi">10.1073/pnas.0408507102</pub-id><pub-id pub-id-type="pmid">15738412</pub-id></mixed-citation></ref><ref id="B47"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hornung</surname><given-names>G.</given-names></name><name><surname>Barkai</surname><given-names>N.</given-names></name></person-group> (<year>2008</year>). <article-title>Noise propagation and signaling sensitivity in biological networks: a role for positive feedback</article-title>. <source>PLoS Comput. Biol</source>. <volume>4</volume>:<fpage>e8</fpage><pub-id pub-id-type="doi">10.1371/journal.pcbi.0040008</pub-id><pub-id pub-id-type="pmid">18179281</pub-id></mixed-citation></ref><ref id="B48"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname><given-names>S.</given-names></name><name><surname>Sultan</surname><given-names>C.</given-names></name><name><surname>Ingber</surname><given-names>D.</given-names></name></person-group> (<year>2006</year>). <article-title>“Tensegrity, dynamic networks, and complex systems biology: emergence in structural and information networks within living cells,”</article-title> in <source>Complex Systems Science in Biomedicine</source>, eds <person-group person-group-type="editor"><name><surname>Deisboeck</surname><given-names>T. S.</given-names></name><name><surname>Kresh</surname><given-names>J. Y.</given-names></name></person-group> (Springer), <fpage>283</fpage>–<lpage>310</lpage><pub-id pub-id-type="doi">10.1007/978-0-387-33532-2_11</pub-id></mixed-citation></ref><ref id="B49"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeong</surname><given-names>H.</given-names></name><name><surname>Mason</surname><given-names>S. P.</given-names></name><name><surname>Barabási</surname><given-names>A.-L.</given-names></name><name><surname>Oltvai</surname><given-names>Z. N.</given-names></name></person-group> (<year>2001</year>). <article-title>Lethality and centrality in protein networks</article-title>. <source>Nature</source><volume>411</volume>, <fpage>41</fpage>–<lpage>42</lpage><pub-id pub-id-type="doi">10.1038/35075138</pub-id><pub-id pub-id-type="pmid">11333967</pub-id></mixed-citation></ref><ref id="B50"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeong</surname><given-names>H.</given-names></name><name><surname>Tombor</surname><given-names>B.</given-names></name><name><surname>Albert</surname><given-names>R.</given-names></name><name><surname>Oltvai</surname><given-names>Z. N.</given-names></name><name><surname>Barabási</surname><given-names>A.-L.</given-names></name></person-group> (<year>2000</year>). <article-title>The large-scale organization of metabolic networks</article-title>. <source>Nature</source><volume>407</volume>, <fpage>651</fpage>–<lpage>654</lpage><pub-id pub-id-type="doi">10.1038/35036627</pub-id><pub-id pub-id-type="pmid">11034217</pub-id></mixed-citation></ref><ref id="B51"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kardas</surname><given-names>D.</given-names></name><name><surname>Nackenhorst</surname><given-names>U.</given-names></name><name><surname>Balzani</surname><given-names>D.</given-names></name></person-group> (<year>2013</year>). <article-title>Computational model for the cell-mechanical response of the osteocyte cytoskeleton based on self-stabilizing tensegrity structures</article-title>. <source>Biomech. Model. Mechanobiol</source>. <volume>12</volume>, <fpage>167</fpage>–<lpage>183</lpage><pub-id pub-id-type="doi">10.1007/s10237-012-0390-y</pub-id><pub-id pub-id-type="pmid">22527364</pub-id></mixed-citation></ref><ref id="B52"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karr</surname><given-names>J. R.</given-names></name><name><surname>Sanghvi</surname><given-names>J. C.</given-names></name><name><surname>Macklin</surname><given-names>D. N.</given-names></name><name><surname>Gutschow</surname><given-names>M. V.</given-names></name><name><surname>Jacobs</surname><given-names>J. M.</given-names></name><name><surname>Bolival</surname><given-names>B.</given-names></name></person-group> (<year>2012</year>). <article-title>A whole-cell computational model predicts phenotype from genotype</article-title>. <source>Cell</source><volume>150</volume>, <fpage>389</fpage>–<lpage>401</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2012.05.044</pub-id><pub-id pub-id-type="pmid">22817898</pub-id></mixed-citation></ref><ref id="B53"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kestler</surname><given-names>H. A.</given-names></name><name><surname>Kühl</surname><given-names>M.</given-names></name></person-group> (<year>2008</year>). <article-title>From individual Wnt pathways towards a Wnt signalling network</article-title>. <source>Philos. Trans. R. Soc. B Biol. Sci</source>. <volume>363</volume>, <fpage>1333</fpage>–<lpage>1347</lpage><pub-id pub-id-type="doi">10.1098/rstb.2007.2251</pub-id><pub-id pub-id-type="pmid">18192173</pub-id></mixed-citation></ref><ref id="B54"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Khalil</surname><given-names>A. S.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2010</year>). <article-title>Synthetic biology: applications come of age</article-title>. <source>Nat. Rev. Genet</source>. <volume>11</volume>, <fpage>367</fpage>–<lpage>379</lpage><pub-id pub-id-type="doi">10.1038/nrg2775</pub-id><pub-id pub-id-type="pmid">20395970</pub-id></mixed-citation></ref><ref id="B55"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Kitano</surname><given-names>H.</given-names></name></person-group> (<year>2001</year>). <source>Foundations of Systems Biology</source>. <publisher-loc>Cambridge, MA</publisher-loc>: <publisher-name>MIT press</publisher-name></mixed-citation></ref><ref id="B56"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kitano</surname><given-names>H.</given-names></name></person-group> (<year>2002a</year>). <article-title>Systems biology: a brief overview</article-title>. <source>Science</source><volume>295</volume>, <fpage>1662</fpage>–<lpage>1664</lpage><pub-id pub-id-type="doi">10.1126/science.1069492</pub-id><pub-id pub-id-type="pmid">11872829</pub-id></mixed-citation></ref><ref id="B57"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kitano</surname><given-names>H.</given-names></name></person-group> (<year>2002b</year>). <article-title>Computational systems biology</article-title>. <source>Nature</source><volume>420</volume>, <fpage>206</fpage>–<lpage>210</lpage><pub-id pub-id-type="doi">10.1038/nature01254</pub-id><pub-id pub-id-type="pmid">12432404</pub-id></mixed-citation></ref><ref id="B58"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klann</surname><given-names>M.</given-names></name><name><surname>Koeppl</surname><given-names>H.</given-names></name></person-group> (<year>2012</year>). <article-title>Spatial simulations in systems biology: from molecules to cells</article-title>. <source>Int. J. Mol. Sci</source>. <volume>13</volume>, <fpage>7798</fpage>–<lpage>7827</lpage><pub-id pub-id-type="doi">10.3390/ijms13067798</pub-id><pub-id pub-id-type="pmid">22837728</pub-id></mixed-citation></ref><ref id="B59"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kobayashi</surname><given-names>H.</given-names></name><name><surname>Kærn</surname><given-names>M.</given-names></name></person-group><name><surname>Araki</surname><given-names>M.</given-names></name><name><surname>Chung</surname><given-names>K.</given-names></name><name><surname>Gardner</surname><given-names>T. S.</given-names></name><name><surname>Cantor</surname><given-names>C. R.</given-names></name> (<year>2004</year>). <article-title>Programmable cells: interfacing natural and engineered gene networks</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>101</volume>, <fpage>8414</fpage>–<lpage>8419</lpage><pub-id pub-id-type="doi">10.1073/pnas.0402940101</pub-id><pub-id pub-id-type="pmid">15159530</pub-id></mixed-citation></ref><ref id="B60"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kramer</surname><given-names>B. P.</given-names></name><name><surname>Viretta</surname><given-names>A. U.</given-names></name><name><surname>Daoud-El Baba</surname><given-names>M.</given-names></name><name><surname>Aubel</surname><given-names>D.</given-names></name><name><surname>Weber</surname><given-names>W.</given-names></name><name><surname>Fussenegger</surname><given-names>M.</given-names></name></person-group> (<year>2004</year>). <article-title>An engineered epigenetic transgene switch in mammalian cells</article-title>. <source>Nat. Biotechnol</source>. <volume>22</volume>, <fpage>867</fpage>–<lpage>870</lpage><pub-id pub-id-type="doi">10.1038/nbt980</pub-id><pub-id pub-id-type="pmid">15184906</pub-id></mixed-citation></ref><ref id="B61"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kwok</surname><given-names>R.</given-names></name></person-group> (<year>2010</year>). <article-title>Five hard truths for synthetic biology</article-title>. <source>Nature</source><volume>463</volume>, <fpage>288</fpage><pub-id pub-id-type="doi">10.1038/463288a</pub-id><pub-id pub-id-type="pmid">20090726</pub-id></mixed-citation></ref><ref id="B62"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>H.</given-names></name><name><surname>DeLoache</surname><given-names>W. C.</given-names></name><name><surname>Dueber</surname><given-names>J. E.</given-names></name></person-group> (<year>2012</year>). <article-title>Spatial organization of enzymes for metabolic engineering</article-title>. <source>Metab. Eng</source>. <volume>14</volume>, <fpage>242</fpage>–<lpage>251</lpage><pub-id pub-id-type="doi">10.1016/j.ymben.2011.09.003</pub-id><pub-id pub-id-type="pmid">21946160</pub-id></mixed-citation></ref><ref id="B63"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liou</surname><given-names>S.-H.</given-names></name><name><surname>Chen</surname><given-names>C.-C.</given-names></name></person-group> (<year>2012</year>). <article-title>Cellular ability to sense spatial gradients in the presence of multiple competitive ligands</article-title>. <source>Phys. Rev. E Stat. Nonlin. Soft Matter Phys</source>. <volume>85</volume>:<fpage>11904</fpage><pub-id pub-id-type="doi">10.1103/PhysRevE.85.011904</pub-id><pub-id pub-id-type="pmid">22400588</pub-id></mixed-citation></ref><ref id="B64"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Long</surname><given-names>B. L.</given-names></name><name><surname>Rekhi</surname><given-names>R.</given-names></name><name><surname>Abrego</surname><given-names>A.</given-names></name><name><surname>Jung</surname><given-names>J.</given-names></name><name><surname>Qutub</surname><given-names>A. A.</given-names></name></person-group> (<year>2013</year>). <article-title>Cells as state machines: cell behavior patterns arise during capillary formation as a function of BDNF and VEGF</article-title>. <source>J. Theor. Biol</source>. <volume>326</volume>, <fpage>43</fpage>–<lpage>57</lpage><pub-id pub-id-type="doi">10.1016/j.jtbi.2012.11.030</pub-id><pub-id pub-id-type="pmid">23266714</pub-id></mixed-citation></ref><ref id="B65"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>T. K.</given-names></name><name><surname>Khalil</surname><given-names>A. S.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2009</year>). <article-title>Next-generation synthetic gene networks</article-title>. <source>Nat. Biotechnol</source>. <volume>27</volume>, <fpage>1139</fpage>–<lpage>1150</lpage><pub-id pub-id-type="doi">10.1038/nbt.1591</pub-id><pub-id pub-id-type="pmid">20010597</pub-id></mixed-citation></ref><ref id="B66"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Luengo-Oroz</surname><given-names>M. A.</given-names></name><name><surname>Duloquin</surname><given-names>L.</given-names></name><name><surname>Castro</surname><given-names>C.</given-names></name><name><surname>Savy</surname><given-names>T.</given-names></name><name><surname>Faure</surname><given-names>E.</given-names></name><name><surname>Lombardot</surname><given-names>B.</given-names></name></person-group> (<year>2008</year>). <article-title>“Can voronoi diagram model cell geometries in early sea-urchin embryogenesis?,”</article-title> in <source>Biomedical Imaging: From Nano to Macro, 2008. ISBI 2008. 5th IEEE International Symposium on</source>, (<publisher-loc>Paris</publisher-loc>), <fpage>504</fpage>–<lpage>507</lpage></mixed-citation></ref><ref id="B67"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ma'ayan</surname><given-names>A.</given-names></name><name><surname>Blitzer</surname><given-names>R. D.</given-names></name><name><surname>Iyengar</surname><given-names>R.</given-names></name></person-group> (<year>2005</year>). <article-title>Toward predictive models of mammalian cells</article-title>. <source>Annu. Rev. Biophys. Biomol. Struct</source>. <volume>34</volume>, <fpage>319</fpage>–<lpage>349</lpage><pub-id pub-id-type="doi">10.1146/annurev.biophys.34.040204.144415</pub-id><pub-id pub-id-type="pmid">15869393</pub-id></mixed-citation></ref><ref id="B68"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Marcotte</surname><given-names>E. M.</given-names></name></person-group> (<year>2001</year>). <article-title>The path not taken</article-title>. <source>Nat. Biotechnol</source>. <volume>19</volume>, <fpage>626</fpage>–<lpage>628</lpage><pub-id pub-id-type="doi">10.1038/90222</pub-id><pub-id pub-id-type="pmid">11433271</pub-id></mixed-citation></ref><ref id="B69"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Michelotti</surname><given-names>N.</given-names></name><name><surname>Johnson-Buck</surname><given-names>A.</given-names></name><name><surname>Manzo</surname><given-names>A. J.</given-names></name><name><surname>Walter</surname><given-names>N. G.</given-names></name></person-group> (<year>2012</year>). <article-title>Beyond DNA origami: a look on the bright future of nucleic acid nanotechnology</article-title>. <source>Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol</source>. <volume>4</volume>, <fpage>139</fpage><pub-id pub-id-type="doi">10.1002/wnan.170</pub-id><pub-id pub-id-type="pmid">22131292</pub-id></mixed-citation></ref><ref id="B70"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Miller</surname><given-names>M.</given-names></name><name><surname>Hafner</surname><given-names>M.</given-names></name><name><surname>Sontag</surname><given-names>E.</given-names></name><name><surname>Davidsohn</surname><given-names>N.</given-names></name><name><surname>Subramanian</surname><given-names>S.</given-names></name><name><surname>Purnick</surname><given-names>P. E. M.</given-names></name></person-group> (<year>2012</year>). <article-title>Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity</article-title>. <source>PLoS Comput. Biol</source>. <volume>8</volume>:<fpage>e1002579</fpage><pub-id pub-id-type="doi">10.1371/journal.pcbi.1002579</pub-id><pub-id pub-id-type="pmid">22829755</pub-id></mixed-citation></ref><ref id="B71"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Mitchell</surname><given-names>M.</given-names></name></person-group> (<year>1998</year>). <source>An Introduction to Genetic Algorithms</source>. <publisher-loc>Cambridge, MA</publisher-loc>: <publisher-name>MIT Press</publisher-name></mixed-citation></ref><ref id="B72"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mobashir</surname><given-names>M.</given-names></name><name><surname>Schraven</surname><given-names>B.</given-names></name><name><surname>Beyer</surname><given-names>T.</given-names></name></person-group> (<year>2012</year>). <article-title>Simulated evolution of signal transduction networks</article-title>. <source>PLoS ONE</source><volume>7</volume>:<fpage>e50905</fpage><pub-id pub-id-type="doi">10.1371/journal.pone.0050905</pub-id><pub-id pub-id-type="pmid">23272078</pub-id></mixed-citation></ref><ref id="B73"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mukherji</surname><given-names>S.</given-names></name><name><surname>van Oudenaarden</surname><given-names>A.</given-names></name></person-group> (<year>2009</year>). <article-title>Synthetic biology: understanding biological design from synthetic circuits</article-title>. <source>Nat. Rev. Genet</source>. <volume>10</volume>, <fpage>859</fpage>–<lpage>871</lpage><pub-id pub-id-type="doi">10.1038/nrg2697</pub-id><pub-id pub-id-type="pmid">19898500</pub-id></mixed-citation></ref><ref id="B74"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Neumann</surname><given-names>H.</given-names></name><name><surname>Neumann-Staubitz</surname><given-names>P.</given-names></name></person-group> (<year>2010</year>). <article-title>Synthetic biology approaches in drug discovery and pharmaceutical biotechnology</article-title>. <source>Appl. Microbiol. Biotechnol</source>. <volume>87</volume>, <fpage>75</fpage>–<lpage>86</lpage><pub-id pub-id-type="doi">10.1007/s00253-010-2578-3</pub-id><pub-id pub-id-type="pmid">20396881</pub-id></mixed-citation></ref><ref id="B75"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nevozhay</surname><given-names>D.</given-names></name><name><surname>Zal</surname><given-names>T.</given-names></name><name><surname>Balázsi</surname><given-names>G.</given-names></name></person-group> (<year>2013</year>). <article-title>Transferring a synthetic gene circuit from yeast to mammalian cells</article-title>. <source>Nat. Commun</source>. <volume>4</volume>, <fpage>1451</fpage><pub-id pub-id-type="doi">10.1038/ncomms2471</pub-id><pub-id pub-id-type="pmid">23385595</pub-id></mixed-citation></ref><ref id="B76"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ozbudak</surname><given-names>E. M.</given-names></name><name><surname>Thattai</surname><given-names>M.</given-names></name><name><surname>Kurtser</surname><given-names>I.</given-names></name><name><surname>Grossman</surname><given-names>A. D.</given-names></name><name><surname>van Oudenaarden</surname><given-names>A.</given-names></name></person-group> (<year>2002</year>). <article-title>Regulation of noise in the expression of a single gene</article-title>. <source>Nat. Genet</source>. <volume>31</volume>, <fpage>69</fpage>–<lpage>73</lpage><pub-id pub-id-type="doi">10.1038/ng869</pub-id><pub-id pub-id-type="pmid">11967532</pub-id></mixed-citation></ref><ref id="B77"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pedraza</surname><given-names>J. M.</given-names></name><name><surname>van Oudenaarden</surname><given-names>A.</given-names></name></person-group> (<year>2005</year>). <article-title>Noise propagation in gene networks</article-title>. <source>Science</source><volume>307</volume>, <fpage>1965</fpage><pub-id pub-id-type="doi">10.1126/science.1109090</pub-id><pub-id pub-id-type="pmid">15790857</pub-id></mixed-citation></ref><ref id="B78"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pe'er</surname><given-names>D.</given-names></name></person-group> (<year>2005</year>). <article-title>Bayesian network analysis of signaling networks: a primer</article-title>. <source>Sci. STKE</source><volume>2005</volume>:<fpage>pl4</fpage><pub-id pub-id-type="doi">10.1126/stke.2812005pl4</pub-id><pub-id pub-id-type="pmid">15855409</pub-id></mixed-citation></ref><ref id="B79"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pfaendtner</surname><given-names>J.</given-names></name><name><surname>De La Cruz</surname><given-names>E. M.</given-names></name><name><surname>Voth</surname><given-names>G. A.</given-names></name></person-group> (<year>2010</year>). <article-title>Actin filament remodeling by actin depolymerization factor/cofilin</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>107</volume>, <fpage>7299</fpage>–<lpage>7304</lpage><pub-id pub-id-type="doi">10.1073/pnas.0911675107</pub-id><pub-id pub-id-type="pmid">20368459</pub-id></mixed-citation></ref><ref id="B80"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pothen</surname><given-names>J. J.</given-names></name><name><surname>Poynter</surname><given-names>M. E.</given-names></name><name><surname>Bates</surname><given-names>J. H. T.</given-names></name></person-group> (<year>2013</year>). <article-title>The inflammatory twitch as a general strategy for controlling the host response</article-title>. <source>J. Immunol</source>. <volume>190</volume>, <fpage>3510</fpage>–<lpage>3516</lpage><pub-id pub-id-type="doi">10.4049/jimmunol.1202595</pub-id><pub-id pub-id-type="pmid">23427255</pub-id></mixed-citation></ref><ref id="B81"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Purnick</surname><given-names>P. E. M.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2009</year>). <article-title>The second wave of synthetic biology: from modules to systems</article-title>. <source>Nat. Rev. Mol. Cell Biol</source>. <volume>10</volume>, <fpage>410</fpage>–<lpage>422</lpage><pub-id pub-id-type="doi">10.1038/nrm2698</pub-id><pub-id pub-id-type="pmid">19461664</pub-id></mixed-citation></ref><ref id="B82"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Qutub</surname><given-names>A. A.</given-names></name><name><surname>Mac Gabhann</surname><given-names>F.</given-names></name><name><surname>Karagiannis</surname><given-names>E. D.</given-names></name><name><surname>Vempati</surname><given-names>P.</given-names></name><name><surname>Popel</surname><given-names>A. S.</given-names></name></person-group> (<year>2009</year>). <article-title>Multiscale models of angiogenesis: integration of molecular mechanisms with cell- and organ-level models</article-title>. <source>IEEE Eng. Med. Biol. Mag</source>. <volume>28</volume>, <fpage>14</fpage>–<lpage>31</lpage><pub-id pub-id-type="doi">10.1109/MEMB.2009.931791</pub-id><pub-id pub-id-type="pmid">19349248</pub-id></mixed-citation></ref><ref id="B83"><mixed-citation publication-type="book"><person-group person-group-type="editor"><name><surname>Rapaport</surname><given-names>D. C.</given-names></name></person-group> (ed.). (<year>2004</year>). <source>The Art of Molecular Dynamics Simulation</source>. ISBN:0521825687. <publisher-loc>Cambridge, UK</publisher-loc>: <publisher-name>Cambridge University Press</publisher-name>, 564. <pub-id pub-id-type="doi">10.1017/CBO9780511816581</pub-id></mixed-citation></ref><ref id="B84"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ro</surname><given-names>D.-K.</given-names></name><name><surname>Paradise</surname><given-names>E. M.</given-names></name><name><surname>Ouellet</surname><given-names>M.</given-names></name><name><surname>Fisher</surname><given-names>K. J.</given-names></name><name><surname>Newman</surname><given-names>K. L.</given-names></name><name><surname>Ndungu</surname><given-names>J. M.</given-names></name></person-group> (<year>2006</year>). <article-title>Production of the antimalarial drug precursor artemisinic acid in engineered yeast</article-title>. <source>Nature</source><volume>440</volume>, <fpage>940</fpage>–<lpage>943</lpage><pub-id pub-id-type="doi">10.1038/nature04640</pub-id><pub-id pub-id-type="pmid">16612385</pub-id></mixed-citation></ref><ref id="B85"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roze</surname><given-names>L. V.</given-names></name><name><surname>Chanda</surname><given-names>A.</given-names></name><name><surname>Linz</surname><given-names>J. E.</given-names></name></person-group> (<year>2011</year>). <article-title>Compartmentalization and molecular traffic in secondary metabolism: a new understanding of established cellular processes</article-title>. <source>Fungal Genet. Biol</source>. <volume>48</volume>, <fpage>35</fpage>–<lpage>48</lpage><pub-id pub-id-type="doi">10.1016/j.fgb.2010.05.006</pub-id><pub-id pub-id-type="pmid">20519149</pub-id></mixed-citation></ref><ref id="B86"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ruder</surname><given-names>W. C.</given-names></name><name><surname>Lu</surname><given-names>T.</given-names></name><name><surname>Collins</surname><given-names>J. J.</given-names></name></person-group> (<year>2011</year>). <article-title>Synthetic biology moving into the clinic</article-title>. <source>Science</source><volume>333</volume>, <fpage>1248</fpage>–<lpage>1252</lpage><pub-id pub-id-type="doi">10.1126/science.1206843</pub-id><pub-id pub-id-type="pmid">21885773</pub-id></mixed-citation></ref><ref id="B87"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Ryan</surname><given-names>D. R.</given-names></name><name><surname>Hu</surname><given-names>J.</given-names></name><name><surname>Long</surname><given-names>B. L.</given-names></name><name><surname>Qutub</surname><given-names>A. A.</given-names></name></person-group> (<year>2013</year>). <article-title>“Predicting Endothelial Cell Phenotypes in Angiogenesis,”</article-title> in <source>ASME 2nd Global Congress on NanoEngineering for Medicine and Biology</source>, (<publisher-loc>Boston, MA</publisher-loc>).</mixed-citation></ref><ref id="B88"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scarselli</surname><given-names>F.</given-names></name><name><surname>Gori</surname><given-names>M.</given-names></name><name><surname>Tsoi</surname><given-names>A. C.</given-names></name><name><surname>Hagenbuchner</surname><given-names>M.</given-names></name><name><surname>Monfardini</surname><given-names>G.</given-names></name></person-group> (<year>2009</year>). <article-title>Computational capabilities of graph neural networks</article-title>. <source>IEEE Trans. Neural Netw</source>. <volume>20</volume>, <fpage>81</fpage>–<lpage>102</lpage><pub-id pub-id-type="doi">10.1109/TNN.2008.2005141</pub-id><pub-id pub-id-type="pmid">19129034</pub-id></mixed-citation></ref><ref id="B89"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schaller</surname><given-names>G.</given-names></name><name><surname>Meyer-Hermann</surname><given-names>M.</given-names></name></person-group> (<year>2005</year>). <article-title>Multicellular tumor spheroid in an off-lattice Voronoi-Delaunay cell model</article-title>. <source>Phys. Rev. E Stat. Nonlin. Soft Matter Phys</source>. <volume>71</volume>:<fpage>51910</fpage><pub-id pub-id-type="doi">10.1103/PhysRevE.71.051910</pub-id><pub-id pub-id-type="pmid">16089574</pub-id></mixed-citation></ref><ref id="B90"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Singhvi</surname><given-names>R.</given-names></name><name><surname>Stephanopoulos</surname><given-names>G.</given-names></name><name><surname>Wang</surname><given-names>D. I. C.</given-names></name></person-group> (<year>1994</year>). <article-title>Effects of substratum morphology on cell physiology</article-title>. <source>Biotechnol. Bioeng</source>. <volume>43</volume>, <fpage>764</fpage>–<lpage>771</lpage><pub-id pub-id-type="doi">10.1002/bit.260430811</pub-id><pub-id pub-id-type="pmid">18615800</pub-id></mixed-citation></ref><ref id="B91"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Slusarczyk</surname><given-names>A. L.</given-names></name><name><surname>Lin</surname><given-names>A.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name></person-group> (<year>2012</year>). <article-title>Foundations for the design and implementation of synthetic genetic circuits</article-title>. <source>Nat. Rev. Genet</source>. <volume>13</volume>, <fpage>406</fpage>–<lpage>420</lpage><pub-id pub-id-type="doi">10.1038/nrg3227</pub-id><pub-id pub-id-type="pmid">22596318</pub-id></mixed-citation></ref><ref id="B92"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smolke</surname><given-names>C. D.</given-names></name><name><surname>Silver</surname><given-names>P. A.</given-names></name></person-group> (<year>2011</year>). <article-title>Informing biological design by integration of systems and synthetic biology</article-title>. <source>Cell</source><volume>144</volume>, <fpage>855</fpage>–<lpage>859</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2011.02.020</pub-id><pub-id pub-id-type="pmid">21414477</pub-id></mixed-citation></ref><ref id="B93"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Song</surname><given-names>H.</given-names></name><name><surname>Payne</surname><given-names>S.</given-names></name><name><surname>Gray</surname><given-names>M.</given-names></name><name><surname>You</surname><given-names>L.</given-names></name></person-group> (<year>2009</year>). <article-title>Spatiotemporal modulation of biodiversity in a synthetic chemical-mediated ecosystem</article-title>. <source>Nat. Chem. Biol</source>. <volume>5</volume>, <fpage>929</fpage>–<lpage>935</lpage><pub-id pub-id-type="doi">10.1038/nchembio.244</pub-id><pub-id pub-id-type="pmid">19915540</pub-id></mixed-citation></ref><ref id="B94"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sozzani</surname><given-names>R.</given-names></name><name><surname>Benfey</surname><given-names>P. N.</given-names></name></person-group> (<year>2011</year>). <article-title>High-throughput phenotyping of multicellular organisms: finding the link between genotype and phenotype</article-title>. <source>Genome Biol</source>. <volume>12</volume>, <fpage>219</fpage><pub-id pub-id-type="doi">10.1186/gb-2011-12-3-219</pub-id><pub-id pub-id-type="pmid">21457493</pub-id></mixed-citation></ref><ref id="B95"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Spicher</surname><given-names>A.</given-names></name><name><surname>Michel</surname><given-names>O.</given-names></name><name><surname>Giavitto</surname><given-names>J.-L.</given-names></name></person-group> (<year>2011</year>). <article-title>“Interaction-based simulations for integrative spatial systems biology,”</article-title> in <source>Understanding the Dynamics of Biological System</source>, eds <person-group person-group-type="editor"><name><surname>Dubitzky</surname><given-names>W.</given-names></name><name><surname>Southgate</surname><given-names>J.</given-names></name><name><surname>Fuß</surname><given-names>H.</given-names></name></person-group> (<publisher-loc>New York, NY</publisher-loc>: <publisher-name>Springer</publisher-name>), <fpage>195</fpage>–<lpage>231</lpage><pub-id pub-id-type="doi">10.1007/978-1-4419-7964-3_10</pub-id></mixed-citation></ref><ref id="B96"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stricker</surname><given-names>J.</given-names></name><name><surname>Cookson</surname><given-names>S.</given-names></name><name><surname>Bennett</surname><given-names>M. R.</given-names></name><name><surname>Mather</surname><given-names>W. H.</given-names></name><name><surname>Tsimring</surname><given-names>L. S.</given-names></name><name><surname>Hasty</surname><given-names>J.</given-names></name></person-group> (<year>2008</year>). <article-title>A fast, robust and tunable synthetic gene oscillator</article-title>. <source>Nature</source><volume>456</volume>, <fpage>516</fpage>–<lpage>519</lpage><pub-id pub-id-type="doi">10.1038/nature07389</pub-id><pub-id pub-id-type="pmid">18971928</pub-id></mixed-citation></ref><ref id="B97"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tabor</surname><given-names>J. J.</given-names></name><name><surname>Salis</surname><given-names>H.</given-names></name><name><surname>Simpson</surname><given-names>Z. B.</given-names></name><name><surname>Chevalier</surname><given-names>A. A.</given-names></name><name><surname>Levskaya</surname><given-names>A.</given-names></name><name><surname>Marcotte</surname><given-names>E. M.</given-names></name></person-group> (<year>2009</year>). <article-title>A synthetic genetic edge detection program</article-title>. <source>Cell</source><volume>137</volume>, <fpage>1272</fpage><pub-id pub-id-type="doi">10.1016/j.cell.2009.04.048</pub-id><pub-id pub-id-type="pmid">19563759</pub-id></mixed-citation></ref><ref id="B98"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takahashi</surname><given-names>K.</given-names></name><name><surname>Arjunan</surname><given-names>S. N. V.</given-names></name><name><surname>Tomita</surname><given-names>M.</given-names></name></person-group> (<year>2005</year>). <article-title>Space in systems biology of signaling pathways–towards intracellular molecular crowding <italic>in silico</italic></article-title>. <source>FEBS Lett</source>. <volume>579</volume>, <fpage>1783</fpage>–<lpage>1788</lpage><pub-id pub-id-type="doi">10.1016/j.febslet.2005.01.072</pub-id><pub-id pub-id-type="pmid">15763552</pub-id></mixed-citation></ref><ref id="B99"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tanaka</surname><given-names>H.</given-names></name><name><surname>Yi</surname><given-names>T.-M.</given-names></name></person-group> (<year>2009</year>). <article-title>Synthetic morphology using alternative inputs</article-title>. <source>PLoS ONE</source><volume>4</volume>:<fpage>e6946</fpage><pub-id pub-id-type="doi">10.1371/journal.pone.0006946</pub-id><pub-id pub-id-type="pmid">19746161</pub-id></mixed-citation></ref><ref id="B100"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thattai</surname><given-names>M.</given-names></name><name><surname>van Oudenaarden</surname><given-names>A.</given-names></name></person-group> (<year>2001</year>). <article-title>Intrinsic noise in gene regulatory networks</article-title>. <source>Proc. Natl. Acad. Sci. U.S.A</source>. <volume>98</volume>, <fpage>8614</fpage>–<lpage>8619</lpage><pub-id pub-id-type="doi">10.1073/pnas.151588598</pub-id><pub-id pub-id-type="pmid">11438714</pub-id></mixed-citation></ref><ref id="B101"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vendruscolo</surname><given-names>M.</given-names></name><name><surname>Dobson</surname><given-names>C. M.</given-names></name></person-group> (<year>2011</year>). <article-title>Protein dynamics: Moore's law in molecular biology</article-title>. <source>Curr. Biol</source>. <volume>21</volume>, <fpage>R68</fpage>–<lpage>R70</lpage><pub-id pub-id-type="doi">10.1016/j.cub.2010.11.062</pub-id><pub-id pub-id-type="pmid">21256436</pub-id></mixed-citation></ref><ref id="B102"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Walker</surname><given-names>D. C.</given-names></name><name><surname>Southgate</surname><given-names>J.</given-names></name></person-group> (<year>2013</year>). <article-title>The modulatory effect of cell–cell contact on the tumourigenic potential of pre-malignant epithelial cells: a computational exploration</article-title>. <source>J. R. Soc. Interface</source><volume>10</volume>, <fpage>1</fpage>–<lpage>12</lpage><pub-id pub-id-type="doi">10.1098/rsif.2012.0703</pub-id><pub-id pub-id-type="pmid">23097504</pub-id></mixed-citation></ref><ref id="B103"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>B.</given-names></name><name><surname>Buck</surname><given-names>M.</given-names></name></person-group> (<year>2012</year>). <article-title>Customizing cell signaling using engineered genetic logic circuits</article-title>. <source>Trends Microbiol</source>. <volume>20</volume>, <fpage>376</fpage>–<lpage>384</lpage><pub-id pub-id-type="doi">10.1016/j.tim.2012.05.001</pub-id><pub-id pub-id-type="pmid">22682075</pub-id></mixed-citation></ref><ref id="B104"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>B.</given-names></name><name><surname>Kitney</surname><given-names>R. I.</given-names></name><name><surname>Joly</surname><given-names>N.</given-names></name><name><surname>Buck</surname><given-names>M.</given-names></name></person-group> (<year>2011</year>). <article-title>Engineering modular and orthogonal genetic logic gates for robust digital-like synthetic biology</article-title>. <source>Nat. Commun</source>. <volume>2</volume>, <fpage>508</fpage><pub-id pub-id-type="doi">10.1038/ncomms1516</pub-id><pub-id pub-id-type="pmid">22009040</pub-id></mixed-citation></ref><ref id="B105"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>Z.</given-names></name><name><surname>Birch</surname><given-names>C. M.</given-names></name><name><surname>Sagotsky</surname><given-names>J.</given-names></name><name><surname>Deisboeck</surname><given-names>T. S.</given-names></name></person-group> (<year>2009</year>). <article-title>Cross-scale, cross-pathway evaluation using an agent-based non-small cell lung cancer model</article-title>. <source>Bioinformatics</source><volume>25</volume>, <fpage>2389</fpage>–<lpage>2396</lpage><pub-id pub-id-type="doi">10.1093/bioinformatics/btp416</pub-id><pub-id pub-id-type="pmid">19578172</pub-id></mixed-citation></ref><ref id="B106"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Win</surname><given-names>M. N.</given-names></name><name><surname>Smolke</surname><given-names>C. D.</given-names></name></person-group> (<year>2008</year>). <article-title>Higher-order cellular information processing with synthetic RNA devices</article-title>. <source>Science</source><volume>322</volume>, <fpage>456</fpage>–<lpage>460</lpage><pub-id pub-id-type="doi">10.1126/science.1160311</pub-id><pub-id pub-id-type="pmid">18927397</pub-id></mixed-citation></ref><ref id="B107"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wodarz</surname><given-names>D.</given-names></name><name><surname>Hofacre</surname><given-names>A.</given-names></name><name><surname>Lau</surname><given-names>J. W.</given-names></name><name><surname>Sun</surname><given-names>Z.</given-names></name><name><surname>Fan</surname><given-names>H.</given-names></name><name><surname>Komarova</surname><given-names>N. L.</given-names></name></person-group> (<year>2012</year>). <article-title>Complex spatial dynamics of oncolytic viruses <italic>in vitro</italic>: mathematical and experimental approaches</article-title>. <source>PLoS Comput. Biol</source>. <volume>8</volume>:<fpage>e1002547</fpage><pub-id pub-id-type="doi">10.1371/journal.pcbi.1002547</pub-id><pub-id pub-id-type="pmid">22719239</pub-id></mixed-citation></ref><ref id="B108"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xie</surname><given-names>Z.</given-names></name><name><surname>Wroblewska</surname><given-names>L.</given-names></name><name><surname>Prochazka</surname><given-names>L.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name><name><surname>Benenson</surname><given-names>Y.</given-names></name></person-group> (<year>2011</year>). <article-title>Multi-input RNAi-based logic circuit for identification of specific cancer cells</article-title>. <source>Science</source><volume>333</volume>, <fpage>1307</fpage><pub-id pub-id-type="doi">10.1126/science.1205527</pub-id><pub-id pub-id-type="pmid">21885784</pub-id></mixed-citation></ref><ref id="B109"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>J.</given-names></name><name><surname>Meng</surname><given-names>X.</given-names></name><name><surname>Hlavacek</surname><given-names>W. S.</given-names></name></person-group> (<year>2010</year>). <article-title>Rule-based modelling and simulation of biochemical systems with molecular finite automata</article-title>. <source>IET Syst. Biol</source>. <volume>4</volume>, <fpage>453</fpage>–<lpage>466</lpage><pub-id pub-id-type="doi">10.1049/iet-syb.2010.0015</pub-id><pub-id pub-id-type="pmid">21073243</pub-id></mixed-citation></ref><ref id="B110"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yeh</surname><given-names>B. J.</given-names></name><name><surname>Rutigliano</surname><given-names>R. J.</given-names></name><name><surname>Deb</surname><given-names>A.</given-names></name><name><surname>Bar-Sagi</surname><given-names>D.</given-names></name><name><surname>Lim</surname><given-names>W. A.</given-names></name></person-group> (<year>2007</year>). <article-title>Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors</article-title>. <source>Nature</source><volume>447</volume>, <fpage>596</fpage>–<lpage>600</lpage><pub-id pub-id-type="doi">10.1038/nature05851</pub-id><pub-id pub-id-type="pmid">17515921</pub-id></mixed-citation></ref><ref id="B111"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yingling</surname><given-names>M.</given-names></name><name><surname>O'Neill</surname><given-names>T.</given-names></name><name><surname>Skalak</surname><given-names>T. C.</given-names></name><name><surname>Peirce-Cottler</surname><given-names>S.</given-names></name></person-group> (<year>2005</year>). <article-title>A cellular automata model of circulating cell adhesion and transmigration in the microvaculature</article-title>. <source>IEEE Syst. Inform. Eng. Des. Symp</source>. <volume>1</volume>, <fpage>356</fpage>–<lpage>361</lpage><pub-id pub-id-type="doi">10.1109/SIEDS.2005.193280</pub-id></mixed-citation></ref><ref id="B112"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>You</surname><given-names>L.</given-names></name><name><surname>Cox</surname><given-names>R. S.</given-names></name><name><surname>Weiss</surname><given-names>R.</given-names></name><name><surname>Arnold</surname><given-names>F. H.</given-names></name></person-group> (<year>2004</year>). <article-title>Programmed population control by cell–cell communication and regulated killing</article-title>. <source>Nature</source><volume>428</volume>, <fpage>868</fpage>–<lpage>871</lpage><pub-id pub-id-type="doi">10.1038/nature02491</pub-id><pub-id pub-id-type="pmid">15064770</pub-id></mixed-citation></ref><ref id="B113"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Young</surname><given-names>E.</given-names></name><name><surname>Alper</surname><given-names>H.</given-names></name></person-group> (<year>2010</year>). <article-title>Synthetic biology: tools to design, build, and optimize cellular processes</article-title>. <source>J. Biomed. Biotechnol</source>. <volume>2010</volume>, <fpage>1</fpage>–<lpage>12</lpage><pub-id pub-id-type="doi">10.1155/2010/130781</pub-id><pub-id pub-id-type="pmid">20150964</pub-id></mixed-citation></ref><ref id="B114"><mixed-citation publication-type="book"><person-group person-group-type="author"><name><surname>Zomaya</surname><given-names>A. Y.</given-names></name><name><surname>Kazman</surname><given-names>R.</given-names></name></person-group> (<year>2010</year>). <article-title>“Simulated annealing techniques,”</article-title> in <source>Algorithms and Theory of Computation Handbook</source>, eds <person-group person-group-type="editor"><name><surname>Atallah</surname><given-names>M. J.</given-names></name><name><surname>Blanton</surname><given-names>M.</given-names></name></person-group> (<publisher-loc>Boca Raton, FL</publisher-loc>: <publisher-name>CRC Press</publisher-name>), 33.</mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Ticri/CIDE/explor/CyberinfraV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000541 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000541 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Ticri/CIDE
|area= CyberinfraV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:3793170
|texte= Systems approaches for synthetic biology: a pathway toward mammalian design
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:24130532" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CyberinfraV1
| This area was generated with Dilib version V0.6.25. |  |