674:
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gene interactions and mathematical models. This issue is being addressed by applying computer-aided design (CAD) software to provide multimedia representations of circuits through images, text and programming language applied to biological circuits. Some of the more well known CAD programs include GenoCAD, Clotho framework and j5. GenoCAD uses grammars, which are either opensource or user generated "rules" which include the available genes and known gene interactions for cloning organisms. Clotho framework uses the
221:
496:. Those demonstrated successfully include pharmaceutical production, and fuel production. However, methods involving direct genetic introduction are not inherently effective without invoking the basic principles of synthetic cellular circuits. For example, each of these successful systems employs a method to introduce all-or-none induction or expression. This is a biological circuit where a simple
685:
and the corresponding increase in competition within the industry have led to a significant drop in price and wait time of gene synthesis and helped improve methods used in circuit design. At the moment, circuit design is improving at a slow pace because of insufficient organization of known multiple
638:
result. All promoters shown are inducible. The activating promoter for the output gene is constitutive, and thus not shown. The constitutive promoter for the output gene keeps it "on" and is only deactivated when (similar to the AND gate) a complex as a result of two input signal gene products blocks
517:
cell, one can add pieces from the toolbox to create a well defined pathway with appropriate synthetic circuitry for an effective feedback system. Because of the basic ground up construction method, and the proposed database of mapped circuitry pieces, techniques mirroring those used to model computer
508:
Development in understanding cellular circuitry can lead to exciting new modifications, such as cells which can respond to environmental stimuli. For example, cells could be developed that signal toxic surroundings and react by activating pathways used to degrade the perceived toxin. To develop such
504:
is introduced to facilitate creation of the product, or inhibition of a competing pathway. However, with the limited understanding of cellular networks and natural circuitry, implementation of more robust schemes with more precise control and feedback is hindered. Therein lies the immediate interest
613:
Signal B are present, then the desired gene product will result. All promoters shown are inducible. Either signal is capable of activating the expression of the output gene product, and only the action of a single promoter is required for gene expression. Post-transcriptional regulation mechanisms
571:
Toggle switch which operates using two mutually inhibitory genes, each promoter is inhibited by the repressor that is transcribed by the opposing promoter. Toggle switch design: Inducer 1 inactivates repressor 1, which means repressor 2 is produced. Repressor 2, in turn, stops transcription of the
512:
Given synthetic cellular circuits represent a form of control for cellular activities, it can be reasoned that with complete understanding of cellular pathways, "plug and play" cells with well defined genetic circuitry can be engineered. It is widely believed that if a proper toolbox of parts is
664:
Engineered systems are the result of implementation of combinations of different control mechanisms. A limited counting mechanism was implemented by a pulse-controlled gene cascade and application of logic elements enables genetic "programming" of cells as in the research of Tabor et al., which
567:
Gene regulation is an essential part of developmental processes. During development, genes are turned on and off in different tissues, changes in regulatory mechanisms may result in genetic switching in a bistable system, the gene switches serve as regulatory molecule binding sites. These are
337:
The goal of synthetic biology is to generate an array of tunable and characterized parts, or modules, with which any desirable synthetic biological circuit can be easily designed and implemented. These circuits can serve as a method to modify cellular functions, create cellular responses to
592:
Signal B are present, then the desired gene product will result. All promoters shown are inducible, activated by the displayed gene product. Each signal activates expression of a separate gene (shown in light blue). The expressed proteins then can either form a complete complex in
475:
with more publications detailing synthetic biological circuits published every year. There has been significant interest in encouraging education and outreach as well: the
International Genetically Engineered Machines Competition manages the creation and standardization of
421:
under the control of the lac promoter. Initially the cells are grown in a medium that does not contain lactose or other sugars, so the new genes are not expressed. Once the cells reach a certain point in their growth,
563:
Gardner et al. used mutual repression between two control units to create an implementation of a toggle switch capable of controlling cells in a bistable manner: transient stimuli resulting in persistent responses.
597:, that is capable of activating expression of the output (shown), or can act separately to induce expression, such as separately removing an inhibiting protein and inducing activation of the uninhibited promoter.
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proteins that activate transcription when they land on a gene switch and thereby express the gene that was expected to operate as a memory device, allowing cell fate decisions to be chosen and maintained.
623:
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metabolism. They discovered that the mechanism that controlled the metabolic "switching" function was a two-part control mechanism on the lac operon. When lactose is present in the cell the
338:
environmental conditions, or influence cellular development. By implementing rational, controllable logic elements in cellular systems, researchers can use living systems as engineered "
322:
449:. The switch is turned on by heating the culture of bacteria and turned off by addition of IPTG. They used green fluorescent protein as a reporter for their system. The second, by
200:
648:
Using negative feedback and identical promoters, linearizer gene circuits can impose uniform gene expression that depends linearly on extracellular chemical inducer concentration.
961:
Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, et al. (April 2006). "Production of the antimalarial drug precursor artemisinic acid in engineered yeast".
550:
Elowitz et al. and Fung et al. created oscillatory circuits that use multiple self-regulating mechanisms to create a time-dependent oscillation of gene product expression.
310:
that interact to create the circuit's behavior. The applications of all three types of circuit range from simply inducing production to adding a measurable element, like
513:
generated, synthetic cells can be developed implementing only the pathways necessary for cell survival and reproduction. From this cell, to be thought of as a minimal
399:. When lactose is absent in the cell the lac repressor inhibits the production of the enzyme β-galactosidase to prevent any inefficient processes within the cell.
1852:
430:" the production of the new protein. Once the cells are induced, it is difficult to remove IPTG from the cells and therefore it is difficult to stop expression.
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is added. IPTG, a molecule similar to lactose, but with a sulfur bond that is not hydrolyzable so that E. coli does not digest it, is used to activate or "
427:
207:
1098:
Lucks JB, Qi L, Whitaker WR, Arkin AP (December 2008). "Toward scalable parts families for predictable design of biological circuits".
673:
488:
Both immediate and long term applications exist for the use of synthetic biological circuits, including different applications for
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or electronic circuits can be used to redesign cells and model cells for easy troubleshooting and predictive behavior and yields.
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Synthetic gene circuits can control gene expression heterogeneity can be controlled independently of the gene expression mean.
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54:
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a cell, it is necessary to create a complex synthetic cellular circuit which can respond appropriately to a given stimulus.
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can prevent the presence of both inputs producing a compounded high output, such as implementing a low binding affinity
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parts as a means to allow undergraduate and high school students to design their own synthetic biological circuits.
1348:
Silva-Rocha R, de
Lorenzo V (April 2008). "Mining logic gates in prokaryotic transcriptional regulation networks".
228:
operon is a natural biological circuit on which many synthetic circuits are based. Top: Repressed, Bottom: Active.
771:
1292:
Gardner TS, Cantor CR, Collins JJ (January 2000). "Construction of a genetic toggle switch in
Escherichia coli".
804:
Gardner TS, Cantor CR, Collins JJ (January 2000). "Construction of a genetic toggle switch in
Escherichia coli".
1791:
171:
1457:"Negative autoregulation linearizes the dose-response and suppresses the heterogeneity of gene expression"
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Fung E, Wong WW, Suen JK, Bulter T, Lee SG, Liao JC (May 2005). "A synthetic gene-metabolic oscillator".
438:
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Elowitz MB, Leibler S (January 2000). "A synthetic oscillatory network of transcriptional regulators".
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Elowitz MB, Leibler S (January 2000). "A synthetic oscillatory network of transcriptional regulators".
193:
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682:
311:
100:
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Purnick PE, Weiss R (June 2009). "The second wave of synthetic biology: from modules to systems".
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111:
44:
1612:
Tabor JJ, Salis HM, Simpson ZB, Chevalier AA, Levskaya A, Marcotte EM, et al. (June 2009).
181:
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Blake WJ, Balázsi G, Kohanski MA, Isaacs FJ, Murphy KF, Kuang Y, et al. (December 2006).
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Fortman JL, Chhabra S, Mukhopadhyay A, Chou H, Lee TS, Steen E, Keasling JD (July 2008).
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Kobayashi H, Kaern M, Araki M, Chung K, Gardner TS, Cantor CR, Collins JJ (June 2004).
339:
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1237:"Balancing a genetic toggle switch by real-time feedback control and periodic forcing"
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Lugagne JB, Sosa
Carrillo S, Kirch M, Köhler A, Batt G, Hersen P (November 2017).
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Computational design and evaluation of DNA circuits to achieve optimal performance
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Proceedings of the
National Academy of Sciences of the United States of America
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Proceedings of the
National Academy of Sciences of the United States of America
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Proceedings of the
National Academy of Sciences of the United States of America
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714:"Programmable cells: interfacing natural and engineered gene networks"
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Two early examples of synthetic biological circuits were published in
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are designed to perform logical functions mimicking those observed in
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Friedland AE, Lu TK, Wang X, Shi D, Church G, Collins JJ (May 2009).
1313:
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876:
825:
497:
414:
396:
117:
1715:"Mining high-throughput experimental data to link gene and function"
1516:"Phenotypic consequences of promoter-mediated transcriptional noise"
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585:
477:
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Currently, synthetic circuits are a burgeoning area of research in
410:
326:
49:
1455:
Nevozhay D, Adams RM, Murphy KF, Josic K, Balázsi G (March 2009).
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457:, showed that three repressor genes could be connected to form a
418:
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that produces self-sustaining oscillations of protein levels in
1234:
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synthesized a photosensitive bacterial edge detection program.
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385:
72:
1011:
1014:"Biofuel alternatives to ethanol: pumping the microbial well"
220:
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Gene regulation: Towards a circuit engineering discipline
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Signal B are present, then the desired gene product will
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for therapeutic use. The gene or genes for producing an
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The first natural gene circuit studied in detail was the
1454:
711:
318:, to implementing completely new systems of many parts.
1663:"Synthetic biology: an emerging engineering discipline"
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1820:
294:. Typically, these circuits are categorized as either
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948:
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1097:
803:
1708:
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437:in 2000. One, by Tim Gardner, Charles Cantor, and
376:preferentially consumes the more easily processed
1398:"On schemes of combinatorial transcription logic"
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1859:
1713:Blaby-Haas CE, de Crécy-Lagard V (April 2011).
1703:
342:" to perform a vast range of useful functions.
1132:
854:
1763:"GenoCAD: CAD Software for Synthetic Biology"
201:
1614:"A synthetic genetic edge detection program"
1507:
1448:
905:
652:Controllers of gene expression heterogeneity
424:isopropyl β-D-1-thiogalactopyranoside (IPTG)
1396:Buchler NE, Gerland U, Hwa T (April 2003).
1061:"Synthetic biology for synthetic chemistry"
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572:repressor 1 gene and the reporter gene.
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1667:Annual Review of Biomedical Engineering
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908:Nature Reviews. Molecular Cell Biology
794:
540:Bacterial tunable synthetic oscillator
537:Mammalian tunable synthetic oscillator
445:, demonstrated a "bistable" switch in
1336:
546:Globally coupled bacterial oscillator
483:
55:Registry of Standard Biological Parts
1680:10.1146/annurev-bioeng-071811-150118
1557:"Synthetic gene networks that count"
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553:
391:is produced to convert lactose into
521:
13:
639:the expression of the output gene.
14:
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505:in synthetic cellular circuits.
286:where biological parts inside a
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1100:Current Opinion in Microbiology
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21:Part of a series of articles on
1661:Cheng AA, Lu TK (2012-01-01).
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526:
402:The lac operon is used in the
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1853:Synthetic Genetic Oscillators
1731:10.1016/j.tibtech.2011.01.001
1362:10.1016/j.febslet.2008.01.060
1030:10.1016/j.tibtech.2008.03.008
693:
280:Synthetic biological circuits
36:Synthetic biological circuits
1533:10.1016/j.molcel.2006.11.003
1059:Keasling JD (January 2008).
543:Coupled bacterial oscillator
306:, depending on the types of
7:
1821:"j5 automated DNA assembly"
406:industry for production of
10:
1884:
1630:10.1016/j.cell.2009.04.048
1261:10.1038/s41467-017-01498-0
345:
316:natural biological circuit
1112:10.1016/j.mib.2008.10.002
950:http://igem.org/Main_Page
683:artificial gene synthesis
312:green fluorescent protein
101:Artificial gene synthesis
772:"Synthetic Biology: FAQ"
660:Other engineered systems
417:protein are placed on a
1719:Trends in Biotechnology
1581:10.1126/science.1172005
1482:10.1073/pnas.0809901106
1423:10.1073/pnas.0930314100
1018:Trends in Biotechnology
739:10.1073/pnas.0402940101
681:Recent developments in
112:Mycoplasma laboratorium
45:Synthetic gene database
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282:are an application of
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182:Do-it-yourself biology
177:Open synthetic biology
1241:Nature Communications
676:
625:
616:ribosome binding site
604:
583:
490:metabolic engineering
324:
223:
151:Expanded genetic code
136:Nucleic acid analogue
1065:ACS Chemical Biology
776:SyntheticBiology.org
380:before switching to
364:on two-sugar media,
83:Synthetic immunology
1802:on 26 December 2014
1573:2009Sci...324.1199F
1567:(5931): 1199–1202.
1473:2009PNAS..106.5123N
1414:2003PNAS..100.5136B
1306:2000Natur.403..339G
1253:2017NatCo...8.1671L
1206:10.1038/nature03508
1198:2005Natur.435..118F
1147:2000Natur.403..335E
983:10.1038/nature04640
975:2006Natur.440..940R
869:2000Natur.403..335E
818:2000Natur.403..339G
782:on 12 December 2002
730:2004PNAS..101.8414K
340:biological machines
292:electronic circuits
146:Unnatural base pair
1773:on 5 February 2016
679:
641:
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484:Interest and goals
335:
331:biological machine
277:
234:: RNA polymerase,
106:Synthetic genomics
1868:Synthetic biology
1796:www.clothocad.org
1467:(13): 5123–5128.
1300:(6767): 339–342.
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1077:10.1021/cb7002434
969:(7086): 940–943.
863:(6767): 335–338.
724:(22): 8414–8419.
688:Biobrick standard
576:Logical operators
554:Bistable switches
494:synthetic biology
459:negative feedback
455:Stanislas Leibler
443:Boston University
314:, to an existing
284:synthetic biology
218:
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141:Xeno nucleic acid
29:Synthetic biology
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812:(6767): 339–42.
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778:. Archived from
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628:Negated AND gate
522:Example circuits
461:loop termed the
372:discovered that
354:. In studies of
304:protein circuits
296:genetic circuits
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389:β-galactosidase
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246:: Operator,
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242:: Promoter,
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164:Other topics
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78:Gene therapy
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1825:j5.jbei.org
1247:(1): 1671.
786:21 December
527:Oscillators
441:working at
439:Jim Collins
408:recombinant
308:biomolecule
250:: Lactose,
156:Mirror life
127:Xenobiology
1830:2015-10-21
1806:2015-10-21
1777:2015-10-21
694:References
352:lac operon
1046:205388761
498:repressor
415:exogenous
397:galactose
118:Protocell
1862:Category
1792:"Clotho"
1749:21310501
1689:22577777
1648:19563759
1599:19478183
1542:17189188
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1038:18471913
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928:19461664
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834:10659857
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586:AND gate
502:promoter
478:BioBrick
467:E. coli.
411:proteins
327:ribosome
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1740:3073767
1697:7319630
1639:2775486
1590:2690711
1569:Bibcode
1561:Science
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865:Bibcode
814:Bibcode
726:Bibcode
690:rules.
607:OR gate
595:cytosol
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419:plasmid
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361:E. coli
346:History
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435:Nature
428:induce
386:enzyme
374:E.coli
73:CRISPR
1693:S2CID
1374:S2CID
1326:S2CID
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1167:S2CID
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830:PMID
788:2011
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453:and
368:and
288:cell
272:lacA
264:lacY
256:lacZ
224:The
1735:PMC
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