Smolke:Research - Revision history

Smolke: /* Engineering yeast as a natural product biosynthesis platform */

Smolke — Tue, 15 Mar 2011 05:15:27 GMT

Engineering yeast as a natural product biosynthesis platform

←Older revision		Revision as of 05:15, 15 March 2011
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	=Systems Engineering of Cellular Behaviors=		=Systems Engineering of Cellular Behaviors=
	==Engineering yeast as a natural product biosynthesis platform==		==Engineering yeast as a natural product biosynthesis platform==
-	''Researchers: Stephanie Galanie, Josh Michener, Michael Siddiqui~~, Isis Trenchard~~, Kate Thodey''	+	''Researchers: Stephanie Galanie, Josh Michener, Michael Siddiqui, Kate Thodey, Isis Trenchard''

	Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from natural sources and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. We are integrating recent advances in synthetic biology to transform the complexity of genetic networks that can be engineered in biological systems to engineer scalable cellular biosynthesis schemes for important classes of natural products. Specifically, we have focused our efforts on purine alkaloid (Win et al., in preparation) and benzylisoquinoline alkaloid (BIA) biosynthesis pathways (Hawkins et al., Nat Chem Biol 2008). The BIAs are a large class of plant secondary metabolites that exhibit diverse pharmacological activities, including anti-HIV, antimicrobial, anticancer, antineoplastic, vasorelaxation, and cholesterol-lowering activities, and activities for treating cardiovascular and autoimmune diseases. Although the BIAs populate a chemical space with many compelling activities, there currently exists no general source for the BIAs as many of the molecules are too complex for synthetic chemical methods and only a select few accumulate to substantial levels in the native plant hosts. The complexity associated with the BIA biosynthesis pathway, in terms of number of enzymes and complexity of chemistries and regulatory strategies, requires the integration of new approaches to cellular biosynthesis for effective implementation. We demonstrated one of the first examples of biosynthesis of an array of BIA molecules in a microbial host (Hawkins et al., Nat Chem Biol 2008), through the integration of enzymes from plants, bacteria, and humans. Ongoing research efforts are directed to the extension of the synthetic BIA pathway into key branches - the early BIA branch (to enable total synthesis from common precursors) and specialty chemical branches (to enable synthesis of morphinan, benzophenanthridine, and bis-BIAs).		Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from natural sources and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. We are integrating recent advances in synthetic biology to transform the complexity of genetic networks that can be engineered in biological systems to engineer scalable cellular biosynthesis schemes for important classes of natural products. Specifically, we have focused our efforts on purine alkaloid (Win et al., in preparation) and benzylisoquinoline alkaloid (BIA) biosynthesis pathways (Hawkins et al., Nat Chem Biol 2008). The BIAs are a large class of plant secondary metabolites that exhibit diverse pharmacological activities, including anti-HIV, antimicrobial, anticancer, antineoplastic, vasorelaxation, and cholesterol-lowering activities, and activities for treating cardiovascular and autoimmune diseases. Although the BIAs populate a chemical space with many compelling activities, there currently exists no general source for the BIAs as many of the molecules are too complex for synthetic chemical methods and only a select few accumulate to substantial levels in the native plant hosts. The complexity associated with the BIA biosynthesis pathway, in terms of number of enzymes and complexity of chemistries and regulatory strategies, requires the integration of new approaches to cellular biosynthesis for effective implementation. We demonstrated one of the first examples of biosynthesis of an array of BIA molecules in a microbial host (Hawkins et al., Nat Chem Biol 2008), through the integration of enzymes from plants, bacteria, and humans. Ongoing research efforts are directed to the extension of the synthetic BIA pathway into key branches - the early BIA branch (to enable total synthesis from common precursors) and specialty chemical branches (to enable synthesis of morphinan, benzophenanthridine, and bis-BIAs).

Smolke: /* Engineering higher-order cellular information processing devices */

Smolke — Tue, 15 Mar 2011 05:14:49 GMT

Engineering higher-order cellular information processing devices

←Older revision		Revision as of 05:14, 15 March 2011
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	==Engineering higher-order cellular information processing devices==		==Engineering higher-order cellular information processing devices==
-	''Researchers: Leo d’Espaux, Yen-Hsiang Wang''	+	''Researchers: Leo d’Espaux, Katie Galloway, Yen-Hsiang Wang''

	We have demonstrated the extension of the single-input RNA device frameworks to the construction of higher-order devices that perform multi-input signal processing in living systems (Win et al., Science 2008; Culler et al., Science 2010), further supporting the power of the developed modular assembly strategy. As an example, my laboratory described extended architectures for rationally assembling RNA components (sensors, actuators, transmitters) into multi-input signal integration devices and built genetic devices that function as logic gates, signal and bandpass filters, and exhibited cooperativity. Our research has demonstrated that the developed design frameworks provide a general approach for the forward engineering of multi-input devices, supporting the combinatorial assembly of many information processing, transduction, and control devices from a smaller number of components. More generally, this work has demonstrated the application of synthetic biology design strategies to scalable platforms for genetic device design and that advances in engineering design can transform the scale, efficiency, and speed with which we can engineer cellular behaviors.		We have demonstrated the extension of the single-input RNA device frameworks to the construction of higher-order devices that perform multi-input signal processing in living systems (Win et al., Science 2008; Culler et al., Science 2010), further supporting the power of the developed modular assembly strategy. As an example, my laboratory described extended architectures for rationally assembling RNA components (sensors, actuators, transmitters) into multi-input signal integration devices and built genetic devices that function as logic gates, signal and bandpass filters, and exhibited cooperativity. Our research has demonstrated that the developed design frameworks provide a general approach for the forward engineering of multi-input devices, supporting the combinatorial assembly of many information processing, transduction, and control devices from a smaller number of components. More generally, this work has demonstrated the application of synthetic biology design strategies to scalable platforms for genetic device design and that advances in engineering design can transform the scale, efficiency, and speed with which we can engineer cellular behaviors.

Smolke at 05:11, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:11:30 GMT

←Older revision		Revision as of 05:11, 15 March 2011
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	[[#Research\|Back to Top]]		[[#Research\|Back to Top]]

-	==~~Designing ‘intelligent’ therapeutic molecules~~==	+	=Systems Engineering of Cellular Behaviors=
-	''Researchers: ~~Ryan Bloom~~, ~~Leo d’Espaux~~, ~~Megan Palmer~~, ~~Jay Vowles~~, ~~Kathy Wei~~''	+	==Engineering yeast as a natural product biosynthesis platform==
		+	''Researchers: Stephanie Galanie, Josh Michener, Michael Siddiqui, Isis Trenchard, Kate Thodey''

-	~~We are designing molecular switches to act as targeted~~ or ~~‘intelligent’ therapeutic~~ molecules. ~~Projects in this area focus~~ on the ~~construction~~ of ~~ligand-regulated RNA-based regulators~~ of ~~gene expression that function~~ in ~~mammalian cells through diverse regulatory mechanisms such as the RNAi pathway or ribozyme-based cleavage~~. ~~Research areas have been initiated~~ in the ~~design~~ of ~~molecular switches~~ for ~~advancing targeted breast cancer treatments~~ and ~~immunotherapy strategies~~. ~~In the area~~ of ~~developing next~~-~~generation cancer therapies~~ and ~~detection strategies~~, ~~RNA switches will be constructed to take different hormone~~ and ~~growth factor biomarkers identified~~ for ~~different breast cancers as input signals~~. ~~In response~~ to the ~~presence~~ of ~~particular set~~ of ~~biomarker indicative~~ of ~~breast cancer~~, ~~these molecules will regulate~~ the ~~expression~~ of ~~target output genes such as genes involved in regulating~~ cellular ~~behavior~~ (~~apoptosis~~, ~~cancer phenotype~~) ~~or genes associated with a monitorable signal~~ (~~detection/diagnosis strategies~~). In the ~~latter area~~, ~~RNA switches~~ will ~~be constructed~~ to ~~take target small molecules or biomarkers~~ for ~~different tumor cells as~~ input ~~signals~~. ~~These molecular switches will be engineered into T cells and respond~~ to the ~~presence~~ of ~~these localized inputs by activating the T cell~~ to ~~kill~~ the ~~nearby tumor cells, thereby developing more effective~~ and ~~safe immunotherapy treatments~~. ~~Cellular engineering projects~~ are ~~currently being conducted in model cell lines~~ and will ~~later effectively be transferred into animal models~~ for ~~these diseases. Both~~ of ~~these projects have translational clinical collaborators at the City of Hope (Professors Carlotta Glackin - breast cancer therapies; Mike Jensen - T cell engineering)~~.	+	Natural products and compounds derived from or inspired by natural products make up a large fraction of drug molecules. Traditional synthesis strategies based on recovery from natural sources and chemical synthesis approaches present many challenges associated with the purity, scale, and complexity of the compounds. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. We are integrating recent advances in synthetic biology to transform the complexity of genetic networks that can be engineered in biological systems to engineer scalable cellular biosynthesis schemes for important classes of natural products. Specifically, we have focused our efforts on purine alkaloid (Win et al., in preparation) and benzylisoquinoline alkaloid (BIA) biosynthesis pathways (Hawkins et al., Nat Chem Biol 2008). The BIAs are a large class of plant secondary metabolites that exhibit diverse pharmacological activities, including anti-HIV, antimicrobial, anticancer, antineoplastic, vasorelaxation, and cholesterol-lowering activities, and activities for treating cardiovascular and autoimmune diseases. Although the BIAs populate a chemical space with many compelling activities, there currently exists no general source for the BIAs as many of the molecules are too complex for synthetic chemical methods and only a select few accumulate to substantial levels in the native plant hosts. The complexity associated with the BIA biosynthesis pathway, in terms of number of enzymes and complexity of chemistries and regulatory strategies, requires the integration of new approaches to cellular biosynthesis for effective implementation. We demonstrated one of the first examples of biosynthesis of an array of BIA molecules in a microbial host (Hawkins et al., Nat Chem Biol 2008), through the integration of enzymes from plants, bacteria, and humans. Ongoing research efforts are directed to the extension of the synthetic BIA pathway into key branches - the early BIA branch (to enable total synthesis from common precursors) and specialty chemical branches (to enable synthesis of morphinan, benzophenanthridine, and bis-BIAs).
		+
		+	In conjunction with the above pathway reconstruction work, we are developing synthetic biology platforms that will advance the application of cellular biosynthesis strategies to natural product drug discovery, development, and production. As one example, we are pioneering approaches for noninvasive and real-time sensing of metabolite levels based on implementing RNA devices that sense key metabolite or cofactors and regulate fluorescent proteins in response to changing input concentrations (Win et al., PNAS 2007). This tool is currently being used to screen enzyme libraries for enhanced activities. As a second example, we will apply RNA devices that regulate the levels of target pathway enzymes in response to changes in the concentrations of key metabolites and cofactors to implement closed loop embedded control of biosynthesis system behavior. As a third example, we are developing approaches for biosynthesis compartmentalization and specialization. These new approaches will provide a general platform for scalable production of diverse natural product families.

	[[#Research\|Back to Top]]		[[#Research\|Back to Top]]

-	==~~Metabolic engineering of Saccharomyces cerevisiae for alkaloid production~~==	+	==Engineering next-generation molecular and cellular therapies==
-	''Researchers: ~~Stephanie Galanie~~, ~~Josh Michener~~, ~~Michael Siddiqui~~, ~~Isis Trenchard~~, ~~Kate Thodey~~''	+	''Researchers: Ryan Bloom, Leo d’Espaux, Katie Galloway, Megan Palmer, Jay Vowles, Kathy Wei, Josh Wolf''

-	~~We are engineering synthetic circuits in yeast for the production~~ of ~~different value-added compounds~~. ~~Current research~~ efforts ~~are~~ focused on the ~~development~~ of ~~Saccharomyces cerevisiae as a microbial host for the total biosynthesis of diverse alkaloid compounds~~. ~~Synthetic metabolic pathways are being assembled for~~ the ~~production~~ of ~~two different classes of alkaloids~~, ~~the purine alkaloids~~ and ~~the benzylisoquinoline alkaloids~~ (~~BIAs)~~. ~~The purine alkaloid pathway~~, ~~resulting~~ in ~~the synthesis of caffeine~~ and ~~similar analogs~~, ~~is being engineered in yeast largely as a model pathway through which~~ to ~~explore general design principles~~ and ~~strategies for integrating molecular switches and assembling signal processing schemes with synthetic metabolic pathways~~. ~~Strategies will be developed for applying these~~ engineered ~~molecular switches for establishing rapid and generalizable pathway optimization screens and selections~~. ~~Furthermore~~, ~~control theory will be used to explore~~ the ~~design parameters for constructing dynamically regulated networks with switch~~-~~based control loops as a way~~ to ~~optimize pathway flux~~. ~~The purine alkaloid pathway enables a more immediate demonstration of~~ these ~~strategies~~ and design ~~principles as aptamers to these metabolites are readily available~~.	+	Cellular behavior is encoded and controlled by complex genetic networks. Synthetic genetic devices that interface with native pathways can be used to change natural networks to implement new forms of control and behavior. We have integrated engineered RNA devices into biological systems to reprogram cellular behavior. Our efforts to date have focused on the design of next-generation molecular and cellular therapeutic strategies. As one example, we demonstrated the application of engineered RNA devices as autonomous controllers over cellular behavior, and specifically as molecular therapies targeted to diseased cells (Culler et al., Science 2010). We engineered RNA devices that detect increased signaling through disease-associated pathways in human cells and rewire these pathways to produce new behaviors, thereby linking disease markers to noninvasive sensing and reprogrammed cellular fates. As another example, we demonstrated the application of engineered RNA devices as key controllers of cell-fate in cellular therapeutic strategies (Chen et al., PNAS 2010). In particular, we implemented drug-responsive RNA devices in mammalian and human T cells that target specific components of the T-cell signaling pathway to regulate T-cell proliferation in vivo through an exogenously applied drug. This work has highlighted advantages afforded by these RNA-based devices in translation to therapeutic applications and addressing key challenges in the design of safer and more effective therapeutic strategies.

-	~~The BIA pathway, resulting in~~ the ~~synthesis~~ of ~~codeine~~, ~~morphine, and sanguinarine, is being explored for generating a microbial host~~ that ~~can (i) readily synthesize an array of BIA~~ molecules ~~with diverse pharmacological activities~~ and ~~(ii) be used~~ to ~~set up rapid functional genomics screens to effectively identify enzymes~~ that ~~can act on these molecules from EST libraries of native plant hosts~~. The ~~BIA pathway is particularly appropriate~~ to this type of metabolic engineering effort as they are a complex class of molecules that are not effectively synthesized through traditional chemical means. In addition, there is no source for many of the intermediate metabolites of pharmaceutical interest, as they do not accumulate in ~~the native hosts~~ and ~~genetic engineering efforts remain challenging~~ in ~~plants~~. As the ~~pathway including the early steps resulting in the synthesis of the BIA backbone (norcoclaurine~~) ~~has not been entirely elucidated from plant hosts, a synthetic network composed of genes from bacteria, humans, and various plants is being assembled and optimized for BIA production in yeast~~. ~~It is anticipated that~~ the ~~molecular tools developed~~ in ~~the purine alkaloid pathway will be readily transferable to the BIA pathway~~. ~~This research effort has a plant biologist collaborator from~~ the ~~University~~ of ~~Calgary (Peter Facchini)~~.	+	Ongoing research efforts are focused on extending the integration of RNA devices with different cellular pathways to achieve reprogramming of diverse cellular behaviors. As one example, we are continuing efforts on the T-cell engineering project to develop tailored RNA devices that respond to clinically-approved drug molecules and to develop integrated systems designs that provide a more robust response. The longer-term goal of this research will be to conduct systemic in vivo studies and ultimately human clinical trials (in collaboration with Dr. Michael Jensen at the Seattle Children’s Research Institute). Future work will explore the implementation of these genetic devices in other cellular therapy applications, such as stem cells. We are also examining the implementation of RNA devices in pathways associated with MAPK signaling and cell cycle.

	[[#Research\|Back to Top]]		[[#Research\|Back to Top]]

Smolke at 05:08, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:08:38 GMT

Show changes

Smolke: /* Engineering higher-order cellular information processing devices */

Smolke — Tue, 15 Mar 2011 05:05:51 GMT

Engineering higher-order cellular information processing devices

←Older revision		Revision as of 05:05, 15 March 2011
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	==Engineering higher-order cellular information processing devices==		==Engineering higher-order cellular information processing devices==
	''Researchers: Leo d’Espaux, Yen-Hsiang Wang''		''Researchers: Leo d’Espaux, Yen-Hsiang Wang''
		+
	We have demonstrated the extension of the single-input RNA device frameworks to the construction of higher-order devices that perform multi-input signal processing in living systems (Win et al., Science 2008; Culler et al., Science 2010), further supporting the power of the developed modular assembly strategy. As an example, my laboratory described extended architectures for rationally assembling RNA components (sensors, actuators, transmitters) into multi-input signal integration devices and built genetic devices that function as logic gates, signal and bandpass filters, and exhibited cooperativity. Our research has demonstrated that the developed design frameworks provide a general approach for the forward engineering of multi-input devices, supporting the combinatorial assembly of many information processing, transduction, and control devices from a smaller number of components. More generally, this work has demonstrated the application of synthetic biology design strategies to scalable platforms for genetic device design and that advances in engineering design can transform the scale, efficiency, and speed with which we can engineer cellular behaviors.		We have demonstrated the extension of the single-input RNA device frameworks to the construction of higher-order devices that perform multi-input signal processing in living systems (Win et al., Science 2008; Culler et al., Science 2010), further supporting the power of the developed modular assembly strategy. As an example, my laboratory described extended architectures for rationally assembling RNA components (sensors, actuators, transmitters) into multi-input signal integration devices and built genetic devices that function as logic gates, signal and bandpass filters, and exhibited cooperativity. Our research has demonstrated that the developed design frameworks provide a general approach for the forward engineering of multi-input devices, supporting the combinatorial assembly of many information processing, transduction, and control devices from a smaller number of components. More generally, this work has demonstrated the application of synthetic biology design strategies to scalable platforms for genetic device design and that advances in engineering design can transform the scale, efficiency, and speed with which we can engineer cellular behaviors.

Smolke at 05:05, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:05:23 GMT

←Older revision		Revision as of 05:05, 15 March 2011
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	''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''		''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''

-	We ~~are exploring the~~ design strategies for ~~constructing molecular switches~~ that ~~act in vivo as both biosensors~~ and ~~ligand~~-~~controlled regulators of~~ gene expression ~~in bacteria, yeast, and mammalian cell culture~~. ~~Much of our effort is focused on~~ the ~~design~~ of ~~nucleic acid~~-based ~~molecular sensors, although~~ the ~~design~~ of ~~some protein-based sensors is being explored as well~~. ~~In the area~~ of ~~trans-acting molecular switches~~, ~~we are exploring the design~~ of ~~sensors~~ that ~~act through diverse gene regulation mechanisms such as~~ the ~~RNA interference (RNAi) pathway, ribozyme-based cleavage,~~ and ~~the antisense pathway~~. In the ~~area~~ of ~~cis-acting molecular switches, we are exploring~~ the ~~design~~ of ~~sensors~~ that ~~act through regulatory mechanisms such~~ as ~~alternative splicing, RNase III cleavage, ribozyme~~-~~based cleavage,~~ and ~~internal ribosome entry site~~ (~~IRES~~) ~~activity~~.	+	We have developed generalizable design strategies for a broad class of RNA molecules, called RNA devices, that process and transmit user-specified molecular input signals to targeted protein outputs, thereby linking molecular computation to gene expression. We proposed a first-generation framework for the construction of single input-single output RNA devices based on the modular assembly of three components exhibiting basic functions (Win et al., Chem Biol 2009): a sensor component, made of an RNA aptamer or binding element; an actuator component, made of an RNA gene regulatory element; and a transmitter component, made of a sequence that couples the sensor and actuator components. The transmitter component regulates the activity of the actuator component based on the binding state of the sensor component, providing genetic insulation and a standardized communication interface. We initially demonstrated RNA devices that function as single-input Buffer and Inverter gates that convert a molecular signal to increased and decreased gene expression output, respectively (Win et al., PNAS 2007).

-	In order to effectively monitor information flow through cellular networks, projects are examining different sensor platforms that can provide temporal and spatial information regarding fluctuations in biomolecule levels. These platforms couple molecular recognition of ~~a ligand-binding event to a conformational change in~~ the ~~sensor molecule. This regulated conformational change is linked~~ to ~~an appropriate readout signal, which enables these molecules to act as cellular biosensors. For example,~~ the ~~output from a~~ molecular ~~binding event may be coupled to~~ the ~~regulation~~ of ~~a targeted gene expression event~~. ~~Therefore, these platforms enable allosteric regulation of the activity of~~ a ~~general gene expression~~ platform, ~~toward a target gene~~ through the ~~binding~~ of a ~~small molecule~~, ~~protein~~, ~~or transcript input~~. ~~Our work on ncRNA design demonstrates the modularity~~, ~~design predictability~~, and ~~specificity inherent in these molecules for cellular control~~. ~~By modifying~~ the ~~input~~ and ~~output modules on these platforms we can achieve user-specified probing and programming of cellular events~~. By ~~modifying the~~ regulatory ~~modules on these platforms~~ we ~~can construct sensors with different temporal~~ and ~~spatial resolution properties~~. ~~For instance~~, ~~projects are exploring other sensor platforms built around the integration of nucleic acid-based switches with~~ protein~~-based sensors to develop rapidly responsive biosensors that act through fluorescence resonance energy transfer~~ (~~FRET~~) ~~signals~~. ~~Protein-based switches are also being explored that function through nuclear receptor-based transcriptional mechanisms. Molecular design techniques are incorporating a combination~~ of ~~rational~~ design ~~strategies~~ and ~~library-based screens~~.	+	One of the key contributions of our work to the field of molecular design is the development of composition frameworks supporting forward engineering and modular assembly approaches. Our design approach thus enables a modular device platform that supports the tailoring of device function (sensing, actuation, computation) through the direct swapping of component modules without time-intensive redesign of the device. Using our design strategy, we have demonstrated novel cis-acting RNA devices that function through a variety of regulatory mechanisms, including ribozyme cleavage (Win et al., PNAS 2007; Win et al., Science 2008), alternative splicing (Culler et al., Science 2010), and RNase III cleavage (Babiskin et al., Mol Sys Biol 2011; Babiskin et al., Nuc Acids Res 2011). We have also demonstrated novel trans-acting RNA devices that function through the RNA interference pathway (Beisel et al., Mol Sys Biol 2008; Beisel et al., Nuc Acids Res 2010) and antisense silencing (Bayer et al., Nat Biotech 2006). By accessing a variety of gene regulatory mechanisms, we have built tailored RNA devices that function in diverse cell types and organisms and that respond to endogenous and exogenous small molecule inputs (Win et al., PNAS 2007; Beisel et al., Mol Sys Biol 2008) and endogenous and heterologous protein inputs (Culler et al., Science 2010). Ongoing research is extending the capabilities of these design platforms by optimizing device architectures and integrating new actuation mechanisms.

	[[#Research\|Back to Top]]		[[#Research\|Back to Top]]

-	==Engineering higher-order cellular information processing ~~capabilities~~==	+	==Engineering higher-order cellular information processing devices==
	''Researchers: Leo d’Espaux, Yen-Hsiang Wang''		''Researchers: Leo d’Espaux, Yen-Hsiang Wang''
		+	We have demonstrated the extension of the single-input RNA device frameworks to the construction of higher-order devices that perform multi-input signal processing in living systems (Win et al., Science 2008; Culler et al., Science 2010), further supporting the power of the developed modular assembly strategy. As an example, my laboratory described extended architectures for rationally assembling RNA components (sensors, actuators, transmitters) into multi-input signal integration devices and built genetic devices that function as logic gates, signal and bandpass filters, and exhibited cooperativity. Our research has demonstrated that the developed design frameworks provide a general approach for the forward engineering of multi-input devices, supporting the combinatorial assembly of many information processing, transduction, and control devices from a smaller number of components. More generally, this work has demonstrated the application of synthetic biology design strategies to scalable platforms for genetic device design and that advances in engineering design can transform the scale, efficiency, and speed with which we can engineer cellular behaviors.

-	~~We are constructing circuits~~ of ~~interacting molecular switches to engineer complex cellular~~ information processing ~~capabilities. Projects~~ in ~~this area explore the design strategies and parameters necessary for programming higher-level~~ cellular ~~logic~~. ~~Specifically~~, ~~efforts~~ are ~~currently focused on the~~ design of ~~different logic gates and filtering circuits composed of~~ molecular ~~switches that regulate the expression of a target gene in response to different combinations of small molecule~~ and ~~protein inputs~~. ~~Current projects~~ are ~~focused on~~ the ~~construction~~ of ~~AND, OR,~~ and ~~NOR gates, which~~ will ~~later be combined to build more complex information processing capabilities~~. ~~In addition~~, ~~filtering circuits are being constructed to process distinct patterns of cellular~~ information. ~~Due to the exhibited modular and programmable nature of these switches~~, ~~the molecular sensor components comprising these signal integration circuits will be applied to project areas described below in metabolic engineering and cellular programming~~.	+	Ongoing research is extending the complexity of information processing schemes that can be reliably implemented in cellular systems by building regulatory networks composed of distinct genetic devices. For example, we are examining device design schemes that will allow for ratiometric or differential sensing of multiple molecular signals, signal amplification, error detection, and signal restoration. We are also examining the implementation of single and multi-layered architectures in genetic pathways that will allow scaling of computational complexity (i.e., multi-input processing and multi-output control), while maintaining reliable information transmission between different layers (i.e., genetic constructs or transcripts).

	[[#Research\|Back to Top]]		[[#Research\|Back to Top]]

Smolke at 05:03, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:03:43 GMT

←Older revision		Revision as of 05:03, 15 March 2011
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	Engineered biological systems that process information, materials, and energy hold great promise for developing solutions to many global challenges, including energy and food production, materials synthesis, and medical advancement. Our ability to engineer biological systems is limited by the foundational tools available for programming cellular behavior (i.e., getting information into and acting on information in living systems) and our understanding of how such systems should be constructed (i.e., probing and accessing information in living systems). By developing genetically encoded technologies for reporting on, responding to, and controlling intracellular components in living systems, we are addressing prominent challenges faced in basic and applied biological research. Our research efforts focus on the design of new molecular tools for performing information processing, computation, and control functions in living systems and the application of these tools to programming biological systems. The resulting advances in our ability to transmit information to and from living systems and implement control within cells themselves, will broadly transform how we interact with and program biology, providing access to otherwise inaccessible information on cellular state and allowing sophisticated exogenous and embedded control over cellular functions.		Engineered biological systems that process information, materials, and energy hold great promise for developing solutions to many global challenges, including energy and food production, materials synthesis, and medical advancement. Our ability to engineer biological systems is limited by the foundational tools available for programming cellular behavior (i.e., getting information into and acting on information in living systems) and our understanding of how such systems should be constructed (i.e., probing and accessing information in living systems). By developing genetically encoded technologies for reporting on, responding to, and controlling intracellular components in living systems, we are addressing prominent challenges faced in basic and applied biological research. Our research efforts focus on the design of new molecular tools for performing information processing, computation, and control functions in living systems and the application of these tools to programming biological systems. The resulting advances in our ability to transmit information to and from living systems and implement control within cells themselves, will broadly transform how we interact with and program biology, providing access to otherwise inaccessible information on cellular state and allowing sophisticated exogenous and embedded control over cellular functions.

-	==Engineering RNA ~~device platforms as programmable sensing~~-~~actuation~~ devices==	+	=Component and Device Engineering=
		+	==Engineering RNA-based cellular information processing, communication, and control devices==
	''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''		''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''

Smolke at 05:02, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:02:32 GMT

←Older revision		Revision as of 05:02, 15 March 2011
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	__TOC__		__TOC__

-	=Engineering RNA device platforms as programmable sensing-actuation devices=	+	=Research Overview=
		+	Engineered biological systems that process information, materials, and energy hold great promise for developing solutions to many global challenges, including energy and food production, materials synthesis, and medical advancement. Our ability to engineer biological systems is limited by the foundational tools available for programming cellular behavior (i.e., getting information into and acting on information in living systems) and our understanding of how such systems should be constructed (i.e., probing and accessing information in living systems). By developing genetically encoded technologies for reporting on, responding to, and controlling intracellular components in living systems, we are addressing prominent challenges faced in basic and applied biological research. Our research efforts focus on the design of new molecular tools for performing information processing, computation, and control functions in living systems and the application of these tools to programming biological systems. The resulting advances in our ability to transmit information to and from living systems and implement control within cells themselves, will broadly transform how we interact with and program biology, providing access to otherwise inaccessible information on cellular state and allowing sophisticated exogenous and embedded control over cellular functions.
		+
		+	==Engineering RNA device platforms as programmable sensing-actuation devices==
	''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''		''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''

Smolke at 05:01, 15 March 2011

Smolke — Tue, 15 Mar 2011 05:01:50 GMT

←Older revision		Revision as of 05:01, 15 March 2011
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	__TOC__		__TOC__

-	==Engineering RNA device platforms as programmable sensing-actuation devices==	+	=Engineering RNA device platforms as programmable sensing-actuation devices=
	''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''		''Researchers: Ryan Bloom, Drew Kennedy, Jay Vowles, Josh Wolf''

Smolke: /* Engineering higher-order cellular information processing capabilities */

Smolke — Tue, 15 Mar 2011 04:03:02 GMT

Engineering higher-order cellular information processing capabilities

←Older revision		Revision as of 04:03, 15 March 2011
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	==Engineering higher-order cellular information processing capabilities==		==Engineering higher-order cellular information processing capabilities==
-	''Researchers: Yen-Hsiang Wang''	+	''Researchers: Leo d’Espaux, Yen-Hsiang Wang''

	We are constructing circuits of interacting molecular switches to engineer complex cellular information processing capabilities. Projects in this area explore the design strategies and parameters necessary for programming higher-level cellular logic. Specifically, efforts are currently focused on the design of different logic gates and filtering circuits composed of molecular switches that regulate the expression of a target gene in response to different combinations of small molecule and protein inputs. Current projects are focused on the construction of AND, OR, and NOR gates, which will later be combined to build more complex information processing capabilities. In addition, filtering circuits are being constructed to process distinct patterns of cellular information. Due to the exhibited modular and programmable nature of these switches, the molecular sensor components comprising these signal integration circuits will be applied to project areas described below in metabolic engineering and cellular programming.		We are constructing circuits of interacting molecular switches to engineer complex cellular information processing capabilities. Projects in this area explore the design strategies and parameters necessary for programming higher-level cellular logic. Specifically, efforts are currently focused on the design of different logic gates and filtering circuits composed of molecular switches that regulate the expression of a target gene in response to different combinations of small molecule and protein inputs. Current projects are focused on the construction of AND, OR, and NOR gates, which will later be combined to build more complex information processing capabilities. In addition, filtering circuits are being constructed to process distinct patterns of cellular information. Due to the exhibited modular and programmable nature of these switches, the molecular sensor components comprising these signal integration circuits will be applied to project areas described below in metabolic engineering and cellular programming.