Difference between revisions of "Research Overview"

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Feedback systems are a central part of natural biological systems and an important tool for engineering biocircuits that behave in a predictable fashion.  The figure at the right gives a brief overview of the approach we are taking to both synthetic and systems biology.  There are three main elements to our research:
+
Feedback systems are a central part of natural biological systems and an important tool for engineering biocircuits that behave in a predictable fashion.  The figure at the right gives a brief overview of the approach we are taking in the area of synthetic biology.  There are three main elements to our current research:
* '''Modeling and analysis''' - we are working to develop rigorous tools for analyzing the phenotype of complex biomolecular systems based on data-driven models.  We are particularly interested in systems involving feedback, since causal reasoning often fails in these systems due to the interaction of multiple components and pathways.   Work in this are includes system identification, theory for understanding the role of feedback, and methods for building and analyzing models built using high-throughput datasets.
+
 
* '''''In vitro'' testbeds''' - we are making use of both transcriptional expression systems and protein expression systems to develop "biomolecular breadboards" that can be used to characterize the behavior of circuits in a systematic fashion as part of the design process. Our goal is to help enable rapid prototyping and debugging of biomolecular circuits that can operate either ''in vitro'' or ''in vivo''.
+
* '''Synthetic cells''' - Advances in synthetic biology and molecular sciences have substantially advanced our ability to produce genetically-programmed synthetic cells from molecular components. These e↵orts provide techniques for the bottom-up construction of cell-like systems that can provide scientists with new insights into how natural cells work and harness the power of biology to create nanoscale, biomolecular machines. Work in the US through the Build-A-Cell consortium and similar e↵orts in other countries have established communities of researchers interested in pursuing the construction of synthetic cells, and these activities are an exciting pathway for exploration of the rules of life. The long term goal of our research is to create genetically-programmed synthetic cells consisting of multiple subsystems operating in an integrated fashion. Unlike more traditional synthetic biology approaches, synthetic cells are non-living: they make use of genetic elements provided by biology, but they do not replicate, mutate, or evolve. Applications range from synthesis of bio-compatible materials, to environmental monitoring and remediation, to self-assembly of complex multi-cellular machines. Pursuing this goal requires fundamental research in biological engineering, aimed at moving from creation of clever biomolecular devices to systematic specification, design, integration, and testing of circuits, subsystems, cells, and multi-component systems.
* '''Biocircuit design''' - engineered biological circuits required a combination of system-level principles, circuit-level design and device technologies in order to allow systematic design of robust systems.  We are working on developing new device technologies for fast feedback as well as methods for combining multiple feedback mechanisms to provide robust operation in a variety of contexts. Our goal is to participate in the development of systematic methods for biocircuit design that allow us to overcome current limitations in device complexity for synthetic biocircuits.
+
 
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* '''Biocircuit modeling and design tools''' - Current approaches in synthetic biology rely on tuning of devices and circuits to work in a specific set of conditions, including the host organism, growth conditions, genetic context, and many other factors. The consequence of this approach is that a device, circuit, or pathway that works in one chassis or environmental context is not likely to work in a different chassis or set of environmental conditions without redesign and tuning. Depending on this application, the lack of robustness for the desired function can slow or even prevent the deployment of synthetic biology technologies, especially in those situations where robustness to context is required by the application.  We are tackling this challenge by making use of tools from control and dynamical systems to provide design rules and a computational framework that allows designers to assess robustness of their designs and to evaluate compensation mechanisms designed to enhance robustness. These techniques will build on existing modeling and design tools (e.g. BioCRNpyler), but will integrate representations of biological context to allow distributions of responses to be computed as used as a means of assessing whether a device or circuit will function robustly across chassis and environmental contexts.
 +
 
 +
* '''Soil synthetic biology''' - We are developing an "open source" toolkit for soil synthetic with the goal of bootstrapping a larger effort that would enable the use of engineered microbes to understand and modulate the complex dynamics of the rhizosphere.  We are identifying and characterizing genetically tractable microbes capable of long-term persistence; creating a toolbox of genetic parts for gene circuits and pathways in soil conditions; and designing, building, and testing stimulus-response circuits operating in soil. Long-term applications include engineering microbial communities to optimize nutrient uptake and improve survival against environmental hazards such as drought, toxins, or pathogens.
  
 
Current projects:
 
Current projects:
* [[Cell-Free Expression of Membrane Proteins with Applications to Drug Discovery]] (Amgen)
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{{#ask:
* [[Establishing microfluidic cell-free systems for the rapid prototyping of synthetic genetic networks]] ([[http:www.hfsp.org|HFSP]])
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  [[Category:Active projects]]
* [[Improvement of E. coli transcription-translation (TX-TL) system]] (Caltech Grubstake)
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  [[Category:Biocircuits projects]]
* [[Theory-Based_Engineering of Biomolecular Circuits in Living Cells]] (AFOSR BRI)
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* [[Model-guided Discovery and Optimization of Cell-based Sensors]] (ONR MURI)
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* [[Programmable Molecular Technology Initiative]] (GBMF)
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* [[Molecular Programming Project]] (NSF)
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* [[Biomolecular Feedback Circuits for Modular, Robust and Rapid Response]] ([[http:www.icb.ucsb.edu|ARO ICB]])
+
}}
  
Recent papers:
+
Recent journal papers:
* {{Hsi+14-acssynbio}}
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{{#ask:
* [[http:pubs.acs.org/doi/abs/10.1021/sb400131a|Linear DNA for rapid prototyping of synthetic biological circuits in an Escherichia coli based TX-TL cell-free system]], Z. Z. Sun, E. Yeung, C. A. Hayes, V. Noireaux, R. M. Murray.  ''ACS Synthetic Biology'', 2013
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  [[Category:Papers]]
* {{fra+11-pnas}}
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  [[type::Journal paper]]
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  [[flags::Biocircuits]]
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<span id=NCS>
 
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We are investigating the specification, design and verification of distributed systems that combine communications, computation and control in dynamic, uncertain and adversarial environments. Our goal is to develop methods and tools for designing control policies, specifying the properties of the resulting distributed embedded system and the physical environment, and proving that the specifications are met. We have recently developed a promising set of results in receding horizon temporal logic planning that allow automatic synthesis of protocols for hybrid (discrete and continuous state) dynamical systems that are guaranteed to satisfy the desired properties even in the presence of environmental action. The desired properties are expressed in the language of temporal logic, and the resulting system consists of a discrete planner that plans, in the abstracted discrete domain, a set of transitions of the system to ensure the correct behaviors, and a continuous controller that continuously implements the plan. Application areas include autonomous driving, vehicle management systems, and distributed multi-agent systems.
+
We are investigating the specification, design and verification of distributed systems that combine communications, computation and control in dynamic, uncertain and adversarial environments. Our goal is to develop methods and tools for designing control policies, specifying the properties of the resulting distributed embedded system and the physical environment, and proving that the specifications are met. In our past work, we have developed a promising set of results in automatic synthesis of protocols for hybrid (discrete and continuous state) dynamical systems that are guaranteed to satisfy the desired properties even in the presence of environmental action. The desired properties are expressed in the language of temporal logic, and the resulting system consists of a discrete planner that plans, in the abstracted discrete domain, a set of transitions of the system to ensure the correct behaviors, and a continuous controller that continuously implements the plan. More recently, we have shifted our focus to design of specifications -- including horizontal and vertical contracts for multi-agent, layered control systems -- and operational test and evaluation of complex control systems that react to environmental conditions.  Application areas include autonomous driving, vehicle management systems, and distributed multi-agent systems.
  
 
Current projects:
 
Current projects:
* [[Resilient Risk-Aware Autonomy for the Exploration of Uncertain and Extreme Environments]] ([[http:kiss.caltech.edu|KISS]]/[[http:jpl.nasa.gov|JPL]])
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{{#ask:
* [[The TerraSwarm Research Center]] (FCRP)
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  [[Category:Active projects]]
* [[iCyPhy: Industrial Cyber-Physical Systems]] (IBM/UTC)
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  [[Category:NCS projects]]
* [[Correct-by-Construction Synthesis of Control Protocols for Aerospace Systems]] (Boeing)
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  | ?agency =
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  | order=descending
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}}
  
 
Recent papers:
 
Recent papers:
* {{wtm13-us}}
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{{#ask:
* {{lotm13-tac}}
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  [[Category:Papers]]
* {{wtm12-tac}}
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  [[flags::NCS]]
 +
  | ?authors =
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  | ?source =
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Latest revision as of 18:40, 23 August 2021

This page contains a brief summary of my group's current research activities, broken up into the two main areas. More information is available on the individual project pages below and also in the recent publications from my group.

Analysis and Design of Biomolecular Feedback Systems

Biocircuits-overview-23Aug2021.png

Feedback systems are a central part of natural biological systems and an important tool for engineering biocircuits that behave in a predictable fashion. The figure at the right gives a brief overview of the approach we are taking in the area of synthetic biology. There are three main elements to our current research:

  • Synthetic cells - Advances in synthetic biology and molecular sciences have substantially advanced our ability to produce genetically-programmed synthetic cells from molecular components. These e↵orts provide techniques for the bottom-up construction of cell-like systems that can provide scientists with new insights into how natural cells work and harness the power of biology to create nanoscale, biomolecular machines. Work in the US through the Build-A-Cell consortium and similar e↵orts in other countries have established communities of researchers interested in pursuing the construction of synthetic cells, and these activities are an exciting pathway for exploration of the rules of life. The long term goal of our research is to create genetically-programmed synthetic cells consisting of multiple subsystems operating in an integrated fashion. Unlike more traditional synthetic biology approaches, synthetic cells are non-living: they make use of genetic elements provided by biology, but they do not replicate, mutate, or evolve. Applications range from synthesis of bio-compatible materials, to environmental monitoring and remediation, to self-assembly of complex multi-cellular machines. Pursuing this goal requires fundamental research in biological engineering, aimed at moving from creation of clever biomolecular devices to systematic specification, design, integration, and testing of circuits, subsystems, cells, and multi-component systems.
  • Biocircuit modeling and design tools - Current approaches in synthetic biology rely on tuning of devices and circuits to work in a specific set of conditions, including the host organism, growth conditions, genetic context, and many other factors. The consequence of this approach is that a device, circuit, or pathway that works in one chassis or environmental context is not likely to work in a different chassis or set of environmental conditions without redesign and tuning. Depending on this application, the lack of robustness for the desired function can slow or even prevent the deployment of synthetic biology technologies, especially in those situations where robustness to context is required by the application. We are tackling this challenge by making use of tools from control and dynamical systems to provide design rules and a computational framework that allows designers to assess robustness of their designs and to evaluate compensation mechanisms designed to enhance robustness. These techniques will build on existing modeling and design tools (e.g. BioCRNpyler), but will integrate representations of biological context to allow distributions of responses to be computed as used as a means of assessing whether a device or circuit will function robustly across chassis and environmental contexts.
  • Soil synthetic biology - We are developing an "open source" toolkit for soil synthetic with the goal of bootstrapping a larger effort that would enable the use of engineered microbes to understand and modulate the complex dynamics of the rhizosphere. We are identifying and characterizing genetically tractable microbes capable of long-term persistence; creating a toolbox of genetic parts for gene circuits and pathways in soil conditions; and designing, building, and testing stimulus-response circuits operating in soil. Long-term applications include engineering microbial communities to optimize nutrient uptake and improve survival against environmental hazards such as drought, toxins, or pathogens.

Current projects:

Recent journal papers:

... further results

Design of Reactive Protocols for Networked Control Systems

Ncs-hierarchical.png

We are investigating the specification, design and verification of distributed systems that combine communications, computation and control in dynamic, uncertain and adversarial environments. Our goal is to develop methods and tools for designing control policies, specifying the properties of the resulting distributed embedded system and the physical environment, and proving that the specifications are met. In our past work, we have developed a promising set of results in automatic synthesis of protocols for hybrid (discrete and continuous state) dynamical systems that are guaranteed to satisfy the desired properties even in the presence of environmental action. The desired properties are expressed in the language of temporal logic, and the resulting system consists of a discrete planner that plans, in the abstracted discrete domain, a set of transitions of the system to ensure the correct behaviors, and a continuous controller that continuously implements the plan. More recently, we have shifted our focus to design of specifications -- including horizontal and vertical contracts for multi-agent, layered control systems -- and operational test and evaluation of complex control systems that react to environmental conditions. Application areas include autonomous driving, vehicle management systems, and distributed multi-agent systems.

Current projects:

Recent papers:

... further results