Example Publications:
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Engineering RNA Devices for Cellular Information Processing, Sensing, & Control
As examples of functional RNA molecules playing key roles in the behavior of natural biological systems have grown, there has been growing interest in the design and application of synthetic counterparts. Our laboratory is exploring the design of functional RNA molecules that couple ligand-binding activities to diverse regulatory activities to create programmable genetic sensors and controllers; thereby providing new tools for accessing and controlling information in biological systems. Our approach focuses on elucidating quantitative design principles and developing modular design platforms supporting a new input/output (I/O) technology for biological systems. By accessing a variety of gene-regulatory mechanisms, we are building tailored RNA control devices that function in a range of organisms, respond to small molecule and protein inputs, and interface with diverse systems. Our I/O technology can be coupled with other genetic devices to build more complex information processing capabilities into living systems, such as signal amplification, error detection, signal restoration, and differential sensing.
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Example Publications:
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Scalable Measurement Platforms for Biological Engineering
Scalable and quantitative measurement technologies for genetic and biochemical function are a key limitation in biological engineering. For example, the design of new biological activities (e.g., functional RNAs, proteins) is limited by our incomplete understanding of sequence-structure-function relationships and low throughput of the design and characterization process. To more fully map the design space, we are developing scalable and massively-parallelizable assays that can rapidly characterize functional activities of 100,000-1,000,000’s of different sequences. Acquiring and analyzing data at this scale is providing greater insights into sequence-activity relationships and will ultimately lead to improved predictive design tools. We are also developing a novel biosensor technology, based on RNA sensors, that supports multiplexed, noninvasive, quantitative measurements of biomolecule levels (e.g., metabolites, proteins) within single cells. This sensor technology can support quantitative, non-destructive measurement of biomolecule levels and activities from over millions of genetic designs within a matter of hours and is being used to efficiently and rapidly evolve enzyme and pathway activities.
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Example Publications:
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Engineering More Efficient Plant Natural Product Biosynthesis PlatformsPlants are a rich source of unique chemical and bioactive structures, including 25% of natural product-derived drug molecules. Although the plant kingdom produces an exceptional diversity and number of natural products, many of which are unique to the plant kingdom, the genes and enzymes for these pathways have not been as extensively investigated as those in microorganisms. Much of the challenges with studying plant pathways associated with specialized metabolism lie in the size and complexity of the plant genomes and the difficulties with predicting and establishing functions of enzymes for new biosynthetic pathways. We are functionally reconstructing complex plant natural product pathways in a microbial biosynthesis platform, Saccharomyces cerevisiae. In addition to developing new production technologies for important classes of therapeutic compounds, our approach allows us to study, probe, and manipulate these pathways in entirely new ways, thereby providing greater insight into the biochemical mechanisms supporting the biosynthesis of these complex molecules in the native plant hosts. We are functionally reconstructing plant natural product pathways comprising 10-20 plant enzymes in our yeast host (e.g., biosynthetic pathways associated with production of diverse plant alkaloid compounds, such as the benzylisoquinoline alkaloids).
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Example Publications:
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Synthetic Biology Platforms Advancing Natural Product Discovery & Production
The functional reconstruction of complex plant pathways associated with specialized metabolism in a microbial host requires new expression tools and design strategies. We are developing tools that can be broadly applied to access many diverse and novel scaffolds and to advance the discovery of new natural product molecules. For example, we are developing our unique RNA sensor technology as a measurement tool to support new approaches to probing and reconstructing biosynthetic pathways. Our genetic sensors are being used to instrument cells with genetically-encoded metabolic dashboards that allow for dynamic snapshots of a cell’s metabolic state over time and an unprecedented capability to rapidly search large design spaces associated with pathway activity, thereby transforming our capabilities to design biosynthesis schemes. As another example, we are developing tools that support spatial engineering and chemical specialization in yeast allowing for new strategies to optimize enzyme activities and specificities in the context of a heterologous microbial host. Finally, novel functional genomics pipelines for natural product discovery are being developed based on the integration of new synthetic biology tools for functional natural product pathway reconstruction, high-throughput measurement technologies, genome sequence information, and bioinformatic tools.
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Example Publications:
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Mammalian Synthetic BiologyA major thrust of our laboratory is to develop genetic control systems for mammalian cells. We have examined different genetic control architectures that allow for conditional control over pathway activation and signaling, ultimately resulting in robust reprogramming of cell fate decisions. These studies have described strategies for identifying key control points within cellular networks and highlighted the roles of feedback and redundancy in building robust control systems. Efforts have focused on the development of computational models that predict the quantitative performance of these control systems and can be used to forward design genetic systems that exhibit desired performance properties. Ongoing work is examining the design of new genetic control platforms and associated computational frameworks that allow for regulation beyond gene expression, for example, by supporting the dynamic programming of protein form and function as well as epigenetic state. Genetic control systems capable of responding to diverse environmental and cellular signals (e.g., drug molecules, disease markers) in mammalian systems will advance safer and more effective therapeutic strategies. For example, we are designing engineered genetic systems that control the survival, proliferation, and cytotoxicity of genetically-engineered T cells in response to clinician-applied drugs and disease markers. Our efforts will result in genetic tools that allow a broad community of researchers to interface with, manipulate, and probe mammalian systems in entirely new ways and that are based on platforms compatible with eventual clinical application, ultimately transforming applied biomedical research.
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Open Positions
If you are interested in joining the laboratory, please contact Christina directly (csmolke@stanford.edu).
Funding
Our research efforts are supported through a combination of grants, contracts, and gifts awarded through federal agencies, foundations, and companies. Current research efforts receive support through:
Smolke Lab Researchers are generously supported through the following fellowships:
- National Institutes of Health (NIGMS, NCCAM, OD)
- National Science Foundation (CBET, CCF)
- Defense Advanced Research Projects Agency (BTO)
- Human Frontiers Science Program
- Novartis Institutes for Biomedical Research
- Agilent Technologies
- Townshend-Lamarre Foundation
Smolke Lab Researchers are generously supported through the following fellowships:
- ARCS Foundation
- A*STAR
- BioX
- NDSEG
- NSF
- Siebel Foundation
- SGF