Fundamental and applied synthetic biology

Through the careful application of genetic engineering, synthetic biological systems can be constructed to harness the biotransformation potential of living organisms. In an era of genome-scale DNA assembly, the lack of accompanying technologies for the functional design and physical implementation of novel biological devices and systems with predictable behaviors is striking. We are interested in developing designable genetic control systems to significantly increase the sizes and complexities of the synthetic biological systems that can be engineered. In our work, we combine biochemical and biophysical modeling, computational design and analysis, in vitro selection, and genetic engineering to construct RNA-based control systems in microbial hosts. We organize our efforts around application testbeds chosen to enable better understanding of biological principles and to address unmet needs for renewable chemicals and low-cost global health materials.

RNA engineering

In nature, functional RNA structures process cellular information and regulate genetic expression at the levels of transcription, translation and RNA degradation. While the molecular recognition properties and control functions of protein regulators can be challenging to predictably modify, in vitro selection can be used to evolve informationally-complex RNA structures that bind target molecules (aptamers) or catalyze specific reactions (ribozymes). We use in vitro selection to generate synthetic ligand-binding aptamers, catalytic ribozymes, and ligand-controlled ribozymes (aptazymes) that we assemble into static or dynamic, ligand-responsive genetic control devices. Because these RNA devices can be designed to meet targeted performance criteria, we can engineer them as programmable biosensors, controllers for metabolic pathways and genetic circuits, and as components for information transfer systems.

Genetic control system design

Functional complexity that emerges from component interactions is a universal feature of physical systems. As a consequence, models and tools for simulating global functions from local component behaviors are essential for understanding and constructing complex devices and systems. Biological systems exhibit functional complexity across multiple scales, from the interactions of RNA, DNA, and protein subunits to those occurring among genes, pathways, circuits, and cells. Creating design-driven approaches applicable to each of these scales will be crucial for increasing the sizes and complexities of engineered synthetic biological systems. When we are successful, our work will facilitate the rapid assembly of specialized RNA-regulated genetic control circuits and scalable information processing mechanisms for programming biological function in response to changing cellular and environmental conditions. Ultimately, we expect our efforts to lead to full-fledged CAD platforms that dramatically improve the efficacy with which complex synthetic biological systems can be engineered and provide routes to investigate fundamental questions about functional RNAs and the role of information and control in biology.