1. Studying network perturbations in disease states
Synthetic biology provides novel tools for elucidating previously unknown or difficult-to-study principles that underlie diseases. Here, we aim to leverage these tools to achieve breakthroughs in our scientific knowledge:
- Using two-component signaling systems in bacteria, we will elucidate the molecular mechanisms which define protein-protein specificity and translate these mechanisms into computational tools.
- Using PHO promoters in yeast, we will study the stochastic behavior of transcriptional bursting. We shall also develop a highly efficient electronic-circuits-based simulator for biochemical equations and protein- protein networks, and use this simulator in the analysis of this system.
- Using tools from synthetic biology, including engineered promoters and inverters, we will make large-scale perturbations to metabolic networks in order to map their function and parameters for biological systems.
- A high-throughput method for deciphering antibiotic-resistance networks. We will utilize antisense-based knockdown libraries from synthetic biology to implement a chemical synthetic lethal screen for potential interactions between primary drug targets and other genes.
2. Engineering scalable synthetic networks
We are developing to establish key frameworks that enable scalable construction of biological systems, a breakthrough capability that will be broadly enabling for basic biology, biotechnology, and human health. Our goals are as follows:
- Engineer scalable synthetic tools – protein-DNA circuits for transcriptional control, RNA-based devices that are programmable based on nucleic acid systems, and protein-protein tools for engineering specific protein interactions.
- Develop framework for computational design and simulation of synthetic networks. These tools shall incorporate biophysical models to translate primary sequence information into biochemical parameters, dynamic simulators of synthetic networks that also capture stochastic behavior using differential equations, and higher-level biological system design based on analysis tools from control theory, including frequency-domain analysis and application of small-scale linearization techniques.
- Develop insulation devices that seek to isolate synthetic circuits from other factors in order to enable scalable biological design. These devices will be complementary with a network approach to understanding the interdependent effects of various biological modules on each other.
3. Targeting malfunctioning biological systems in key diseases
We are working to address these problems with systems-level approaches using synthetic RNA-based circuits to sense, compute, and destroy cancerous cells, programmable differentiation of stem cells into insulin-producing beta-islet cells for diabetes, and synthetic engineered viruses to target antibiotic-resistant bacteria. Specifically, we aim to develop the following:
- Develop novel RNAi-based circuits to detect and destroy cancer cells using transcriptome-level analysis
- Engineer artificial tissue homeostasis system that maintains a steady population of insulin producing cells
- A high-throughput, quantitative, and reliable method to identify genes that can be targeted by phage for synergistic improvement of antibiotic killing.