Since the advent of genetic engineering in the 1970s, engineered cells have been used to produce recombinant proteins and chemicals. Recently, interest in cellular engineering for chemical production has been intensified with the depletion of non-renewable resources. The past decade has witnessed the potential of synthetic biology, an emerging field where engineering principles are applied to biology in order to create programmable cells for real-world applications. However, engineering biology is quite different from other engineering disciplines, and many challenges remain to make living systems conform to engineering principles. First, unlike electronic or mechanical parts, genetic parts tend to change. Cells work for themselves and disfavor exploitation against their survival. Thus, recombinant DNA is often mutated if no selective pressure exists to maintain its function. Second, orthogonality is difficult to implement in biology. Orthogonality means that system components can be varied independently without affecting the performance of the other components. It is the prerequisite for dividing a system into small parts and developing them independently. In non-biological systems, there are many simple strategies to ensure orthogonality. For example, a series of chemical reactions can be confined to separate reactors to prevent side reactions. In contrast, various reactions and interactions occur in a bacterial cell. Thus, there is a high chance of cross-talks even when a single recombinant gene is introduced.
The key to solving such problems is to implement synthetic control over biological processes such as evolution, gene expression, and chemical reactions. My research interests are focused on developing and controlling microbes that are able to process multiple input signals and to produce desirable outputs. Specifically, I aim to create synthetic gene circuits in order to control metabolic pathways and improve productivity of biomass-based chemicals and drugs. Combining 1) my expertise in the design and construction of orthogonal metabolic pathways and genetic circuits and 2) my experience in the biotechnology industry, I will help transform synthetic biology from a "toy" building practice into an application-oriented engineering activity.
Long Term Vision
Many applications require cells to integrate multiple environmental signals and to implement synthetic control over biological processes. Genetic circuits enable cells to perform computational operations, interfacing biosensors and actuators. Despite advances in the rational construction of genetic circuits, practical applications of genetic circuits have yet to be realized. Cells equipped with an "internal cell state controller" may respond quickly to fluctuation of pH and O2/acetate/redox levels in a heterogeneous large bioreactor, leading to less stress and more production. Autonomously navigating cells can be created to detect and destroy toxic chemicals, pathogens, and tumor cells. Engineering cells in a lab scale is entirely different from creating microbial cell factories and environmental janitors that face various changing signals. For such real-world applications, systems must be robust and resistant to mutations for an extended use. In addition, orthogonal genetic parts are needed to build complex circuits. My long term goal is constructing programmable cells that are able to process multiple input signals and to produce desirable outputs to solve energy, environment, and health problems. It is time to create useful biological systems rather than toy systems.
1. Programmed Killing of Parasite Eggs by Probiotic
Gates Foundation (Role: PI)
This project addresses parasite infection in people in developing countries. While there are drugs to help kill parasite worms and eggs in the body, there is no long-term strategy to prevent disease transmission. We have proposed to engineer probiotic bacteria that would be added to donated foods, reproduce in the intestine where parasite eggs are produced, and come out of the body with the eggs in waste. The probiotic bacteria contain a genetic circuit, or a computer, which distinguishes the outside conditions from those in the human body. Once the bacteria come out of the human body with the eggs, the genetic circuit triggers a “suicide bomb,” killing the parasite eggs and the bacteria in the process, eliminating any potential harm to humans or to the environment.
2. Hybrid Conversion of Lignin: Trees to Fat
Washington University I-CARES (Role: PI)
The overarching goal of this research is to develop a novel hybrid process based on the thermochemical and microbial conversion of lignin into triacylglycerols (TAGs), biodiesel precursors.
3. Designing Nitrogen Fixing Ability in Oxygenic
National Science Foundation (Role: Co-PI)
The goal of this project is to determine the design principles to establish nitrogen fixing ability in an oxygenic photosynthetic organism, cyanobacterium.
4. CAREER: Engineering Biological Robustness through
National Science Foundation (Role: PI)
The overarching goal of this project is to understand the principles of biological robustness by building genetic circuits from the bottom-up.
5. Systems Biology of Rhodococcus opacus to Enable Production of Fuels and Chemicals from Lignocelluose
Department of Energy (Role: Co-PI)
The goal of this project is to interrogate the metabolic networks and genetic regulation that control the utilization of and tolerance to thermochemically depolymerized liginin, focusing on phenolics, in R. opacus.
6. Engineering Probiotics to Manipulate Neurotransmitters
Office of Naval Research, Young Investigator Program (Role: PI)