Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

The proposal describes a program in synthetic biology, a field based on modifying living cells for human-designed purposes. Our long-term objectives are to explore methods of systematic biological system design, including mathematical and computational approaches to design new biological controllers, as well as implementing these systems experimentally in bacteria and yeast cells, to test and validate the theoretical efforts. We also aim to put our cellular systems to work, applying them to the solution of real-world problems. This research effort is interdisciplinary in nature, drawing on knowledge from physical/biological chemistry, molecular biology, biological physics, nonlinear dynamics, and engineering.

1. Development and validation of synthetic biology design methods
   We will experimentally test recently-developed theoretical methods for designing homeostatic control systems that maintain a biological state despite perturbations. Building libraries of variants of a multi-node genetic control system will allow us to explore a region of parameter space suggested by the mathematics, and test the system responses to perturbations.

Moving beyond our previously-developed methods, we will explore the potential of frequency-response approaches in synthetic biology. Cells can be perturbed with periodic inputs of different frequencies, and putting many such measurements together allows us to build up a frequency-response profile. Engineers use these to systematically design new controllers, and we will create and characterize the frequency-response characteristics of our library of controller variants, to provide a toolbox of response profiles and lay the foundation for frequency-based design methods in synthetic biology.

1. Investigations of the feasibility and utility of cellular solutions for real-world problems
   Cheaply-grown cells have the potential to offer inexpensive solutions to real-world problems. We will investigate the potential real-world impact of a system that uses yeast cells to detect antibodies, thus acting as an inexpensive diagnostic/surveillance tool. By engineering cells with antigens and antibody-binding domains on their surfaces, we can potentially arrange for them to produce a simple visual signal (a “dot” or “no dot” output), at a low cost-per-test and without requirements for specialized equipment or training. (And in the best case, without even the need for electricity!) We will extend our preliminary results that show successful detection of Chagas disease antibodies to new disease targets (malaria and dengue fever), while making a systematic study of the exact conditions that optimize the system's functionality and the mechanisms underlying its visual output.