CAREER: Enabling Functional Biological Programs

This Faculty Early Career Development (CAREER) grant will benefit the national interest by supporting research into the systematic development of techniques and tools to accomplish artificial biological regulation, thereby intending to facilitate synthetic programs that control biological protein and molecule production. These programs will profoundly impact human health, climate targets, energy supplies, food security, agriculture, supply chain resilience, and national security.

Incomplete understanding of the reasons for poor synthetic program robustness and lack of reliability, and an inability to predict the emergent behavior of biosystem interactions, are great engineering challenges. Such incomplete understanding is due to complex biological interactions at multiple structural and temporal scales, as well as nonlinearities, stochasticity, non-modularity, and measurement difficulties when organisms are alive.

Consequently, synthetic programs often have unintended behaviors and limited functionality. To increase program functionality, this project will investigate adding new control programs that are external to the biology, a "cyber-biological system." Output biological protein and molecule production will be regulated via external sensing, computation, and actuation.

This project will also encourage early enthusiasm in science, technology, engineering, and mathematics (STEM) by adding blood clotting concepts to a popular game with high female play. Gains in bioengineering stimulation and engagement over baseline will be assessed.

The state-of-the-art in cyber-biological control is to overcome biological complexity when testing new program function by restricting program use to single celled model organisms, single triggers to a biological cascade, or a single environment condition, often with a single disturbance. The research goal of this project is to further this state-of-the-art via a unique yet broadly-applicable testbed of blood coagulation control, which will enable functional programs for mammalian systems that have multiple interacting cells, proteins, and small molecules, and that encompass multiple functions and timescales while subject to multiple disturbances.

Thus, this project will: (1) establish the control of safety-critical biological systems with characteristic nonlinearities; (2) extend powerful and pervasive linear feedback control design methods for use with nonlinear biochemical dynamics; and (3) compensate for innate biological stochasticity. These aims will respectively address knowledge gaps in control, analysis, and diagnostics.

Nonlinear control advances will apply to nonnegative systems beyond biology such as manufacturing plants, thermodynamics, air traffic flow, multi-agent communication, network congestion, filtering, sampled data, and economics. Testbed experiments will drive integration. The educational goal of this project is to increase female student STEM participation, to help address the substantial gender divide that exists in STEM in the southeastern US.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.