CAREER: Enabling Functional Biological Programs

该学院早期职业发展（CAREER）补助金将通过支持技术和工具的系统开发研究来实现人工生物调节，从而促进控制生物蛋白质和分子生产的合成计划，从而有利于国家利益。这些计划将对人类健康、气候目标、能源供应、粮食安全、农业、供应链弹性和国家安全产生深远影响。对合成程序鲁棒性差和缺乏可靠性的原因的不完全理解，以及无法预测生物系统相互作用的紧急行为，是巨大的工程挑战。这种不完整的理解是由于复杂的生物相互作用在多个结构和时间尺度，以及非线性，随机性，非模块化，和测量困难时，生物体是活着的。因此，合成程序通常具有非预期的行为和有限的功能。为了增加程序功能，本项目将研究增加新的控制程序，这些程序是生物学外部的，一个“网络生物学系统”。“输出生物蛋白质和分子的生产将通过外部传感，计算和驱动来调节。该项目还将通过将凝血概念添加到一个受欢迎的女性游戏中来鼓励早期对科学，技术，工程和数学（STEM）的热情。将评估生物工程刺激和参与超过基线的收益。网络生物控制的最新技术是在测试新程序功能时克服生物复杂性，方法是将程序使用限制在单细胞模型生物体、生物级联的单一触发或单一环境条件（通常具有单一干扰）。该项目的研究目标是通过一个独特但广泛适用的血液凝固控制测试平台来进一步发展这一最先进的技术，这将使具有多种相互作用的细胞，蛋白质和小分子的哺乳动物系统的功能程序成为可能，并且在受到多种干扰的同时包含多种功能和时间尺度。因此，该项目将：（1）建立具有特征非线性的安全关键生物系统的控制;（2）扩展强大和普遍的线性反馈控制设计方法，用于非线性生化动力学;（3）补偿固有的生物随机性。这些目标将分别解决控制、分析和诊断方面的知识差距。非线性控制的进步将应用于生物学以外的非负系统，如制造厂，热力学，空中交通流量，多智能体通信，网络拥塞，过滤，采样数据和经济学。试验台实验将推动集成。该项目的教育目标是提高女学生STEM参与率，以帮助解决美国东南部STEM中存在的巨大性别鸿沟。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.