Muldoon J J, Kandula V, Hong M, Donahue P S, Boucher J D, Bagheri N, Leonard J N
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL 60208, USA.
Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.
Sci Adv. 2021 Feb 19;7(8). doi: 10.1126/sciadv.abe9375. Print 2021 Feb.
Genetically engineering cells to perform customizable functions is an emerging frontier with numerous technological and translational applications. However, it remains challenging to systematically engineer mammalian cells to execute complex functions. To address this need, we developed a method enabling accurate genetic program design using high-performing genetic parts and predictive computational models. We built multifunctional proteins integrating both transcriptional and posttranslational control, validated models for describing these mechanisms, implemented digital and analog processing, and effectively linked genetic circuits with sensors for multi-input evaluations. The functional modularity and compositional versatility of these parts enable one to satisfy a given design objective via multiple synonymous programs. Our approach empowers bioengineers to predictively design mammalian cellular functions that perform as expected even at high levels of biological complexity.
对细胞进行基因工程改造以实现可定制功能是一个新兴领域，具有众多技术和转化应用。然而，系统地对哺乳动物细胞进行工程改造以执行复杂功能仍然具有挑战性。为满足这一需求，我们开发了一种方法，能够利用高性能基因元件和预测性计算模型进行精确的基因程序设计。我们构建了整合转录和翻译后控制的多功能蛋白质，验证了描述这些机制的模型，实现了数字和模拟处理，并有效地将遗传电路与传感器相连以进行多输入评估。这些元件的功能模块化和组成通用性使人们能够通过多个同义程序满足给定的设计目标。我们的方法使生物工程师能够预测性地设计哺乳动物细胞功能，即使在高度复杂的生物学环境下也能按预期发挥作用。
