To support their survival, cells adapt to environmental disturbances by maintaining a constant internal milieu. Robust perfect adaptation is a strategy that utilizes integral feedback to promote adaptation by robustly driving regulated physiological variables to their pre-disturbance levels. Present in natural systems, this stringent regulatory strategy promises to enable the engineering of sophisticated genetic programs with diverse applications. Here, we present the first synthetic implementations of integral and proportional-integral feedback controllers in mammalian cells. We show that the integral controller robustly and precisely maintains a desired level of a transcription factor, in spite of induced disturbances and network perturbations. Augmenting proportional feedback reduces stochastic variability while maintaining robust perfect adaptation. We demonstrate the benefits of these controllers in mitigating the impact of resource burden and investigate their use in cell therapy. The synthetic biological realization of robust perfect adaptation holds promise for substantial advances in industrial biotechnology and cell-based therapies.

中文翻译：

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用于哺乳动物细胞稳健完美适应的基因工程比例积分反馈控制器

为了支持它们的生存，细胞通过维持恒定的内部环境来适应环境干扰。稳健的完美适应是一种策略，它利用积分反馈通过将受调节的生理变量稳健地驱动到干扰前的水平来促进适应。这种严格的监管策略存在于自然系统中，有望实现具有多种应用的复杂遗传程序的工程。在这里，我们展示了哺乳动物细胞中积分和比例积分反馈控制器的第一个综合实现。我们表明，尽管存在诱导干扰和网络扰动，积分控制器仍能稳健且精确地维持所需的转录因子水平。增加比例反馈可减少随机变异性，同时保持稳健的完美适应。我们展示了这些控制器在减轻资源负担的影响方面的好处，并研究了它们在细胞治疗中的应用。强大的完美适应的合成生物学实现为工业生物技术和基于细胞的疗法的重大进步提供了希望。