The problem of controlling cells endowed with a genetic toggle switch has been recently highlighted as a benchmark problem in synthetic biology. It has been shown that a carefully selected periodic forcing can balance a population of such cells in an undifferentiated state. The effectiveness of these control strategies, however, can be hindered by the presence of stochastic perturbations and uncertainties typically observed in biological systems and is therefore not robust. Here, we propose the use of feedback control strategies to enhance robustness and performance of the balancing action by selecting in real-time both the amplitude and the duty-cycle of the pulsatile inputs affecting the toggle switch behavior. We show, via in silico experiments and realistic agent-based simulations, the effectiveness of the proposed strategies even in the presence of uncertainties, stochastic effects, cell growth, and inducer diffusion. In so doing, we confirm previous observations made in the literature about coherence of the population when pulsatile forcing inputs are used, but, contrary to what was proposed in the past, we leverage feedback control techniques to endow the balancing strategy with unprecedented robustness and stability properties. We compare via in silico experiments different external control solutions and show their advantages and limitations from an in vivo implementation viewpoint.

中文翻译：

---

通过自适应脉冲反馈控制平衡具有合成拨动开关的细胞群体。

最近已经强调了控制具有遗传拨动开关的细胞的问题，将其作为合成生物学中的基准问题。已经表明，精心选择的周期性强迫可以平衡处于未分化状态的这类细胞的群体。然而，由于通常在生物系统中观察到的随机扰动和不确定性的存在，可能会阻碍这些控制策略的有效性，因此这种鲁棒性不强。在这里，我们建议使用反馈控制策略来通过实时选择影响切换开关行为的脉动输入的幅度和占空比来增强平衡动作的鲁棒性和性能。通过计算机模拟实验和现实的基于代理的模拟，我们展示了 即使存在不确定性，随机效应，细胞生长和诱导物扩散的情况下，所提出策略的有效性。这样，我们确认了以前使用搏动性强迫输入时有关人口连贯性的文献观察结果，但与过去提出的相反，我们利用反馈控制技术赋予平衡策略以前所未有的鲁棒性和稳定性。属性。我们通过计算机模拟实验比较了不同的外部控制解决方案，并从体内实施的角度展示了它们的优势和局限性。与过去提出的相反，我们利用反馈控制技术为平衡策略赋予了空前的鲁棒性和稳定性。我们通过计算机模拟实验比较了不同的外部控制解决方案，并从体内实施的角度展示了它们的优势和局限性。与过去提出的相反，我们利用反馈控制技术为平衡策略赋予了空前的鲁棒性和稳定性。我们通过计算机模拟实验比较了不同的外部控制解决方案，并从体内实施的角度展示了它们的优势和局限性。