Conversing with cells at the fundamental level

从根本上讲，所有生物系统都是通过单分子尺度上的复杂分子相互作用来运作的。为了在基础水平上观察细胞和组织的运作或与之相互作用，有必要在分子水平上进行观察和相互作用。这些相互作用的规模最好用十亿分之一米或纳米(Nm)来衡量。我们希望使生物学家能够在这个基本的分子水平上与活细胞进行双向相互作用。我们提出了一个工作在纳米尺度上的生物换能器系统。这些将在用户的编程控制下感知和控制化学环境。这需要三项新技术：纳米级生物换能器，将这些生物换能器输送到细胞环境的系统，以及一种在纳米级与生物换能器交谈的方式。在这个概念验证提案中，我们将解决其中的两项：制造生物换能器并与它们交谈。已经有了交付它们的概念证明(然而，这仍然是一个可怕的挑战)。生物换能器面临的关键挑战是找到一种方法来改变它们的行为，以便它们能够在用户的控制下感知或影响周围环境。我们建议将新的可切换试剂与纳米传感器探针的新研究相结合来实现这一点。与生物传感器交谈的关键挑战是在不干扰细胞的情况下在纳米级与它们进行通信。由于这超出了传统光学显微镜的分辨率，我们建议制作一种超分辨率光学纳米显微镜，它利用生物换能器的可切换特性来获得纳米分辨率。这种方法将允许对生物传感器进行实时、广域和3D寻址。实现与细胞对话的技术非常重要，将给生命科学带来革命性的变化--不仅提供了一种了解基础水平上正在发生的事情的方法，而且还提供了一种让科学家在同一水平上进行交谈和互动的方法。

At the fundamental level all biological systems operate through complex molecular interactions at the scale of single molecules. In order to observe or interact with the operation of cells and tissues at the fundamental level it is necessary to observe and interact at the molecular level. The scale of these interactions is best measured in billionths of a metre or the nanometre (nm).We want to enable biologists to be able to have two way interaction with living cells at this fundamental, molecular level.We propose a system of biotransducers operating at the nm scale. These will sense and control the chemical environment under the programmed control of the user.This requires three new technologies: nm-scale biotransducers, a system to deliver these biotransducers to the cellular environment and a way to speak to the biotransducers at the nanometre scale.In this proof of concept proposal we will tackle two of these: making biotransducers and talking to them. There is already proof of concept for delivering them (however, this is still a formidable challenge).The key challenge for the biotransducers is making a way to switch their behaviour so that they can be made to sense or influence their surroundings under the control of the user. We propose to combine newly available switchable agents with new research into nanosensor probes to achieve this.The key challenge for talking to the biotransducers is to communicate with them at the nanometre scale without disturbing the cells. Since this is beyond the resolution of conventional optical microscopes we propose to make a super-resolving optical nanoscope which exploits the switchable properties of the biotransducers to get nm resolution. This approach will allow real-time, wide-field and 3D addressing of the biotransducers.The technology to enable conversations with cells is hugely important and will revolutionise the life sciences - not only providing a way to see what is going on at the fundamental level but a way for the scientist to talk back and interact at the same level.