21ENGBIO A Universal and Controllable Interface between Synthetic Cells and Living Cells

一个不断发展的研究领域是从离散的积木中创造出“合成细胞”。通过这项研究，我们可以了解生命是如何开始和进化的。此外，由于合成细胞是完全模块化的，不能自我复制，它们有望成为新型药物输送系统，并作为连接生物和非生物材料的工具。这些界面可能被用来研究或修改活组织，而不需要进行基因改造。将合成细胞与活细胞连接的方法通常是通过模拟活细胞中的特定过程而产生的，而不是其他相互竞争的过程。然而，目前还没有通用的方法来允许合成细胞与活细胞使用广泛的信号分子进行通信。例如，两种最常见的方法依赖于识别信号分子，这些分子将自己穿过合成的细胞膜，或者使用在细胞膜上形成孔的蛋白质。然而，除了不是通用的，这两种方法都有显著的缺点和局限性。我们将产生一种方法，允许释放任何大小的信号分子。这将是将合成细胞用作研究工具和药物输送装置的一步改变。我们的方法将模仿大脑中神经元的交流。神经递质被保存在小隔间的神经元中。神经递质在突触的释放是通过这些小隔间与细胞膜的融合来实现的，通过迫使它们聚集在一起。我们将产生包含小隔间的合成细胞。这些小隔间将能够装满任何大小的信号分子。小隔间与合成细胞膜的融合，就像在神经元中看到的那样，将通过使用DNA和RNA链的混合来启动。DNA和RNA的互补是这一功能的理想选择，因为它是强大的和可编程的。通过在小隔间中加入功能信号分子，我们将把这些合成细胞与邻近的活细胞连接起来，以控制它们的功能。对于现实世界的应用，合成细胞的功能需要被触发，理想情况下是远程刺激，以抑制不需要的合成细胞活动。光是一种理想的刺激，因为它可以在空间和时间的精确时间点远程应用。为了实现这一点，我们将加入一个光激活模板，我们之前已经从这个模板生成了具有功能的合成细胞。我们连接合成细胞和活细胞的方法将是通用的和远程可控的。通过将神经递质包裹在小隔间内，这种外部控制的释放可能被用作合成细胞和神经元之间的计算机-大脑接口。此外，由于任何分子都可以被包裹在合成的细胞器中，并在光线下释放，因此有可能将精确的药物靶向任何活细胞。这项旨在拓宽合成细胞功能的基础研究项目有可能彻底改变该研究领域，并带来合成细胞的现实潜力。

A growing area of research is the creation of 'synthetic cells' from discrete building blocks. Through this research we can gain an understanding of how life started and evolved. Additionally, as synthetic cells are completely modular and cannot self-replicate, they offer promise as novel drug delivery systems and as tools to interface living and non-living materials. These interfaces might be used to study or modify living tissue, without the need for genetic modification. Approaches to interface synthetic cells with living cells often arise from mimicking specific processes in living cells, without other competing processes. However, currently there are no universal methods to allow synthetic cells to communicate with living cells using a wide range of signal molecules. For instance, the two most common approaches rely on identifying signal molecules that will move across the synthetic cell membrane by themselves, or the use of proteins that form holes in the membranes. However, beyond not being universal, both approaches have significant downsides and limitations. We will generate a method that allows the release of any-sized signal molecule. This will be a step change in the use of synthetic cells as research tools and drug delivery devices. Our approach will mimic the communication of neurons in the brain. Neurotransmitters are held within neurons in small compartments. Release of neurotransmitters at the synapse is achieved by the fusion of these small compartments to the cell membrane, by forcing them together. We will generate synthetic cells that contain small compartments. These small compartments will be able to be filled with any-sized signal molecule. Fusion of the small compartment to the synthetic cell membrane, like is seen in neurons, will be initiated by using a mix of DNA and RNA strands. DNA and RNA complementarity is ideal for this function as it is strong and programmable. By incorporating functional signal molecules within the small compartments, we will then interface these synthetic cells with neighbouring living cells to control their function.For real world application, the function of synthetic cells needs to be triggered, ideally with a remote stimulus, to inhibit the synthetic cell activity where it is not wanted. Light is an ideal stimulus as it can be applied remotely at a precise point in space and time. To achieve this, we will incorporate a light-activated template that the synthetic cells with function from, which we have previously generated.Our method to interface synthetic and living cells will be universal and remote controllable. By encapsulating neurotransmitters within the small compartments, this externally controlled release might be used as a computer-brain interface between synthetic cells and neurons. Additionally, as any molecule could be encapsuled in the synthetic organelles and released with light, there is the potential for precision drug targeting to any living cell. This basic research project to broaden the functionality of synthetic cells has the potential to revolutionise the research area and bring about the real-world potential of synthetic cells.