An engineering rulebook for interfacing living and non-living cells

我们能否对活细胞进行逆向工程，制造出与生物细胞完全相似的人造细胞？这些人造细胞能否被用作在生理环境中执行定制任务的微型机器，并作为深入了解生物过程的模型？近年来，在这两个问题上取得了巨大的进展，预示着一个通过设计创造生物学的时代即将到来。这些进步是通过借用精密工程原理实现的，这些原理长期以来与帮助塑造现代世界的机械/电气设备有关。人造细胞具有细胞的尺寸，包含生物机制（DNA、蛋白质、脂质、代谢物），并且可以被设计成具有生命的一些基本特征。技术的融合使它们能够在尺寸、形态、内容、分区和功能的精细控制下被制造和操纵。人工细胞现在可以通过编程来提高浓度梯度，根据外界刺激制造蛋白质，进行复制，并相互交流。这些成就意味着人工细胞在现实世界中的应用——作为治疗剂、生物传感器、自我修复材料、生物/酶反应器——正在接近现实。在这项研究中，目标是超越模拟细胞，并开始使用生物细胞作为合成系统中不可或缺的功能组件，在这个系统中，生物和合成物质混合在一起——从本质上讲，使用活细胞作为嵌入式模块，直接利用生物学的力量和多功能性。绕过从零开始制造新模块的限制，而是劫持经过进化而形成的细胞成分，将使人工细胞的复杂性和能力发生重大变化，并将在生物设计中开辟未知的研究领域。在过去的三年里，作为ESPRC的博士后研究员，我(I)通过微流体、光学捕获和生物膜工程方面的开创性进展，开发了物理科学创新和技术基础，为这一努力奠定了基础，这些进展相当于人工细胞构建的工具包；（ii）通过初步研究证明了这种生物混合方法的可行性。在这项研究中，在这些进展的基础上，将实现生物细胞和合成细胞之间的全面整合，前者将被用作电池、传感器和反应堆。化学上和物理上“连接”合成的和有生命的部件将需要开发新的技术，并设计一个工程规则手册。将探讨三种不同的杂交路线：(i)物理杂交，其中生物细胞和人工细胞相互封装，形成一个统一的实体。种群杂交，即生物和人工细胞种群通过空间相互通信，交换信息和材料。（iii）网络化杂交，人工细胞和生物细胞通过人工间隙连接在一个大规模的组织样网络中。总之，我将确定生物和合成系统可以融合到什么程度，并开始建立一个新兴研究领域的基础，以连接人工生物学和生物生物学。这个项目雄心勃勃，涉及多个学科。它涵盖了物理和生命科学、工程和医学领域。该项目依赖于行业参与，包括在两个行业合作伙伴的实习。它也有一系列的领导目标，这些目标与研究型目标同等重要，并包含一个培训计划，帮助我成为一名科学领导者。由于这些原因，UKRI未来领袖奖学金提供的灵活、长期和跨委员会的支持是至关重要的。

Can we reverse engineer living cells and manufacture artificial cells that resemble their biological counterparts from the bottom up? Can these artificial cells be used as micromachines that perform bespoke tasks in physiological environments and as models to gain insights into biological processes? Recent years have seen tremendous advances relating to both these questions, heralding an era of making biology by design. These advances have been made possible by borrowing precision engineering principles long associated with mechanical/electrical devices that helped shape the modern world. Artificial cells have cellular dimensions, incorporate biological machinery (DNA, proteins, lipids, metabolites), and can be designed to possess some of the fundamental features of life. A convergence of technologies has allowed them to be manufactured and manipulated with fine control of the size, morphology, content, compartmentalisation, and function. Artificial cells can now be programmed to swim up concentration gradients, manufacture proteins in response to external stimuli, replicate, and communicate with one another. These accomplishments mean that real-world application of artificial cells - as therapeutic agents, biosensors, self-healing materials, bio/enzymatic reactors - is nearing a reality. In this fellowship, the aim is to go beyond mimicking cells and start using biological cells as integral functional components in a composite system where living and synthetic matter are intermingled - in essence, to use living cells as embedded modules, directly harnessing the power and versatility of biology. Bypassing the limitations associated with making new modules from scratch, and instead hijacking cellular components that have been sculpted through evolution, will enable a step change in artificial cell sophistication and capabilities, and will open up unchartered research areas in biodesign.Over the past three years as an ESPRC Postdoctoral Fellow, I have (i) developed the physical science innovations and technological groundwork that will underpin this endeavour through pioneering advances in microfluidics, optical trapping, and biomembrane engineering that amount to a toolkit for artificial cell construction, and (ii) demonstrated the feasibility of this biohybrid approach through preliminary studies. In this fellowship, building on these advances will achieve full integration between biological and synthetic cells, with the former being used as batteries, sensors, and reactors. Chemically and physically 'wiring up' synthetic and living components will require new technologies to be developed and an engineering rulebook to be devised. Three different hybridisation routes will be explored: (i) Physical hybridisation, where biological and artificial cells are encapsulated within one another to form a unified entity. (ii) Population hybridisation, where biological and artificial cell populations communicate with another through space, exchanging information and material. (iii) Networked hybridisation, where artificial and biological cells are linked through artificial gap junctions in a large-scale tissue-like network.In summary, I will determine how far living and synthetic systems can be fused, and start establishing the foundations of an emerging research area that bridges artificial and living biology. This project is highly ambitious and multi-disciplinary. It covers the physical and life sciences, engineering, and medical spheres. The project relies on industry engagement and includes placements at two industrial partners. It also has a series of leadership objectives, which are of equal importance to the research-focussed ones, and contains a training programme to help me become a scientific leader. For these reasons, the flexible, long-term, and cross-council support offered by the UKRI Future Leaders Fellowship is critical.