2022BBSRC-NSF/BIO: Self-replicating synthetic cells programmed by RNA

2022BBSRC-NSF/BIO：由RNA编程的自我复制合成细胞

• 批准号: BB/Y000196/1
• 负责人: Lorenzo Di Michele
• 金额: $ 56.15万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY000196%2F1
• 关键词: 2022BBSRC; NSF; BIO; Self; replicating

For as long as us humans have been aware that there is a clear difference between living and inanimate matter, we have been trying to answer a fundamental question: what makes something alive?This question has many possible answers, often at odds with each other, but most definitions of life agree on one point: Life should be able to self-replicate. Cell replication indeed underpins some of the most fundamental characteristics of life-forms, such as their ability to evolve, grow, morph, and adapt to their environment. Having noted how central self-replication is to life, another question naturally emerges: is it possible to build from scratch something that can replicate itself, like a living cell?Surely, if we could, it would be the first step towards creating new living things from inanimate matter, which would help us understand the principles that may have led to life emerging on planet earth in the first place, and hold dramatic technological potential.Thanks to an international team of UK and US scientists, combining expertise in nanotechnology, molecular biology, biophysics, and computational science, we will address this fundamental question, attempting to construct synthetic devices that mimic all critical steps of the replication cycle of biological cells: 1) replication of the genetic material, 2) segregation of the genetic material in different parts of the cell, 3) growth of the cell and 4) its division in two offspring cells.Many researchers have, over the years, worked on this problem, and succeeded in building synthetic systems capable of competing some of these individual steps. However, achieving all of them with the same system remains difficult. One key hurdle is that it is very challenging with synthetic systems to couple the replication of the genetic material with the growth and division of the enclosure that contains it, so that one step triggers the other.Our approach solves this problem by re-thinking the role of nucleic acids. In living cells, nucleic acids are predominantly information carriers, with DNA serving as the long-term storage of genetic information and RNA as a substrate to temporarily hold this information while it is used to build proteins. The latter, alongside few other macromolecules (themselves synthesised by protein-based machinery), constitute the main structural elements of the cell.In our self-replicating synthetic cells, however, nucleic acids (DNA and RNA) will play BOTH genetic AND structural roles. Our "synthetic cells" will be made primarily out of synthetic RNA nanostructures produced from a DNA genetic code. The RNA nanostructures will be designed to form cell-like devices capable of growing and dividing, as more RNA is produced from DNA, hence establishing a strong connection between genetic and structural replication, which was missing in previous attempts.By building these nucleic-acid-based, self-replicating synthetic cells, we will not only be able to gauge our ability to imitate life forms and answer questions relative to the origin of life, but we will also pave the way to game-changing technological applications. Synthetic cells constructed from the "bottom-up" are indeed regarded as potentially very valuable in diagnostics and therapeutics, whereby these programmable devices could operate in the body, recognise the presence of a disease, and efficiently tackle it by locally producing and releasing therapeutic payloads. The ability to self-replicate (in a controlled and safe manner) would be crucial for extending the lifespan of the devices, and thus the efficacy of their therapeutic action to the point that it could rival that of cutting-edge therapies based on reprogrammed biological cells.

只要我们人类意识到生命和无生命的物质之间存在明显的差异，我们就一直在试图回答一个基本问题：什么使某事活着？这个问题有很多可能的答案，通常是彼此相反的，但大多数生活的定义都同意：生活应该能够自我复制。细胞复制确实是生命形成的一些最基本特征的基础，例如它们的发展，成长，变体和适应其环境的能力。注意到生活对生命有多重要，自然而然地出现了另一个问题：是否有可能从刮擦建立可以复制自己的东西，例如一个活着的细胞，例如活细胞？当然，如果可以的话，这将是从无生命的物质中创造新的生物的第一步在纳米技术，分子生物学，生物物理学和计算科学中，我们将解决这个基本问题，试图构建生物细胞复制复制周期的所有关键步骤的合成器件：1）遗传材料的复制，2）2）3）细胞中的遗传学者的遗传材料的隔离，3）cell and of twe and of twe and Mants cells and of twe Cells and 4）corns。解决了这个问题，并成功地构建了能够竞争这些单个步骤的合成系统。但是，使用相同系统实现所有这些都很困难。一个关键的障碍是，对于合成系统而言，将遗传物质的复制与包含遗传物质的生长和分裂进行复制和分裂是非常具有挑战性的，因此，一个步骤触发了另一个步骤。您的方法通过重新思考核酸的作用来解决这个问题。在活细胞中，核酸主要是信息载体，DNA用作遗传信息和RNA的长期存储，作为底物，在用于构建蛋白质的同时暂时持有该信息。后者与其他少数大分子（通过蛋白质基于蛋白质的机械合成）构成了细胞的主要结构元素。但是，在我们的自我复制合成细胞中，核酸（DNA和RNA）将起遗传和结构的作用。我们的“合成细胞”将主要由DNA遗传密码产生的合成RNA纳米结构制成。 RNA纳米结构将被设计成形成能够生长和分裂的细胞样设备，因为DNA产生了更多的RNA，因此在先前尝试中缺少遗传和结构复制之间存在牢固的联系，这是在遗传和结构复制之间缺失的。构建这些基于核酸的，自我修复的合成细胞，我们还可以衡量生命的态度，并逐步了解生命的问题，以使我们的能力相对构想，以弥补生命的范围，以使生命变得越来越重要，以使生命构成生命，并将其起源，以使其起来，并将其起源，以使其起来，并将其起源，以使生命逐渐成立，并将其起源，以使生命逐渐成立，并将其起源于生命。改变游戏的技术应用。从“自下而上”构建的合成细胞确实被认为在诊断和治疗学中可能非常有价值，因此这些可编程设备可以在体内运行，识别疾病的存在，并通过局部产生和释放治疗载荷来有效地解决它。自我复制的能力（以受控和安全的方式）对于延长设备的寿命至关重要，因此其治疗作用的功效是可以与基于重编程生物细胞的尖端疗法相媲美的。