Origins of Biology: How energy flow structures metabolism and heredity at the origin of life

生命起源是科学界最具标志性的问题之一。几十年来的研究似乎在所谓的“益生菌”条件下合成生命的基本构件方面取得了很好的进展。这些构件包括组成DNA中遗传物质的核苷酸。然而，这种益生化学与已知细胞的实际生物化学之间几乎在每一个方面都存在严重的脱节。为了缩小地球化学和生物化学之间的差距，并阐明生命的基本规律，我们提出了一种不同的方法来解决这个问题，基于生命本身。我们以生命的一个重要规则--跨膜能量流动为出发点。生命的这一特征在整个生命之树上就像遗传密码本身一样被深深地保存着。然而，尽管能量流在生物学中的重要性怎么强调都不为过，但所涉及的特定机制--质子(氢离子)通过膜的流动--的起源和进化意义历来被忽视。最近关于重建最早细胞的性质的工作现在正在开辟新的可能性。我们最重要的假设是，质子在膜上的流动可以推动二氧化碳和氢气之间的困难反应，形成用于制造所有其他细胞构件的碳“骨架”。我们认为，类似的过程可以在结构化的益生环境中驱动，如热液喷口，产生熟悉的细胞新陈代谢和生化。特别是，我们假设遗传信息最先出现在这种环境中。严格地说，遗传遗传是另一种生长形式，即基因模板被重复复制(加倍)并传递。我们认为，它的神秘起源(尽管有许多线索，几十年来一直拒绝解释)最适合在原始细胞活跃生长的背景下被理解，这是由通过结构化环境的能量流驱动的。我们将探索这个基本的组织原理：跨越障碍的能量流驱动有机分子的合成-生长-以及遗传所需的构建块。我们的具体目标是：(I)了解生长的驱动力；(Ii)使用生物学作为原代谢的指南；以及(Iii)解决原始细胞中遗传密码的起源。我们之前已经详细介绍了可能的机制。在这项资助中，我们将严格模拟从严格的无机但有结构的环境(如热液系统中跨越无机屏障的地质上持续的质子梯度)到形成具有基本遗传形式的简单原细胞，最后到在原细胞中出现真正的遗传遗传的步骤。我们将使用微流控反应器和基于细胞化学的可能的益生菌条件的筛选相结合的方式，通过实验来测试这种计算模型的预测。我们将把实验结果反馈到模型中，以完善我们的概念，并最终提供对生命能量规则的连贯、完整的理解。我们广泛的试验数据为这里提出的工作提供了强有力的证据。我们相信这些规则将有助于阐明在一个地质活跃但贫瘠的星球上驱动生命存在的力量。我们主要感兴趣的是理解支配生命出现的规则，但我们的工作也包括寻找宇宙其他地方生命的程序，指导未来的空间探索。在国内，这项工作对理解我们自己的新陈代谢结构具有重要意义，潜在地阐明了终生健康和疾病中代谢流的正常和变化模式。最后，使用一种仿生的能量流形式将二氧化碳固定为有机分子，可以促进碳捕获生产合成汽油，为能源安全提供净零排放解决方案。

The origin of life is one of the most iconic questions in science. Work over decades has seemingly made good progress in synthesizing the basic building blocks of life under purportedly 'prebiotic' conditions. These building blocks include the nucleotides that make up the genetic material in DNA. However, there is a serious disconnect between this prebiotic chemistry and the actual biochemistry of known cells in almost every respect. To close this gap between geochemistry and biochemistry and elucidate the fundamental rules of life, we propose a different approach to the problem, grounded in life itself.We take as our starting point an important rule of life - energy flow across membranes. This feature of life is as deeply conserved across the tree of life as the genetic code itself. Yet while the importance of energy flow in biology cannot be overstated, the origin and evolutionary implications of the specific mechanism involved - the flow of protons (hydrogen ions) across membranes - has historically been neglected. Recent work on reconstructing the properties of the earliest cells is now opening up new possibilities. Our overarching hypothesis is that the flow of protons across membranes can drive the difficult reaction between carbon dioxide and hydrogen gas to form the carbon 'skeletons' that are used to make all the other building blocks of cells. We propose that analogous processes can be driven in structured prebiotic environments such as hydrothermal vents, giving rise to the familiar metabolism and biochemistry of cells. In particular, we hypothesize that genetic information first arose in this setting. Genetic heredity is strictly another form of growth, in which a genetic template is repeatedly copied (doubled) and passed on. We propose that its mysterious origins (which have resisted interpretation over decades, despite many clues) can best be understood in the context of actively growing protocells, driven by energy flow through a structured environment.We will explore this fundamental organizing principle: energy flow across barriers drives the synthesis of organic molecules - growth - and the building blocks needed for genetic heredity. Our specific objectives are to: (i) understand the driving force for growth; (ii) use biology as a guide to protometabolism; and (iii) resolve the origins of the genetic code in protocells. We have previously detailed possible mechanisms. In this grant, we will rigorously model the steps going from a strictly inorganic but structured setting (such as geologically sustained proton gradients across inorganic barriers in hydrothermal systems) to the formation of simple protocells with a rudimentary form of heredity, and finally to the emergence of true genetic heredity in protocells. We will test the predictions of this computational modelling experimentally, using a combination of microfluidic reactors and screening of possible prebiotic conditions based on the chemistry of cells. We will feedback the results of experiments into the models to refine our concepts and ultimately deliver a coherent, integrated understanding of the energetic rules of life. Our extensive pilot data gives strong credence to the work proposed here.We believe these rules will help to elucidate the forces that drive life into existence on a geologically active but sterile planet. We are primarily interested in understanding the rules that govern the emergence of life but our work also hasimplications for the search for life elsewhere in the universe, guiding future space exploration. At home, this work has vital implications for understanding the structure of our own metabolism, potentially elucidating both normal and altered patterns of metabolic flux in lifelong health and disease. Finally, fixing carbon dioxide as organic molecules using a biomimetic form of energy flow could facilitate carbon capture to produce synthetic gasoline, giving a net zero-emissions solution to energy security.