Life emerges when protons flow across a membrane—and this grant will model and test how that energy flow first turned simple chemistry into cells with heredity. The origin of life has long been studied by trying to replicate prebiotic chemistry in a test tube, but those lab-made building blocks bear little resemblance to how actual cells work. This project closes that gap by starting with a universal rule of life—proton flow across membranes—and asking whether it can drive the carbon-dioxide-to-carbon-skeleton reactions that build cells, and eventually support genetic copying. If the hypothesis holds, the work will produce a coherent, experimentally tested model of how life arises from a sterile, geologically active planet. That could guide the search for life elsewhere in the solar system. It could also reveal the energetic rules governing human metabolism, with implications for lifelong health and disease. And a biomimetic process that fixes carbon dioxide into organic molecules using proton gradients might offer a net-zero route to synthetic fuel. This is fundamental science. It asks how life begins, not how to fix a specific problem tomorrow. But understanding those rules has, historically, reshaped medicine, energy, and exploration in ways no one could predict.
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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 has implications 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.
Amandine MARECHAL (Co-Investigator)Andrew Pomiankowski (Co-Investigator)Finn Werner (Co-Investigator)Giuseppe Battaglia (Co-Investigator)Joanne Santini (Co-Investigator)John Ward (Co-Investigator)Nick Lane (Principal Investigator)Nicolas Szita (Co-Investigator)Stefanie Frank (Co-Investigator)
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