Metabolism is the “beating heart of the cell”. New research from ELSI retraces the history of metabolism from the primordial Earth to the modern day (left to right). The history of compound discovery over time (white line) is cyclic, almost resembling an EKG.
(Image credit: NASA’s Goddard Space Flight Center/Francis Reddy/NASA/ESA)
A missing piece of Earth’s evolutionary timeline may have been found. Using computational modeling, a team of scientists explored how working backwards from modern biochemistry could help map out how simple, non-living chemicals present on early Earth gave rise to complex molecules that led to the emergence of life as we know it.
Researchers believe modern metabolism — the life-sustaining biochemical processes that occur within living beings — evolved from the primitive geochemical environment of ancient Earth, drawing on available materials and energy sources. While an interesting idea, however, evidence for the transition from primitive geochemistry to modern biochemistry is still missing.
Past modeling studies have provided valuable insights, but have always run into a snag: their models of the evolution of metabolism have consistently failed to produce many of the complex molecules used by modern life — and the reason why is not clear.
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Notably, there is uncertainty surrounding continuity in this metabolic timeline, specifically the degree to which ancient biochemical processes that may have disappeared over time shaped the metabolic processes we know today.
“In particular, chemical reactions that are unrelated to biochemistry have been invoked as missing steps in early biosynthetic pathways, suggesting that records of these chemical transformations were lost throughout the history of evolution,” the study team from the Tokyo Institute of Technology and the California Institute of Technology wrote in a paper describing the new missing link. “It remains unclear to what extent ‘extinct’ biochemistry is necessary to enable the generation of modern metabolism from early Earth environments.”
To unravel this puzzle the scientists sought to model possible evolutionary pathways that could have taken modern metabolism from its early Earth predecessors to the present day. They therefore explored biochemical evolution on a biosphere level, meaning on the scale of an entire ecosystem, and integrated influences and factors such as geochemical and atmospheric environments, as well as how organisms might interact.
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“It has long been hypothesized that the roots of biochemistry lie in the geochemistry of the early Earth,” Seán Jordan, associate professor in biogeochemistry and astrobiology at Dublin City University, who was not involved in the study, told Space.com. “The suggestion that remnants of ancient metabolic pathways may be hidden in the modern biosphere, and as yet undetected, is fascinating and exciting.”
The team used the Kyoto Encyclopedia of Genes and Genomes database, which has catalogued just over 12,000 biochemical reactions, as the model’s repository for all possible biochemical reactions that could have taken place and evolved during the studied timeline. Researchers then simulated the expansion of a chemical reaction network starting from a set of initial compounds that would have been found on early Earth. These included various metals and inorganic molecules, such as iron, hydrogen sulfide, carbon dioxide and ammonia, as well as organic substrates that could have been formed through ancient carbon-fixing reactions.
“Using a network expansion algorithm to trace a path from early geochemistry to complex metabolic networks appears to be a solid, iterative approach to this question,” Jordan said.
However, as with other modelling experiments, the researchers’ model initially failed to reproduce even a fraction of the molecules used in modern biochemical processes, leaving the vast majority unreachable from the seed compounds. Hypothesizing that these results were limited because the data set only included known catalogued biochemical reactions, the researchers expanded the Kyoto database to include a set of hypothetical biochemical reactions too, adding 20,183 new pathways.
To construct a model of the evolutionary history of metabolism at the biosphere scale, the research team compiled a database of 12,262 biochemical reactions from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. (Image credit: Goldford, J.E., Nat Ecol Evol (2024))
Repeating the experiment with this expanded reaction set resulted in only a slight increase in scope, “suggesting that neither currently catalogued nor predicted biochemistry contains transformations required to reach the vast majority of known metabolites.”
The authors noticed that a key precursor to a class of compounds called purines, which are important building blocks for biological molecules such as DNA and RNA, was not found in the model’s expansion scope. In fact, a quick test in which adenine, a common purine derivative, was added to the pool of seed compounds resulted in an approximately 50% increase in the number of modern biomolecules the model was able to predict.
Further experimentation confirmed what the authors called a “purine bottleneck,” which seemingly prevents the emergence of metabolism from geochemical precursors in the model. The issue appeared to be linked to the dataset of modern biochemical reactions, where the production of purines, like adenosine triphosphate (ATP), is autocatalytic. This means multiple steps in the synthetic pathway of ATP require ATP itself — without ATP, new ATP cannot be created. This self-cycling was causing the model to reach a standstill.
To resolve the bottleneck, the scientists hypothesized that this self-catalyzing dependence may have been more “relaxed” in primitive metabolic pathways as the role ATP currently plays could have been carried out by inorganic molecules known as polyphosphates. Replacing ATP in the database’s reactions (only eight in total required this change), nearly all of contemporary core metabolism could be achieved.
“We might never know exactly, but our research yielded an important piece of evidence: only eight new reactions, all reminiscent of common biochemical reactions, are needed to bridge geochemistry and biochemistry,” Harrison Smith, one of the study’s authors said in a press release. “This does not prove that the space of missing biochemistry is small, but it does show that even reactions which have gone extinct can be rediscovered from clues left behind in modern biochemistry.”
“The big question that remains unanswered is whether we can show experimentally that the steps from geochemistry to biochemistry are possible following a trajectory such [this],” added Jordan. “These findings should encourage others in the field to keep probing this transition. It shows us that the blueprint to the chemistry that led to the emergence of life can be found in extant biochemistry.”
The study was published in March in the journal Nature Ecology & Evolution.
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A chemist turned science writer, Victoria Corless completed her Ph.D. in organic synthesis at the University of Toronto and, ever the cliché, realized lab work was not something she wanted to do for the rest of her days. After dabbling in science writing and a brief stint as a medical writer, Victoria joined Wiley’s Advanced Science News where she works as an editor and writer. On the side, she freelances for various outlets, including Research2Reality and Chemistry World.
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