How and where did the first forms of life arise? These are the main questions driving research at the Institute of Molecular Evolution at Heinrich Heine University Düsseldorf (HHU). In a new publication in Science Advances, an international team led by Düsseldorf biologists uncovers pioneering insights into the network of chemical reactions that the very first cells used to make the building blocks of life and which sources of energy they used to drive those reactions. They retraced the origin of enzymes during life’s earliest divergence into bacteria and archaea, and found evidence for two independent origins of life for free-living cells.
If we could go back 4 billion years in time and watch as the first cells emerged on Earth, what would we see? “We would see two very different kinds of cells emerging, pioneer bacteria and pioneer archaea, making their first attempts at life outside the confines of a hydrothermal vent” says Natalia Mrnjavac, biologist at the University of Düsseldorf and lead author on the new publication in Science Advances.
There, Mrnjavac and an international team of scientists report investigations of genomes, protein structures and chemical reactions that probe the very earliest phases of microbial evolution before there were free living cells. “These comparisons are giving us unprecedented insights into the phase of evolution when metabolism catalysed by enzymes was arising from spontaneous reactions catalysed by metals in the Earth’s crust” says Düsseldorf biologist William Martin, senior author of the study.
The approach that the team took differs from all previous investigations of early evolution by looking at the entire set of chemical reactions that cells use to make the building blocks of life (amino acids, RNA bases and vitamins) from compounds present on the early Earth: hydrogen gas, ammonia and CO 2 . This set of 420 chemical reactions is called metabolism. The chemical reactions themselves are as universally conserved as the genetic code.
Martin: “The surprise is that the enzymes that catalyse those reactions are not conserved across the evolutionary divide that separates bacteria and archaea. We found that the last universal ancestor of all cells, LUCA , possessed enzymes for only about half of the reactions of metabolism. The other half was catalysed by metals in the environment where LUCA arose.”
“Metals that naturally occur in hydrothermal vents can replace a surprisingly large number of enzymes in metabolism” says Harun Tüysüz, inorganic chemist from the Max-Planck-Institut für Kohlenforschung and the IMDEA Materials Institute in Madrid, and co-author on the study.
“The closer we look, the more clearly we can see that early biochemical evolution was a hybrid of enzymatic and metal catalysts” says Joseph Moran from the University of Ottawa, Canada, an international leader in the use of metals to catalyse metabolic reactions, replacing enzymes and cofactors.
A big step forward in the present study was that the team could reconstruct four phases of early evolution of catalysis: metal-only, a metal-enzyme hybrid in LUCA, followed by divergent evolution towards the ancestors of the bacteria and archaeal lineages. In those lineages, new enzymes were arising, replacing inorganic catalysts provided by the environment where metabolism arose.
“We can see cases where the ancestors of bacteria and archaea independently evolved structurally distinct enzymes to catalyse the same essential metabolic reaction,” says Mrnjavac, “such parallel inventions could have paved the way to the independent emergence of free-living bacteria and archaea.”
And where did the energy come from to drive these reactions forward? Today the energy in metabolism mainly comes in the form of ATP, but ATP is a complicated molecule, made by enzymes, not a compound that was lying around for free in hydrothermal vents. “We have identified a new source of energy at metabolic origin” says Manon Schlikker from the Düsseldorf team. Among the metals that naturally occur in hydrothermal vents are palladium, an excellent catalyst known and used by chemists for a century. “When we react phosphite, a form of phosphorus that naturally occurs in hydrothermal vents, with organic compounds, we get metabolic phosphorylation reactions overnight in water. Phosphite and palladium replace ATP and enzymes; it’s amazing, and it makes early evolution a lot easier to grasp” says Schlikker.
The study is the first focused investigation into the reaction set called metabolism. That reaction set is a highly interconnected network of 420 reactions, with many compounds participating in multiple reactions. Such networks can be mathematically challenging to deal with. But among the authors are Prof. Mike Steel, from the University of Canterbury in New Zealand, and Prof. Daniel Huson from the University of Tübingen. Experts when it comes to networks, they devised a new method to order metabolic reactions from the simplest to the most complex, possibly recapitulating the order in which metabolic reactions arose at origins. “The first question,” says Steel, “is whether or not a unique order exists for these reactions. Once we could prove that there is one, the algorithm to order them became tractable.”
It is part of our human condition to want to know about our origins, where we come from, where life started and how the first cells on Earth made a living. And what is the larger significance of the new findings? Martin: “The new data leave only one conclusion. The bacteria and archaeal lineages made the transition to the free-living state independently. Only free-living cells are alive. Let’s call it by name: we are looking at one origin of the genetic code, but two origins of life.”
In addition to researchers from HHU, the international team included scientists from the Universities of Canterbury (New Zealand), Rostock, Constance, Ottawa (Canada), Strasbourg und Tübingen, the Max-Planck-Institute for Terrestrial Microbiology in Marburg and the Max-Planck-Institut für Kohlenforschung in Mülheim/Ruhr plus the IMDEA Materials Institute in Madrid (Spain).
Biologists divide life forms into two categories: Eukaryotes – advanced cells with a cell nucleus – and the more ancient cells lineages without a nucleus: the prokaryotes. The prokaryotes comprise the two primordial lineages of life: Bacteria and Archaea. Many prokaryotes can survive in extreme conditions such as high temperatures, acid or alkaline environments. Many inhabit hydrothermal vents on the ocean floor where, in some theories, life is thought to have arisen.
Natalia Mrnjavac, Nadja K. Hoffmann, Manon L. Schlikker, Maximilian Burmeister, Loraine Schwander, Carolina García García, Max Brabender, Mike Steel, Daniel H. Huson, Sabine Metzger, Quentin Dherbassy, Bernhard Schink, Mirko Basen, Joseph Moran, Harun Tüysüz, Martina Preiner, William F. Martin; Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent; Science Advances 12, eaef3128 (2026)
Science Advances
Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent
5-Aug-2026