A starting place for early life? AF archive/Alamy Stock Photo

A set of chemical reactions occurring spontaneously in Earth’s early chemical environments could have provided the foundations upon which life evolved.

The discovery that a version of the Krebs cycle, which occurs in most living cells, can proceed in the absence of cellular proteins called enzymes suggests that metabolism is older than life itself.

Metabolism describes the fiendishly complex network of reactions that enable organisms to generate energy and the molecules they need to survive, grow and reproduce.


The Krebs cycle – also known as the tricarboxylic acid (TCA) cycle – is at the heart of this network. It describes a circular chain of reactions that generates precursors of amino acids and lipids used to build proteins and membranes, and molecules that help the cell to produce its energy.

But how did such a complex cycle develop in the first place?

One idea is that it began only after RNA, a fundamental building block of life, came into being. Metabolic reactions are catalysed by proteins called enzymes, for which RNA provides the template – at least in modern cells.

There is, however, a problem with this “RNA world” hypothesis: if the reactions didn’t already occur immediately in early life forms and provide them with a survival advantage, then there would have been no selective pressure to drive the evolution of enzymes. Furthermore, RNA itself is made from products of metabolism.

So an alternative explanation is that the Krebs cycle existed from the outset, and early life forms simply adopted it and developed enzymes to make it more efficient.

However, modern enzymes that catalyse this cycle all use very different mechanisms to do so. The idea that the type of simple, inorganic molecule that might have existed naturally in the early oceans could catalyse such a diverse set of reactions was once dismissed by RNA-world proponents as an “appeal to magic”.

No magic trick

Now Markus Ralser at the Francis Crick Institute in London and his colleagues appear to have pulled such a molecule out of the hat, and no magic wand was necessary.

Ralser previously showed that two other crucial metabolic pathways – glycolysis and the pentose phosphate pathway – could be catalysed by metal ions present on early Earth rather than the enzymes that catalyse them in modern cells.

But sceptics of the “metabolism first” idea have pointed out that these pathways only seem to run in one direction, whereas earliest life would have needed both in order to work, and the starting material for these pathways, glucose, is unlikely to have existed on early Earth.

Unable to so far provide a satisfactory answer to these problems, Ralser has shifted his focus to the Krebs cycle. Unlike with glucose, the chemicals involved at various points of the Krebs cycle have been identified on meteorites and in laboratory recreations of Earth’s early oceans – so we know they were around.

“We may not be able to solve where glucose comes from so easily,” says Ralser. “But if we can provide proof that the Krebs cycle could originate from a single, non-enzymatic catalyst, then we would have a very strong case that what we say about the origins of metabolism is true.”

So his team took chemicals involved in the Krebs cycle and exposed them to chemicals that would have been present in early ocean sediments. Nothing happened, until they introduced a compound called peroxydisulphate, a source of highly reactive agents called sulphate radicals.

This triggered a sequence of 24 chemical reactions that were very similar – although not identical – to those seen in the Krebs cycle today.

“The most surprising thing is that again a single molecule acts as the catalyst for all of the reactions we discovered,” says Ralser. “The simplicity of it is super-exciting because it gives you a plausible feeling about how it could have all started.”

Sulphate radicals would had been found in abundance near hydrothermal vents, which have been suggested as possible locations at which life started, or near to sulphur-rich sediments.

Ralser believes that these hardwired chemical reactions provided a template upon which the evolutionary machinery could build once it came into being.

Unfinished cycle

However, the enzyme-free Krebs cycle that Ralser observed isn’t the complete biochemical cycle as it operates in modern cells. That may have come later, after enzymes evolved.

Furthermore, the sulphate-driven cycle has so far only been shown to run in one direction (the oxidative one). In some species, the Krebs cycle can also run in reverse and help to incorporate CO 2 into the building of new carbohydrates. Some think it may therefore have been involved in early carbon fixation, in which case you’d expect to see the cycle spontaneously turning in this direction too.

Until researchers can demonstrate both these things, they cannot claim that metabolism came before cells and life, some experts think.

“This is a neat paper and the findings are striking and careful,” says Nick Lane, an evolutionary biochemist at University College London. “But this is strictly the oxidative Krebs cycle, which is certainly not ancient. It probably became oxidative after the rise of molecular oxygen in the atmosphere.

“Before that, there was a reductive Krebs cycle, which fixed CO 2 using H 2 , and which is still found in some ancient bacteria,” says Lane. “They are not simulating the reductive Krebs cycle at all.”

What’s more, even if all three fundamental metabolic pathways – the Krebs cycle, pentose phosphate pathway and glycolysis – can proceed in the absence of enzymes, there’s still the question of how life’s other components came into being.

“With the metabolic pathway alone, you have a very good starting point for life, but it is not life, just a chemical-reaction network,” says Ralser. “You also need things like membranes to contain the reactions, and the genetic machinery that enables inheritance.

“How do you bring these elements together in one environment and in non-extreme conditions, and make them work?” he asks. “This is still a big challenge.”

Journal reference: Nature Ecology & Evolution: DOI: 10.1038/s41559-017-0083

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