A discovery by scientists at Scripps Research and the Georgia Institute of Technology could shed light on the evolution of life on Earth and pave the way for more efficient biofuel production.
Early Earth was a volatile and inhospitable place, marked by extreme temperatures, widespread volcanic activity, and a thin, primitive atmosphere. Yet somehow, the basic molecular components of life, such as sugars, amino acids, and nucleotides, emerged from this chaos. One long-standing theory among chemists holds that ribose, a sugar that forms the structural backbone of RNA, arose spontaneously through a chemical process. However, new research challenges this idea.
In a study published in Chem, scientists from Scripps Research and the Georgia Institute of Technology question the validity of the “formose reaction” hypothesis. This hypothesis proposes that simple formaldehyde molecules reacted under early Earth conditions to form ribose. But the new findings reveal a key limitation: under controlled experimental conditions, the formose reaction does not yield linear sugars like ribose. Instead, it predominantly produces branched sugar structures, which are incompatible with the formation of RNA.
These results not only reshape our understanding of how life’s essential molecules may have originated, but also offer insights that could influence synthetic biology and biofuel production strategies.
“The concept of the formose reaction as a prebiotic source of ribose needs serious reconsideration,” says corresponding author Ramanarayanan Krishnamurthy, professor of chemistry at Scripps Research. “Other models and options should be explored if we want to understand how these sugar molecules arose on early Earth.”
The formose reaction was serendipitously discovered in 1861 and has been a leading hypothesis for prebiotic sugar formation ever since. During the reaction, formaldehyde molecules spontaneously and repeatedly react with each other to create larger molecules: first two formaldehydes react to create a two-carbon molecule, which then reacts with another formaldehyde to create a three-carbon molecule, and so on and so on, until all the formaldehyde has been used up.
The reaction is slow to begin but then accelerates uncontrollably. As more and more complex sugars are made, the reaction mixture turns from colorless, to yellow, to brown, to black. “It’s almost like caramelization,” says Krishnamurthy.
Exploring Controlled Conditions
“The problem is it’s a very messy reaction, and if ribose is formed at all, it’s a minuscule part and only one among hundreds and thousands of compounds that will be formed,” says Krishnamurthy. “We wanted to understand why this reaction is so complex, and whether it can be controlled.”
Usually, the formose reaction is conducted at high temperatures and in a very basic environment (at a high pH of 12 or 13). In this case, the researchers decided to test the reaction under milder conditions: at room temperature and at a pH of around 8, which they say is likely to be closer to the conditions present on prebiotic early Earth. To monitor the abundance and types of sugars produced, they used a high-powered analytical technique known as nuclear magnetic resonance (NMR) spectroscopy and labeled the starting molecules. The mixture was monitored over several days.
They showed that the reaction is possible even under mild conditions, but that the results are just as complex and uncontrollable as usual.
“The reactivity of formaldehyde doesn’t allow you to stop at a particular stage,” says Krishnamurthy. “Even with very mild reaction conditions it goes on until all of the formaldehyde is consumed, which means it’s very difficult to control or stop the reaction in order to form intermediate sugars.”
Implications for the Origin of Life and Industry
The NMR data revealed that all of the larger sugars produced had branched structures. Since almost all of the sugars that are used as molecular building blocks in living organisms are linear and unbranched, this suggests that the formose reaction cannot explain the origins of biotic sugars.
“Our results cast doubt on the formose reaction as the basis for the formation of linear sugars,” says co-senior author Charles Liotta, Regents’ Professor Emeritus of the Georgia Institute of Technology.
Though the study’s mild reaction conditions failed to create the linear sugars necessary to explain the origins of RNA, the methods could be useful for the biofuel industry, where branched sugars are a desirable commodity.
“Our work might be helpful for biofuel production, since we found that with milder conditions, we can more cleanly produce branched sugars that can be used for green fuel,” says Krishnamurthy.
This isn’t necessarily the end for origins of life research on the formose reaction, but the researchers hope to spur different lines of thinking.
“Our goal was to point out all the problems that you will face if you are thinking about the formose reaction in the context of the prebiotic sugar synthesis, but we aren’t saying this is the endpoint; our results might inspire somebody to come up with a better way to somehow overcome these issues,” says Krishnamurthy. “We encourage the community to think differently and search for alternative solutions to explain how sugar molecules arose on early Earth.”
Reference: “Abiotic aldol reactions of formaldehyde with ketoses and aldoses—Implications for the prebiotic synthesis of sugars by the formose reaction” by Scot M. Sutton, Sunil Pulletikurti, Huacan Lin, Ramanarayanan Krishnamurthy and Charles L. Liotta, 23 April 2025, Chem.
DOI: 10.1016/j.chempr.2025.102553
This work was supported by the NASA Exobiology Program NNH20ZA001N-EXO Grant 20-EXO-0006.
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