Origin of life twist: New study challenges longstanding hypothesis on how first sugars formed

LA JOLLA, CA—The prebiotic Earth was a harsh and unstable environment, characterized by intense heat, active volcanoes and little atmosphere. How, then, did the molecular building blocks of life first form? Among chemists, it’s widely thought that one of these building blocks—a sugar known as ribose, which forms the backbone of RNA—was produced spontaneously. But a new study suggests otherwise.

Scripps Research and Georgia Institute of Technology scientists call this commonly held hypothesis into question in Chem on April 23, 2025. According to the “formose reaction” hypothesis, formaldehyde molecules spontaneously reacted to create ribose. But using controlled reactions, the researchers have now found the formose reaction can only produce sugars with branched structures—not linear sugars like ribose that are essential for life. These insights can help scientists understand how life arose on Earth, as well as design biofuel production.

“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.

“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.”

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.”

In addition to Krishnamurthy and Liotta, authors of the study, “Abiotic aldol reactions of formaldehyde with ketoses and aldoses—Implications for the prebiotic synthesis of sugars by the formose reaction,” are Sunil Pulletikurti and Huacan Lin of Scripps Research; and Scot Sutton of the Georgia Institute of Technology.

This work was supported by the NASA Exobiology Program NNH20ZA001N-EXO Grant 20-EXO-0006.

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr-Skaggs, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.