Rediscovering an Extinct Biochemical Reaction

In the mid-20th century, scientists Stanley Miller and Harold Urey sought to imitate the processes that led to the origin of life. In their famous experiment, which would later bear their names, they recreated a miniature "creation environment" — a reconstruction of the "primordial soup" thought to represent the chemical conditions of Earth's early aqueous and atmospheric environment. Their findings revealed that under such hypothetical conditions, complex organic compounds, including amino acids—the building blocks of proteins essential to all life on Earth—could form from simple inorganic precursors. In other words: they demonstrated that geochemistry could transform into biochemistry.

Now, nearly seventy years later, researchers from Japan and the United States aim to take this quest a step further in exploring the mysteries of existence. In a new study published in the journal Nature Ecology & Evolution, they attempt to simulate metabolic biochemical reactions that took place in the cells of ancient organisms but have been lost over time. This quest to uncover nature’s lost pathways is a formidable challenge, and much like the Miller-Urey experiment, it seeks to bridge the gap between geochemistry and biochemistry using indirect evidence.

The famous Miller-Urey experiment simulated the chemical conditions hypothesized to have existed in early Earth's atmosphere and oceans, demonstrating how the 'primordial soup' could have formed. The setup of the Miller-Urey experiment | Francis Leroy, Biocosmos / Science Photo Library

A Detective Operation

The researchers started by compiling over 12,000 known biochemical reactions from a comprehensive database maintained by Kyoto University. To this, they added more than 20,000 hypothetical biochemical reactions.  Combining this extensive dataset with current knowledge about the chemical composition of early Earth’s soil, water reservoirs, and atmosphere, they attempted to construct a model simulating the step-by-step development of metabolic processes in Earth’s early organisms. However, despite their efforts, the model accounted for only about five percent of the compounds found in modern biochemistry.

One common approach to overcoming such a deadlock is to incorporate modern compounds that didn’t exist on early Earth into the model. However, this would be akin to depicting classical Greece and equipping Aristotle with a contemporary smartwatch - anachronistic and fundamentally inaccurate. Instead, the researchers adopted a more innovative and realistic strategy. They asked: which biochemical reactions might have existed in the past but are now extinct? In other words, they sought to identify biochemical reactions that were essential for the emergence of modern biochemical processes but have since disappeared over billions of years of evolution.

It is known that early Earth’s environment was rich in inorganic materials that could have substituted for some of the molecules involved in today’s biochemical reactions. This makes it plausible that the metabolism of ancient organisms relied on such materials in reactions that have since disappeared. For example, sulfur-containing molecules, such as hydrogen sulfide (H₂S) and sulfur dioxide (SO₂), served as key energy sources for single-celled organisms during critical evolutionary periods and contributed to enriching early Earth’s atmosphere with oxygen. This search for lost reactions led the researchers to identify a bottleneck in their model related to one of the most important molecules in the biological world: ATP.

The Currency of Life

Adenosine triphosphate (ATP) is a high-energy organic molecule composed of hydrogen, carbon, phosphorus, and oxygen, chemically classified within the purine family. ATP serves as the universal energy carrier, fueling countless cellular processes, including protein synthesis and signal transduction. However, ATP presents a paradox: producing new ATP molecules requires using up existing ones.  This cyclical dependency raises a fundamental question: How were the first ATP molecules ever formed?

The researchers proposed that in the earliest stages of life, metabolic reactions may have relied on a different molecule—polyphosphate—rather than ATP. Unlike ATP, polyphosphate is an inorganic molecule devoid of carbon atoms, originating from geochemical processes.  This suggests that polyphosphate could have predated the emergence of organic life. When the team incorporated polyphosphate into their model, they discovered that just eight metabolic reactions were sufficient to generate more than half of the organic compounds found in modern biochemistry. Moreover, their model provided a framework for tracing the evolution of metabolism, potentially providing insights into the timing of the emergence of key chemical reactions.

ATP fuels diverse cellular processes, including protein synthesis, signal transduction, and more. Molecular structure of ATP | Shutterstock, Steven_Mol

I Will Have Order Here! 

Another question the researchers sought to address using their model was whether the evolution of biochemistry is linear — where chemical reactions develop sequentially—or mosaic-like, where reactions from different periods combine to form new ones. According to the researchers, the answer is both: linear and non-linear evolution each contribute to the emergence of new biochemical processes.

While this is compelling, it still doesn’t fully address the study’s original question: which biochemical reactions once existed but are now extinct? Harrison Smith, a co-author of the study from the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology, offers this perspective: “We might never know exactly, but our research yielded an important piece of evidence: only eight new reactions [...] are needed to bridge geochemistry and biochemistry. 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”

This research uncovers yet another layer of the profound connection between humans and the Earth — a bond acknowledged as early as the third chapter of Genesis: “For dust you are, and to dust you shall return.” It’s a humbling reminder of humanity’s place within the natural world, offering both perspective and an invitation for deeper reflection.