Scientists discover a billion-year epic written about the chemistry of life

The origin of life on Earth has long been a mystery that has eluded scientists. An important question is how much of the history of life on Earth has been lost to time. It is very common for a single species to ‘phase out’ through a biochemical reaction, and if this happens in enough species, such reactions can effectively be ‘forgotten’ by life on Earth.

But if the history of biochemistry is full of forgotten reactions, could there be a way to find out? This question inspired researchers from the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology and the California Institute of Technology (CalTech) in the US. They reasoned that forgotten chemistry would appear as discontinuities or “breaks” in the path that chemistry takes from simple geochemical molecules to complex biological molecules.

The early Earth was rich in simple compounds such as hydrogen sulfide, ammonia and carbon dioxide – molecules not usually associated with sustaining life. But billions of years ago, early life depended on these simple molecules as a raw material source. As life evolved, biochemical processes gradually transformed these precursors into compounds that still exist today. These processes represent the earliest metabolic pathways.

To model the history of biochemistry, ELSI researchers—specially appointed Associate Professor Harrison B. Smith, Specially Appointed Associate Professor Liam M. Longo, and Associate Professor Shawn Erin McGlynn, in collaboration with CalTech research scientist Joshua Goldford—needed an inventory of all known biochemical reactions, to understand what types of chemistry life can perform.

They turned to the Kyoto Encyclopedia of Genes and Genomes database, which has cataloged more than 12,000 biochemical reactions. With the reactions in hand, they began to model the step-by-step development of metabolism.

Previous attempts to model the evolution of metabolism in this way have consistently failed to produce the most widespread, complex molecules used in contemporary life. However, the reason was not entirely clear. When the researchers ran their model, they found, as before, that only a few compounds could be produced. The research has been published in the journal Nature ecology and evolution.

One way around this problem is to give the stagnant chemistry a boost by manually supplying modern compounds. The researchers took a different approach: they wanted to determine how many responses were missing. And their hunt led them back to one of the most important molecules in all of biochemistry: adenosine triphosphate (ATP).

ATP is the energy currency of the cell because it can be used to power reactions (such as building proteins) that would not otherwise occur in water. However, ATP has a unique property: the reactions that form ATP themselves require ATP. In other words, unless ATP is already present, there is no other way to make ATP in contemporary life. This cyclical dependency was the reason why the model stopped.

How can this “ATP bottleneck” be solved? It turns out that the reactive part of ATP is remarkably similar to the inorganic compound polyphosphate. By allowing ATP-generating reactions to use polyphosphate instead of ATP – modifying just eight reactions in total – almost all of modern-day nuclear metabolism could be achieved. The researchers were then able to estimate the relative ages of all common metabolites and ask targeted questions about the history of metabolic pathways.

One such question is whether biological pathways are constructed linearly – adding one reaction after another in a sequential manner – or whether the reactions of the reaction chains evolved as a mosaic, in which reactions from vastly different ages are combined into something new forms. The researchers were able to quantify this and discovered that both types of pathways occur almost equally throughout the metabolism.

But returning to the question that inspired the study: How much biochemistry is lost over time? “We may never know exactly, but our research has provided an important piece of evidence: Only eight new reactions, all reminiscent of common biochemical reactions, are needed to bridge geochemistry and biochemistry,” says Smith .

“This does not prove that the space of missing biochemistry is small, but it does show that even reactions that are extinct can be rediscovered based on clues left behind in modern biochemistry,” Smith concludes.