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Life Has a New Ingredient

Inosine could be a potential route to the first RNA and the origin of life on Earth

by Harvard University
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An artist captures what our infant Earth may have looked like. Volcanoes, storms, and thermal pools provided the essential chemical ingredients that reacted to create the first life. Scientists are trying to figure out the sequence of reactions necessary to do just that.

Our prehistoric Earth, bombarded with asteroids, rife with bubbling geothermal pools, may not seem hospitable to humankind today. But somewhere in this pre-life world, the right chemicals came together in the precise sequence necessary to form our essential building blocks. How? For decades, scientists have attempted to create miniature replicas of infant Earth in the lab. There, they hunt for the chemical pathways that led to life on Earth.

It’s attractive to chase our origin story. But this pursuit can bring more than just thrill. Knowledge of how Earth built its first cells could inform our search for extraterrestrial life. If we identify the ingredients and environment required to spark spontaneous life, we could search for similar conditions on planets across our universe.
Life needs three major pieces: protein, DNA, and RNA. Today, many origin-of-life researchers believe that RNA formed first, though some scientists hypothesize that proteins and polymers predated genetic material. A complex but versatile molecule, RNA stores and transmits genetic information, helps synthesize proteins, and acts as a catalyst for myriad reactions, making it a capable candidate for the backbone of the first cells.

To verify this “RNA World Hypothesis,” researchers face two challenges. First, they need to identify which ingredients reacted to create RNA’s four nucleotides—adenine, guanine, cytosine, and uracil (A, G, C, and U). And second, they need to determine how RNA stored and copied genetic information in order to replicate itself.

So far, scientists have made significant progress finding precursors to C and U. But A and G remain elusive. Now, in a paper published in PNAS, Jack W. Szostak, professor of Chemistry and Chemical Biology at Harvard University, along with first author and graduate student Seohyun (Chris) Kim suggest that RNA could have started with a different set of nucleotide bases. In place of guanine, RNA could have relied on a surrogate—inosine. 

“Our study suggests that the earliest forms of life (with A, U, C, and I) may have arisen from a different set of nucleobases than those found in modern life (A, U, C, and G),” said Kim. How did he and his team arrive at this conclusion? Lab attempts to craft A and G, purine-based nucleotides, produced too many undesired side products. Recently, however, researchers discovered a way to make versions of adenosine and inosine—8-oxo-adenosine and 8-oxo-inosine—from materials available on primeval Earth. So, Kim and his colleagues set out to investigate whether RNA constructed with these analogs could replicate efficiently.
But, the substitutes failed to perform. Like a cake baked with honey instead of sugar, the final product may look and taste similar, but it doesn’t function as well. The honey-cake burns and drowns in liquid. The 8-oxo-purine RNA still attempts its duties, but it loses both the speed and accuracy needed to copy itself. If it replicates too slowly, it falls apart before completing the process. If it makes too many errors, it cannot serve as a faithful tool for propagation and evolution.
Despite their inadequate performance, the 8-oxo-purines brought an unexpected surprise. As part of the test, the team compared 8-oxo-inosine’s abilities against a control, inosine. Unlike its 8-oxo counterpart, inosine enabled RNA to replicate with high speed and few errors. It “turns out to exhibit reasonable rates and fidelities in RNA copying reactions,” the team concluded. “We propose that inosine could have served as a surrogate for guanosine in the early emergence of life.”

Szostak and Kim’s discovery hones in on a potential chemical path to primordial RNA and the first life. In time, their work might confirm RNA’s primary role in our origin story. Or, scientists might find that early Earth offered multiple paths for life to grow. Eventually, armed with this knowledge, scientists could identify other planets that have the essential ingredients and determine whether we share this universe or are, indeed, alone.