May 11, 2022

How life could have arisen on an ‘RNA world’

It’s the ultimate chicken-and-egg conundrum. Life doesn’t work without tiny molecular machines called ribosomes, whose job is to translate genes into proteins. But ribosomes themselves are made of proteins. So how did the first life arise?

Researchers may have taken the first step toward solving this mystery. They’ve shown that RNA molecules can grow short proteins called peptides all by themselves—no ribosome required. What’s more, this chemistry works under conditions likely present on early Earth.

“It’s an important advance,” says Claudia Bonfio, an origin of life chemist at the University of Strasbourg who was not involved in the work. The study, she says, provides scientists a new way of thinking about how peptides were built.  

Researchers who study the origin of life have long considered RNA the central player because it can both carry genetic information and catalyze necessary chemical reactions. It was likely present on our planet before life evolved. But to give rise to modern life, RNA would have had to somehow “learn” to make proteins, and eventually ribosomes. “At the moment, the ribosome simply falls from the heavens,” says Thomas Carell, a chemist at Ludwig Maximilian University of Munich.

A clue to this riddle came from previous lab work. In 2018, Carell and his colleagues were trying to understand how RNA’s four “canonical” bases could have formed from simpler molecules. In modern cells, these RNA bases—guanine, uracil, adenine, and cytosine—make up the genetic letters in messenger RNA (mRNA) that the ribosomes read and translate into proteins. However, other “noncanonical” RNA bases are also ubiquitous in modern cells, carrying out a variety of roles. These include stabilizing binding between canonical RNAs and the “transfer RNAs” that help the ribosomes convert mRNA’s genetic code into proteins.

Carell and his colleagues noticed that some of these noncanonical RNAs could have been synthesized from simple molecules on early Earth. They and others went on to show that some noncanonical bases could bind to amino acids, the building blocks of proteins, raising the possibility they could also link them together into peptides.

Now, Carell’s team reports that a pair of noncanonical RNA bases can do just that. They started with pairs of RNA strands, each made up of strings of RNA bases linked together in a chain. These pairs of strands were complementary, enabling them to recognize and bind to each other. At one end of the first strand—called the “donor” strand—they included a noncanonical RNA base, called a t6A, which is able to bind an amino acid. On the end of the second RNA strand—called the “acceptor” strand—they added another noncanonical RNA base, called mnm5U.

Carell’s team found that when the complementary donor and acceptor RNA strands bound together, the mnm5U grabbed ahold of the amino acid on the t6A. With the addition of just a bit of heat, t6A let go and passed its amino acid over to mnm5U, and the complementary strands disassociated and drifted apart.

But the process could repeat. A second donor strand carrying another amino acid could then bind to the acceptor strand, and pass over its amino acid, which was linked to the first. The process could create peptide chains up to 15 amino acids long, the team reports today in Nature.

Carell and his colleagues also found that when complementary RNA strands containing pairs of noncanonical RNA bases bind together, amino acids that they initially share strengthen the bonding of the two RNA strands. The upshot, Bonfio says, is that on early Earth, the formation of peptides and RNAs may have been synergistic: RNAs may have helped form peptides, and peptides may have help stabilize and form ever-longer RNAs.

She and Carell say this synergy could have produced a vast chemical diversity of RNAs, peptides, and combinations of the two that could then have given rise to the complex chemistry needed for life—all without the need for ribosomes.

Carell acknowledges the work is just “a first steppingstone.” Researchers still need to demonstrate how RNA strands—containing canonical bases or otherwise—could have selected for specific strings of amino acids needed for actual proteins. But with one stepping stone in place, origin of life researchers now have an idea of where to look next.

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