In a 2018 study, Carell and his team reported that the classic nucleotides and the noncanonical nucleotides likely all evolved at the same time before the dawn of life. Some of those in transfer and ribosomal RNAs were present in the last universal common ancestor of all organisms.
Here were “relics of an old RNA world sitting next to each other directly at the oldest part of the system,” Carell said. “So we said, OK, these are our fossils — and let’s see what the fossils can tell us.”
They developed a model for a different kind of peptide-growing process. They imagined two RNA strands capped by these unusual nucleotides, one that they loaded with an amino acid using the stronger bond. After getting the first amino acid to hop to the second strand, they could reload the first strand with another amino acid. By cyclically heating and cooling the system, they could repeatedly break and make bonds between the amino acids on the two chains, flipping the amino acids from one strand to the other and extending the chain.
In effect, if building a peptide is like assembling a tower from building blocks, the new process adds amino acids by adding blocks to the top of a growing stack, while ribosomal protein synthesis extends the tower by moving it atop new pieces at the bottom.
Testing their theory involved a set of experiments that Carell called a “tedious” and “brutal tour de force” — but in the end, they showed that the process could indeed produce peptides up to 13 amino acids long.
The process falls far short of the protein translation seen in cells. The most important missing feature is that ribosomes are translating instructions for a specific protein encoded in the mRNA. In the novel system, “we grow relatively random peptides,” Carell said.
But the researchers did succeed in showing that peptides could be built up purely by RNA in a stepwise manner, which is “something that had not been done before,” Bonfio said. All in all, the demonstrated process is a vital step toward molecular recognition, she said, even though it’s not a primitive version of a ribosome.
“It’s a really beautiful example of chemistry,” said Sara Walker, an associate professor at Arizona State University who was not part of the study. But she and Lee Cronin, chair of chemistry at the University of Glasgow, both thought that the system might be over-engineered or too unrealistic to mimic what could have happened at the start of life.
For others, however, the work’s mimicry of the primordial world is less important than the doors it opens to further study. Because the findings show that a peptide and an RNA can evolve together, it’s clear that “this can experimentally and chemically be done,” said Nizar Saad, a research assistant professor at Nationwide Children’s Hospital’s Center for Gene Therapy in Ohio. An RNA-peptide world “is what the scientific community is going towards now,” Saad said.
An RNA-Peptide World
“I don’t want to replace the RNA world theory,” Carell said. But “I think we need an extension” to make it more plausible. He thinks that rather than evolving their complexity separately, RNA and peptides did it together as a single molecule, complementing each other’s functions.
A coevolving chimera of RNA and peptides would offer the best scenario for the evolution of life, Carell said. He and his team found not only that the RNA molecules were helping the peptides grow, but that the peptides were bringing stability to the RNA molecules.
As the structure of the chimera eventually got longer and more complex, the peptide portion might have stabilized the RNA enough for it to start self-replicating and evolving. Meanwhile, the RNA might have let the peptide part acquire a structure sophisticated enough to allow it to start catalyzing chemical reactions. Eventually, the parts could have split apart and started to interact in ways that more closely resembled what happens in a ribosome.
Carell and his team are next hoping to learn if they can get their unorthodox RNA molecules to grow specific peptides from encoded information. They then hope to see whether the peptide can develop catalytic functions that might help the RNA to replicate.
Whatever successes or failures lie ahead, it will always be hard to know exactly what happened billions of years ago. “We cannot go back in time, so whatever you construct in the field, somebody can always say, I think it all happened differently,” Carell said. “And if somebody comes up with a better model, [it’s] more than welcome. This is how science develops.”
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