Unlocking the secrets of life with the ancient RNA code

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By journalsofus.com


DNA and RNA life art concept

New findings from the Salk Institute provide strong evidence for the RNA world hypothesis, revealing an RNA enzyme that precisely replicates and evolves RNA strands. This discovery underscores the potential role of RNA in early evolution and brings scientists closer to synthesizing RNA-based life, offering insights into the origins and complexity of life. Credit: SciTechDaily.com

Salk scientists reveal RNA capabilities that enable Darwinian evolution at the molecular scale and bring researchers closer to the production of autonomous RNA life in the laboratory.

Charles Darwin described evolution as “descent with modification.” Genetic information in the form of DNA Sequences are copied and transmitted from one generation to the next. But this process must also be somewhat flexible, allowing slight gene variations to emerge over time and introduce new traits into the population.

But how did all this start? At the origins of life, long before cells, proteins and DNA, could a similar type of evolution have taken place on a simpler scale? In the 1960s, scientists including Salk Fellow Leslie Orgel proposed that life began with the “RNA World,” a hypothetical era in which small, fibrous RNA molecules ruled the early Earth and established the dynamics of Darwinian evolution.

Modeling the origins of life

The hammerhead sequences copied by the lower-fidelity polymerase move away from their original RNA sequence (top) and lose their function over time. Hammerhead sharks catalyzed by the higher fidelity polymerase retain their function and develop more adapted sequences (below). Credit: Salk Institute

Groundbreaking research on the role of RNA in early evolution

New research from the Salk Institute now provides new insights into the origins of life and presents compelling evidence supporting the RNA world hypothesis. The study, published in Proceedings of the National Academy of Sciences (PNAS) on March 4, 2024, introduces an RNA enzyme that can make precise copies of other functional RNA strands, while allowing new variants of the molecule to arise over time. These remarkable capabilities suggest that the earliest forms of evolution may have occurred at the molecular scale in RNA.

The findings also bring scientists closer to recreating RNA-based life in the lab. By modeling these primitive environments in the laboratory, scientists can directly test hypotheses about how life may have begun on Earth, or even on other planets.

“We are chasing the dawn of evolution,” says lead author and Salk President Gerald Joyce. “By revealing these new capabilities of RNA, we are uncovering the potential origins of life itself and how simple molecules could have paved the way for the complexity and diversity of life we ​​see today.”


Scatter plots show the evolution of hammerhead shark populations over multiple rounds of evolution. Hammerheads copied by the lower fidelity polymerase (52-2) move away from the original RNA sequence (white outlines) and lose their function. Hammerhead sharks copied by the new higher-fidelity polymerase (71-89) retain their function and new functional sequences emerge over time. Credit: Salk Institute

The unique functionality of RNA and the quest for replication fidelity

Scientists can use DNA to trace the history of evolution from modern plants and animals to the first single-celled organisms. But what happened before is still unclear. Double-stranded DNA helices are excellent for storing genetic information. Many of those genes ultimately code for proteins: complex molecular machines that carry out all kinds of functions to keep cells alive. What makes RNA unique is that these molecules can do a little of both. They are made up of extended nucleotide sequences, similar to DNA, but they can also act as enzymes to facilitate reactions, just like proteins. So is it possible that RNA served as a precursor to life as we know it?

Scientists like Joyce have been exploring this idea for years, focusing especially on RNA polymerase ribozymes: RNA molecules that can make copies of other RNA strands. For the past decade, Joyce and his team have been developing RNA polymerase ribozymes in the lab, using a form of directed evolution to produce new versions capable of replicating larger molecules. But most have a fatal flaw: they are not able to copy the sequences at a high enough speed. accuracy. Over many generations, so many errors are introduced into the sequence that the resulting RNA strands no longer resemble the original sequence and have lost their function completely.

Until now. The latest RNA polymerase ribozyme developed in the lab includes a series of crucial mutations that allow it to copy a strand of RNA with much greater precision.

David Horning, Gerald Joyce and Nikolaos Papastavrou

From left to right: David Horning, Gerald Joyce and Nikolaos Papastavrou. Credit: Salk Institute

In these experiments, the RNA strand that is copied is a “hammerhead,” a small molecule that cleaves other RNA molecules into pieces. The researchers were surprised to discover that the RNA polymerase ribozyme not only accurately replicated functional hammerhead sharks, but over time, new variations of hammerhead sharks began to emerge. These new variants behaved similarly, but their mutations made them easier to replicate, increasing their evolutionary fitness and leading them to eventually dominate the lab’s hammerhead population.

“We have long wondered how simple life was in its beginnings and when it acquired the ability to start improving,” says first author Nikolaos Papastavrou, a research associate in Joyce’s lab. “This study suggests that the dawn of evolution could have been very early and very simple. “Something at the level of individual molecules could sustain Darwinian evolution, and that could have been the spark that allowed life to become more complex, moving from molecules to cells and multicellular organisms.”

The findings highlight the critical importance of replication fidelity in making evolution possible. The copying precision of RNA polymerase must exceed a critical threshold to maintain heritable information across multiple generations, and this threshold would have increased as evolving RNAs increased in size and complexity.

The future of RNA research and autonomous life

Joyce’s team is recreating this process in laboratory test tubes, applying increasing selective pressure on the system to produce better-performing polymerases, with the goal of one day producing an RNA polymerase that can replicate itself. This would mark the beginning of autonomous RNA life in the laboratory, which the researchers say could be achieved within the next decade.

Scientists are also interested in what else could happen once this mini “RNA World” has gained more autonomy.

“We have seen that selection pressure can improve RNAs with an existing function, but if we let the system evolve for longer with larger populations of RNA molecules, can new functions be invented?” says co-author David Horning, a scientist in Joyce’s lab. “We are excited to answer how early life might increase its own complexity, using the tools developed here at Salk.”

The methods used in Joyce’s lab also pave the way for future experiments that test other ideas about the origins of life, including what environmental conditions might have best supported the evolution of RNA, both on Earth and on other planets.

Reference: “RNA-catalyzed evolution of catalytic RNA” by Nikolaos Papastavrou, David P. Horning and Gerald F. Joyce, March 4, 2024, proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2321592121

The work was supported by POT (80NSSC22K0973) and the Simons Foundation (287624).



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