Stylized rendering of the full-length hammerhead ribozyme RNA molecule
Source: Wikipedia
On way of looking at cellular life is that it is based on RNA, not DNA. In that model, DNA is RNA's data store. All the functional processes that DNA codes for are first transcribed into RNA and short lengths of RNA still regulate some of the cell processes. RNA can even act as a catalyst playing the role normally performed by protein enzymes - proteins that are themselves transcriptions of RNA triplet codes for amino acid sequences.
On that model, early self-replicating systems were based on RNA, and DNA was late to the game.
Now three researchers at the Salk Institute for Biological Studies, La Jolla, California, USA, have shown how such a system could have bootstrapped from simple, self-catalysing lengths of RNA which not only self-replicate but can continue to do so even when there are variations stemming from faulty replications. This system would have created the variation needed for Darwinian evolution by natural selection as some variant performed better in terms of competing for resources and ultimately making more copies, so coming to predominate in the pool of RNA-based organisms.
How the scientists discovered this is the subject of a research paper in PNAS which sadly is behind a paywall with only the abstract and statement of significance freely available. It is also the subject of a news release from the Salk Institute.
Since the team refer to an RNA structure known as the 'hammerhead ribozyme', it might help to understand a little about it first:
Do you have any information on the 'hammerhead ribozyme'? Yes, the hammerhead ribozyme is a small catalytic RNA molecule that cleaves other RNA molecules in a sequence-specific manner. It is one of the best-characterized ribozymes and has been extensively studied in the field of RNA biochemistry and molecular biology..
The hammerhead ribozyme gets its name from its secondary structure, which resembles the head of a hammer. It consists of three helical regions connected by loops, with a conserved catalytic core formed by conserved sequences within the loops. This core region contains the catalytic residues responsible for RNA cleavage.
The hammerhead ribozyme functions by binding to a target RNA molecule through Watson-Crick base pairing interactions with its substrate-binding arms. Once bound, the ribozyme catalyzes the cleavage of the target RNA at a specific site, typically a purine-pyrimidine dinucleotide sequence.
The discovery and study of hammerhead ribozymes have contributed significantly to our understanding of RNA catalysis and have potential applications in biotechnology and gene therapy. Researchers have engineered hammerhead ribozymes for various purposes, including the specific cleavage of target RNA molecules for gene silencing or as tools for studying RNA structure and function.
Modeling the origins of life: New evidence for an “RNA World”
Salk scientists unveil RNA capabilities that enable Darwinian evolution at a molecular scale, and bring researchers closer to producing autonomous RNA life in the laboratory
Charles Darwin described evolution as "descent with modification." Genetic information in the form of DNA sequences is copied and passed down from one generation to the next. But this process must also be somewhat flexible, allowing slight variations of genes to arise over time and introduce new traits into the population.But how did all of this begin? In the origins of life, long before cells and proteins and DNA, could a similar sort of evolution have taken place on a simpler scale? Scientists in the 1960s, including Salk Fellow Leslie Orgel, proposed that life began with the “RNA World,” a hypothetical era in which small, stringy RNA molecules ruled the early Earth and established the dynamics of Darwinian evolution.
From left: David Horning, Gerald Joyce, and Nikolaos Papastavrou.
New research at the Salk Institute now provides fresh insights on the origins of life, presenting compelling evidence supporting the RNA World hypothesis. The study, published in Proceedings of the National Academy of Sciences (PNAS) on March 4, 2024, unveils an RNA enzyme that can make accurate copies of other functional RNA strands, while also allowing new variants of the molecule to emerge over time. These remarkable capabilities suggest the earliest forms of evolution may have occurred on a molecular scale in RNA.
The findings also bring scientists one step closer to re-creating RNA-based life in the laboratory. By modeling these primitive environments in the lab, scientists can directly test hypotheses about how life may have started on Earth, or even other planets.
Hammerhead sequences copied by the lower-fidelity polymerase drift away from their original RNA sequence (top) and lose their function over time. Hammerheads catalyzed by the higher-fidelity polymerase retain function and evolve fitter sequences (bottom).Credit: Salk InstituteScientists can use DNA to trace the history of evolution from modern plants and animals all the way back to the earliest single-celled organisms. But what came before that remains unclear. Double-stranded DNA helices are great for storing genetic information. Many of those genes ultimately code for proteins—complex molecular machines that carry out all sorts of functions to keep cells alive. What makes RNA unique is that these molecules can do a bit of both. They’re made of extended nucleotide sequences, similar to DNA, but they can also act as enzymes to facilitate reactions, much like proteins. So, is it possible that RNA served as the precursor to life as we know it?We're chasing the dawn of evolution. By revealing these novel capabilities of RNA, we're 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.
Gerald Joyce, senior author
President
Salk Institute for Biological Studies
La Jolla, California, USA.
Scientists like Joyce have been exploring this idea for years, with a particular focus on RNA polymerase ribozymes—RNA molecules that can make copies of other RNA strands. Over the last 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 come with a fatal flaw: they aren’t able to copy the sequences with a high enough 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 entirely.
Until now. The latest RNA polymerase ribozyme developed in the lab includes a number of crucial mutations that allow it to copy a strand of RNA with much higher accuracy.
In these experiments, the RNA strand being copied is a “hammerhead,” a small molecule that cleaves other RNA molecules into pieces. The researchers were surprised to find that not only did the RNA polymerase ribozyme accurately replicate functional hammerheads, but over time, new variations of the hammerheads began to emerge. These new variants performed similarly, but their mutations made them easier to replicate, which increased their evolutionary fitness and led them to eventually dominate the lab’s hammerhead population.
We’ve long wondered how simple life was at its beginning and when it gained the ability to start improving itself. This study suggests 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 might have been the spark that allowed life to become more complex, going from molecules to cells to multicellular organisms.
Nikolaos Papastavrou, first author
Research associate
Salk Institute for Biological Studies
La Jolla, California, USA.The findings highlight the critical importance of replication fidelity in making evolution possible. The RNA polymerase’s copying accuracy must exceed a critical threshold to maintain heritable information over multiple generations, and this threshold would have risen as the evolving RNAs increased in size and complexity. Joyce’s team is re-creating 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 beginnings of autonomous RNA life in the laboratory, which the researchers say could be accomplished within the next decade. The scientists are also interested in what else might occur once this mini “RNA World” has gained more autonomy.Scatterplots show the evolving populations of hammerheads across multiple rounds of evolution. Hammerheads copied by the lower-fidelity polymerase (52-2) drift away from the original RNA sequence (white contours) and lose their function. Hammerheads copied by the new higher-fidelity polymerase (71-89) retain function, with new functional sequences emerging over time.Credit: Salk InstituteThe methods used in the Joyce lab also pave the way for future experiments testing other ideas about the origins of life, including what environmental conditions could have best supported RNA evolution, both on Earth and on other planets.We’ve 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? We’re excited to answer how early life could ratchet up its own complexity, using the tools developed here at Salk.
David Horning, co-author
Staff scientist
Salk Institute for Biological Studies
La Jolla, California, USA.
And more detail is in the abstract to the paper in PNAS:
SignificanceSo, one step close towards closing creationism last remaining refuge for their ever-shrinking little god. All that was needed to get 'RNA world' was the right combination of nucleotides in the RNA molecule from the millions of possible combinations to arise just once and the process could take off to become self-sustaining and subject to improvement and refinement by Darwinian natural selection, just as Darwin had predicted, only at a molecular level he could not have been aware of.
An RNA enzyme with RNA polymerase activity was used to replicate and evolve an RNA enzyme with RNA-cleavage activity. The fidelity of the polymerase is sufficient to maintain heritable information over the course of evolution, with a succession of variants of the RNA-cleaving RNA enzyme arising that have progressively increasing fitness. The RNA-catalyzed evolution of functional RNAs is thought to have been central to the early history of life on Earth and to the possibility of constructing RNA-based life in the laboratory.
Abstract
An RNA polymerase ribozyme that was obtained by directed evolution can propagate a functional RNA through repeated rounds of replication and selection, thereby enabling Darwinian evolution. Earlier versions of the polymerase did not have sufficient copying fidelity to propagate functional information, but a new variant with improved fidelity can replicate the hammerhead ribozyme through reciprocal synthesis of both the hammerhead and its complement, with the products then being selected for RNA-cleavage activity. Two evolutionary lineages were carried out in parallel, using either the prior low-fidelity or the newer high-fidelity polymerase. The former lineage quickly lost hammerhead functionality as the population diverged toward random sequences, whereas the latter evolved new hammerhead variants with improved fitness compared to the starting RNA. The increase in fitness was attributable to specific mutations that improved the replicability of the hammerhead, counterbalanced by a small decrease in hammerhead activity. Deep sequencing analysis was used to follow the course of evolution, revealing the emergence of a succession of variants that progressively diverged from the starting hammerhead as fitness increased. This study demonstrates the critical importance of replication fidelity for maintaining heritable information in an RNA-based evolving system, such as is thought to have existed during the early history of life on Earth. Attempts to recreate RNA-based life in the laboratory must achieve further improvements in replication fidelity to enable the fully autonomous Darwinian evolution of RNA enzymes as complex as the polymerase itself.
This of course makes the transition from pre-biotic molecules in solution to self-replicating molecules and eventually metabolising entities enclosed in a cell membrane all a matter of the operation of physics and chemistry, with no need for magic anywhere in the process. Creationism’s soon-to-homeless small god should be packing its bags right now. So, all that will be left by way of a home for it will be the carefully constructed gaps in creationists’ knowledge and understanding.
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