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Putting the RNA World Theory to the Test with “Pistol”


Proponents of the RNA World theory for the origin of life need to produce the goods: RNA molecules that can store information and perform useful reactions and reproduce themselves and form spontaneously in a plausible prebiotic environment. A new candidate has emerged.

Behold Pistol: a “self-cleaving ribozyme,” announced in the Proceedings of the National Academy of Sciences. We know that the three authors from Yale — Nguyen, Wang and Steitz — think it is relevant to the origin of life, because they tell us so in the opening paragraph about the “Significance” of their paper.

Based on the “RNA world” theory, ribozymes likely carried out biochemical reactions long before organisms evolved to use protein enzymes as biocatalysts. The continued discovery of new structures for small self-cleaving ribozymes has shed light on conserved mechanisms in evolution, such as acid-base catalysis for self-cleavage reaction. Here, we present the crystal structure of a newly discovered class of self-cleaving ribozymes called Pistol and how it likely uses the phosphoester transfer mechanism for self-cleavage. The results presented here suggest that Pistol uses an evolutionarily conserved cleavage mechanism that is like other self-cleaving ribozymes, such as Twister, Hammerhead, Hairpin, and Hepatitis Delta Virus ribozymes. [Emphasis added.]

That’s it? The ribozyme commits suicide? Like other ribozyme candidates? Next.

There’s not much else to say. Still, let’s read on and see if they can explain what on earth this Pistol has to redeem itself without shooting the RNA World in the foot. We searched for the phrases “RNA World” and “origin of life.” The latter is not found. The former is only mentioned one more time in the Introduction:

The “RNA world” hypothesis speculates that RNA carried out the majority of biochemical reactions before the evolution of complex protein enzymes. Ribozymes are noncoding RNA that carry out catalytic activities. Unlike protein enzymes, only a handful of ribozymes have known biological functions. Their biological functions range from regulating gene expression (e.g., riboswitches) and performing peptidyl-transfer reactions (e.g., ribosome) to removing intron sequences in genes (e.g., self-splicing Group I intron ribozymes). The biological functions and mechanism of these ribozymes have been discovered through structural and biochemical studies.

So far, we learn that only a “handful” of ribozymes are known, they have some jobs to do in living cells, and the RNA World hypothesis “speculates.” We would really like to see some testable science, not speculation.

Specifically, the RNA World hypothesis needs to satisfy four requirements:

  1. A ribozyme must form spontaneously in plausible prebiotic conditions. No intelligent design allowed.

  2. It must be able to replicate itself before the first cell appears, so that natural selection can kick in.

  3. It must do something useful for a future living organism.

  4. It must store the information on how to do that useful something. (Note: cutting yourself in half is a poor candidate for a useful function.)

A self-cleaving RNA like Pistol misses the boat on at least three of these requirements. In living cells, the Pistol class of ribozymes does have a function, participating in the destruction of other RNA molecules (while committing suicide in the process). The authors say:

Small self-cleaving ribozymes have been discovered in all evolutionary domains of life. They can catalyze site-specific RNA cleavage, and as a result, they have relevance in gene regulation.

But having a function now in cells tells us nothing about any prebiotic ribozyme, because Pistol is synthesized from DNA. How could a naked RNA in a primordial soup emerge without any help from encoded information?

We learn from a paper in Nature Chemical Biology that Pistol was discovered in 2015. It was a rare find.

Enzymes made of RNA catalyze reactions that are essential for protein synthesis and RNA processing. However, such natural ribozymes are exceedingly rare, as evidenced by the fact that the discovery rate for new classes has dropped to one per decade from about one per year during the 1980s. Indeed, only 11 distinct ribozyme classes have been experimentally validated to date. Recently, we recognized that self-cleaving ribozymes frequently associate with certain types of genes from bacteria. Herein we exploited this association to identify divergent architectures for two previously known ribozyme classes and to discover additional noncoding RNA motifs that are self-cleaving RNA candidates. We identified three new self-cleaving classes, which we named twister sister, pistol and hatchet, from this collection, suggesting that even more ribozymes remain hidden in modern cells.

We learn a little more about what Pistol does from a paper in the journal RNA (2015):

Self-cleaving ribozymes are widespread across all domains of life and their architectural diversity is unmatched by any other type of natural catalytic RNA. These ribozymes have the ability to cleave their ribose-phosphate backbone at specific sites via internal phosphoester transfer with rate constants that typically exceed 10 million fold over that of spontaneous RNA degradation. The nine known self-cleaving ribozyme classes are able to accomplish this function by using a variety of structures that form unique catalytic cores….

All of this is irrelevant to the origin of life. We’ve only been told that RNA ribozymes are exceedingly rare, and they are not nearly as versatile as protein enzymes. All the ribozymes described have been found in living cells, coded by DNA for specific functions. But in the primordial soup could it happen? In the Illustra film Origin, Ann Gauger explains how delicate RNA is in the lab. How much more unlikely would it form spontaneously in the “absolute mess” of the chemical soup, as Paul Nelson describes the primordial ocean? Tim Standish adds, “If you just look at an RNA molecule, it seems to fall to pieces” — even faster in water!

In Susan Mazur’s book The Origin of Life Circus, leading origin-of-life researchers describe the utter disaster of the RNA world scenario in one-on-one interviews she recorded in person.

  • Lawrence Krauss tells her (p. 35): “The question is, can RNA result naturally? That’s been a big stumbling block.

  • David Deamer tells her (p. 43) that the RNA and DNA monomers don’t link up naturally: “the laws of thermodynamics do not allow them to polymerize because there is a tremendous energy barrier to getting them to form bonds.” That’s especially true in water, he says, which breaks down (hydrolyzes) RNA.

  • Sara Walker tells Mazur that researchers need to move away from the RNA World, “because most of the origin-of-life community don’t think that’s the definitive answer.” Walker herself says, “I don’t see how an RNA world with only RNA can work” (p. 68).

  • Loren Williams tells her the original RNA World (“all RNA, all the time, and nothing else”) is unreasonable and dead. RNA can’t have done everything originally claimed. “Another problem is related to the origin of RNA itself. Where did RNA come from? Where did RNA precursors come from?” (p. 96).

  • Steven Benner tells Mazur (p. 81), “we don’t know how useful function is distributed among sequence spaces. You have 4 raised to the power of 100 different sequences of RNA 100 nucleotides long. We don’t know how productive function is distributed there compared to destructive function.” Chances are destructive processes are increased as much as productive processes, he adds. On page 151-152, Benner lists four major “paradoxes” of the RNA world: the tar problem, the water problem, the entropy problem and the destruction problem.

  • RNA-world champion Nick Hud has abandoned the idea that RNA would form on its own. He’s looking for candidates of not only proto-RNA, but “pre-proto-RNA” because, as Mazur reminds him, “RNA itself falls apart” (p.87).

  • Stuart Kauffman tells Mazur that they “tried for 40 years to get single-stranded RNA molecules to replicate, perhaps hundreds of chemists, and they all failed. It should work. But it hasn’t. And after 40 years or 50 years, you think – maybe it’s the wrong idea. People really tried hard” (p. 111).

  • Jack Szostak ups the time estimate to 60 years that researchers have worked on this problem of non-enzymatic replication. “The problem is RNA falls apart,” he says (p. 218).

  • Norm Packard tells Mazur, “There are issues with the RNA world approach. The main one is how do you get RNA starting to get produced in the first place” (p. 297). He envisions an enzyme doing it. This speculation, of course, leads to an obvious problem: “But how do you get that enzyme?”

  • Pier Luigi Luisi is merciless in his attack, calling the RNA world a “baseless fantasy.” Mazur puts his criticisms in bold print on pages 362-363, where he finds it “full of conceptual flaws,” including its origin, the thermodynamics, the sequencing problem, the concentration problem, and more. The story of RNA turning into ribozymes he calls “chemical non-sense” (p. 363).

Luisi then makes a confession so bold, Mazur says, “It’s remarkable to hear you say that.”

The real problem is to make ordered sequences of amino acids, of or course ordered sequences of nucleic acids — and on that the prebiotic RNA world is absolutely silent. But this view of the prebiotic RNA world is still the most popular. I think it is a case of social science psychology more than science itself.

We’re reminded of Harold S. Bernhardt’s description of the RNA world: “the worst theory of the early evolution of life (except for all the others).”

With these comments from leaders in the origin-of-life field in mind, we return to the Pistol paper. Don’t you think it’s a bit disingenuous of the authors to mention the RNA world? Given their findings only show programmed function within living organisms that build the ribozymes from the DNA code, what possible relevance does that have to a “baseless fantasy” with so many paradoxes and problems? Could they be engaging in “social science psychology more than RNA itself”?

You decide. We’ll stick with the positive. We do know of a cause now in operation that can “make ordered sequences” of building blocks and get them to interact in functional ways. That cause (need one say?) is intelligence.

Photo: Starting pistol at athletic event, East Germany, by Bundesarchiv, Bild 183-79908-0001 / CC-BY-SA 3.0 [CC BY-SA 3.0 de], via Wikimedia Commons.

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