Referee 1: Eugene Koonin
I basically agree with Bernhardt. The RNA World scenario is bad as a scientific hypothesis: it is hardly falsifiable and is extremely difficult to verify due to a great number of holes in the most important parts. To wit, no one has achieved bona fide self-replication of RNA which is the cornerstone of the RNA World. Nevertheless, there is a lot going for the RNA World (Bernhardt summarizes much of the evidence, and I add more below) whereas the other hypotheses on the origin of life are outright helpless. Moreover, as argued in some detail elsewhere
], the RNA World appears to be an outright logical inevitability. ‘Something’ had to start efficiently replicating to kick off evolution, and proteins do not have this ability. As Bernhardt rightly points out, it is not certain that RNA was the first replicator but it does seem certain that it was the first ‘good’ replicator. To clarify, this does not imply that the primordial RNA World did not have peptides; on the contrary, it is plausible that peptides played important roles but they were not initially encoded in RNA.
Moreover, straightforward observations on modern proteins indicate that the role of RNA in the ancient translation system was much greater that it is in the modern system. Indeed, Class I aminoacyl-tRNA synthetases (aaRS) represent only a small branch on the complex evolutionary tree of Rossmann-like domains, so the common ancestor of all 10 Class I aaRS emerged after extensive diversification of this particular class of protein domains had already taken place. Accordingly, one is compelled to conclude that a high-fidelity translation system that alone would enable extensive protein evolution existed already at the late stages of the hypothetical RNA World
All this discussion is not pointless play with hypotheses. Realization of the unique status of the RNA World among the origin of life scenarios is critical for maintaining the focus of research on truly important directions such as experimental and theoretical study of the evolution of ribozymes rather than futile attempts to debunk the RNA World.
Referee 2: Anthony Poole
Harold Bernhardt’s review of the RNA world hypothesis is readable and timely. He presents a very open-minded review of recent results and how they impact on old ideas, and distills a large amount of material. Aside from the admirable attempt to synthesize a vast array of ideas, a valuable contribution hidden within is the critical assessment of the view that the RNA world hypothesis needs to be abandoned in favour of a peptides-first model.
Author’s response: I have revised the abstract and introduction to include reference to my critique of the ‘proteins (or peptides) first’ hypothesis.
While I doubt that anyone seriously excluded peptides as part of a prebiotic milieu, the primacy of peptides does need careful consideration. In this regard, the explicit explanation of why a pre-genetic code origin of proteins will not be detectable from comparative genomic analyses is an important contribution. Perhaps this is obvious to some, but in light of a growing view that non-ribosomal peptide synthesis preceded ribosomal peptide synthesis, it would seem that the community needs a reminder, and Bernhardt spells it out in a very informative manner. Another issue with arguing for non-ribosomal peptide synthesis preceding the ribosome is that there is an enormous difference in information input versus output. As discussed in[
]], megaenzymes like cyclosporin are ~15000 amino acids in length and produce products of 11 amino acids in length – a factor of 104is not trivial. While non-ribosomal peptide synthetases are modular and could in principle be engineered into minimal entities, the challenge of equalizing information input and output is significant regardless of one’s favoured prebiotic starting point. It is clear from reading Bernhardt’s review that the RNA community is much closer to this than those who seek to replace primordial RNA-based replication with peptide-based replication.
Referee 3: Michael Yarus (nominated by Laura Landweber)
Almost always, progress to new understanding is sporadic, with insights coming in separated locales. Difficulties temporarily immobilize discussion, but then are surmounted by a successful theory. This sometimes inchoate stagger toward a broader, more self-consistent argument is all that can be expected, even of an ultimately successful idea. Discussions of the RNA world sometimes forget this, and demand e.g., the ultimate replicase today! But this essay by Harold Bernhardt remembers what has happened for other successful evolutionary ideas, like the big tree. For all its successes, the tree is still being questioned under extreme prejudice in certain quarters, as is the RNA world.
Contrariwise, here we have here a sympathetic review of the support for the RNA world, which specifically makes the point that it fits our descent better than other ideas (You look like the son of a montmorillonite to me, ya mangy mutant!). It will be useful to those who want an entry to the RNA world literature, and could easily serve as the crux of a university course.
However, this is also its weakness; the text is polite and respectful, even to those whose ‘contribution’ has been otherwise. It treats even loony ideas (‘we need proteins to evolve translation!’) with deference. Or to put it in other words, it is edgeless – some attitude would be welcome. Some choice between hypotheses should go with the territory; some consequent make-or-break predictions are the responsibilities of a guide. But as a gentle introduction, you will not find better.
Author’s response: In revising the manuscript, I have – to some degree inadvertently – added a bit more bite!