Editing Openai/686aedb2-60b0-8003-98a8-e1766cf496a6 (section)

=== Assistant:  ===
===== Harold S. Bernhardt’s 2012 essay is a self-consciously “warts-and-all” defence of the RNA-world idea: he calls it “the worst theory … except for all the others.” He reviews the four classic objections to an RNA world and then turns his fire on the main rivals. The structure makes it easy to see who he is criticising and why. RNA World is worst except all o… =====

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===== 1. Chemistry still incomplete – especially for purine nucleotides. =====
# Copying fidelity & speed – no ribozyme has achieved open-ended self-replication.
# Need for an energy source – he tentatively couples acidic environments to proton-motive force.

He concludes these are technical rather than categorical problems and bets that incremental lab progress will chip away at them. RNA World is worst except all o…

===== Support for his stance =====
* Better pre-biotic syntheses. Sutherland’s team has now extended one-pot routes to both purine and pyrimidine ribonucleotides and to lipid–RNA co-synthesis, mitigating the “too complex” objection. pmc.ncbi.nlm.nih.gov<ref>{{cite web|title=pmc.ncbi.nlm.nih.gov|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC10351881/|publisher=pmc.ncbi.nlm.nih.gov|access-date=2025-11-16}}</ref>
* Non-enzymatic replication strides. 2024 modelling and bench work from the Szostak and Georgia Tech groups show template copying of 4-base mixed sequences assisted by activated oligonucleotides and “NERPE” primer-extension platforms, directly attacking the fidelity problem Bernhardt flagged. biorxiv.org<ref>{{cite web|title=biorxiv.org|url=https://www.biorxiv.org/content/10.1101/2024.07.17.603910v1.full.pdf|publisher=biorxiv.org|access-date=2025-11-16}}</ref>ssdl.gatech.edu<ref>{{cite web|title=ssdl.gatech.edu|url=https://ssdl.gatech.edu/2024/01/31/nerpe-non-enzymatic-rna-primer-extension/|publisher=ssdl.gatech.edu|date=2024-01-31|access-date=2025-11-16}}</ref>
* Nucleotide-bias overcome. A 2025 NAR paper reports near-uniform copying yields for A- and U-rich templates by tweaking leaving groups – progress Bernhardt predicted was possible. academic.oup.com<ref>{{cite web|title=academic.oup.com|url=https://academic.oup.com/nar/article/52/22/13515/7893325|publisher=academic.oup.com|access-date=2025-11-16}}</ref>

Challenges / new wrinkles
* RNA-peptide world. Experiments generating peptide-decorated RNA chimeras under plausible pre-biotic conditions suggest a hybrid stage, partly vindicating “co-evolution” advocates and softening Bernhardt’s dismissal of peptides-first. nature.com<ref>{{cite web|title=nature.com|url=https://www.nature.com/articles/s41586-022-04676-3|publisher=nature.com|access-date=2025-11-16}}</ref>
* Proteins-first phylogenetics continues. Caetano-Anollés’ camp keeps publishing protein-centric trees; they have not disproved RNA-first, but the debate has broadened rather than closed.

Overall, none of the post-2012 data decisively overturn Bernhardt’s critiques; most reinforce his view that RNA-world weaknesses are being eroded experimentally.

===== Yes. He has published on tRNA evolution (2016) and origin-of-life chemistry (2021 Maillard reaction), both consistent with an RNA-centric outlook, and in a 2019 interview reiterated that RNA world remains “the best hypothesis we’ve got right now.” mdpi.com<ref>{{cite web|title=mdpi.com|url=https://www.mdpi.com/2075-1729/6/1/10|publisher=mdpi.com|access-date=2025-11-16}}</ref>scholar.google.com<ref>{{cite web|title=scholar.google.com|url=https://scholar.google.com/citations?hl=en&user=HgBBirMAAAAJ|publisher=scholar.google.com|access-date=2025-11-16}}</ref>curioussciencewriters.org<ref>{{cite web|title=curioussciencewriters.org|url=https://curioussciencewriters.org/articles/2019/08/10/the-origin-of-life-did-ancient-rna-act-alone/|publisher=curioussciencewriters.org|date=2019-08-10|access-date=2025-11-16}}</ref> =====

===== Bernhardt himself leaves the door open, expecting refinements (e.g., an acidic-ice setting or an RNA-peptide transitional stage) rather than a wholesale abandonment. The field today largely agrees: the centre of gravity is still “RNA first, possibly with helper peptides or XNAs,” not a radically different paradigm. Recent comprehensive syntheses still treat RNA world as the baseline to beat. pmc.ncbi.nlm.nih.gov<ref>{{cite web|title=pmc.ncbi.nlm.nih.gov|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC10351881/|publisher=pmc.ncbi.nlm.nih.gov|access-date=2025-11-16}}</ref> =====

===== - It is one of the most-cited critical yet pro-RNA reviews; even detractors quote its “worst theory … except all the others” line. crev.info<ref>{{cite web|title=crev.info|url=https://crev.info/2024/11/rna-world-suffers-a-backhand-blow/|publisher=crev.info|access-date=2025-11-16}}</ref> =====
* Its balanced tone—acknowledging flaws while skewering rivals—makes it a common starting point for graduate seminars.
* Subsequent advances have tended to fill the specific gaps he catalogued, so the paper has aged well as a roadmap of outstanding problems rather than a dated polemic.

Bottom line: Bernhardt’s blows at metabolism-first and proteins-first still stand; the RNA-world objections he listed have weakened thanks to fresh chemistry and replication data. The field has expanded to encompass RNA-peptide hybrids, but no competitor has yet offered a more complete, experimentally grounded alternative.