Synlett 2017; 28(01): 36-55
DOI: 10.1055/s-0036-1588646
© Georg Thieme Verlag Stuttgart · New York

Our Odyssey to Find a Plausible Prebiotic Path to RNA: The First Twenty Years

Nicholas V. Hud*
  • School of Chemistry and Biochemistry, Georgia Institute of Technology, 311 Ferst Drive, Atlanta, GA 30332-0400, USA   Email:
Further Information

Publication History

Received: 05 September 2016

Accepted after revision: 13 October 2016

Publication Date:
05 December 2016 (eFirst)

Dedicated to Professor Frank A. L. Anet on the occasion of his 90th birthday.


This account provides an overview of results from experimental studies motivated by an ongoing search for the origin of RNA. Twenty-five years ago, I became fascinated by the possibility that the origin of life was facilitated by an enzyme-free, prebiotic form of the polymerase chain reaction (PCR); a process potentially enabled by molecular self-assembly and driven by an oscillating environment on the early Earth. After numerous unsuccessful attempts to assemble the mononucleotides of extant RNA, I embraced the hypothesis that RNA is a product of chemical or biological evolution, which eventually led to the identification of candidate molecules for the nucleobases of proto-RNA (the ancestor of RNA). These heterocycles self-assemble as monomers in water, are found in carbonaceous chondrites, are produced in model prebiotic reactions, and readily react with ribose to form nucleosides. This progress toward finding a plausible prebiotic synthesis of a hypothetical proto-RNA illustrates how origins research can lead to exciting and unexpected chemistries, particularly when chemical models are subjected to rigorous experimentation and regular revision in response to positive and negative results.

1 Inspiration and Initial Thoughts on the Origin of RNA

2 The Guidance and Influence of Professor Frank A. L. Anet

3 Proposing a Hypothetical, but Chemically Sound, Origin of RNA

4 Experimental Studies of Intercalation-Mediated Assembly and Synthesis

5 Considering Purine–Purine Base Pairs Before Watson–Crick

6 Considering Pyrimidine/Triazine Proto-Nucleobases

7 Addressing The Nucleoside Problem; a Bonus

8 Prebiotic Polymerization and Replication, On the Next Horizon?

9 Conclusions and Reflections