The origin & evolution of RNA: Molecular midwives and their role in nucleic acid polymerization

Alex George

The transition from the world of RNA to DNA four billion years ago required a helping-hand.

The origin of life has long been predicted to have arisen from simple, self-replicating molecular systems. Many scientists have supported the RNA world hypothesis which states that RNA was the first form of life on earth due to its versatility as bearers of genetic information as well as having the ability to catalyze chemical reactions [1].

Before the evolution of DNA, RNA effectively played the role of both DNA (genetics), and proteins, which serve as catalysts for many biochemical processes. However, the origin of these biopolymers and their evolutionary pathways was still unclear. In a pre-biotic environment free of proteins and enzymatic activity, the spontaneous emergence of RNA polymers remains improbable even with all the necessary components of RNA present in excess. However, researchers at Georgia Tech have proposed that small molecules named "molecular midwives" could possibly serve as a mechanism for the evolution of life's earliest molecules.

Dr. Nicholas Hud, a professor in the School of Chemistry & Biochemistry at Georgia Tech, is the primary figure behind this groundbreaking research. The Hud lab is actively working to uncover how molecules like DNA and RNA first appeared with the origin of life on Earth four billion years ago. The lab's "molecular midwives" theory suggests that small molecules acted as templates via non-covalent interactions with the chemical building blocks of RNA to catalyze the formation of RNA. These molecules would aid in the 'birth' of proto-RNA, however they would not be necessary once protein-based means for replication evolved [2].

"We envision molecular midwives facilitating the selection and preorganization of the free bases by acting as nanometer-scale templates upon which the nucleoside bases stack in aqueous solution" said Hud in a publication published in the Journal of Chemical Biodiversity [2].

These molecules would therefore have to be small enough to intercalate between the stacks of nitrogenous bases found in DNA and RNA. In order to test this idea, Proflavin, a small compound known to bind between the bases of DNA and RNA, was used as an intercalating agent for the synthesis of a DNA double helix. Hud, along with a team of graduate students discovered that proflavin greatly accelerates the rate at which two oligonucleotides (short DNA molecules) join into a double helix [3] (Fig. 1).

With regard to the formation of RNA, Dr. Hud theorizes that molecular midwives such as proflavin could create a means in which nucleotides could stack and base-pair with each other and eventually lead to the formation of an RNA helix which would greatly promote the formation of more RNA molecules. This would then allow for RNA to evolve via self-replication and eventually form DNA. These results therefore support the lab's hypothesis that molecular midwives functioned as 'prebiotic cofactors' before the appearance of ribozymes and other protein enzymes. The Hud lab plans on testing other potential 'molecular midwives' in the future and further elucidate the formation of the first RNA molecules which were critical in the evolution of life to what it is today.


  • 'The RNAWorld: The Nature of Modern RNA Suggests a Prebiotic RNAWorld', 3rd edn., Eds. R. Gesteland, J.F . Atkins, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2006.
  • Hud, N.V., Jain, S.S., Li, X. and Lynn, D.G. (2007) Addressing the Problems of Base Pairing and Strand Cyclization in Template-Directed Synthesis, Chem. Biodiv. 4, 768-783.
  • S. S. Jain, F. A. L.Anet, C. J.Stahle , N. V.Hud, Angew. Chem., Int. Ed. 2004, 43, 2004.