The eightfold path to non-enzymatic RNA replication

Considerable evidence supports the RNA World hypothesis of an early phase of life, prior to the evolution of coded protein synthesis, in which cellular biochemistry and genetics were largely the province of RNA (reviewed in [1,2]). The central question concerning the origin of life has thus become: how did the RNA World emerge from the prebiotic chemistry of the early earth? The emergence of the RNA World can be divided, conceptually, into two phases: first, the prebiotic synthesis of ribonucleotides and of RNA molecules, and second, the replication of genomic RNA molecules within replicating protocells. As recently as 2004, Leslie Orgel, one of the great founding fathers of the field of prebiotic chemistry, suggested that "the abiotic synthesis of RNA is so difficult that it is unclear that the RNA World could have evolved de novo on the primitive earth" [3]. While a complete solution to the problem is not yet in hand, major advances have recently been made in this area, primarily from the Sutherland lab [4-6], such that there is now considerable optimism that a robust pathway to the assembly of ribonucleotides and RNA oligomers will eventually be found.Unfortunately, even given prebiotically generated RNA templates and abundant ribonucleotides, we do not understand how cycles of template-directed RNA replication could occur. RNA replication is fundamental to the RNA World model of early life, as it is essential for the transmission of useful genetic information (and variation) from mother cells to daughter cells. Although early discussions of the RNA World neglected the cellular nature of life, it is clear that the emergence of Darwinian evolution required spatial localization, so that potentially useful RNAs could accrue an advantage for themselves [7,8]. A cellular (i.e. membrane delimited) structure is a simple way to accomplish this, and provides a direct connection to the cellular structure of all modern life. At first glance, localization on the outer surfac