Journal of Theoretical Biology 222 (2003) 127–134 The roads to and from the RNAworld Jason P. Dworkina, Antonio Lazcanob,*, Stanley L. Millerc a Laboratory for Extraterrestrial Physics, Code 691, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA b Facultad de Ciencias, Univ. Nacional Autonoma de Mexico, Apdo. Postal 70-407, Cd. Universitaria, Mexico D.F. 04510, Mexico c Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0506, USA Received 29 January 2001; accepted 11 November 2002 Abstract The historical existence of the RNAworld, in which early life used RNAfor both genetic information and catalytic ability, is widely accepted. However, there has been little discussion of whether protein synthesis arose before DNAor what preceded the RNAworld (i.e. the pre-RNAworld). We outline arguments of what route life may have taken out of the RNAworld: whether DNAor protein followed. Metabolic arguments favor the possibility that RNAgenomes preceded the use of DNAas the informational macromolecule. However, the opposite can also be argued based on the enhanced stability, reactivity, and solubility of 2-deoxyribose as compared to ribose. The possibility that DNAmay have come before RNAis discussed, although it is a less parsimonious explanation than DNAfollowing RNA. r 2003 Elsevier Science Ltd. All rights reserved. Keywords: Pre-RNAworld; RNAworld; Ribose; Deoxyribose; Prebiotic evolution 1. Introduction This proposal stems from the discovery of catalytic activity in RNA( Cech et al., 1981; Guerrier-Takada One of the most important questions facing the study et al., 1983), and it has often been cited as the solution to of the origin of life is the nature of the first genetic the problem of whether life first arose as DNAor material. It is usually stated that the transition from protein. The RNAworld and its catalytic repertoire non-life to life occurred when this genetic material began have been extensively discussed (Orgel, 1986; Beaudry to accumulate and replicate in the primitive environ- and Joyce, 1992; Piccirilli et al., 1990; Szostak and ment. The importance of RNAin the origin of life has Ellington, 1993; Ellington, 1994; Gesteland and Atkins, been asserted by so many researchers for so many years 1993; Joyce, 1998, 2002). There has been some discus- that it has been generally assumed that RNAwas among sion about the transition from the pre-RNAworld into the first informational polymers (see for example, the RNAworld ( Orgel, 1986, 1989; Schwartz et al., Belozerskii, 1959; Brachet, 1959; Oparin, 1961; Rich, 1987; Joyce, 1989; de Duve, 1993; Piccirilli, 1995; Miller, 1962; Buchanan, 1965; Haldane, 1965; Woese, 1967; 1997). The possibilities of a simultaneous origin of RNA Crick, 1968; Orgel, 1968; Kuhn, 1972; Eigen and and DNA( Oro! and Stephen-Sherwood, 1974)orof Schuster, 1979; White III, 1982). DNAbefore proteins ( Benner et al., 1987, 1989, 1993) The RNAworld is a hypothetical period of the early have also been addressed. As summarized by Kumar biosphere when both the information needed for life and and Yarus (2001) there is an increasing amount of the enzymatic activity of living organisms were con- experimental evidence suggesting that protein synthesis tained in RNAmolecules ( Gilbert, 1986; Joyce, 2002). evolved in an RNAworld. However, very little has been said about the transition from the RNAworld to the modern world of DNA/RNA/protein (where DNA stores the information, RNAserves auxiliary functions, *Corresponding author. Tel.: +52-5-56224823; fax: +52-5- 561660451. and protein does the catalysis). The primary focus has E-mail addresses: [email protected] (J.P. Dworkin), alar@ been based on the observations on the importance of hp.fciencias.unam.mx (A. Lazcano), [email protected] (S.L. Miller). RNA, including the RNA primer involved in DNA 0022-5193/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0022-5193(03)00020-1 128 J.P. Dworkin et al. / Journal of Theoretical Biology 222 (2003) 127–134 replication, the assumption of the lateness of DNAas a advantage in a drying scenario for the synthesis of more stable archive of genetic information (Ferris and nucleosides or their precursors (Fuller et al., 1972a, b). Usher, 1983; Lazcano et al., 1988a, b, 1992; Benner et al., 2-Deoxyribose may have been more reactive under 1989; Poole et al., 2000), and the study of the evolution prebiotic conditions: for example it reacts about 150 of ribonucleotide reductases as an essential step in the times faster than ribose with the alternative base urazole transition from the RNAto the extant DNA/RNA/ to form the nucleoside at 25C(Dworkin and Miller, protein world (Follmann, 1982; Harder, 1993; Reichard, 2000). In addition, Larralde et al. (1995) have shown 1993; Freeland et al., 1999). that 2-deoxyribose decomposes 2.6 times more slowly The hypothesis that the RNAworld, which may have than does ribose at 100C. Other advantages of DNA been preceded by simpler living entities, eventually over RNAare that it has one fewer chiral center, has evolved into the DNA/protein world which had all the greater stability at the pH of the current ocean (8.2), and characteristics of modern biochemistry, is currently the does not has the 2050 and 3050 ambiguity in polymeriza- most favored one. However, there are other alternatives. tions. The purpose of this paper is to discuss these other Many origin of life researchers interested in carbohy- possibilities. In this paper we address the possibility that drates have focused on ribose on the assumed existence deoxyribose came before ribose, and then whether DNA of an RNAworld which pulled its ribose from the came before protein synthesis or the reverse. Other prebiotic soup. As a result there have been very few aspects of this question have been discussed by Freeland studies on prebiotic sources of 2-deoxyribose or on the et al. (1999). We also examine the various ways to shift synthesis of this and other sugars via primitive from the pre-RNAworld to the RNAworld, including biocatalysts. The possibility that deoxyribose derivatives the possibility that DNAcame before RNA.Although played a role in early biological evolution following the we agree that the most parsimonious interpretation of pre-RNAworld deserves further attention. Thus, pre- the available evidence favors the precedence of RNA biotic and early biosynthetic pathways for deoxyribose over proteins and DNA, it is also true that evolution synthesis are as important to investigate as those for does not always follow the straightest course. The ribose (Dworkin and Miller, 1996). discussion presented here is clearly speculative, but it is hoped that it will be a guide for further experiments. 3. How to get out of the RNA world 2. The prebiotic availability of deoxyribose It is generally assumed that the RNAworld lasted for a relatively small period of time, but alternative view- Are there any arguments that could be used to favor points have been proposed (Benner and Ellington, 1987; the existence of a DNAworld (devoid of proteins) over Benner et al., 1987). This is primarily due to the the most familiar RNAworld? The prebiotic synthesis conjunction of the presumed inefficiency of primitive of deoxyribose from glyceraldehyde and acetaldehyde is ribozymes combined with the instability of RNA poor (Oro! and Cox, 1962), but the prebiotic synthesis of (Woese, 1967; Miller and Orgel, 1974) as well as its ribose is not vastly better (Shapiro, 1988). There are subunits (especially ribose) (Larralde et al., 1995). With other potential prebiotic pathways being explored for the exception of low temperatures, no mechanism has the synthesis of ribose from small phosphorylated been discovered that could enhance the stability of RNA aldehydes in the presence of hydroxide minerals under and its components under prebiotic conditions. How- neutral conditions (Krishnamurthy et al., 1999), but ever, there is an increasing large amount of empirical equivalent pathways to 2-deoxyribose have not been evidence demonstrating the versatility and ample studied. Although sugars are currently out of favor as catalytic repertoire of ribozymes. Although it has been prebiotic reagents, the presence of sugar acids, including claimed that RNAviruses may be the last remnants of both ribosugar- and deoxysugar acids in the 4.6 Â 109 the RNAworld ( Maizels and Weiner, 1994), it is clear years old Murchison meteorite suggest that they may that the latter no longer exists. Thus, it is important to have been present in the primitive Earth, derived from ask what evolutionary pathway life took from it to the the accretion of extraterrestrial sources (Cooper et al., modern world of DNA/RNA/protein. 2001) or from endogenous processes involving formal- If we assume that the transition from the RNAworld dehyde and its derivatives. into the modern world took place through small It has been argued (Robertson and Miller, 1995; evolutionary steps, then there are at least two possible Robertson et al., 1996) that drying lagoon conditions pathways out of the RNAworld to consider. These could have acted as a prebiotic reactor. The solubility of pathways lead to DNAas the informational molecule 2-deoxyribose is 30 molal (Dworkin, 1997) while ribose with RNAas the catalyst, or to RNAas the informa- is 20 molal (Goldberg and Tewari, 1989)at25C. The tional molecule with protein as the catalyst. This is greater solubility of 2-deoxyribose would be a slight illustrated in Fig. 1. The path out of the RNAworld J.P. Dworkin et al. / Journal of Theoretical Biology 222 (2003) 127–134 129 polymerases were non-specific toward the nature of their template and nucleotide substrates (Lazcano et al., 1988b). Combining catalytic and information functions in similar molecules (RNAand DNA) could have allowed for an easy transition for early organisms (Fig. 1). The optimization of these functions is best handled with separate molecules once the newly formed DNA/RNA organisms had established them- Fig.