Setting the stage: the history, chemistry, and geobiology behind RNA

Abstract

No community-accepted scientific methods are available today to guide studies on what role RNA played in the origin and early evolution of life on Earth. Further, a definition-theory for life is needed to develop hypotheses relating to the "RNA First" model for the origin of life. Four approaches are currently at various stages of development of such a definition-theory to guide these studies. These are (a) paleogenetics, in which inferences about the structure of past life are drawn from the structure of present life; (b) prebiotic chemistry, in which hypotheses with experimental support are sought that get RNA from organic and inorganic species possibly present on early Earth; (c) exploration, hoping to encounter life independent of terran life, which might contain RNA; and (d) synthetic biology, in which laboratories attempt to reproduce biological behavior with unnatural chemical systems.

Figure 1.

The origin of life as a historical question cannot be studied directly. There are, however, many indirect ways to approach the question. Four of these are illustrated here. The bottom wedge represents approaches that work backwards in time from contemporary biology to more ancient forms of life, The top wedge represents approaches that work forward in time from organic species presumably available on early Earth to the first Darwinian chemical systems. The left wedge represents approaches that hope to discover an alien or weird form of life by exploration, a form of life whose structure might constrain models for how terran life emerged. The right wedge represents efforts in the laboratory to create artificial Darwinian systems, systems that might further constrain models of how terran life emerged, even if they are not constrained by current models for the environment on early Earth. Benner et al. (2007) Adv Enzymol Mol Biol Protein Evol 75: 1–132.

Figure 2.

Shown in magenta are RNA fragments attached to many cofactors that are widely distributed in modern terran metabolism, and therefore placed in the last common ancestor of all known life on Earth. Because those RNA fragments do not participate in the chemistry of the metabolic reaction, they are not likely to have arisen convergently, but rather reflect an episode of life on Earth when RNA was the only encoded component of biocatalysis, and used these fragments as “handles.” Under this hypothesis, the absence of a magenta RNA cofactor on biotin implies that it arose after the RNA World.

Figure 3.

The red bonds in this general structure for RNA are all thermodynamically unstable with respect to hydrolysis in water, and suffer from a standard organic reaction mechanism by which they can hydrolyze.

Figure 4.

A scheme to obtain one of the red bonds in Figure 3 (Powner et al. 2009). For those accepting Shapiro's critique of an “RNA first” model for life's origin (Shapiro 2007), this scheme offers much to criticize. Compounds such as glyceraldehyde are not formed under conditions in which they accumulate. Glyceraldehyde and cyanamide are incompatible. Hands-on intervention by intelligent chemists must control their ratios and availabilities. To get the 2′,3'-cyclic phosphate of cytidine. pyrophosphate and the key intermediate must be heated in urea or formamide (certainly available on early Earth), but as a different reaction medium. Some regard this as an example of “synthetic organic chemistry,” not “prebiotic chemistry,” others disagree (Benner 2009).

Figure 5.

In an effort to find a mineral-stabilized route to pentoses and pentuloses, HJ Kim et al. (in prep.) propose a “premetabolic cycle” under the control of mineral borate. Compounds and reactions involved in the cycle are shown in green; the cycle fixes formaldehyde (HCHO) operating clockwise. Prebiotic compounds in blue feed the cycle. Leakage from the cycle indicated by black arrows emerging from green compounds; in each case but one, these lead directly or indirectly to pentoses and pentuloses, which are stabilized by borate. Whether this represents long sought experimental support for a “metabolism first” model for the origin of life, or the way in which pentoses and pentuloses emerged prebiotically, is disputable.

Figure 6.

Some unnatural nucleic acid structures that have been developed by synthetic biologists as RNA-like (but not RNA) molecules possibly capable of supporting Darwinian evolution, including the expanded genetic alphabet (left) that supports six-letter PCR and the phosphoramidate linkage that supports enzyme-free primer extension (Stutz et al. 2007).

Figure 7.

“Six letter PCR” showing products of amplification of an amplicon containing two adjacent nonstandard nucleotides.