Understanding how life emerged on Earth is one of the greatest challenges facing modern chemistry. A new way of looking at the synthesis of RNA sidesteps a thorny problem in the field.
It is well established that the evolution of life passed through an early stage in which RNA played central roles in both inheritance and catalysis1 — roles that are currently played by DNA and protein enzymes, respectively. But where did the RNA come from?
Experiments reported by Powner et al.2 (page 239 of this issue) provide fresh insight into the chemical processes that might have led to the emergence of information-coding nucleic acids on early Earth.
For 40 years, efforts to understand the prebiotic synthesis of the ribonucleotide building blocks of RNA have been based on the assumption that they must have assembled from their three molecular components: a nucleobase (which can be adenine, guanine, cytosine or uracil), a ribose sugar and phosphate. Of the many difficulties encountered by those in the field, the most frustrating has been the failure to find any way of properly joining the pyrimidine nucleobases — cytosine and uracil — to ribose3 (Fig. 1a). The idea that a molecule as complex as RNA could have assembled spontaneously has therefore been viewed with increasing scepticism. This has led to a search for alternative, simpler genetic polymers that might have preceded RNA in the early history of life.
But Powner et al.2 revive the prospects of the 'RNA first' model by exploring a pathway for pyrimidine ribonucleotide synthesis in which the sugar and nucleobase emerge from a common precursor (Fig. 1b). In this pathway, the complete ribonucleotide structure forms without using free sugar and nucleobase molecules as intermediates. This central insight, combined with a series of additional innovations, provides a remarkably efficient solution to the problem of prebiotic ribonucleotide synthesis.
The key to Powner and colleagues' approach was to overcome the deeply ingrained prejudice that carbon–oxygen chemistry (which leads to sugar formation) and carbon–nitrogen chemistry (which leads to nucleobase formation) should be kept separate for as long as possible. One does not have to look far to find the source of this prejudice. Incubation of formaldehyde — a simple carbon–oxygen compound — in alkaline solution rapidly yields a mixture of dozens of sugars3, which subsequently react to yield an intractable tar of insoluble products. Similarly, simple carbon–nitrogen compounds, derived from cyanide and ammonia, react with each other to generate not only the standard nucleobases, but also many other compounds. It is perfectly reasonable to expect that uncontrolled mixing of these two complex processes would lead to a chemical combinatorial explosion: the synthesis of millions of different organic compounds, of which the desired biological precursor molecules would be a vanishingly small fraction. But in a remarkable example of 'systems chemistry', in which reactants from different stages of a pathway are allowed to interact, Powner et al.2 show that phosphate tames the combinatorial explosion, allowing oxygenous and nitrogenous reactants to interact fruitfully.
The authors' path to RNA begins with the same starting materials used in many recent studies of prebiotic chemistry, but differs in the order in which they are combined. When the structurally simplest sugar, glycolaldehyde, reacts with the simplest derivative of cyanide and ammonia, cyanamide, a complex mixture of undesired compounds is formed. But Powner et al. add a third ingredient — phosphate — to the mix. In their reaction, phosphate acts as both a pH buffer and a catalyst, thereby short-circuiting the network of possible unwanted reactions and leading instead to the fast, efficient synthesis of a key intermediate known as 2-aminooxazole (Fig. 1b).
One of the goals of those developing theories of prebiotic chemistry is to identify geochemically plausible means of purifying key intermediates away from contaminants that might cause trouble in later reactions. The remarkable volatility of 2-aminooxazole suggests that it could be purified by sublimation, as it undergoes cycles of gentle warming from the sun, cooling at night (or at higher altitudes) and subsequent condensation. The compound would thus behave as a kind of organic snow, which could accumulate as a reservoir of material ready for the next step in RNA synthesis.
Phosphate continues to have several essential roles in the remaining steps of Powner and colleagues' pathway, in one case causing depletion of an undesired by-product, and in another saving a critical intermediate from degradation. The penultimate reaction of the sequence, in which the phosphate is attached to the nucleoside, is another beautiful example of the influence of systems chemistry in this set2 of interlinked reactions. The phosphorylation is facilitated by the presence of urea4; the urea comes from the phosphate-catalysed hydrolysis of a by-product from an earlier reaction in the sequence.
The authors wrap up their synthetic tour de force by using ultraviolet light to clean up the reaction mixture. They report that ultraviolet irradiation destroys side products while simultaneously converting some of the desired ribocytidine product to ribouridine (the second pyrimidine component of RNA). The development of this complex photochemistry required remarkable mechanistic insight from Powner and colleagues, who not only correctly predicted that ultraviolet irradiation would destroy the majority of the by-products, but also that the desired ribonucleotides would withstand such treatment.
The authors' careful study2 of every potentially relevant reaction and side reaction in their sequence is a model of how to develop the fundamental chemical understanding required for a reasoned approach to prebiotic chemistry. By working out a sequence of efficient reactions, they have set the stage for a more fruitful investigation of geochemical scenarios compatible with the origin of life.
Of course, much remains to be done. We must now try to determine how the various starting materials could have accumulated in a relatively pure and concentrated form in local environments on early Earth. Furthermore, although Powner and colleagues' synthetic sequence yields the pyrimidine ribonucleotides, it cannot explain how purine ribonucleotides (which incorporate guanine and adenine) might have formed. But it is precisely because this work opens up so many new directions for research that it will stand for years as one of the great advances in prebiotic chemistry.
Joyce, G. F. & Orgel, L. E. in The RNA World (eds Gesteland, R. F., Cech, T. R. & Atkins, J. F.) 23–56 (Cold Spring Harbor Laboratory Press, 2006).
Powner, M. W., Gerland, B. & Sutherland, J. D. Nature 459, 239–242 (2009).
Orgel, L. E. Crit. Rev. Biochem. Mol. Biol. 39, 99–123 (2004).
Lohrmann, R. & Orgel, L. E. Science 171, 490–494 (1971).
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