The chemical feat strengthens theory that the first life on Earth was based on RNA.



Single strand ribonucleic acid, RNA research and therapy.

RNA has been synthesized in conditions that may have resembled those on the early Earth.Credit: Alamy



If Thomas Carell is right, around 4 billion years ago, much of Earth might have been blanketed with a greyish-brown kind of mineral. This was no ordinary rock, however: it consisted of crystals of the organic molecules that scientists now call A, U, C and G. And some of these, the theory goes, would later serve as the building blocks of RNA, the evolutionary engine of the first living organisms, before DNA existed.

Carell, an organic chemist, and his collaborators have now demonstrated a chemical pathway that — in principle — could have made A, U, C and G (adenine, uracil, cytosine and guanine, respectively) from basic ingredients such as water and nitrogen under conditions that would have been plausible on the early Earth. The reactions produce so much of these nucleobases that, millennium after millennium, they could have accumulated in thick crusts, Carell says. His team describes the results in Science on 3 October1.

The results add credence to the ‘RNA world’ hypothesis, says Carell, who is at the Ludwig Maximilian University of Munich in Germany. This idea suggests that life arose from self-replicating, RNA-based genes — and that only later did organisms develop the ability to store genetic information in the molecule’s close relative, DNA. The chemistry is also a “strong indication” that the appearance of RNA-based life was not an exceedingly lucky event, but one that is likely to happen on many other planets, he adds.

In previous work in 2016, Carell’s team had found chemical reactions that spontaneously yielded the nucleobases A and G2. A separate group had done a similar proof-of-principle3 for the other two, U and C in 2009. But the two pathways seemed incompatible with each other, requiring different conditions, such as divergent temperatures and pH.

Now, Carell’s team has shown how all nucleobases could form under one set of conditions: two separate ponds that cycle through the seasons, going from wet to dry, from hot to cold, and from acidic to basic, and with chemicals occasionally flowing from one pond to the other. The researchers first let simple molecules react in hot water and then allowed the resulting mix to cool down and dry up, forming a residue at the bottom that contained crystals of two organic compounds.

They then added water back, and one of the compounds dissolved and was washed away into another reservoir. The absence of that water-soluble molecule allowed the other compound to undergo further reactions. The researchers then mixed the products again, and their reactions formed the nucleobases.

“This paper has demonstrated marvellously the chemistry that needs to take place so you can make all the RNA nucleosides,” says Ramanarayanan Krishnamurthy, a chemist at Scripps Research in La Jolla, California. But he and other researchers often warn that this and similar results are based on hindsight and might not offer credible guidance as to how life actually evolved.

The next major problem Carell wants to tackle is what reactions could have formed the sugar ribose, which needs to link to nucleobases before RNA can form.



doi: 10.1038/d41586-019-02622-4



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RNA nucleosides built in one prebiotic pot



For decades, the RNA world has been one of the most influential hypotheses regarding the origins of life on Earth. In this hypothetical era before the emergence of DNA and proteins, “life” on primordial Earth consisted of RNA molecules that both store genetic information and catalyze self-replication reactions (1). Despite its popularity with researchers, the RNA world hypothesis has suffered from its own origins conundrum: A mechanism for the simultaneous prebiotic synthesis of RNA nucleosides from both the purine and pyrimidine families has long eluded scientists (2). Although disparate prebiotic syntheses have been demonstrated for the two classes of RNA nucleosides (34), no single geochemical scenario has generated both. Now, on page 76 of this issue, Becker et al. (5) report on chemistry that accomplishes this long-awaited goal.


A possible solution to a very old problem

Nucleosides, one of the building blocks of RNA, do not form spontaneously in a plausibly prebiotic manner from their chemical substructures, nucleobases and ribose. Becker et al. show that when non-natural nucleobases are mixed with ribose and subjected to environmental wet-dry cycles, intermediate molecular species are formed that can easily be converted to the natural nucleosides in model prebiotic reactions.




“Prebiotic” processes are those that could conceivably have contributed to the origin of life on the primitive Earth. A fundamental difficulty with the prebiotic formation of RNA is that the RNA nucleobases (the purines, adenine and guanine; and the pyrimidines, cytosine and uracil) are reluctant to spontaneously form a bond with the sugar ribose; this glycosidic bond holds the nucleobases to the phosphate-ribose backbone of RNA. Within the past decade, a focus on the pyrimidine nucleosides yielded two completely different, experimentally supported approaches for prebiotic nucleoside synthesis. In one, the pyrimidine base is built along with ribose in a concerted fashion (3). In the other, pyrimidines slightly different from those found in modern RNA formed alternative nucleosides that might have served as subunits of an ancestral form of RNA (6). Unfortunately, neither approach suggested a corresponding prebiotic synthetic mechanism for purine nucleosides that is likely to succeed to a similar degree.

Stepping up to this challenge, Becker et al. (4) demonstrated, in 2016, a plausible prebiotic synthesis of purine nucleosides from formamidopyrimidines (FaPys), a sort of “unraveled” form of a purine that readily reacts with ribose in water to form nucleosides (4). Once the FaPy nucleoside is formed, raising the solution’s pH induces a ring-closure reaction that produces the intact purine nucleoside. Although this approach was considered an important advance in the field of prebiotic chemistry, there was no obvious way to reconcile this synthesis with the previously demonstrated disparate prebiotic syntheses of pyrimidine nucleosides by a dissimilar chemical pathway (3). How could two totally different synthesis routes to the purine and pyrimidine nucleosides occur in unison to produce the necessary subunits of RNA, presumably in the same prebiotic milieu?

In the new study, Becker et al. present an alternative prebiotic synthesis of pyrimidine nucleosides under geochemical conditions designed to be compatible with their previously published synthesis of the purine nucleosides (5). Using a similar strategy for the pyrimidine nucleosides, the authors formed a heterocyclic precursor (which can be viewed as a “scrambled” pyrimidine nucleobase) in a model prebiotic reaction mixture, which then reacted with ribose to form a non-natural ribonucleoside not found in modern RNA. The subsequent addition of specific prebiotic reagents—an iron catalyst and hydrogen sulfide—induced a rearrangement in the heterocyclic moiety to yield a cytosine nucleoside. This product can then be converted, under prebiotic reaction conditions, to a uracil nucleoside (7).

The non-natural nucleoside precursors used by Becker et al. for both the RNA purine and pyrimidine nucleosides are formed by wet-dry cycling—a method used for inducing chemical reactions by evaporating an aqueous solution of the reactants at increased temperatures. The dried reactants coalesce into a highly concentrated, low–water activity state, where their condensation (that is, the joining through covalent bond formation with the release of water molecules) becomes thermodynamically favorable. This wet-dry method for driving model prebiotic reactions spans the history of prebiotic chemistry research and has proven its utility for producing other chemical bonds necessary for formation of RNA (28), lipid precursors (9), and peptides (1011). Unlike volcanic eruptions and meteorite impacts—events that often are proposed as drivers of prebiotic reactions—wet-dry cycles would have been regular events on all exposed land of the prebiotic Earth, as they are driven by reliable fluctuations in temperature (e.g., daynight or seasonal cycles) and water activity (e.g., rainfall, tides, or geothermal activity in hydrothermal fields). With the simultaneous formation of purine and pyrimidine nucleosides, Becker et al. provide further evidence for the relevance of prebiotic wet-dry cycles (see the figure).

In 2004, Orgel, a pioneer in the field of prebiotic chemistry, reviewed the previous four decades of efforts to uncover plausible prebiotic reactions that would support the existence of an RNA world (2). At that time, Orgel argued that the synthesis of nucleosides was “the weakest link” in the proposed chain of prebiotic reactions that lead to RNA products. As mentioned above, in the ensuing years, model prebiotic reactions were developed in which extant pyrimidine nucleosides are prepared by building the nucleobases along with the sugar in a concerted reaction (rather than joining preformed bases and a sugar) (3). Furthermore, organic chemists discovered heterocycles that react with ribose in wet-dry cycles to provide possible ancestral RNA nucleosides (6). Now, Becker et al. present what is arguably the most direct prebiotic route to the RNA nucleosides.

Given this progress, do origins-of-life researchers consider the problem of prebiotic nucleoside formation to be solved by a variety of approaches? Alas, like many seminal scientific problems, crucial advances often yield more questions than answers. It is now fair to ask which experimentally demonstrated route reflects the true historical origin of RNA in the primordial soup. Also, did the various proposed synthesis methods contribute to the emergence of life simultaneously or at different times during the hypothetical RNA world era? Grappling with such issues is far more gratifying than wallowing in the despair that overshadowed the field two decades ago, when many prebiotic chemists believed that a plausible, prebiotic solution to the synthesis of nucleosides was impossible. Not anymore.




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