Back to the Future with RNA and XNA

  • The Prebiotic ‘RNA World’ Predates our DNA-Based Genetics  
  • What About Other Life-Forming Nucleic Acid (XNA)? 
  • New Research Discovers Synthetic XNA Providing Possible Clues 
Taken from via Bing Images.

Taken from via Bing Images.

Hopefully, I’ve piqued your interest by hijacking the award-winning film title Back to the Future as the lead-in for this blog. Now let me briefly outline why it’s apropos for coupling with RNA and XNA—i.e. molecules like RNA and DNA but curiously different, as you’ll see herein.

My metaphorical connection between Back to the Future and nucleic acids comes from currently captivating theories about RNA preceding DNA in molecular evolution of life, and—more intriguingly—whether XNA played a primordial role back then, or might in the future.

Said another way, evolution of all forms of life must logically derive from molecular evolution—in my opinion. Consequently, current terrestrial life-encoding genetic molecules of DNA and RNA must have a past and future. But what molecules did they arise from eons ago, and what molecules will they possibly become eons from now?

While we don’t have Doc’s time machine to go back eons to learn what was—or travel eons forward to learn what will be—some clever scientists in the recent past, and many more now, have been investigating how we, like Marty, can conjure compelling theories of what might be foreseen by looking back in time, in a molecular sense.

Ancient, Prebiotic Genetics

As previously commented on here, researchers have been interested in molecular evolution since 1924 when Soviet biologist Alexander Oparin proposed a theory of the origin of life on Earth through gradual chemical changes in carbon and other key atoms in the “primordial soup” of evolving matter. Following Watson & Crick’s discovery of the genetic code in double-stranded DNA in the 1950s, and Sydney Brenner’s elucidation of the existence of mRNA in the 1960s, increasing attention has been directed to how these two particular classes of nucleic acid molecules became the principal basis of all living organisms today.

Taken from via Bing Images.

Taken from via Bing Images.

The short version of this fascinating topic, which can be read about in detail in a lengthy review by Gerald Joyce, proposes that there was an initial evolution of what Walter Gilbert called ‘the RNA World” in his 1986 Nature publication with that provocative title. This prebiotic RNA-centric stage of molecular evolution on Earth is supported by data showing that folded, 3-dimensional RNA structures can have catalytic functions (ribozymes). Moreover, this functionality includes RNA replication using molecular “building blocks” that may also arise from ribozyme-mediated metabolism.

According to Joyce, RNA is capable of performing all of the reactions of protein synthesis; however, this “crowning achievement” of the RNA world “also began its demise.” Thus, evolution of proteins began to provide protein enzymes to increase molecular diversity and—importantly—lead to DNA building blocks for creating DNA-based genomes that were more stable and complex than RNA.

Timeline of events in the early history of life on Earth, with approximate dates in billions of years before the present. Taken from Joyce in Nature.

Timeline of events in the early history of life on Earth, with approximate dates in billions of years before the present. Taken from Joyce in Nature.

What are the Xs in XNAs?

While the aforementioned sequence of molecular evolution pictured above is widely held to be a compelling theory, puzzling questions remain as to how and why RNA and DNA specifically evolved from a complex, molecularly “cluttered”—according to Joyce—cauldron of prebiotic chemicals that presumably included all sorts of nucleic acid-like molecules.

One theoretical viewpoint is that there is a fine balance of dynamic forces between molecular entities which are unstable enough to be reactive—thus being able to form new, larger conjugates—yet stable enough to persist—thus serving either as templates for replication or enzymes to create protein enzymes. Simply put, very special chemical properties of RNA, DNA, and proteins enabled these molecules to become the “big winners” here on Earth as life evolved.

If this is the case, are there “losers” that nevertheless have genetic potential under conditions different from those presently existent on Earth? Maybe under conditions that will exist eons from now, when terrestrial and climatic conditions change drastically. Or perhaps these “losers” could thrive today if present on other so-called “Goldilocks planets” having conditions favorable for some form of life.

All of this leads to what Taylor et al. have stated succinctly in their recent Nature publication that has received much attention:

Catalysis by nucleic acids (and by biopolymers in general) requires as a minimum the presence of chemically functional groups and a framework for their precise arrangement. Synthetic genetic polymers (XNAs) with backbones based on congeners of the canonical ribofuranose share with RNA and DNA a capacity for heredity, evolution and the ability to fold into defined three-dimensional structures, forming ligands (aptamers). 

Remarkably, they have discovered that XNAs (aka Xeno nucleic acids)—exemplified by the structures shown below—can support the evolution of enzymes (XNAzymes), which is considered a key event in the origin of life, pre-dating the appearance of protein enzymes.


XNAzymes comprised of repeating units of ANA, FNA, HNA, or CENA were found by screening corresponding pools of random-sequence oligomers to find specific sequences that exhibited RNA endonuclease (“cutting”) or RNA ligase (“joining”) activities. They also discovered a FNAzyme that ligates FANA oligomers.

These discoveries, which were made using TriLink’s triphosphates of ANA and triphosphorylated RNA, led Taylor et al. to offer the following conclusion:

Evolution of catalysis independent of any natural polymer has implications for the definition of chemical boundary conditions for the emergence of life on Earth and elsewhere in the Universe.

In my opinion, this purposefully vague, scientifically couched statement implies that these stunning discoveries with XNA support the possibility of non-DNA/non-RNA–based forms of life on Earth under different “boundary conditions” that may exist in the future, or on other planets—now.

Regarding the latter, Benner et al. have reviewed the principles of organic chemistry and concluded that life—defined as a chemical system capable of Darwinian evolution—may exist in a wide range of environments. These include non-aqueous solvent systems at low temperatures, or even supercritical dihydrogen-helium mixtures that exist in the Universe. They noted that the only absolute requirements may be a thermodynamic disequilibrium and temperatures consistent with chemical bonding.

Incidentally, if you’re curious (as I am) about the availability of fluorine in the early Universe for possible incorporation into FNA, I found a publication on calculations that support the presence of HF and F shortly after the Big Bang.

After researching and thinking about all of the aforementioned science, my mind conjured up Star Trek-like visions of traveling at warp speed “to boldly go where no man has gone before” in search for XNA-based life. Alas, I was born too soon for that.

Human, Klingon, Cardassian and Romulan representatives meet their primeval ancestor in the Alpha Quadrant. Taken from Wikipedia “The Chase” (Star Trek: The Next Generation; Season 6, Episode 20).

Human, Klingon, Cardassian and Romulan representatives meet their primeval ancestor in the Alpha Quadrant. Taken from Wikipedia “The Chase” (Star Trek: The Next Generation; Season 6, Episode 20).

On the other hand, I believe that intergalactic planetary exploration will indeed happen in the future. I’ve always enjoyed reading “The Chase” (Star Trek: The Next Generation; Season 6, Episode 20), which involves Starship Enterprise Captain Picard (Patrick Stewart) and crew discovering puzzling “number blocks” that they ultimately deduce to be fragments of “compatible DNA strands” (think XNAs) recovered by others from different worlds all over the galaxy. The crew eventually believe that they have discovered an “embedded genetic pattern that is constant throughout many different species.” They speculate that this was left by an early race that pre-dates all other known civilizations, and would ultimately explain why so many races are humanoid.

Needless to say, I also enjoyed researching and composing this blog, which I hope you found interesting.

As always, your comments are welcomed.

2 thoughts on “Back to the Future with RNA and XNA

  1. Frank,
    Thanks for the compliment.

    By coincidence, this interesting publication just appeared in one of my PubMed alerts:

    What RNA World? Why a Peptide/RNA Partnership Merits Renewed Experimental Attention.

    First and last sentences of the Abstract are s follows.

    We review arguments that biology emerged from a reciprocal partnership in which small ancestral oligopeptides and oligonucleotides initially both contributed rudimentary information coding and catalytic rate accelerations, and that the superior information-bearing qualities of RNA and the superior catalytic potential of proteins emerged from such complexes only with the gradual invention of the genetic code.
    [A] scenario documents a path to increasing complexity that obviates the need for a single polymer [RNA] to act both catalytically and as an informational molecule.

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