Origins of Life Solved? Mechanism for Prebiotic RNA Synthesis Published

Following on the heels of yesterday’s post concerning abiogenesis, an article published in Nature Communications titled: Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides makes to bold claim of providing a potential mechanism to prebiotic RNA synthesis: the synthesis of RNA in the absence of biological organisms.

If you’re familiar with abiogenesis theories and hypotheses, you can feel free to skip this paragraph, as I’ll offer a brief explanation. Abiogenesis is the mechanism whereby life arises from non living chemicals, and is one of the most difficult questions to address in biology/biochemistry. There are a variety of different hypotheses surrounding how abiogenesis might have occurred, though a detailed discussion of these mechanisms is out of the scope of this post. The two main competing theories of abiogenesis are the RNA world hypothesis and the metabolism first hypothesis. RNA world proponents tend to find this idea appealing, as RNA is capable of retaining and transmitting biological information, as well as catalyzing it’s own synthesis. Recall that DNA stores biological information in a chemical form. RNA is the sister molecule to DNA, and provides a transcript for the synthesis of the cell’s working molecules, proteins. Thus RNA can function in place of both DNA and protein, theoretically. In contrast, proponents of the metabolism first hypothesis tend to believe that RNA is too complicated of a molecule to have arisen on its own, and required the development of some crude metabolic activities to direct the synthesis of RNA and other biological molecules.

The article of interest reports having found a plausible route to the prebiotic synthesis of RNA nucleotides, which again, is the main complaint of the metabolism first proponents. Though prebiotic RNA synthesis mechanisms have been proposed in the past, what has remained elusive is a finding a single chemical mechanism by which both classes of nucleotides — purines and pyrimidines — could have formed (Figure 1).

Fig.0205
Figure 1. Two Classes of nucleotide bases: Pyrimidines and Purines. Note that RNA utilizes A, G, C, & U, whereas DNA uses A, G, C, and T.

Previous research and data suggested that the two classes of nucleotides must be synthesized separately, under mutually incompatible conditions. To my knowledge, this study is the first to report a mechanism whereby both purines and pyrimidines can be synthesized from a common precursor molecule, hypothesized to exist in the prebiotic world. The authors report that two molecules: 8-oxo-adenosine and 8-oxo-inosine, both of which are purine ribonucleotides, can be synthesized under the same chemical conditions, utilizing the same chemical precursors required for synthesis of pyrimidine ribonucleotides.

Perhaps more importantly than being able to utilize the same pathway, the authors report the mechanism provides a stereochemically pure product that matches the stereochemistry of the RNA nucleotides found in biological systems. Assuming this is true, it seems potentially very significant. One of the biggest difficulties with any origin of life scenario is producing these stereochemically pure compounds, and it’s a significant hurdle to overcome. (If you’re unfamiliar with this topic read this.)

“The mechanism we’ve reported gives both classes of molecule the same stereochemistry that is universally found in the sugar scaffold of biological nucleic acids, suggesting that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids,” said Dr Shaun Stairs (UCL Chemistry), first author of the study.

All of this sounds reasonable enough, so what’s my problem?

As is typical, I have a number of difficulties, but I’ll start here:

Constitutional analysis of purine and pyrimidine ribonucleotides suggests that nucleobase construction on a preformed sugar moiety would provide the simplest strategy for divergent monomer synthesis (Fig. 1). Given the lack of specificity observed during direct glycosidation of purine nucleobases, we have previously suggested that a tethered purine synthesis would overcome the limitation of intramolecular glycosidation.

Translation: We analyzed the structures of these molecules and determined that building them on a pre-existing sugar backbone would make the synthesis easier. Furthermore, when bonding the sugar and nucleotide base together, we find that the base and sugar tend to come together in a variety of unproductive ways, therefore we eliminate this problem by synthesizing the nucleotide directly on the sugar backbone.

Though I can appreciate taking things from a reductionist perspective–I am a molecular biologist after all–and I further appreciate that this particular study is addressing the issue of purine and pyrimidine synthesis, what troubles me is taking two extremely significant aspects of RNA synthesis for granted. Formation of the homochiral sugar backbone is a substantial problem for any RNA world based theory, and this particular research assumes the presence of that structure and moves forward.

I’ll reiterate that I appreciate the desire to study the synthesis of purines and pyrimidines separately, but when your entire theory rests on the presence of molecule (sugar backbone) for which there is not only no evidence of, but no plausible mechanism for its prebiotic synthesis, it’s a problem.

That said, the authors include a mechanism whereby the sugar and base components of the nucleotide are synthesized simultaneously. This reaction scheme is shown in Figure 2 below.

Figure 2
Figure 2. Reaction scheme for the prebiotic synthesis of ribonucleotides from prebiotic precursors.

Synthesis of the purine/pyrimidine nucleotides begins with “Divergence B” as shown in Figure 2, and from this structure pyrimidine nucleotides can be synthesized directly, and oxidized purine nucleotides can be produced as well.

The question is how do we reach “Divergence B” and is it reasonable to assume that the prebiotic world would be able to synthesize this molecule in any substantial amount. The methods section of the paper details how this synthesis performed (Edited by TRR for clarity):

  1. Glycolaldehyde (5; 1 g, 16.7 mmol) and potassium thiocyanate (3.24 g, 33.3 mmol) were dissolved in water (3 ml).
  2. The mixture was cooled to 0 °C and HCl (37%, 2.10 ml) was added drop wise.
  3. The reaction mixture was incubated for 2 h at room temperature and then at 80 °C
  4. After 24 h the starting material had been consumed and the reaction was cooled to room temperature
  5. The organics were then extracted into ethyl acetate (3 × 50 ml), washed with brine (3 × 30 ml) and dried over MgSO4.
  6. The solvent was removed under reduced pressure and the resulting solids were crystallized from CH2Cl2 to yield 2-thiooxazole (Compound 4b, Figure 2.)
  7. 2-Thiooxazole (Compound 4b, Figure 2.) and 4,4-dimethyl-4-silapentane-1-sulfonic acid (DSS; 20 mg; internal standard) were dissolved in D2O* (1.5 ml) to give a 500 mM solution of 4b.
  8. The solution was adjusted to pD 7 with NaOD (4 M) and 250 or 500 μl was added to glyceraldehyde
  9. The solutions were stirred at 60 °C for 24 h and the solution was re-adjusted to pD 7 every 6 h
  10. Aliquots (50 μl) were taken after 24 h, diluted with D2O (450 μl) and analysed by NMR spectroscopy.

*D stands for deuterium, a heavier isotope of the the hydrogen atom.

This is the sugar backbone that from where the authors are starting their purine/pyrimidine synthesis. Again, the authors reiterate that the chemicals used to synthesize this backbone are all plausible prebiotic chemicals, but chemical precursors are only half of the equation, conditions are just as important, if not more so.

Ignoring the concentrations of chemicals used in these reactions for the sake of clarity, an investigation of the conditions is important in trying to understand whether this is a plausible route to the prebiotic synthesis of ribonucleotides. Consider the conditions at each step of the synthesis:

  • Steps 1 – 3 have dramatic changes in temperature over a relatively short period of time: From freezing (0°C), to room temperature (23°C, 73°F), to hotter than pretty much anywhere on the surface of the Earth (80°C, 175°F). These aren’t temperature shifts observed anywhere on the Earth, with perhaps the exception of the hydrothermal vents on the ocean floor.
  • If the temperature changes noted above could be accounted for by some process on the Earth, step two of the procedures noted above represents an extreme change in pH, changing probably 4 or 5 pH units, or 10,000 to 100,000 times more acidic than the solution was originally. Even if the extreme temperature shifts noted above could be accounted for, it’s extremely unlikely to take place with a simultaneous massive change in pH.
  • Steps 5 & 6 represents are all purification steps that would not have taken place in the prebiotic world.
  • Step 8 contains another massive shift in pH, from extremely low pH in step 2 to a neutral pH here.
  • Step 9 requires that the solution be held at 60°C (140°F) for 24 hours with the pH corrected to neutral every so often.

Thus in order for the synthesis of these purine/pyrimidine ribonucleotides on this sugar backbone to make sense, the prebiotic synthesis of the sugar backbone itself has to make sense. Because synthesis of this sugar backbone requires dramatic and unrealistic changes in both pH and temperature, complicated purification and extraction procedures, in addition to long incubations under unchanging conditions, the prebiotic synthesis of this sugar backbone precursor in quantities substantial enough to support the development of self-replicating RNA strands seems extremely unlikely, and is at best, speculative handwaving at a more-or-less intractable and perhaps insoluble problem.

Since there’s lots of good organic chemistry here, and good deal of bench work went into authoring this paper, I won’t call it Lame Science; it certainly doesn’t qualify as Unscientific Rubbish, and I’m not going to start a new category called “Overstated Science,” but that’s what this research amounts to. Interesting and scholarly? Sure. A possible answer to the origins of life question? Not even close.

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