This week’s issue of New Scientist contains an interesting article bearing the headline “First Life: The Search for the First Replicator.” As a means to circumvent the chicken-and-egg problem pertinent to the relationship of DNA and proteins, author Michael Marshall attempts to revive the fashionable (but scientifically bankrupt) scenario of an RNA world.
In brief, RNA exhibits both information-carrying capacity and catalytic activity. Arguments for the RNA world include the fact that RNA makes up a large proportion of ribosomes (the protein factory of the cell). Furthermore, in eukaryotes (organisms with nucleated cells), components of genes that don’t code for proteins (called “introns”) are spliced out of an RNA transcript before translation. RNA molecules are involved in many of the RNA-splicing processes, and it has been documented that some RNA introns have self-splicing capability: that is to say, they can excise themselves, though at a slower rate than proteins can do so. Further observations that are taken as evidence for the plausibility of the RNA world thesis include the existence of RNA viruses, which use RNA as their genetic material that is translated directly into proteins.
The New Scientist article states the chicken-and-egg conundrum (which the RNA world thesis is invoked to resolve) up-front
When biologists first started to ponder how life arose, the question seemed baffling. In all organisms alive today, the hard work is done by proteins. Proteins can twist and fold into a wild diversity of shapes, so they can do just about anything, including acting as enzymes, substances that catalyse a huge range of chemical reactions. However, the information needed to make proteins is stored in DNA molecules. You can’t make new proteins without DNA, and you can’t make new DNA without proteins. So which came first, proteins or DNA?
The solution? The article continues,
The discovery in the 1960s that RNA could fold like a protein, albeit not into such complex structures, suggested an answer. If RNA could catalyse reactions as well as storing information, some RNA molecules might be capable of making more RNA molecules. And if that was the case, RNA replicators would have had no need for proteins. They could do everything themselves.
It was an appealing idea, but at the time it was complete speculation. No one had shown that RNA could catalyse reactions like protein enzymes. It was not until 1982, after decades of searching, that an RNA enzyme was finally discovered. Thomas Cech of the University of Colorado in Boulder found it in Tetrahymena thermophila, a bizarre single-celled animal with seven sexes (Science, vol. 231, p. 4737).
After that the floodgates opened. People discovered ever more RNA enzymes in living organisms and created new ones in their labs. RNA might not be as good for storing information as DNA, being less stable, nor as versatile as proteins, but it was turning out to be a molecular jack of all trades. This was a huge boost to the idea that the first life consisted of RNA molecules that catalysed the production of more RNA molecules — “the RNA world,” as Harvard chemist Walter Gilbert dubbed it 25 years ago (Nature, vol. 319, p. 618).
The article goes on to cite Johnston et al. (2001), in which it was reported that a ribozyme (called R18) could catalyze the type of polymerization required for RNA replication, namely, the extension of an RNA primer by up to 14 ribonucleotides using nucleoside triphosphates and the coding information of an RNA template. As the New Scientist article acknowledges, however, R18 itself is 189 ribonucleotides in length, whereas the longest RNA it can make contains just 20 ribonucleotides. Thus, the RNAs it builds are not even close to its own length, a requisite for self-replicating RNA. But not to worry, we are told. After all, Wochner et al. (2011) have identified a ribozyme (called tC19Z) that can copy RNA sequences up to 95 ribonucleotides in length: the problem, of course, being that this isn’t even half (about 48%) of its own length.
New Scientist is, of course, completely ignoring the real issue. That is the problem of attaining RNA molecules in the first place from inorganic material. As I wrote recently, at the heart of Darwinian theory lies the concept that evolution must strike a balance between reliable reproduction of a species on the one hand, and opportunistic variation on the other. A poor replicator is much more likely to degrade through inaccurate copying than to be enhanced by evolution. There thus exists a threshold before the cumulative improvement of a replicator can occur by selection. A replicator must already have a reasonably good performance level before it can improve on that performance. At that point, however, we are running perilously close to yet another Catch-22. If (as I think is a legitimate assumption), this threshold performance level may be attained only with a sequence substantially longer than the minimum required for folding, one is faced with the even greater improbabilities of attaining such a replicator by a blind search.
RNA is also notoriously unstable. Ribose sugar possesses a free hydroxyl (OH) group in its pentose ring, making it prone to hydrolysis (where the free hydroxyl group attacks the phosphodiester bond, thus breaking the phosphate bonds which are holding the structure together). This renders RNA much less stable than DNA.
Moreover, as I documented in a review of Nick Lane’s book, the conundrum of making the individual ribonucleotides is only part of the story. They will only polymerize if the nucleotides are present at high concentrations. When the nucleotides are present in high concentrations, it is conceivable that they would spontaneously polymerize (this, of course, ignores the problem of sequence-specificity, but we can leave that aside). In the case of low concentration, conversely, the RNA breaks down into its constituent nucleotides. But here’s the thing: Synthesis of the novel RNA strand requires that nucleotides be consumed (thus decreasing their concentration). The pool of nucleotides, therefore, would have to be perpetually replenished at a rate faster than it is consumed. Please see my response to Nick Lane’s notions of the origin of life in hydrothermal vents for a rebuttal to a common attempted resolution of this problem.
Another problem pertains to the fact that the formose reaction (the chemical reaction which some have theorized could have led to the emergence of ribose on the prebiotic earth) will not produce sugars in the presence of nitrogenous substances. This includes peptides, amino acids, and amines. This leads one again into a confounding paradox: If the prebiotic environment contained amino acids, it would have prevented sugars (and, as a consequence, RNA or DNA) from forming. On the flip side of the coin, if the prebiotic world contained no amino acids, protein synthesis would not be possible. Related to this is the problem of nucleotide bases, which requires the abundance of nitrogen-rich chemicals, something which would also limit the production of ribose sugars.
The New Scientist article discusses a couple of other pertinent problems: “…where did the energy to drive this activity come from? There must have been some kind of metabolic processes going on — but RNA does not look up to the job of running a full-blown metabolism.” And “Proteins have many more functional groups than RNAs.” Indeed. Ribozymes possess very few of the many functions performed by protein-based enzymes.
The solution? Marshall tells us,
…there is a way to make a single tool much more versatile: attach different bits to it, like those screwdrivers that come with interchangeable heads. The chemical equivalents are small helper molecules known as cofactors.
Proteins use cofactors to extend even further the range of reactions they can control. Without cofactors, life as we know it couldn’t exist, Ferr�-D’Amar� says. And it turns out that RNA enzymes can use cofactors too.
This is accompanied by a citation of Suga et al. (2003) and Breaker et al. (2004). In the case of the former, it was reported that a ribozyme could oxidize alcohol with the aid of the cofactor NAD+. In the case of the latter, it is reported that glmS (a natural ribozyme) also uses a cofactor. Of course, the details of where these cofactors may have emerged from in the prebiotic context is conveniently omitted.
More than halfway through the New Scientist article, Marshall finally gets to the part we’ve all been waiting for. He writes, “there is still one huge and obvious problem: where did the RNA come from in the first place?”
RNA molecules are strings of nucleotides, which in turn are made of a sugar with a base and a phosphate attached. In living cells, numerous enzymes are involved in producing nucleotides and joining them together, but of course the primordial planet had no such enzymes. There was clay, though. In 1996, biochemist Leslie Orgel showed that when “activated” nucleotides — those with an extra bit tacked on to the phosphate — were added to a kind of volcanic clay, RNA molecules up to 55 nucleotides long formed (Nature, vol. 381, p. 59). With ordinary nucleotides the formation of large RNA molecules would be energetically unfavourable, but the activated ones provide the energy needed to drive the reaction.
This suggests that if there were plenty of activated nucleotides on the early Earth, large RNA molecules would form spontaneously. What’s more, experiments simulating conditions on the early Earth and on asteroids show that sugars, bases and phosphates would arise naturally too. It’s putting the nucleotides together that is the hard bit; there does not seem to be any way to join the components without specialised enzymes. Because of the shapes of the molecules, it is almost impossible for the sugar to join to a base, and even when it does happen, the combined molecule quickly breaks apart. [emphasis added]
Yes, indeed. In order to obtain nucleosides (i.e., base and ribose), one would need to begin with a mixture of nitrogenous bases and ribose and an appropriate condensing agent. To obtain nucleotides requires the mixing of nucleosides with phosphate and a different condensing agent. But putting the subcomponents together to form nucleotides (and subsequently polymerizing them) is ultimately trivial compared to generating the required sequence-specificity.
In the meantime John Sutherland, at the MRC Laboratory of Molecular Biology, has been doggedly trying to solve the nucleotide problem. He realised that researchers might have been going about it the wrong way. “In each nucleotide, you see a sugar, a base and a phosphate group,” he says. “So you assume you need to make those building blocks first and then stick them together…and it doesn’t work.”
Instead he wondered whether simpler molecules might assemble into a nucleotide without ever becoming sugars or bases. In 2009, he proved it was possible. He took half a sugar and half a base, and stuck them together — forming the crucial sugar-base link that everyone had struggled with. Then he bolted on the rest of the sugar and base. Sutherland stuck on the phosphate last, though he found that it needed to be present in the mixture for the earlier reactions to work (Nature, vol. 459, p. 239).
This study does partially address one, though only one, of the many outstanding difficulties associated with the RNA world scenario, the most popular current theory of the undirected chemical evolution of life. Starting with several simple chemical compounds, Powner and colleagues successfully synthesized a pyrimidine ribonucleotide, one of the building blocks of the RNA molecule.
Nevertheless, this work does nothing to address the much more acute problem of explaining how the nucleotide bases in DNA or RNA acquired their specific information-rich arrangements, which is the central topic of my book [Signature in the Cell: DNA and the Evidence for Intelligent Design]. In effect, the Powner study helps explain the origin of the “letters” in the genetic text, but not their specific arrangement into functional “words” or “sentences.”
Moreover, Powner and colleagues only partially addressed the problem of generating the constituent building blocks of RNA under plausible pre-biotic conditions. The problem, ironically, is their own skillful intervention. To ensure a biologically-relevant outcome, they had to intervene — repeatedly and intelligently — in their experiment: first, by selecting only the right-handed isomers of sugar that life requires; second, by purifying their reaction products at each step to prevent interfering cross-reactions; and third, by following a very precise procedure in which they carefully selected the reagents and choreographed the order in which they were introduced into the reaction series.
Thus, not only does this study not address the problem of getting nucleotide bases to arrange themselves into functionally specified sequences, but the extent to which it does succeed in producing biologically relevant chemical constituents of RNA actually illustrates the indispensable role of intelligence in generating such chemistry.
Toward the end of the article, Marshall entertains the hydrothermal vent hypothesis, as well as the notion that life began in ice (for problems with the former, see my comments here; for problems with the latter, see this article).
To conclude, Michael Marshall’s New Scientist article does not even come close to demonstrating the feasibility of the RNA world hypothesis, much less the origin of the sequence-specific information necessary for even the simplest of biological systems. Since information is a phenomenon uniformly associated with intelligent causes, it follows inductively that intelligent design constitutes the best — most causally sufficient — explanation for the information-content of the hereditary molecules DNA and RNA.