First Happy New Year to all. Now, for the matter at hand.

Traditionally, the scientific field of origin-of-life research has been divided into two camps based on what theorists propose came first: replication or metabolism. The “replicators-first” group think that once molecules (like DNA or RNA) capable of self-replication appeared, metabolism was sure to follow. The other group counters that  replication is not possible without enzymes and metabolic processes in place first.

Both sides are probably right, since proteins require genes (DNA) in order to be made, and DNA requires protein enzymes to replicate itself. Without enzymes and metabolism, it’s hard to imagine efficient and accurate replication. But without replication, any advanced metabolism that arises in a particular proto-cell cannot survive into the next generation.

The most widely held scientific theory for any part of abiogenesis is that an “RNA world” of life arose first and then morphed into the modern DNA world. The idea came from the finding that some RNA molecules (like the ribosome) can act as pretty good catalysts called ribozymes. The implication was that RNA could be both a replicator and metabolic catalyst at the same time, thus solving the dilemma of which came first. And a lot of evidence was gathered to support the theory.

But the excitement about RNA as a major step in the origin of life faced several stubborn problems. Further research showed that the efficiency and accuracy of RNA replication in the absence of protein enzymes was really not good enough to allow for a stable informational state. One of the most serious issues was the tendency of long RNA strands to “self-anneal”: to fold up and stick to themselves or to other RNA strands. The annealing reaction is about a thousand times faster than spontaneous non-catalyzed replication, so left on its own, RNA will probably never replicate itself.

Enter Jack Szostack, the Harvard biochemist, Nobel Laureate, and a leading light in RNA World research. Szostack’s research group was actively trying to solve the annealing problem, and he had a brilliant idea. While there were no proteins around at this stage, there were amino acids, and it was likely that two or a few amino acids could be joined together in a small chain called an oligopeptide by an RNA molecule with catalytic activity like the modern ribosome. Szostak said in the introduction to his breakthrough 2016 paper:

In order for subsequent rounds of replication to be possible, reannealing of the separated single strands must occur on a time scale that is comparable to or slower than the rate of strand copying.

He reasoned that an oligopeptide might be able to interact with an RNA strand in a way that would prevent annealing or at least slow it down long enough to allow time for replication. If true, this could also be the origin of the evolution of longer peptides and eventually proteins. And, in a wonderful set of experiments, it worked! From the abstract of the paper:

…oligoarginine peptides slow the annealing of complementary oligoribonucleotides by up to several thousand-fold; This method for enabling further rounds of replication suggests one mechanism by which short, non-coded peptides could have enhanced early cellular fitness, potentially explaining how longer, coded peptides, i.e. proteins, came to prominence in modern biology.

The impact this paper had on the field of origin of life research is hard to exaggerate:. A major stumbling block to acceptance of RNA World as a viable hypothesis was overturned. Despite my long-held skepticism, I also began to accept the possibility that RNA World might have happened. It all made perfect sense. Better replication by longer and better peptides would give a selective advantage to a cell, allowing for evolution of more advantageous RNA sequences and the birth of long proteins.

But science is not an easy pursuit. (I can say that with authority after 35 years.) Things go wrong. A lot. And as shocking as it is, things can go wrong for Nobel Laureates also. As it turned out, Szostack’s great idea was wrong, and the Nature paper showing the evidence in favor of the idea was also wrong. In a retraction published on November 23, 2017, Szostack wrote:

…we have been unable to reproduce observations suggesting that arginine-rich peptides allow the non-enzymatic copying of an RNA template in the presence of its complementary strand… we now understand that the data reported in the published article are the result of false positives that arose from … random errors, including transfer and concentration errors, affected the ratio of the concentrations of the RNA template and its complementary strand…in reality these reactions did not contain enough complementary strands to completely inhibit the reaction.

What that paragraph means is that others in his lab were unable to reproduce the same results that are reported in the paper, and they found out why. Somebody made some mistakes, and the results were not due to what they thought, but were an example of that most terrible of all words for lab scientists – an artefact. In other words, the results were a mistake. But even worse news came next. When carefully doing the experiments again, and avoiding all errors, they found the opposite of what they first reported and had hoped to find:

Subsequent experiments suggested that arginine-rich peptides may not slow the reannealing of complementary strands, and that what we had previously interpreted as a decrease in annealing rate was actually an artefact…

In other words, it looks like peptides do NOT slow reannealing, and therefore there is still no known mechanism for RNA to self-replicate. It ain’t over yet. I am sure many labs with tweak the experimental conditions in all kinds of ways to see if something will work. And it might. But it doesn’t look likely, and if things stay as they are now, RNA world and origin-of-life research is back to square one.

What is the lesson here? Szostack admitted to Retraction Watch that “In retrospect, we were totally blinded by our belief [in our findings]…we were not as careful or rigorous as we should have been… in interpreting these experiments.” Yes, I have been there. It’s really hard for a scientist to remain objective and skeptical when everything seems to work just right, and your hypothesis is supported by the experimental data.

The other lesson is that the origin of life has no easy answers, and in fact I can’t think of another field in modern biology where the answers seem to be so hard. Maybe that itself is telling us something.