It’s generally believed that the most complex systems of our world began from very simple things. Then, as a force of survival, evolution began to occur, and things gradually became more complex. This same perspective applies to science’s general understanding of the origin of life. The entire complexity of the molecular system, and life as we know it, all began from something very small, and has evolved into the concept of genetics and modern biology.
For a long time, scientists have posited that this simple “thing” from which life began is Ribonucleic acid (RNA), a polymeric molecule that’s essential for a wide range of biological functions, including building proteins and regulating genes.
This is because the RNA has a unique capacity to serve as both a template and a catalyst: RNA can make copies of itself in a process called self-replication, and it can also catalyze the reaction of self-replication, thereby aiding itself in making many copies of itself. Sophisticated and powerful at the same time.
While this may explain how a single polymer copied itself into what we now know as the complex genetic system, there are some plot holes in the story. Firstly, most RNA molecules are quite large (about 150 nucleotides long) and structurally complex. And this raises questions: how can a molecule so complex be able to copy itself accurately without any mutations? And more importantly, how did these complex molecules emerge? In addition, these RNAs are often folded, and their folded nature inhibits self-replication. So while the RNA World Hypothesis – the notion that earlier life forms may have used RNA to store genetic material before DNA took over that role – sounds plausible, this hasn’t been proven in a lab setting.
In this new study published in Science in February, scientists might just have cracked the code and taken us a step further in finding proof to support the RNA World hypothesis.
“We were interested in seeing if it's possible to build a very simple chemical system that starts replicating itself, mutating, and evolving. The idea is that something like that could be what happened at the origins of life,” said Edoardo Gianni, corresponding author on the paper. He explained further that when considering the origin of life, you couldn’t have all the complex components of living cells; you need something as simple as possible to get started, and the goal of this research was to find out if such a chemical compound exists.
The scientists created a pool of random short RNA sequences and searched for those that could catalyze templated polymerization; basically, those that could copy themselves and speed up the reaction of copying themselves.
From a pool of thousands of randomly selected short RNA motifs, they found three ribosomes that met these criteria: they were short, they copied themselves, and they sped up the reaction of copying themselves. After further evolution and engineering on these three, the result was an even smaller ribozyme, just 45 nucleotides long with RNA polymerase activity. The RNA was rightly named Quite Tiny (QT45).
After studying QT45, they found that it had several criteria to support its role in the origin of life theory. When the scientists used trinucleotide triphosphates as building blocks for the polymerization reaction, they found that the RNA could not only copy trinucleotides, it could also copy longer building blocks like oligonucleotides and shorter ones like mono- and dinucleotide triphosphates.
In addition, the QT ribozyme did not need to be physically attached or sequence-matched to the RNA it copied. Instead, it could just find it, bind loosely, do the job of replication, and move on, like a real enzyme.
RNA is quite a fragile molecule, so the scientists endeavored to make the environment as conducive as possible for it to demonstrate its ability.
So, instead of supplying single nucleotides, the scientists used trinucleotide triphosphates as substrates. These are three-base building blocks that allow RNA to copy itself in larger steps. This makes the process of replication easier for the RNA molecules. Trinucleotide triphosphates also bind strongly to RNA.
RNA molecules have the habit of folding into complex shapes. Think of a long rope that finds it difficult to stay in a straight line. This makes copying cumbersome, but with the trinucleotide triphosphates strongly bound to them, replication can still occur even when the RNA molecules are folded. Trinucleotide triphosphates also prevent the RNA molecules from sticking together, further enhancing replication.
Hence, using triplet substrates means that the RNA doesn't have to be too evolved or complex to get the job of replication done. Even the simplest, most primitive samples can work.
Another thing they did was to place the RNA in eutectic ice (partially formed frozen water). This is based on prior knowledge that eutectic ice stabilizes RNA and concentrates the substrates needed for replication.
Creating a coordinated environment for the RNA molecules to carry out these essential reactions is a great initiative, but it also raises questions. If so much intervention had to occur for these reactions to be successful, could they have happened of their own accord in a prebiotic world, without such interventions?
“There was always this question of how such a fragile molecule was going to survive on the early Earth, where you have volcanoes erupting and meteorites raining down,” said Phil Holliger, another corresponding author of the paper.
According to Holliger, we may never have a definite answer to that until we can actually travel back in time. However, research currently says that the early Earth was probably in temperatures similar to what we see today, so there is a possibility that there could have been ice to stabilize RNA, especially in the cold seasons.
Holliger intimated that the unknowability of the true origin of life is one of the limitations of this study. “You can’t ever really know if this is what actually happened,” he said. “The origin of life is unknown and essentially unknowable. You can’t go back. However, the study provides a path of maximum plausibility whereby all the steps that have been proposed to occur have been demonstrated as possible.”
Ultimately, this study has brought us a step closer to understanding how life could have begun on early Earth. “This paper shows genuine polymerase activity in ribozymes as short as 39 nucleotides long, and a 45-nucleotide-long version was good enough to complete synthesis of its own strand (and its template),” said James Attwater, a research fellow at University College, London, who was not involved in the research. “Considering how complexity scales with RNA length, self-copying activity is possible in a much smaller format, and this is a massive step towards bridging chemistry and biology,” he said.
Beyond giving us some insight into how life could have begun on early Earth, this study also raises questions about the possibility of life arising in other parts of the universe, like on the growing number of exoplanets we’ve been discovering.
The study appeared in Science.
