How the earliest life on Earth may have replicated itself

Liquid brine containing replicating RNA molecules is concentrated in the cracks between ice crystals, as seen with an electron microscope
Liquid brine containing replicating RNA molecules is concentrated in the cracks between ice crystals, as seen with an electron microscope

Scientists in Philipp Holliger’s group in the LMB’s PNAC Division have created a new type of genetic replication system to demonstrate how the first life on Earth – in the form of RNA – could have replicated itself.

Our understanding of life’s early history is limited but a popular theory for the earliest stages of life on Earth is that it was founded on strands of RNA, a chemical cousin of DNA. Like DNA, RNA strands can carry genetic information using a code of four bases, but RNA strands can also fold up into enzymes, called ribozymes. The ribozymes form active three-dimensional structures that can carry out chemical reactions underpinning life – perhaps even replication of RNA. To test this theory of an ‘RNA world’, scientists have been trying to recreate a self-replicating RNA in the laboratory. So far however, scientists have only developed ribozymes that could copy straight strands of RNA – when the RNA was folded it blocked the ribozyme from copying it. This prevented ribozymes, which need to be folded to work, from copying themselves – they could not self-replicate.

James Attwater, helped by others in Philipp’s group, has now engineered a ribozyme that can copy folded RNA strands, letting it for the first time make a copy of itself. The big difference came from the building blocks it used. Normally when copying RNA, ribozymes would add single bases (C, G, A or U) one at a time, however the scientists hypothesised that using different building blocks – multiple bases joined together – might overcome the problem of folded ribozymes blocking their own replication. The new, optimal ribozyme uses three bases joined together as a ‘triplet’ – the triplets enable the ribozyme to copy folded RNA strands because the triplets bind more strongly and cause them to unravel, allowing replication to occur. Conducting experiments at -7°C, which concentrates the RNA molecules in a liquid brine in tiny gaps between the ice crystals that form when the water freezes (and which also stabilises the RNA enzymes), James isolated ribozymes that could copy short stretches of folded RNA. He then engineered the best version to be able to copy pieces of itself, and assemble them together into new full synthetic copies. Moreover, triplets seemed to hit a ‘sweet spot’ of building block size, as they maintained accuracy of RNA replication, which could be compromised with longer building blocks.

This research may take us a step closer to a better understanding of one of the greatest mysteries in chemistry and biology: the origin of life. The discoveries in this work make the idea that life was founded on self-replicating RNAs much more plausible, and studying the mechanisms used by this artificial ribozyme may tell us a lot about how ribozymes could have behaved on the early Earth. Knowing how life can operate at the molecular level might also help to guide the search for life on other planets. This new synthetic biology of triplet based RNA replication might also have biotechnological applications, such as adding specific chemical modifications to polymers.

This work was funded by the MRC.

Further references

Paper in eLife
Philipp’s group page
MRC Press Release