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Experimental evolution of an RNA world

How did the first life on Earth arise? We may never know for sure, but can we at least demonstrate one or more mechanisms that could have led to life as we know it? Not yet, but this week’s paper seems like a significant step towards that goal. “Self-sustained replication of an RNA enzyme” was published in Science by Tracey Lincoln and Gerald Joyce.

Most species have protein-based enzymes (running the biochemical reactions needed for growth and reproduction) and DNA-based heredity (passing genetic information to the next generation), with RNA serving various other functions. Under the “RNA-world” hypothesis, however, RNA molecules once served both as enzymes and for heredity. Some viruses use RNA as their hereditary material and some RNA molecules still act as enzymes, with a key role in protein synthesis, for example.

Can we recreate the early RNA world in a laboratory? What is the simplest system that could evolve by natural selection, eventually leading to something that would be universally recognized as alive?

1) The system would need to be able to reproduce using materials available in its environment.
2) The system would need to be open-ended, in the sense that a very large number of variants are possible, not just a few.
3) Copying accuracy would need to be good, but not 100%, so that there is some possibility of evolutionary change.
4) The occasional error would need to be propagated in copies, i.e., in successive generations.
5) Different versions (i.e., with or without a particular error) would have to reproduce at different rates.

An RNA molecule that could copy itself or – this is important – any variant of itself that arose through past copying errors, might meet these requirements. Another option would be two or more RNA molecules that have the collective ability to reproduce. This was achieved a few years ago, using a pair of RNA enzymes that copied each other, but the rate of reproduction was low. There are at least three ways that the rate of reproduction could have been improved: a) let the system run for a few years or millennia and see what evolves, b) intelligent design of faster RNA enzymes, or c) directed evolution. Nobody knows how to design faster RNA enzymes from first principles – maybe we aren’t intelligent enough – but the Joyce lab has lots of expertise in creating conditions under which populations of molecules evolve desired characteristics, in ways analogous to natural selection.

They introduced random changes to the RNA enzymes and selected for faster reaction time, discarding those that failed to react within a specified amount of time. After six cycles of mutation and selection, they analyzed the faster enzymes that resulted. All of them had a “G-U wobble pair.” Usually, G pairs with C and A with U (the RNA equivalent of the DNA “letter” T), but G can pair with U. G-U pairs have previously been found to be important to the activity of some naturally occurring RNA enzymes.

Not being inclined to argue with evolution’s wisdom, Lincoln and Joyce “installed” the G-U pair in the two mutually copying enzymes (and in the RNA pieces the enzymes join to copy each other). That worked great: the evolution-inspired enzyme pair multiplied 25-fold in five hours (faster than many bacteria) before running out of materials. Like bacteria, they resume growth if a drop is transferred to a new tube with fresh materials. So this system clearly meets criterion #1 above, although it’s worth noting that the materials required for reproduction would not necessarily have been available to early RNA reproducers on Earth.

What about the other criteria? The RNA molecules are large enough to meet criterion #2, but can variants also reproduce themselves? They showed that some variants can, at least, making 12 different pairs of RNA enzymes that could work together to copy each other. Criterion #3 and 4 were also met: each enzyme pair usually copied itself, but sometimes one partner joined together the wrong pieces, creating a “recombinant” enzyme. Because the choice of which subunits to join depending on pairing between RNA bases, these recombinants made recombinant partners, which then made accurate copies of the recombinants.

Finally, they met criterion #5, demonstrating the differences in reproductive success among different versions of the enzymes, as required for evolution by natural selection. They started with the 12 pairs of mutually copying RNA enzymes and let this “population” evolve. After repeated transfers to tubes with fresh materials, the population was dominated by three pairs of enzymes. Interestingly, all three were recombinants. One of the original 12 pairs was still fastest if only its own subunits were present as materials to join, but a particular recombinant did best in a more chemically diverse environment.

The materials provided by the experimenters were relatively complex: RNA molecules half the size of the RNA enzymes. There was no attempt in this paper to explain how such complex molecules arose. Instead, they are looking forward to investigating stages of evolution slightly more recent than mere self-replication from ready-made materials, such as evolution of an RNA enzyme that would help lipids for a “cell membrane” to enclose a population of reproducing RNA. I look forward to this next paper. This one closes:

“Ultimately, the system should provide open-ended opportunities for discovering novel function, something that probably has not occurred on Earth since the time of the RNA world but presents and increasingly tangible research opportunity.”

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