New system shows the earliest life could cooperate despite “cheaters”

Physics is filled with papers where the authors don't actually do anything—at least not anything empirical. Instead, they explore the math behind a topic and try to gain new theoretical insights, leaving it to someone else to find out whether their insights are actually reflected in the behavior of the real world.

But physics doesn't have a monopoly on this, and there have been plenty of papers in biology that are filled with math and explore how a theoretical population would behave. One area where that's had a big impact on thinking has been in studying the origin of life, where researchers have been struggling to understand how a set of simple self-copying molecules could make their way towards something that looks more like a cell. Now, two Japanese researchers have taken some of these theoretical ideas and shown they can hold in an actual biochemical system.

Overcoming selfishness

We'll go through the theoretical background first. The work focuses on a challenge faced by the Earth's first self-replicating RNA molecules, namely that they probably weren't that great at self-replicating. Modern cells have multiple systems composed of collections of proteins that identify and repair errors in DNA. The earliest self-replicating molecules had none of that, and probably picked up lots of errors that could disable them. This problem gets worse as the self-replicating molecule grows in complexity, since a longer molecule would mean an increased chance for things to go wrong.

This could potentially act as a barrier to adding any new functions to these molecules, since new functions would involve additional RNA, increasing the chance that a mutation somewhere would make the RNA inviable.

Theoretical biologists solve this issue by proposing a division of labor. Rather than one big molecule with lots of functions, they suggest early life had a large population of RNA molecules, with several copies of each type. This means that damage to any one molecule would still leave others of that type functioning. And, by having multiple types of molecules, you could allow each type to evolve new or more refined functions separately.

But that creates a new problem: selfish RNA. An RNA that's been inactivated by a mutation can still be copied, so it's possible for "cheaters" to evolve—RNAs that don't perform a useful function, but still use up resources as they're being copied. Cheaters, in mathematical simulations, eventually reach large enough portions of a population of self-replicating molecules that the population as a whole shuts down and stops replicating.

But if simulations identified the problem, they've also helped us identify a potential solution: cells. By dividing up a large population of self-replicating molecules, cells increase the odds that that some of the small, divided populations will replicate without any disabling mutations. Because each cell is competing against all the others, the ones that are able to go on replicating will eventually outcompete their peers.

Out of paper

All of this looks reasonable on paper. But does any of it work in the real world? Ryo Mizuuchi and Norikazu Ichihashi of Osaka University devised a system to find out. It contains all the proteins used by bacteria to translate an RNA into protein. While the first cells didn't have anything like this elaborate collection of proteins, this is meant to be a model system for testing ideas, and the proteins make things simpler. These proteins were placed into "cells" formed by hitting a mixture of fat and water with high-energy sound, which causes the fats to create small spheres around a bit of the water/protein mix.

The system was then supplied with two RNAs. One encoded an enzyme that could copy the RNA molecules. The second encoded an enzyme that prepared individual RNA bases for use by the first. If both RNAs were present, the system would translate them into proteins that, combined, would ensure the RNAs that encoded them were replicated. After allowing time for the replication to take place, the "cells" were provided with more fat and raw materials, and hit with another blast of sound. This caused the replicated molecules to spread out and start afresh.

So, while the system's not fully self-replicating—lots of stuff needs to be supplied—the two RNA molecules could ensure their own duplication. That allowed Mizuuchi and Ichihashi to follow them across multiple generation of duplication, tracking their population dynamics and evolution.

And, to a large extent, the system showed that the theoretical ideas held up well to the real world (to the extent that this model two-RNA system reflects something "real").

First off, Mizuuchi and Ichihashi found that the initial conditions really matter. If there's a very low starting number of RNAs in each cell, the blast of sound that's meant to refresh the conditions would simply start diluting the functional RNAs out. The population would quickly grind to a halt. Too large a starting number, and cheaters would quickly appear in every cell, which would gradually grind to a halt. This took a bit longer, but was equally fatal.

At a point in between the two, however, the average number of RNAs per cell would stay within a narrow range for generation after generation. In other words, it confirmed some theoretical ideas and gave the researchers a chance to explore the evolution of cheaters.

Selfish but cooperative

Even in a population where the number of RNAs is in the "just right" range, cheaters do evolve. But they only involve a small enough number of cells that the population of cells chugs on. And, in doing so, the RNAs pick up changes and evolve.

Mizuuchi and Ichihashi found that this evolution is a bit complex. The mutations the RNAs pick up are selfish, in that they get copied more efficiently than the starting RNAs. Each evolved RNA also find ways to hog the resources, cutting down the replication of their original partner when tested together. This selfish behavior means that the pair of RNAs (one evolved, one original) tend to replicate more slowly than the original pair.

But when two RNAs that have evolved are paired, the replication rate ended up higher than any other combination. It seems that each RNA evolved to adapt to its partner's selfishness, keeping the system duplicating at a rapid pace.

This work has limited direct application to the origin of life, as it's thought that proteins were either small and limited or not around at all. But the system Mizuuchi and Ichihashi devised is sufficient to test some of the theoretical ideas that have been suggested, which makes it a valuable tool for understanding which ideas are worth pursuing more vigorously.

Nature Ecology & Evolution, 2018. DOI: 10.1038/s41559-018-0650-z  (About DOIs).