A network of molecules, building each other at the dawn of life

By Ed Yong | October 17, 2012 1:00 pm

Every time one of the cells in your body divides, it has to double its quota of DNA so that each daughter cell gets a complete set. DNA is a replicator—a molecule that can be accurately duplicated, admittedly with some help from proteins. DNA has been doing this for billions of years, well before there were humans, before animals existed, and probably before the first cells evolved.

But what came before DNA? Probably RNA, a related molecule. Certain types of RNA can store genetic information, just like DNA. And much like proteins, they can fold into three-dimensional shapes to speed up chemical reactions, among other functions—these are called ribozymes.

The dominant theory is that an “RNA world” preceded the origin of life. It’s possible that the Earth’s first true replicators were RNA molecules that could fold up to speed up their own replication. They copied themselves. They did so imperfectly, creating daughter molecules with slightly different sequences. Some of them copied themselves more efficiently, and left more descendants than their peers. Gradually, the entire population evolved towards ever more efficient replication.

But there’s a problem with this story. The RNA molecule we’re talking about would have been long and folded into a complex ribozyme. But the ribozymes that scientists can make today are simple, and made from very short pieces of RNA. You can imagine a simple molecule gradually growing and evolving into a more complex one, but that idea has problems too. Mathematical models predict that this burgeoning replicator would be unable to copy itself accurately enough, and would start accumulating errors. After a while, it would face an “error catastrophe”, where the build-up of mistakes crippled it.

But what if there wasn’t just one RNA replicator copying itself? What if, instead, there was a whole network of them? This idea was originally floated in 1971 by Nobel-winning chemist Manfred Eigen. “He came to the conclusion that an individual replicator couldn’t persist for very long, and came up with the idea of a hypercycle,” says Niles Lehman from Portland State University. That is, molecule A helps B to copy itself. B helps C, C helps D and so on, eventually looping back to A.

Eigen predicted the existence of hypercycles using mathematics. Now, Lehman has created something similar in a test tube. It’s a contrived set-up, and it doesn’t confirm that such networks were genuinely involved in the origin of life, but it shows that they can form, and that they become more complex over time. As James Attwater and Philipp Holliger from the University of Cambridge write in an accompanying piece, the study makes “a persuasive case for the benefits of cooperation even at this nascent stage of life. The first genes may not have been so selfish, after all.”

In an earlier study, Lehman showed that a bacterium called Azoarcus has a ribozyme that can be broken into separate fragments, which can then reassemble themselves. Now, he has found that these fragments can create a network that looks like one of Eigen’s hypercycles.

Lehman’s student Nilesh Vaidya tweaked the original ribozyme to create three versions that differed by a single letter. He then broke each one in two. Each pair of fragments can assemble into the full thing, but very inefficiently. They work better as a network. Vaidya specifically designed the ribozymes so that when the first pair of halves come together, they speed up the assembly of the second pair. This second complete ribozyme speeds up the assembly of the third pair, and this third ribozyme speeds up the union of the first pair.

When he mixed all six fragments together, that’s exactly happened. They assembled each other into full ribozymes up to 6 times faster than each individual pair could do on their own, and producing 125 times more of the finished products. The “cooperative” cycles, where the pairs assembled each other beat the “selfish” ones, where they assembled themselves.

These six fragments were engineered very precisely, and early pools of RNA were hardly that specific. To show that networks can form out of more chaos, the team created pools of many different fragments, which could assemble into 48 variations of the Azoarcus ribozyme. “We threw them all in a test tube and let them go,” says Lehman.

By the end of the experiment, the team had a test tube full of millions of ribozymes, including all 48 possible versions. Some of them could only have been produced by networks, and they far outnumbered those that could have assembled themselves. The team found that over time, the networks became more complicated. At first, the fragments team up as simple pairs, but these are later supplanted by cycles of three members, and eventually huge networks involving almost every fragment. There was a succession from “selfish replicators” to “cooperative systems”.

But Eors Szathmary, an evolutionary biologist from Eötvös Loránd University in Hungary, says that the paper is “conceptually seriously flawed”. He takes issue with Lehman’s claims that the RNA molecules are cooperating with one another. In a truly cooperative system, one ribozyme would speed up the replication of another. Through the action of the first, you’d end up with two copies of the other. That’s not what’s happening in Lehman’s setup. His molecules are speeding up each other’s formation. There are no new copies; just fused versions of the originals. “It is meaningless to speak about the cooperation of replicators,” Szathmary says.

Lehman concedes that there is a distinction, but he sees his assembling fragments as a forerunner to the replicators we are familiar with today – where RNA molecules are strung together bit by bit from their component “letters”. His argument is that such a self-building molecule could arise from the increasingly complex networks that he saw in his experiment.

Nick Lane, a biochemist from University College London, says it’s “impressive” that RNA networks can arise in this way”, but he is unconvinced that such networks could actually have formed on our primordial planet, or stuck around long enough to be useful.

The problem is energy. It takes a lot of it to make RNA, even today with the help of proteins. Lane thinks that the networks would not have been able to reproduce by catalysing themselves. They would have needed help from minerals and other chemicals. “This inevitably makes the RNA world somewhat ‘dirty’,” he says. “I imagine that such dirty catalysis could play havoc with nice tidy RNA networks. My overall sense is that this is interesting but probably too clean and tidy to be really meaningful in any realistic early earth setting.”

Reference: Vaidya, Manapat, Chen, Brunet, Hayden & Lehman. 2012. Spontaneous network formation among cooperative RNA replicators. Nature http://dx.doi.org/10.1038/nature11549

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CATEGORIZED UNDER: Molecular biology

Comments (7)

  1. Stefan

    “‘The first genes may not have been so selfish, after all.’”

    That’s an unfortunate misunderstanding of Selfish Gene Theory. Cooperation does not contradict the theory; it is consistent with it.

    Otherwise, fascinating article. I always enjoy reading your work.

  2. “When he mixed all six fragments together, that’s exactly happened.” Did you out a word?

  3. davem

    How come long strings of RNA eventually fail, but DNA doesn’t? Doesn’t DNA split into RNA during replication?

  4. Claudiu Bandea

    According to the ‘RNA world’ hypothesis, which is based on the findings that RNA molecules can serve both as carriers of genetic information and as enzymes, life started with self-replicating RNA molecules. Very little is known about the early synthesis of the ribo-nucleotide monomers and the synthesis of the first RNA molecules, so the scenarios about the ‘RNA world’ usually start with ready-made, self-replicating RNA molecules.

    It is refreshing to see that a few decades after the ‘RNA world’ hypothesis was advanced, we are ready to update it by suggesting that the participating RNA molecules were rather small and they interacted with each other, apparently in a cooperative mode.

    For those who want to see where this hypothesis might be a few decades from now, I suggest an alternative model on the origin of life on Earth ( http://precedings.nature.com/documents/3888/version/1) in which the RNA molecules were even smaller! As a matter of fact, they were so small that initially they were represented by a single ribonucleotide!

  5. amphiox

    How come long strings of RNA eventually fail, but DNA doesn’t?

    RNA is less stable than DNA, and therefore mutates faster, and the longer the strand the more mutations it will accumulate. If the mutation rate is too high, then harmful mutations accumulate faster than natural selection can weed them out, and your population of replicators suffers an error catastrophe and falls apart. Thus there is a maximum length which an RNA genome can be before it falls prey to error catastrophe (the largest RNA viruses approach this limit), and there is a maximum length which a DNA genome can also be, but that maximum length for DNA is billions and billions of base pairs, and as far as we currently know, no organism on earth has approached it.

    Doesn’t DNA split into RNA during replication?

    No. Double stranded DNA splits into single stranded DNA, each strand then becomes the template on which another strand is assembled, replicating the DNA.

    DNA is transcribed into RNA which is then translated into proteins. But this is protein synthesis (gene expression) but not DNA replication.

  6. What’s missing in this model is why the molecules would replicate to start with. What natural process would tend to get that started? What’s in it for the molecules that start doing it? Sure, once they start, I can see that the ones that do it best and most often will tend to be the dominant ones in the primordial soup, but what gets the ball rolling?

  7. Brian the Tall

    @amphiox (and by extension davem)

    “RNA is less stable than DNA, and therefore mutates faster, and the longer the strand the more mutations it will accumulate”

    I have never heard this as an explanation like this… and I’m not sure it’s accurate. I will fully admit that my knowledge of mutation isn’t encyclopedic, but a) RNA has a higher thermal stability but lower chemical stability; how does instability lead to high mutation rate? Mutation rate is dependent primarily on the accuracy of the replicator, and secondarily on mechanisms of damage, repair, modification, etc, yes? Setting aside stability, I recognize that RNA viruses have high(er) mutation rates, but I understand that as an artifact of viral evolution, and then only for certain types of replication. The T7 bacteriophage RNA polymerase has a low error rate.

    Ed’s article does discuss messy replicators, but I don’t think that is the question being asked or answered?

    Rather: RNA is a much more flexible molecule than DNA. DNA is very rigid, forming only a few of the possible types of bonds, and sticking to certain angles. This means that a single mutation in DNA has very little effect on the overall structure. In contrast, RNA can form many, many more structures and fold into complex shapes because it can make these other bonds; this is actually *why* RNA is so cool and capable of acting like an enzyme… but it also means a single change can have a VERY big (and potentially deleterious) effect on the molecule. What this means in context is that an RNA can *tolerate* many fewer mutations than RNA before it’s structure is compromised.

    If you’d like to get a very first hand demonstration of this, I strongly recommend trying out the RNA folding game eteRNA, where you will quickly see how a single base-pair change can radically alter the whole structure.

    For a much, MUCH more in depth explanation of nucleotide folding, see Geometric nomenclature and classification of RNA base pairs by Leontis and Westhof: http://www.ncbi.nlm.nih.gov/pubmed/11345429

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