Life probably began with a molecule, or set of molecules, that could make copies of themselves. Now we have taken a big step towards creating such molecules ourselves.
Over the last four decades, biologists have made lots of progress towards creating self-replicating molecules in the lab. However, their efforts have been thwarted by an apparent paradox.
Now and his colleagues at the MRC Laboratory of Molecular Biology in Cambridge, UK say they have found the answer.
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There are many reasons to think that the first self-replicating molecule was made of RNA, which still plays a big part in living cells today. RNA can store information in its sequence, just like DNA. It can also fold into complex shapes and act as an enzyme, driving important chemical reactions.
The RNA paradox
Inspired by this idea, many groups have been creating RNA enzymes that can make copies of other RNA molecules.
The problem is that these RNA enzymes can only copy RNA molecules that have not folded into complex shapes, says Holliger. 鈥淭he moment the RNA molecule folds, the enzyme gets stuck.鈥�
Therein lies the paradox. RNA can only act as an enzyme if it folds itself, but RNA enzymes cannot replicate a folded RNA 鈥� so it seems no RNA enzyme can replicate itself.
Holliger鈥檚 solution is to change the building blocks the RNA enzyme uses when building a new RNA.
Each RNA is a chain of smaller molecules called nucleotides. In living cells today, RNA enzymes build new RNAs by adding one nucleotide at a time.
But Holliger鈥檚 new RNA enzyme builds RNA out of 鈥渢rinucleotides鈥�: slightly larger molecules, which are simply three nucleotides already joined together. He calls his enzyme 鈥渢5+1鈥�.
When the trinucleotides bind to complementary sequences on a folded RNA molecule, they open up the structure, says Holliger. The t5+1 can then join up the trinucleotides in the right sequence.
In need of coddling
While t5+1 can make copies of itself, it needs help. 鈥淚t still needs a lot of tender loving care in the lab to do that,鈥� says Holliger.
For starters, t5+1 was given only trinucleotides to use as building blocks, rather than the mix of nucleotides likely to be found in nature.
鈥淭rimers [trinucleotides] are plausible products of prebiotic chemistry,鈥� says , who is also at the MRC Laboratory of Molecular Biology but was not part of the team. 鈥淗owever, pure trimers are unlikely.鈥�
What鈥檚 more, once t5+1 had made segments of its own sequence, the team purified the segments and added them back in high concentrations to complete the synthesis.
So there is still a long way to go to create a self-replicator that works by itself. 鈥淗owever, it鈥檚 an important step towards that goal,鈥� Holliger says.
Another problem with t5+1 is that it is a big molecule, made of two separate pieces that are 135 and 153 nucleotides long respectively. 鈥淭he chances of finding it by chance are incredibly slim and this problem isn鈥檛 easily circumvented, even if the ribozyme can be assembled from shorter pieces,鈥� says Sutherland.
Born in ice?
Holliger鈥檚 team carried out the reactions in icy water. However, he says they could have occurred in a range of environments on the early Earth, from icy areas on land to the cool undersea hydrothermal vents known as alkaline vents. Some biologists think alkaline vents are the most likely place for life to have evolved.
Even if biologists do finally create a molecule capable of replicating itself without help, there will be no way to prove that this is how life began. All we can do is map out the most plausible path, Holliger says. Such efforts will also help reveal whether it is easy or hard for life to emerge in general, and thus how likely we are to find life on other planets.
The fact that the t5+1 enzyme assembles RNAs from trinucleotides is eerily similar to the way information is encoded in DNA and RNA today. Every 鈥渨ord鈥� of the genetic code contains three nucleotide 鈥渓etters鈥�.
However, this may be a coincidence. Holliger says there is no reason to think there is any connection.
eLife
