Synthetic biologists have made a lot of progress in developing “orthogonal” genetic systems. DNA and RNA have been made with synthetic base pairs, and cells have been coaxed to produce proteins with synthetic amino acids. This expands the genetic code beyond the standard letters used by life on Earth, which could potentially open up new functions.
It also helps us understand more about life itself. Is there some deep reason why life uses only so many base pairs and amino acids? Or did life on Earth land on this genetic system by luck? Just how alien can life really be?
The Ribosome Problem
Despite the progress in exploring alternate genetic codes, one major sticking point has been the ribosome. All life on Earth uses a two-part ribosome to translate mRNA into proteins. We can change the small subunit to translate mRNAs with a different start signal, but to really expand the range of amino acids life can use, we would have to change the large subunit.
This is much more difficult because the two subunits are not monogamous; after making a baby protein they split apart and find another partner. So if we tried to evolve new large subunits inside cells, they would have flings with native small subunits, they’d either get stuck or make broken protein babies, and the host cell would die.
RiboT: A Single-Subunit Ribosome
To get around this road block, Cedric Orelle and Erik Carlson, working in the labs of Michael Jewett and Alexander Manklin in Chicago, made RiboT – life’s first known single-subunit ribosome. In a clever bit of rearranging, they connected the two main rRNAs with short tethers (hence the T), as seen to the left. Amazingly, this unprecedented-in-the-history-of-life bio-machine was able to fully support the growth of E. coli (albeit, at half speed).
RiboT pities the fool who uses bipartite protein translation machines.
As proof of principle, the team also made an orthogonal RiboT that recognized an alternate ribosome binding site. Even more intriguingly, they mutated the large subunit half of RiboT to read through an RNA sequence that stalls normal ribosomes, even though the mutation would be dominantly lethal in untethered ribosomes.
This work is cool just for showing, once again, that fundamental designs not found anywhere in nature can nevertheless support life. But it also opens up brand new possibilities. For example, we can now imagine cells with two completely orthogonal genetic codes operating side by side. The standard system would be left alone to keep a cell alive while an “alien” code could produce enzymes with synthetic amino acids too big or unwieldy for the standard ribosome.
I pity the fool who doesn’t check out this paper, in Nature, August 2015