In a breakthrough, scientists have created the first stable semi-synthetic organism – a single-celled bacterium – that may play important roles in drug discovery and other applications. Life’s genetic code has only ever contained four natural bases. These bases pair up to form two base pairs – the rungs of the DNA ladder – and they have simply been rearranged to create all life as we know it, from bacteria to humans.
Building on earlier research in which they synthesised a DNA base pair, scientists at The Scripps Research Institute (TSRI) in the US created a new bacterium that uses the four natural bases (called A, T, C and G), which every living organism possesses, but that also holds as a pair two synthetic bases called X and Y in its genetic code.
Researchers have now shown that the single-celled organism can hold on to the synthetic base pair as it divides.
“We’ve made this semi-synthetic organism more life-like,” said Floyd Romesberg, professor at TSRI.
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Researchers said the work could be used to create new functions for single-celled organisms that play important roles in drug discovery and much more.
They had earlier showed that E coli bacteria could hold a synthetic base pair in their genetic code. However, they could not keep the base pair in their code indefinitely as they divided.
The X and Y base pair was dropped over time, limiting the ways the organism could use the additional information possessed in their DNA.
“If the semi-synthetic organism is going to really be an organism, it has to be able to stably maintain that information,” said Romesberg.
Researchers developed the means for the single-celled organism to retain the artificial base pair.
They optimised a tool called a nucleotide transporter, which brings the materials necessary for the unnatural base pair to be copied across the cell membrane.
The researchers discovered a modification to the transporter that that made it much easier for the organism to grow and divide while holding on to X and Y.
They then optimised their previous version of Y, creating a chemically different molecule that can be better recognised by the enzymes that synthesise DNA molecules during DNA replication. This made it easier for cells to copy the synthetic base pair.
Researchers then used gene editing tool CRISPR-Cas9 to design their organism to see a genetic sequence without X and Y as a foreign invader.
A cell that dropped X and Y would be marked for destruction, leaving the scientists with an organism that could hold on to the new bases.
Their semi-synthetic organism was thus able to keep X and Y in its genome after dividing 60 times, leading the researchers to believe it can hold on to the base pair indefinitely.
The research was published in the journal PNAS.