Science News

New letters in the DNA alphabet

Thu, 8th May 2014

Chris Smith

A new pair of artificial DNA letters have been engineered into bacteria by US scientists.

The discovery of the structure of DNA in the 1950s by biochemical pioneers James Watson and Francis Crick revealed that life's recipe book is written DNA new basesusing an alphabet of 4 letters, A, C, T and G.

Now a team in the US have created two new letters, catchily called d5SICS and dNAM, and persuaded E. coli bacteria to incorporate and use them.

The synthetic nucleotides were written into a small circle of DNA called a plasmid, alongside a gene coding for resistance to an antibiotic. So long as the bugs kept the synthetic DNA letters in the plasmid, the antibiotic resistance gene would remain active, enabling the bacteria to grow despite the antibiotic being present.

The artificial DNA letters were added by the scientists to the bacterial culture medium. To enable the bugs to pick them up, Scripps Institute scientist Floyd Romesburg and his colleagues also added a transporter gene, called NTT, borrowed from algae, to move them inside the cells.

Thus equipped, and so long as the scientists maintained the supply of the new nucleotides in the culture media, the bacteria multiplied, producing and sharing copies of the plasmid containing the new genetic letters.

Introducing new genetic letters like this opens up a whole new vista of gene manipulation. New genetic codes can be written so that new synthetic chemicals can be used by cells and assembled into complex compounds and specialised switches can be engineered into DNA to control gene activity.

But, as commentators Ross Thyer and Jared Ellefson ask in a News and Views article in Nature, where the research is published, given the ability to expand the genetic alphabet in this way, one must ask why life settled in the first place on just the four genetic letters seen naturally?


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As I understand it, synthetic biologists have added two new letters in the DNA alphabet.
These two new letters are copied across into new DNA strands as the cell divides.

I expect the next challenges are:

To ensure there are enough of these two new letters "floating around" in the cell nucleus while the DNA divides...

Which may involve new/imported genetic pathways to sythesise these new letters.

Ensuring the new letters are transcribed into RNA.

And reprogramming the ribosomes so that when it sees these new letters, it selects a new amino acid to build into the protein it is assembling

Which may involve new genetic pathways to synthesise the new amino acid (and have it floating around near the ribosomes in the right quantities)

This is a significant proof of concept, but it opens up a web of additional challenges which must be solved before it can be used for real benefit (apart from "signing" genetically engineered DNA).

It does mean that any new cells (or animals) using these new letters would have trouble breeding with others that are unable to transcribe these new letters. evan_au, Fri, 16th May 2014

I listened to a story about this on the CBC. It really made me wonder if there isn't some sticking point - why wouldn't nature have already come up with it with billions of years of evolution? Why aren't their different types of genetic material? cheryl j, Thu, 29th May 2014

There are 4 base nucleotides in DNA (represented by the letters C, A, T, G), and a triplet of these is a codon (AAA - TTT). With this structure you can make 64 different combinations: 4x4x4=64. This is more than enough to select the 20-22 amino acids used in bacteria, plants, animals and mitochondria, plus a few codons used for "punctuation" (eg a "stop" symbol)*.

There are already enough different codons to select perhaps 60 amino acids, but life on Earth is not using 60 amino acids, and several codons actually code for the same amino acid. If there were 60 amino acids in use, the cell would need to generate significant quantities of 60 amino acids, rather than the current 20, to use the extra combinations. It's not clear what benefits these extra proteins would bring to a protein or enzyme.

With 2 extra letters, there are now 6 base nucleotides in this artificial DNA, and a triplet of these allows 216 different combinations: 6x6x6=216. But this means that a cell must now have around 200 amino-acid-carrying Transfer RNAs floating around near the ribosome, instead of the current 60 or so. The ribosome must also "try" a lot more tRNAs before it finds the "right" one, slowing down protein synthesis.

So perhaps it is a tradeoff between flexibility and speed?

Some people have suggested that with more combinations, DNA could include an error-correcting code to cope with mutations - but this introduces frightful complexity in to the ribosome. It also does not deal with currently-uncorrectable errors like double-stranded breaks. Plus, radiodurans seems to survive quite well with existing DNA repair mechanisms.

* There have been some recent suggestions that the different triplets coding for the same amino acid may help with protein construction: If there are multiple tRNAs which select the same amino acid, but the tRNAs had different concentration near the ribosome, then there would be a "fast" and a "slow" version of the same amino acid. Placing "pauses" in the production of proteins may help with folding of the protein, or with regulating the production rate. evan_au, Thu, 29th May 2014

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