Semi-synthetic bug extends ‘life's alphabet’

By Jonathan Amos
Science correspondent, BBC News

image copyrightSynthorx
image caption"All life that we know is encoded within four letters that form two base pairs"

Scientists have produced a semi-synthetic version of a bacterium that has an extended genetic code.

All Earth's lifeforms use four chemical units, or bases, arranged in pairs within DNA, to drive their biology.

The modified E. coli bug produced at The Scripps Research Institute in California incorporates two more bases that were wholly designed in the lab.

The team tells Nature magazine that its altered bacterium could be used to make a range of novel drugs and materials.

Prof Floyd Romesberg and colleagues have been working towards this study result since the 1990s.

They had previously shown how the new bases - known as d5SICS and dNaM, or X and Y for simplicity - could be stably incorporated as a pair into the DNA molecule in vitro, in the "test tube".

The latest advance sees them introduce this supplemented DNA into a living organism.

What is more, the modified E. coli bug is able to copy the extended DNA and pass it down the generations.

'New complexity'

At the moment, the introduced base pair plays no active role in the bacterium's biology. But Prof Romesberg's team plans to change that in the future by giving X and Y some function.

In normal DNA, it is the sequence of the natural base chemicals - which pair adenine (A) with thymine (T); and cytosine(C) with guanine (G) - that encodes the genes.

And it is the genes that hold the recipes for cells to make chains of amino acids.

These chains are then folded into the protein molecules that build and maintain the organism - be that an animal, a plant, or even just a simple bacterium.

With an extended DNA "alphabet", it should, in principle, be possible to encode proteins from new, unnatural amino acids.

This would be a route to making novel therapeutics, plastics and other materials.

Engineered bacteria are already used to churn out a host of substances on an industrial scale, such as insulin for diabetics.

But the type of synthetic biology pursued by the Scripps team offers the promise of manufacturing more complex chemicals - and more precisely - that are beyond current technologies.

"All life that we know is encoded within four letters that form two base pairs," Prof Romesberg told BBC Radio 4's Inside Science programme.

"All the diversity, from the simplest bacterial cell up to the complexity of the human - all that diversity is encoded in a very simple genetic alphabet. And if you peer back through evolution, as far back as we can see, that's always been the way it was; life has always been encoded in two base pairs. And now we have a third."

'Fail-safe system'

The scientists say the system they have produced is very safe in that its semi-synthetic bacterium cannot maintain its extended DNA unless it is kept in very particular conditions with a constant supply of their special triphosphate bases.

"If you spilled the flask on the ground and got them on your shoes and walked outside, the organisms would be out in the environment, but they would not have the triphosphates provided to them any longer and they wouldn't be able to replicate DNA with the unnatural base pair," Prof Romesberg explained.

"As a result, the semi-synthetic component of their genome would simply revert to natural. That's a fail-safe against escape into nature."

Prof Paul Freemont from Imperial College London said the research was an exciting step, helping to move synthetic biology principles from the test tube into living organisms.

And he also applauded the Scripps team's approach to safety.

"What people are concerned about, and quite rightly so, is that if we are redesigning biological systems - what's the chance of those redesigns getting taken up by natural systems? Clearly, that's a worry for the whole field. And what this is potentially allowing us to do is to think about designing DNA as a synthetic code that would be very unlikely to be taken up by, or interface with, normal living biological systems," he told the BBC. and follow me on Twitter: @BBCAmos

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