Scientists, in a world first, have announced that they have added two letters to the genetic code that forms the chemical blueprint for life.
They said they had modified a bacterium so that it incorporated and replicated two DNA ingredients that are not found in nature.
The experiment, they said, was designed to show that the alphabet for DNA, which has existed for hundreds of millions of years, can be expanded through human intervention.
This is the first step on a longer road that could lead to revolutionary drugs and innovations in nanotechnology, they said.
DNA - deoxyribonucleic acid - is the set of hereditary instructions for making and sustaining life.
A long molecule in the heart of a cell, it comprises a double-stranded helix in the form of a twisted zipper. Its "teeth" are millions of so-called base pairs of letters, meaning chemicals that match up with each other.
Adenine teams up with thymine to creating the A-T base pair, while cytosine links up with guanine to make the C-G base pair.
The new work, reported in the scientific journal Nature, adds a third, man-made pair to the helix.
However, the inclusions only survive with external help and are removed from the genome once this support is removed.
"Life on Earth in all its diversity is encoded by only two pairs of DNA bases, A-T and C-G," said Floyd Romesberg at Scripps Research Institute at La Jolla, California.
"What we've made is an organism that stably contains those two plus a third, unnatural pair of bases."
- New pair -
Researchers have worked for nearly two decades on finding new molecules to serve as new DNA bases, the goal being to create proteins that have never existed before.
But the search faces many challenges.
The new base pair would have to fit snugly alongside natural bases in the DNA code and not disrupt replication or transcription, the first step in creating a protein.
During these processes, the DNA "zipper" is opened, segments of it are copied to provide a template, and the zipper then closes up again.
Another problem is to make sure that the inserted base pairs are not attacked and removed by the cell's DNA repair mechanism.
In the new study, the researchers made a circular piece of DNA called a plasmid that contained the natural A-T and C-G combinations, as well as an unnatural base pair, called d5SICs and dNaM.
The plasmid was then inserted into a common bacterium, Escherichia coli.
But then another problem surfaced: as the base pair does not exist in nature, the molecular building blocks to replicate them in the cell are also absent.
The researchers found the answer by adding these building blocks to the solution in which the E. coli was suspended.
They also genetically engineered the E. coli so that it exuded an algae protein that, like a beast of burden, hauled these blocks across the cell membrane.
The new-fangled plasmid replicated smoothly and with very few flaws - something that is essential for maintaining healthy DNA - and the unnatural base pairs were not weeded out of the code.
Researcher Denis Malyshev stressed that the process was controlled by two mechanisms, the building blocks in the fluid and the protein transporter.
Without them, the new base pairs left the DNA code, leaving the bacterium to function happily on its A-T C-G combination - in other words, there could be no runaway replication of unnatural code.
The next step will be to get the new letters into RNA (ribonucleic acid), a slimmed-down derivative of DNA that helps to crank out proteins.
In a commentary also carried by Nature, biologists Ross Thyer and Jared Ellefson at the University of Texas at Austin warned that scientists had to address public fears about tampering with DNA or creating artificial organisms.
"Attempts to expand the genetic alphabet bravely question the idea of the universal nature of DNA, and potentially draw criticism about the wisdom of tinkering with it," they said.