First Life with “Alien” DNA Created in Lab

An engineered bacterium is able to copy DNA that contains unnatural genetic code

The addition of new letters to the 'alphabet of life' could enable biologists to vastly expand the range of proteins that they could synthesize. Credit: National Nanotechnology Initiative

For billions of years, the history of life has been written with just four letters A, T, C and G, the labels given to the DNA subunits contained in all organisms. That alphabet has just grown longer, researchers announce, with the creation of a living cell that has two 'foreign' DNA building blocks in its genome.

Hailed as a breakthrough by other scientists, the work is a step towards the synthesis of cells able to churn out drugs and other useful molecules. It also raises the possibility that cells could one day be engineered without any of the four DNA bases used by all organisms on Earth.

What we have now is a living cell that literally stores increased genetic information, says Floyd Romesberg, a chemical biologist at the Scripps Research Institute in La Jolla, California, who led the 15-year effort. Their research appears online today inNature.

Each strand of the DNA's double helix has a backbone of sugar molecules and, attached to it, chemical subunits known as bases. There are four different bases: adenine (A), thymine (T), cytosine (C) and guanine (G). These letters represent the code for the amino-acid building blocks that make up proteins. The bases bind the two DNA strands together, with an A always bonding to a T on the opposite strand (and vice versa), and C and G doing likewise.

Test-tube letters Scientists first questioned whether life could store information using other chemical groups in the 1960s. But it wasnt until 1989 that Steven Benner, then at the Swiss Federal Institute of Technology in Zurich, and his team coaxed modified forms of cytosine and guanine into DNA molecules. In test-tube reactions, strands made of these funny letters, as Benner calls them, copied themselves and encoded RNA and proteins.

The bases engineered by Romesbergs team are more alien, bearing little chemical resemblance to the four natural ones, Benner says. In a 2008 paper, and in follow-up experiments, the group reported efforts to pair chemicals together from a list of 60 candidates and screen the 3,600 resulting combinations. They identified a pair of bases, known as d5SICS and dNaM, that looked promising. In particular, the molecules had to be compatible with the enzymatic machinery that copies and translates DNA.

We didnt even think back then that we could move into an organism with this base pair, says Denis Malyshev, a former graduate student in Romesbergs lab who is first author of the new paper. Working with test-tube reactions, the scientists succeeded in getting their unnatural base pair to copy itself and be transcribed into RNA, which required the bases to be recognized by enzymes that had evolved to use A, T, C and G.

The first challenge to creating this alien life was to get cells to accept the foreign bases needed to maintain the molecule in DNA through repeated rounds of cell division, during which DNA is copied. The team engineered the bacteriumEscherichia colito express a gene from a diatom a single-celled alga encoding a protein that allowed the molecules to pass through the bacterium's membrane.

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First Life with "Alien" DNA Created in Lab