Scientists create new lifeform with added DNA base pair

May 9, 2014

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Scientists at The Scripps Research Institute (TSRI) have engineered a bacterium whose genetic material includes an added pair of DNA “letters” (bases) not found in nature.

The research was intended to created new proteins — and even new organisms — that have never existed before.

“Life on Earth in all its diversity is encoded by only two pairs of DNA bases, A-T and C-G, and what we’ve made is an organism that stably contains those two plus a third, unnatural pair of bases,” said TSRI Associate Professor Floyd E. Romesberg, who led the research team.

“This shows that other solutions to storing information are possible and, of course, takes us closer to an expanded-DNA biology that will have many exciting applications — from new medicines to new kinds of nanotechnology.”

The report on the achievement appears May 7, 2014, in an advance online publication of the journal Nature.

How to engineer synthetic life

The team synthesized a stretch of circular DNA known as a plasmid and inserted it into cells of the common bacterium E. coli. The plasmid DNA contained the natural T-A and C-G base pairs along with the new unnatural base pair that Romesberg’s laboratory had discovered: two molecules known as d5SICS and dNaM.

The goal: get the E. coli cells to replicate this semi-synthetic DNA as normally as possible. To do that, the researchers had to first supply the molecular building blocks artificially, by adding them to the fluid solution outside the cell.

Then, to get the building blocks, known as nucleoside triphosphates, into the cells, they had to find special triphosphate transporter molecules that would do the job. For that, they used a species of microalgae, that could import the unnatural triphosphates.

The team found, somewhat to their surprise, that the semi-synthetic plasmid replicated with reasonable speed and accuracy, did not greatly hamper the growth of the E. coli cells, and showed no sign of losing its unnatural base pairs to DNA repair mechanisms.

The next step will be to demonstrate the in-cell transcription of the new, expanded-alphabet DNA into the RNA that feeds the protein-making machinery of cells. “In principle, we could encode new proteins made from new, unnatural amino acids — which would give us greater power than ever to tailor protein therapeutics and diagnostics and laboratory reagents to have desired functions,” Romesberg said. “Other applications, such as nanomaterials, are also possible.”

What about risks of a runaway new life form? According to Denis A. Malyshev, a member of the Romesberg laboratory who was lead author of the new report, “the new bases can only get into the cell if we turn on the ‘base transporter’ protein. Without this transporter or when new bases are not provided, the cell will revert back to A, T, G, C, and the d5SICS and dNaM will disappear from the genome.”

Other contributors to the paper, “A semi-synthetic organism with an expanded genetic alphabet,” were Kirandeep Dhami, Thomas Lavergne and Tingjian Chen of TSRI, and Nan Dai, Jeremy M. Foster and Ivan R. Corrêa Jr. of New England Biolabs, Inc.

The research was funded in part by the National Institutes of Health.

Abstract of Nature paper