Once they have created a synthetic copy of the bacteria, scientists can begin to eliminate genes to determine which are essential.
Such an accomplishment would then allow scientists to create synthetic life-forms that may one day produce biofuels, clean up toxic waste, and fight global warming. (Related: "Gene-Altered Plant, Tree Can Suck Up Toxins" [October 15, 2007].)
"So, this is only the beginning," Smith said.
But completing that second step was no easy feat.
While scientists can pretty easily assemble short sequences of DNA—or order them out of a catalog—synthesizing entire genomes is difficult.
That's because as more base pairs of the four building blocks of DNA—adenine, cytosine, guanine, and thymine—are stitched together, the strands tend to weaken and eventually break.
Prior to this research, for instance, the longest synthesized string contained 32,000 base pairs of DNA. The M. genitalium genome is 582,970 base pairs.
So the researchers broke up the genome into 101 segments, called cassettes, each containing between 5,000 and 7,000 base pairs of genetic code.
The researchers also took steps at this stage to address concerns that the technology could be misused to engineer a deadly virus or that an unforeseen innocent error could lead to bacteria run amok.
The researchers added watermarks to the code to differentiate the synthetic DNA from genomes of wild M. genitalium. They also inserted a gene to block the ability of the synthetic genome to infect human or animal hosts.
Much of the cassette assembly work was outsourced to genetics companies.
Back at the lab, meanwhile, Smith and his colleagues devised a process to stitch the 101 cassettes into a full synthetic genome.
They combined increasingly larger sections of the genome together in a test tube with linking and repair enzymes found in the bacterium Escherichia coli until they had four overlapping quarter genome sections.
After unsuccessfully trying to combine the quarters into halves in E. coli, the team switched to brewers' yeast, and the genome came together through a process the yeast uses to repair damaged DNA.
"That was pretty remarkable," Smith said, explaining that scientists had not known that a single yeast cell would pick up all the overlapping pieces and correctly assemble them.
"Yeast will play a big part in the future in assembling large DNA molecules," he added.
Smith and his colleagues report the assembly process in a paper published on the Web site of the journal Science.
"Important Changes" to Genetics
Drew Endy is an assistant professor in the department of biological engineering at the Massachusetts Institute of Technology in Cambridge and an expert in the field of synthetic biology. He was not involved in this study.
In an email, he said "reconstructing a natural bacterial genome from scratch is a great technical feat."
While genomes up to eight million base pairs have previously been assembled from existing DNA fragments, he noted the new accomplishment heralds "important changes in the science of genetics."
By 2012, he added, the technology should exist to routinely design and construct genomes of any bacteria or single-celled organism with a membrane-bound nucleus.
"Which also means," he said, "that it will be possible to construct some mammalian chromosomes."
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