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Venter Institute Scientists Report First Synthetic Genome

NEW YORK (GenomeWeb News) – Taking a significant step closer to their goal of creating a synthetic organism, researchers at Maryland’s J. Craig Venter Institute reported today that they have created the first synthetic genome.
 
The team used both in vitro and in vivo techniques to create what JCVI President Craig Venter calls “the largest molecule of a defined structure made by humans,” some 20 times bigger than the largest DNA molecule constructed before it. A paper describing the creation of this 582,970 base pair genome, dubbed Mycoplasma genitalium JCVI-1.0, appeared in the journal Science online today.
 
“It’s indeed a large molecule. And this entire process began with four bottles of chemicals,” Venter said in a conference call with reporters today. “We’re obviously excited about what the team here has accomplished. It’s an important — but not final — step.”
 
Rutgers University biochemist Richard Ebright, who was not involved in the study, told GenomeWeb Daily News, “I think it’s an extremely important. This sets the stage for the complete reprogramming of an organism with synthetic DNA.”
 
Last June, JCVI researchers made headlines for transplanting the genome from one bacterium, Mycoplasma mycoides, into another, M. capricolum — an achievement that Ebright calls a landmark in synthetic biology. The institute says its latest work marks “the second of three key steps toward the team’s goal of creating a fully synthetic organism.”
 
In the next stage of this endeavor, researchers hope to create living cells based entirely on a synthetic genome. But so far that target has eluded the group.
 
“It’s not just a slam dunk, or we would be announcing it today,” Venter said, emphasizing that the group still has major obstacles to overcome. Even so, he said, it’s on the horizon. “I will be equally surprised and disappointed if we can’t do it in 2008.”
 
Creating long stretches of synthetic DNA is notoriously difficult. Consequently, the previous synthetic DNA record holder for length was just 32,000 base pairs.
 
“When we started this work several years ago, we knew it was going to be difficult because we were treading into unknown territory,” the paper’s senior author Hamilton Smith, who led the synthesis project, said in a statement.
 
Smith and his colleagues’ approach involved synthesizing smaller packages of DNA and cobbling them together in Escherichia coli and in the yeast Saccharomyces cerevisiae. In total, they synthesized 101 of these overlapping cassettes, each between 5,000 and 7,000 base pairs long and containing one or more complete genes.
 
The team assembled the building blocks, which were synthesized at Blue Heron Technology, DNA2.0, and GENEART, into increasingly larger pieces in E. coli, until they had built quarter-genomes. That’s when they ran into trouble: assembling half or whole genomes in E. coli proved impossible.
 
Instead, they turned to S. cerevisiae — an organism that generally tolerates larger pieces of DNA — and finished building the genome on a yeast artificial chromosome using a technique called transformation-associated recombination.
 
To ensure a faithful genome copy, the 17 JCVI scientists used extensive sequencing, re-sequencing the M. genitalium genome at the project’s outset and periodically sequencing their constructs.
 
But JCVI-1.0 is not an exact M. genitalium genome replica. The researchers deliberately disrupted an infectivity gene with an antibiotic resistance marker. They also inserted watermarks, short sequences or duplications, to differentiate their handiwork from the natural M. genitalium genome.
 
Additionally — as the group discovered only recently — they inadvertently disrupted an essential RNA coding region, a mistake that will have to be repaired before they can hope to successfully transplant the genome, Smith told reporters today. If and when the group successfully transplants the synthetic genome, they still have a way to go before reaching their ultimate goal of creating — and being able to tinker with — a minimal synthetic M. genitalium genome.
 
Venter and his colleagues have long expressed interest in creating synthetic organisms that can be used to fuel bioenergy projects. Because of its relatively small genome size, M. genitalium has become a candidate organism whose pared down, bare-bones genome may one day become the skeleton from which new synthetic genomes are created.
 
The synthetic “life by design” concept may be ambitious, but it’s not the only approach to harnessing life for industrial purposes. Other organizations — notably DuPont — have focused on inserting or deleting genes in existing biological systems.
 
While Venter said that Synthetic Genomics, a company he founded in 2005 to commercialize his work in this area, is doing similar genetic engineering as well, he insists that ground-up, designer organisms will ultimately lead the way. “I am 100 percent certain it will be the process of choice,” Venter said during the call. But, he added, “We’re a long way from getting there.”

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