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JCVI Team Creates Functional Microbe Controlled By Synthetic Genome

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A team of J. Craig Venter Institute researchers reported online today in Science that they have successfully created the first functional bacterial cells controlled by a synthetic genome.

The researchers amalgamated several of their previously reported approaches for the study, which involved creating a synthetic Mycoplasma mycoides genome called JCVI-syn1.0 and transplanting it into a M. capricolum strain. In so doing, the team was able to produce functional, self-replicating cells that closely resemble natural M. mycoides cells.

"This work provides a proof of principle for producing cells based on genome sequences designed in the computer," senior author Craig Venter and his colleagues wrote. "[T]he approach we have developed should be applicable to the synthesis and transplantation of more novel genomes as genome design progresses."

"This is the first self-replicating species we've had on the planet whose parent is a computer," Venter said today during a telephone briefing with reporters.

In early 2008, researchers from the Venter Institute reported on the first synthetic genome, creating four M. genitalium quarter-genomes that were assembled in yeast. The team subsequently streamlined this process so that dozens of pieces of the M. genitalium genome could be assembled in yeast in a single step.

Because M. genitalium grows very slowly, the researchers explained, they decided to design a new synthetic genome based on the sequence of another species — the M. mycoides subspecies capri — for their current synthetic transplant work.

JCVI researchers previously showed that they could transfer a natural M. mycoides genome into M. capricolum — most recently using yeast as a stop en route in this transplant process.

For the current study, funded by Synthetic Genomics, the team designed cassettes for building a synthetic M. mycoides subspecies capri GM12 genome based on finished genome sequences for two M. mycoides strains — one used as a genome donor in a previous genome transfer study and another containing a transplanted genome that was cloned in yeast.

The latter strain was primarily used as the design reference, the researchers noted, with the synthetic genome matching that genome at all but 19 harmless polymorphisms.

Similar to synthetic genomes designed at JCVI in the past, the team tossed watermark sequences into the synthetic genome, placing them at sites that weren't expected to affect cell growth or viability. Such watermarks are intended "to absolutely make clear that the DNA was synthetic," Venter said.

The watermark sequences used in the new M. mycoides synthetic genome were designed using a code containing frequent stop codons that represents all of the letters in the English alphabet as well as punctuation, Venter explained. These watermarks not only contain the names of nearly four dozen study authors and project contributors, but also a web address and three quotations, he added, including quotes from James Joyce and Richard Feynman.

The Washington-based company Blue Heron synthesized the cassettes, each about 1,080 base pairs long, and these cassettes were then assembled via a series of steps in yeast and Escherichia coli, using multiplex PCR and restriction enzyme analyses to find and verify complete synthetic genomes.

Next, the team transplanted complete synthetic genomes into M. capricolum subspecies capricolum cells lacking restriction enzymes that would chop up the transferred genome, which had been unmethylated during its detour in yeast.

Once they had found cells harboring the synthetic genome, the researchers tested the functionality, characteristics, and growth patterns of the recipient cell, comparing those transplanted with either fully synthetic or semi-synthetic genomes.

Indeed, they found that cells transplanted with the complete synthetic M. mycoides genome are capable of self-replication, have phenotypic and growth patterns resembling natural M. mycoides cells, and produce a set of proteins that appears to be nearly identical to those found in M. mycoides, though their growth rate was slightly higher than natural control cells in at least one set of experiments.

Even so, the researchers cautioned, synthetic genome transplantation is far from simple and relies on precise genetic information.

"[O]btaining an error-free genome that could be transplanted into a recipient cell to create a new cell controlled only by the synthetic genome was complicated and required many quality control steps," the team noted, pointing to a problem they encountered when they inadvertently attempted to transplant a synthetic genome carrying a lone deletion in an essential gene.

"One wrong base out of over one million in an essential gene rendered the genome inactive, while major genome insertions and deletions in non-essential parts of the genome had no observable impact on viability," they wrote.

Overall though, those involved in the study are optimistic that their approach holds potential for creating synthetic cells with a range of applications — including bugs that can be used for everything from biofuel production and environmental cleanup to vaccine production.

"If the methods described here can be generalized, design, synthesis, assembly, and transplantation of synthetic chromosomes will no longer be a barrier to the progress of synthetic biology," the researchers concluded. "We expect that the cost of DNA synthesis will follow what has happened with DNA sequencing and continue to exponentially decrease. Lower synthesis costs combined with automation will enable broad applications for synthetic genomics."

For instance, Venter noted that the team plans to tackle the problem of making synthetic algae cells in the near future.

"I have no doubt that [co-author Daniel Gibson] and the team can easily make a synthetic algae chromosome," he said. "I think the biology will be challenging because we have to find an appropriate recipient cell to boot up that chromosome. Both have to happen in parallel."

Venter said Synthetic Genomics has filed multiple patents related to the methods used in various stages of the synthetic cell research on behalf of JCVI.

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