Rewriting Life

Synthetic Genome Reboots Cell

A genome built from scratch is a step toward synthesizing novel organisms.

In the culmination of a project spanning 15 years, scientists at the J. Craig Venter Institute have engineered the first cell controlled by a synthetic genome.

Starting from scratch: Scientists rebooted bacterial cells by transplanting a synthetic version of the Mycoplasma mycoides genome manufactured in the lab. The synthetic genome includes a marker gene that makes a blue compound, so the synthetic cells form blue colonies (top). The naturally occurring M. mycoides genome lacks that gene, so the wild-type cells form white colonies (bottom).

“This is the first time that the information of a genome sequence has been turned back into life,” says Chris Voigt, a synthetic biologist at the University of California, San Francisco, who was not involved in the project. “It’s really remarkable.”

Using a method developed in 2008, the researchers, led by genomics pioneer Craig Venter, synthesized the genome of a tiny bacterium called Mycoplasma mycoides, containing just over a million DNA base pairs. Next they transplanted the synthetic genome into a related bacterium, Mycoplasma capricolum, in a process they had previously perfected using nonsynthetic chromosomes.

Once the recipient cells incorporated the synthetic genome, they immediately began to carry out the instructions encoded within the genome. The cells manufactured only M. mycoides proteins, and within a few rounds of self-replication, all traces of the recipient species were gone. The results were published Thursday in the online edition of the journal Science.

To distinguish their synthetic genome from the naturally occurring version, the researchers encoded a series of watermarks into the sequence. They began by developing a code for writing the English alphabet, as well as punctuation and numbers, into the language of DNA–a decoding key is included in the sequence itself. Then they wrote in their names, a few quotations, and the address for a website people can visit if they successfully crack the code.

In terms of creating synthetic life, this project is a proof of principle: aside from the watermarks and a handful of gene deletions to reduce the species’ ability to cause disease, the synthetic genome essentially recreates a naturally occurring one. Venter hopes that in the future, the synthetic genomic technology can be used to design and develop entirely new organisms, with wide-ranging practical applications.

Venter and his colleagues are working with Novartis and the National Institutes of Health to synthesize cassettes–clusters of genes that could be inserted into a synthetic genome–for every known flu virus in an effort to streamline the vaccine manufacturing process. They envision a system where, if a new strain such as H1N1 emerged, developing a vaccine would be as straightforward as shuffling genes encoding the relevant viral fragments into a synthetic genome. This could then yield a cell that could be used to quickly manufacture the product.

The researchers are also collaborating with ExxonMobil to overhaul algal cells into living fuel factories that would efficiently convert carbon dioxide into hydrocarbons that could be processed in refineries. “There are no existing cells that we’ve been able to find that do that process efficiently enough to make it economically viable,” says Venter.

Other potential applications include designing synthetic microbes that could purify water or manufacture chemicals or food ingredients. “I predict within a decade, any cell that’s used in industrial processes will be made synthetically,” says Venter.

To this end, the researchers plan to eventually develop a kind of universal recipient cell that could “boot up” any donor genome. The transplant process has proven to be the most technically challenging aspect of building a synthetic cell, says Venter, and it would be ideal to avoid a new round of troubleshooting for each new system that is developed.

For now, says Voigt, the biggest hurdle in realizing the potential of synthetic genomics is the gap between our ability to synthesize DNA and our ability to design it. “That’s going to be the next generation of research,” he says. “The technology around building DNA is mature now, and it’s going to be the toolbox to design it that comes next.”

Beyond practical applications, Venter also hopes that synthetic cells will help elucidate the basics workings of life, perhaps allowing researchers to decipher exactly what every component of a bacterial cell does. Although the genomes of countless organisms have now been sequenced, says Venter, we still don’t fully understand how even the simplest life forms function. “We want to try to make one of these cells the best-understood cellular system in biology,” he says.

Venter also points to what the cells–powered by genomes made in a lab from four bottles of chemicals, based on instructions stored on a computer–reveal about what life is. “This is as much a philosophical as a technological advance,” he says. “The notion that this is possible means bacterial cells are software-driven biological machines. If you change the software, you build a new machine. I’m still amazed by it.”

The development highlights the fact that we are moving out of the era where cells and DNA must be physically transferred from one location to another, says Voigt, to one in which biology is an information science. It would now be possible to sequence an organism’s genome in San Francisco, e-mail the sequence across the country, and bring that organism into being in a lab in Maryland. “Just the information alone is able to reconstruct that organism and convert it back into life,” says Voigt.

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