For now, synthetic bacteria with custom-made metabolisms exist only on the blackboard, and it could take a decade before the chalk dust gives way to living creatures. But there is growing evidence that, just maybe, it could happen.Last summer researchers from the State University of New York at Stony Brook proved that it’s possible to synthesize an organism-albeit one found in nature-from nothing more than genome sequence information and chemicals in a test tube. Molecular biologist Eckard Wimmer and his colleagues used a combination of DNA synthesizers and brute force to reconstruct in DNA the 7,500-letter-long polio genome sequence. Next, they converted that sequence into RNA, a biochemical cousin of DNA that makes up many viral genomes, combined that RNA with enzymes and other molecules in a test tube, and watched as whole polio viruses assembled spontaneously. It was the first time scientists had ever synthesized a virus-or any other organism for that matter-from scratch.
When the work was announced, many scientists called it a publicity stunt, arguing that the Stony Brook team had chosen to build a dangerous microbe in a bid for headlines. But the work did highlight a very real technological problem: assembling long strands of DNA by conventional means is an almost prohibitively time-consuming task. Researchers like the ones at Stony Brook first synthesize short fragments using conventional DNA synthesizers. Such machines use a complicated series of chemical reactions to attach each DNA letter to the next. Because errors can occur at each step, the longer the fragment, the more errors it contains; so researchers typically limit fragments to fewer than 80 letters. To assemble longer DNA strands, they toss the fragments sequentially into test tubes, together with enzymes that link the fragments end to end. This process introduces a multitude of tiny, single-letter errors though. Detecting and correcting those errors adds more work and more time to the job. Had the Stony Brook team chosen an organism with a genome longer than 7,500 letters, it might still be working on the project.
But that might be about to change. Glen Evans, CEO of San Diego, CA-based Egea Biosciences, thinks his company has a solution-one that could help propel the idea of engineering wholly new organisms into reality. “It took the polio researchers two years to synthesize the virus,” says Evans. “We could have done that in less than a week.”
The source of Evans’s bravado is his company’s newly developed machine, which can rapidly synthesize long strands of DNA with relatively good accuracy: the device makes a mistake only once for every 10,000 DNA letters, or bases, Evans says, whereas conventional techniques typically have an error rate of one in 100. Right now Evans’s DNA-writing machine is accurate enough to make several genes at once, but he hopes to get the error rate down low enough to make the larger DNA strands that are required for building entire genomes. Evans first conceived of the technology at the University of Texas Southwestern Medical Center, where he was director of the Human Genome Sequencing Center. When researchers completed a draft of the human genome, he says, “we realized we had read the genetic code, but we didn’t have the ability to write the genetic code.”
To fill that gap, he built a gene-writing system that combines hardware and software. Using the software, a researcher can design a protein-a new drug, for instance-on a computer, which in turn determines the sequence of DNA bases needed to encode the protein. “It’s kind of like word processing for DNA,” says Evans. The hardware, essentially a robotic chemistry lab, assembles long stretches of DNA automatically, circumventing what would otherwise require endless hours of tedium for humans. The machine first synthesizes fragments of the gene, each measuring 50 to 100 letters long, and arrays the fragments into tiny wells. It then grabs each fragment in sequence, attaching one to the next with a customized cocktail of enzymes and ultimately producing the whole gene, which can amount to a few thousand bases. Evans says Egea has developed a prototype machine that, thanks to automation, can synthesize 10,000 bases in just two days. He says the technology could be extended to yield in a matter of weeks highly accurate strands 100,000 bases in length-long enough to make a very simple bacterial genome. Automation and robotics also allow for careful control of each chemical reaction in the process. That control, combined with the enzyme cocktail, helps keep long DNA strands largely free of the errors that plague conventionally made strands.
Though Venter and other researchers bent on creating synthetic organisms will still have a lot of scientific heavy lifting to do before they’re able to design new genomes readily, technology like Egea’s, says MIT’s Knight, could lighten the burden of genome construction. And a handful of biotech companies are now also getting into the business of souped-up DNA synthesis. “Pretty soon, we won’t have to store DNA in large refrigerators,” says Knight. “We’ll just write it when we need it.”