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Gene pioneer J. Craig Venter makes smallest-yet bacterial genome

Another step toward synthetic organisms

Mark Wilson/Getty Images

Genome trailblazer J. Craig Venter, along with a team of researchers, has now created a minimal genome for bacteria — one that contains only 473 genes, less than the smallest-known naturally-occurring bacterial organism. The new genome may help provide crucial clues to scientists about which genes are necessary for life.

The study, published in Science, reveals that basic biology had missed a third of genes thought to be essential for life. Venter likened the process of determining essential and inessential genes to attempting to deconstruct a Boeing 777 to find out how it works. "You can remove the engine from the right wing, and notice it can fly and land," he said in a call with reporters. "You don’t notice it’s essential" until the engine on the left wing is also removed.

"Pretty incredible""It’s pretty incredible," said Brett Baker, an associate professor at the University of Texas, Austin. He wasn’t involved in the study. "They’re going through and cataloging all the genes and figuring out which ones are necessary to live, and that’s pretty amazing — they found a lot." These essential genes with unknown functions are good targets for future research, Baker said. They may be able to tell researchers more about the essential building blocks of life, since one of the biggest problems in genomics is that scientists don’t know what the majority of genes do.

The work doesn’t have any immediate applications, though there may eventually be industrial uses, such as biofuels and agriculture. Mainly the goal was to provide knowledge, Venter said. And learning that a third of essential genes have functions that are unknown "is a key finding, even if there are no other uses for this organism," he said.

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(C. Bickel/Science)

Venter’s team didn’t create life from scratch, though. Instead they culled genes from an existing organism, as an expansion of work published in the journal Science in 2010. That’s when Venter’s team synthesized the only chromosome in a bacteria called Mycoplasma mycoides. The researchers replaced the DNA in another bacteria, Mycoplasma capricolum, with their artificial genes, creating what they called Syn 1.0. It was, at the time, the largest piece of DNA that had ever been synthesized, and the first time any synthesized DNA was accurate enough to replace a cell’s original DNA.

The next step was to determine the minimum number of genes required for life and reproduction. To do that, the researchers began slicing away genes from Syn 1.0 — using the then-current knowledge about which genes were thought to be necessary for life. They created two possible genomes using this method. Both failed when transplanted into M. capricolum cells.

For their next effort, the group split Syn 1.0’s 901 genes into eight parts, and began removing chunks before reassembling the DNA and transplanting it to a cell. If the cell died, they’d removed something crucial. This experimental approach eventually led to Syn 2.0, a microbe with fewer genes than any independent organism — and then today’s Syn 3.0, with even fewer still.

A "big leap forward"That makes Syn 3.0 a "big leap forward" from the 2010 paper, according to Christopher Voigt, a professor of biological engineering at the Massachusetts Institute of Technology. (He wasn’t a study author.) While other people have made minimal genomes in the past, and the method of engineering isn’t new, the way that Venter’s team reorganized the cell DNA has "all the human design elements - it’s simple, modular, organized - yet still viable in a living cell," Voigt said in a press release from the Genetic Expert News Service. "If human designers can create an ordered, structured alternative to how life is found in nature, that would speak to the complexity of biology simply being an artifact of how it was shaped by evolution."

The method Venter’s team used is also an important approach to genetics, said Adam Arkin, the director of the Berkeley Synthetic Biology Institute. By attempting to slice away anything inessential, the group found "a huge number of surprises even in that minimal genome which couldn’t have been found by looking at genome sequences," he wrote in an email. "It is a profound result and very elegantly presented."

The organism’s minimal genome is dependent in part on its stable lab environment — the medium it grows in is far more uniform than a natural setting would be. So the organism requires fewer genes to deal with temperature fluctuations or food sources. Syn 3.0 also included genes that would allow it to grow fast enough to make a good lab model, as Venter admitted in the press call. (Those genes could have been knocked out, but then it would have taken another five years to complete the study, he said.) Knowing what lab medium it would be in allowed for knocking out genes that might correspond to other environments. "Every genome is context-specific, and depends on the chemicals in the environment available" to it, Venter said. "There’s no such thing as a true minimal genome without context."