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Syn 3.0 minimal genome cells
A photomicrograph shows a cluster of JCVI-Syn3.0 cells, which live and reproduce using a minimal synthetic genome. (Credit: Thomas Deerinck and Mark Ellisman / NCMIR / UCSD)

Scientists say they’ve pared down a microbe’s genome to the minimum necessary for life – a mere 473 genes – but they still don’t know what a third of those genes do.

“These findings are very humbling in that regard,” said genomics pioneer Craig Venter, one of the authors of the study published today by the journal Science.

Syn 3.0 builds on two decades of work to figure out the genetic mechanisms of life – including the creation of Syn 1.0, the first organism to make use of a synthesized genome. That breakthrough, announced in 2010, involved taking the reverse-engineered genetic code from one bacteria species (Mycoplasma mycoides), adding some artificial DNA markers, and then inserting it into the cell of a different species (Mycoplasma capricolum).

Since then, Venter and his colleagues at the nonprofit J. Craig Venter Institute, and at a commercial sister venture called Synthetic Genomics, have been sorting out what’s optional and what’s essential in the genome to keep such organisms alive and reproducing.

At first, the team tried to design a minimal genome from scratch. “Every one of our designs failed,” Venter said. The researchers had to fall back on trial-and-error cycles of designing, building and testing genomes. They subtracted and added genes hundreds of times. When they came up with the minimum set that worked, they reordered the genes for efficiency’s sake.

“We call it defragging the genome,” Venter said.

https://www.youtube.com/watch?v=4ywjThNbfYk

As they worked, researchers found that some genes duplicate functions, meaning one can take over for the other in the event of a genetic fault. That complicated the task of getting down to the minimum. Venter compared the challenge to figuring out what it takes to keep a twin-engine Boeing 777 jet in the air: If you just take out one engine at a time, neither engine seems essential.

“You don’t really discover the essentiality until you remove the second one,” he explained.

The other challenge had to do with those 149 mystery genes. Because the functions of the genes are unknown, the researchers didn’t know they were needed until they were gone. That shows how far geneticists still have to go in understanding how life works.

“We know about two-thirds of essential biology. We’re missing a third,” Venter said.

Project leader Clyde Hutchison, a researcher at the J. Craig Venter Institute, said some of the genes appear to play a role in transporting small molecules around the cell. But the details still have to be worked out, and that’s a priority for future research, he said.

On one level, the creation of Syn 3.0 stands as an impressive technical achievement for basic biology and genetic sequencing. “It’s a tour de force,” Harvard geneticist George Church told Science.

On another level, stripped-down genomes like Syn 3.0 could serve as industrial-scale platforms for genetic engineering. The researchers already have filed a patent application for Syn 3.0, Venter said.

Daniel Gibson, vice president of DNA technology for Synthetic Genomics, called the minimal genome a “very useful chassis” on which the machinery for making biofuels, pharmaceuticals, polymers and other products could be installed. He said Synthetic Genomics is already tweaking the pig genome with the aim of producing transplantable pig organs that would be accepted more readily by the human immune system.

Syn 3.0 isn’t likely to stand as the ultimate minimal genome for life. For one thing, the code was optimized so that it reproduced readily in a lab medium rather than in the natural environment. For another, different species may well have different sets of essential genes. “There will be lots of minimal genomes as these same approaches get applied to other types of biological cells,” Venter said.

The fact that researchers are still in the dark about a third of even the smallest viable genome is likely to serve as a cautionary tale as researchers take greater advantage of gene-editing tools. “It’s vastly premature to talk about editing the human genome until we know a whole lot more,” Venter said.

Venter said the project also suggests that it’s too limiting to think about life’s machinery in purely gene-centric terms. “I think we’ve shown that we need a genome-centric view of life, looking at functions across the genome,” he said. “Life is much more like a symphony orchestra than a piccolo player.”

Hutchison, Gibson and Venter are among 23 authors of the study published in Science, “Design and Synthesis of a Minimal Bacterial Genome.”

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