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This man-made cell has the smallest genome ever — but a third of its genes are a mystery

The new life-form could help scientists figure out what the most basic building blocks of life are. (Rachel Orr/Washington Post illustration; images from iStock)
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The new life is born with a jolt: A fresh genome, built from scratch with human hands, is pushed into a host cell using an electric current. One cell quickly becomes a colony of a billion, and a completely unique living organism is alive.

It's not science fiction — or even a recent breakthrough. Scientists created the first synthetic bacterium back in 2010 using this method. But in a new study published Thursday in Science, they've taken this proof of concept a step further. Their latest single-cell creation has what they're calling a "minimal genome." They've created an organism that has just 473 genes, the smallest known genome of any living organism. With fewer, it wouldn't be able to sustain itself. Their hope is that bringing a genome down to its minimum components will help scientists figure out the most basic building blocks of life. As it stands, even this minimal genome has many genes with unknown purposes.

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The work is led by J. Craig Venter and Clyde Hutchison, both of the J. Craig Venter Institute. Together with the rest of their research team, Venter and Hutchison have been working to understand the basic components of the genome for more than 20 years. Venter is known for leading private-sector efforts to sequence the human genome for the first time, in addition to booting up the first "synthetic life" in 2010.

But creating a "minimal genome" has been a long-term goal.

"We knew we could boot up a virus from our synthetic DNA, but nobody had ever transplanted a microbial genome, specifically one made from scratch with four bottles of chemicals," Venter told The Washington Post. "So [the 2010 paper] was the control experiment to see if any of this was possible."

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"We used most of the genome sequence of a known species, so it had a reasonable chance of working," he said. Even then, it took years to get right: When scientists sequence a genome, they're able to accept one error in a thousand genes or so, but to build a DNA code that will support life, you need to be pretty much error-free.

"Once we knew that worked, we could really start from scratch," he said.

Venter and his colleagues wanted to create a cell that had only the genes absolutely necessary to support life. More and more organisms are getting their genomes sequenced, but the purpose of all the data contained in our genetic codes remains largely mysterious. By getting back to basics, they reasoned, scientists might stand a chance of actually understanding the purpose of every single gene in a living cell.

The group used existing literature to create several close-to-minimal genomes, then knocked out different genes until they came to the smallest that still allowed the cell to live and replicate itself. In doing so, they found that many genes thought to be nonessential to life were actually one-half of gene pairs with the same function. One of those genes might appear nonessential on its own — like a jet engine that could be shut down without causing the plane to crash — but if its buddy was also taken away, the cell would die. Those kinds of tricky redundancies are what make studying the core genes of life so difficult.

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But even their pared-down synthetic cell — dubbed JCVI-syn3.0 — has a whopping one-third of its genes totally unaccounted for.

"There were 149 genes of unknown function. We expected maybe 5 or 10 percent. I don’t think anyone would have imagined getting down to a minimal cell with 32 percent," Venter said. Even with a cell that can barely support itself, it seems, the task of hunting out gene function will still be daunting.

Venter is hopeful that other labs will step up to the plate. "There could be labs out there who have already sequenced a similar gene and the protein associated with it and worked on its function, but haven't published yet," he said. "Maybe there are even studies out there that have been published in obscure journals that we haven't seen. In any case, we might quickly resolve a lot of these."

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Other labs may even go on to create yet smaller genomes. "It says a minimal bacterial genome, not the minimal," Venter said during a news conference held by Science on Wednesday. For one thing, this is a minimal genome for one particular kind of bacterial cell. If someone tried to make a new yeast cell with a minimal genome, for example, the result would be very different.

Venter and his team also made the choice not to knock out quite as many genes as were possible, strictly speaking, because they needed JCVI-syn3.0 to replicate quickly enough for practical lab use.

"You have to define what life is going to mean each time," Venter told The Post. In this case, life meant a bacterial cell that could grow rapidly in a glucose culture. If speed hadn't been a priority, they could have trimmed the genome down a bit smaller. And if they'd wanted the cell to survive in conditions less sweet than a petri dish, they would have needed to give it a bigger genomic arsenal. "As soon as you want the cell to adapt to some environmental stress, it might not do it with the genes it has, it might just die," he said.

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In an email to The Post, Harvard University professor George Church, who wasn't involved in the new paper, called it "a solid study worthy of celebration" but pointed out that gene editing using the CRISPR method is also coming along rapidly. It's likely that editing will be more practical than building from scratch in many instances.

But Venter's institute has a lot of lofty goals for their synthetic biology techniques. They're working on the prototype of a device that sends digital translations of DNA across the globe, allowing for a sort of 3-D printer that spits out tailor-made vaccines, proteins and microbes on demand. He has suggested that missions to Mars might send home the genomes of any microbes found on the Red Planet, allowing scientists on Earth to create aliens in the lab before our astronauts even come home. Unsurprisingly, the far-flung science fiction-like applications of Venter's work have caused outcry in the past, prompting visions of out-of-control Franken-microbes.

The researchers hope to see tailor-made microbes built for new applications in medicine, biofuels and agriculture. But for now, they have more basic science in mind.

"We want to understand every component in a living cell," Venter said. "We're just trying to understand the basic components of life."

This post was originally published on March 24th. It has been updated. 

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