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Scientists Build A Live, No-Frills Cell That Could Have A Big Future

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In 2010, scientists plopped the genetic material of one <em>Mycoplasma</em> bacterium into another type to create the self-replicating cells shown above. Six years later, they've come out with an even simpler synthetic organism that has fewer genes.

Scientists announced Thursday that they have built a single-celled organism that has just 473 genes — likely close to the minimum number of genes necessary to sustain its life. The development, they say, could eventually lead to new manufacturing methods.

Around 1995, a few top geneticists set out on a quest: to make an organism that had only the genes that were absolutely essential for its survival. A zero-frills life.

It was a heady time.

"That was the first time anybody had seen the complete genome of anything," says J. Craig Venter, a genome scientist and founder and CEO of the J. Craig Venter Institute. Back then, he and his colleagues had just sequenced the complete genomes of two types of bacteria and were shocked to see how different they were from each other, in terms of their DNA.

"We were amazed at the lack of similarity of the two, even at the most fundamental level," he says, and it got them thinking philosophically. "We were asking basic fundamental questions of life. What did we think might comprise the most primitive cell? What would be the gene content of this thing?"

Two decades later, in this week's issue of the journal Science, Venter's team published one possible answer. Their research report describes a new organism they've put together, using only 473 genes. That gives it the smallest genome of any known living thing that is able to reproduce on its own. (For comparison, humans each have about 20,000 genes).

"You cannot live without all but one or two of the genes in this genome," says Venter.

The little cell marks one incremental step in a larger, two-pronged scheme: to understand what genes are essential for life, and eventually to design what could be a process of mass production — armies of cells that could spit out pretty much any molecule that's desired.

To make the simplified bacterium, which the scientists are calling JCVI - syn3.0 for now, they started with a bacterium that's already very simple ­-- Mycoplasma mycoides. In its natural state, M. mycoides is a parasite found in cattle and goats. Next, the scientists fashioned a little bacterial heaven — a material that the bacterium could live on that would provide all the food it could ever want. Then, they started tossing out genes.

(Ever heard of the Japanese organizer, Marie Kondo, who gives tips on how to declutter homes by taking each object in it and asking if it's worth keeping around? These biologists took that same approach to the M. mycoides genome.)

If a gene could be removed without disrupting the cell's ability to live, grow and reproduce, it was deemed nonessential. Out it went. They chucked out a bunch of genes involved in transporting and metabolizing different kinds of food, since the cell they were working with had plenty of sugars to keep it going. They kept in almost all of the genes responsible for reading genetic material and creating more. They also kept a few that would allow the cell to reproduce quickly enough for them to observe that growth in the lab. And they added some specific DNA that could serve as a "watermark," indicating the lab that had assembled it — the J. Craig Venter Institute.

Based on estimates that biologists have been making for decades, Venter's team thought the modified bacterium would only need about 250 genes to eke out a bare existence. But, says Venter, it ended up requiring a lot more genes than that.

For example, the researchers also had to leave in 149 genes that are apparently essential for the cell's survival — though they don't know what that genetic material actually does. "Many of these genes probably encode universal proteins whose functions are yet to be characterized," the scientists report. And there are versions of these genes in a lot of different organisms, they say.

"It's remarkable that there are still so many genes in their minimal genome that we don't know anything about other than that they are needed," Drew Endy, a bioengineer at Stanford University who was not involved in this research, tells Shots. "Only when you try to build something do you find out what's truly required," he says.

A lot of organisms, including humans, have swaths of genes with unknown functions. That, says Venter, is the next step: figuring out what the heck all those essential genes actually do.

"If we can't understand what happens in a cell with less than 500 genes, imagine how complicated it's going to be to understand our 20,000-some genes in the human genome," Venter says. "So, it's essential for understanding all of life to understand the basic components."

The group also has a long-range goal: engineering tailored cells that could mass-produce chemicals that are hard to make now.

"Our long-term vision has been to design and build synthetic organisms on demand," says Dan Gibson, a synthetic biologist with the Venter Institute and an author on the paper. "We believe that these cells would be a very useful chassis for many industrial applications, from medicine to biochemicals, biofuels, nutrition and agriculture," he says.

He and his colleagues view their "minimal cell" as a useful starting point. Venter describes the cell as sort of like the frame of a car.

"Early on, for example, Rolls Royce or Bugati, they made a car frame with an engine and provided those to a lot of different body makers that would style and make cars that look different from one another, but they were all based on the same chassis," he says.

Similarly, he says, minimal cells of various varieties could serve as starting points for engineering cells that digest or produce certain chemicals. "It's a basic component that we can add things to," says Venter, like a gene from a deep-sea creature that would allow a cell to eat carbon dioxide and spit out methane — a fuel.

"You could design cells and choose the type of metabolism you want," says Venter. "If you just have a cassette of those genes that you can just plug in, that will enable design to go much faster," he says.

Because the cells wouldn't have any extra genes, the researchers explain, they would be easier to engineer. And organizing genes by their function would be helpful.

That sort of genetic engineering could be considered intelligent design for the purpose of mass production — of anything from pharmaceutical chemicals to fuel, which is why this kind of work by the Venter Institute has, over the years, been funded in part by the U.S. Department of Energy and the Defense Advanced Research Projects Agency. (Most of these scientists' funding comes from Venter's ventures, the endowment of the non-profit institute, and a for-profit company he started called Synthetic Genomics, Inc.)

Synthetic Genomics, Inc. has already applied for a patent on the process of making this minimal genome.

George Church, another pioneer in the field of genomics and a professor of genetics at Harvard Medical School, says the process Venter's team describes in this week's study is nowhere near those applications yet.

"I think the main reason it should be celebrated is that it is an achievement of a 20-year goal," says Church. Making a minimal bacterial genome is not easy, and contributes to basic science. "That's a labor of love on a pretty out-of-the-way pure science project for 20 years," he says.

Still, that accomplishment is a long way from revolutionizing genetic manipulation, Church says, noting that scientists have manipulated genomes before, and made minimal genomes in the past. They've also put new DNA into existing organisms using methods like CRISPR. That method, for example, has allowed scientists to edit out parts of the pig genome so that it can make organs that a human body would not reject during transplantation.

The method described in the research published Thursday — for designing an entire genome and plopping it into a cell — "hasn't been proven to work in any organism outside of Mycoplasma mycoides," Church says. "It doesn't even work in Mycoplasma genitalium, last time I checked." That's a very close relative of M. mycoides.

And to get to the point where people can design whole genomes to produce chemicals or biofuel, the whole process would have to be shown to be speedy, cost-effective and widely applicable, Church adds.

In the meantime, he says, let's not forget that this entire field brings up some tricky what-ifs. For example, what if an engineered organism accidentally got out of the lab?

"Most of the organisms we manipulate in the laboratory are so weak they wouldn't survive outside the laboratory," Church says, "so, from a safety standpoint, it's probably a solved problem for these very weak strains."

But, he says, "Anything that has a chance — even a remote chance — of spreading through the wild should be something we're very cautious [with], and have mechanisms in place to limit it and/or reverse it."

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