Published online 20 May 2010 | Nature | doi:10.1038/news.2010.253

News

Researchers start up cell with synthetic genome

A fully synthesized genome transforms one species of bacterium into another.

A chemical marker (blue) shows the ability of a single bacterium with synthesized genome to spawn a viable colony.Science/AAAS

Scientists have built a bacterial genome from scratch and used it to 'reboot' a cell from a different species of bacterium.

Daniel Gibson and his colleagues at the J. Craig Venter Institute in Rockville, Maryland, synthesized the genome of the bacterium Mycoplasma mycoides, consisting of about 1.1 million base pairs. Having assembled the genome inside a yeast cell, they transplanted it into a cell from a closely related species, Mycoplasma capricolum. After the newly made cell had divided, the cells of the bacterial colony that it formed contained only proteins characteristic of M. mycoides.

The success clears the way for developing and testing new variants of existing organisms.

"With this approach we now have the ability to start with a DNA sequence and design organisms exactly like we want," says Gibson. "We can get down to the very nucleotide level and make any changes we want to a genome."

Scientists have already developed many good ways of engineering genes, he adds, but this technique provides an unprecedented ability to make many changes to a genome at once, and to add segments of DNA that aren't found in nature but might be designed to perform useful functions.

Step by step

Creating a 'synthetic cell', as described in a report published online in Science today1, meant putting together a series of previously developed steps. First, the team established a method for transplanting natural DNA from M. mycoides into M. capricolum (see 'Genome transplant makes species switch'). Then, working with Mycoplasma genitalium, a species whose genome is about half the length of that of M. mycoides, the group stitched together a synthetic donor genome and cloned it in a yeast cell (see 'Genome stitched together by hand').

But the scientists couldn't transplant the newly made DNA into a different bacterial species. Bacteria recognize foreign invaders by the lack of chemical marks called methyl groups on their DNA; synthetic DNA would share the same deficit. To get around the problem, the group developed a way to add methyl groups to an engineered genome. They also disabled the destructive enzyme in the recipient M. capricolum cell (see 'Scientists devise new way to modify organisms').

The custom-built genome is a near-exact replica of its natural counterpart, with just a few nonessential genes removed and a small number of sequence errors that don't affect the organism's function. The group also added four special 'watermark sequences' to help to distinguish it from the original version. The sequences contain a hidden code of names and sentences, along with a URL and an e-mail address for would-be decoders to contact.

"It's a pretty significant achievement," says Christopher Voigt, a synthetic biologist at the University of California, San Francisco. "What's neat here is that it's really the first time in which the information from a genome is all that was required to rebuild the DNA and convert that into a living cell."

New toolkit

So far, it's not clear how being able to engineer a whole, functioning genome will be useful, researchers say. James Collins, a biomedical engineer and a Howard Hughes Medical Institute investigator at Boston University in Massachusetts, says that, in principle, "it potentially makes it considerably easier to make large-scale changes to a genome, and to introduce large-scale pathways of interest into an organism". That might mean, for example, engineering large networks of genes into bacteria which will make biofuels or proteins for treating disease.

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But researchers don't yet understand enough about genetic networks to design them in this way. "There needs to be a lot of work in understanding how to go about designing a genetic system at the scale of the genome," Voigt says. "We don't really have a framework to think at that level."

Also, says Collins, synthesizing DNA is expensive and, at least for now, most groups don't have the resources to engineer whole genomes.

Gibson says that his team is now trying to make different types of synthetic cell, using different pairs of bacteria. The group also plans to use the approach to continue work on its project to create a 'minimal' cell that contains only the genes necessary for a cell's most basic survival. "We finally have an assay for determining the functionality of a genome," says Gibson. "So we want to start whittling away at this genome and try to determine the smallest number of genes needed to sustain life." 

See also 'Sizing up the 'synthetic cell''

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  • #61369

    I think the original DNA was synthesized chemically ex vivo (not using cellular polymerases) and the cellular machinery was used only to propagate the synthesized product.

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