Transplanting a Genome

Researchers have taken a big step toward creating synthetic genomes.

Forget kidneys and hearts: genomics pioneer J. Craig Venter has spearheaded a much tinier transplantation procedure. Scientists at the J. Craig Venter Institute, in Maryland, have transferred an entire genome from one bacterium to another. They say the findings, which are described today in the journal Science, mark a significant advance toward the goal of creating synthetic genomes. Venter and his colleagues ultimately aim to build genomes from scratch and transplant them into bacterial cells in order to create custom-made, fuel-producing microorganisms.

Pioneer bug: J. Craig Venter announced this week that his institute has transplanted a bacterial genome, transforming one species into another. The bottom image shows the colonies of the transformed Mycoplasma mycoides bacterium.

“This paper is a landmark in biological engineering,” said Barbara Jasny, Science’s deputy editor, at a press conference on Wednesday. “It takes us from the ability to move one gene or a set of genes to the ability to move an intact genome.”

Scientists started with two species of mycoplasma, a type of bacteria that lack cell walls and have very small genomes. They then isolated the DNA of one species, which had been given an additional gene to make it resistant to an antibiotic, and transplanted it through the cell membrane of the second species. As the host bacteria grew and divided in the presence of this antibiotic, cells carrying the original chromosomes disappeared, leaving only cells containing the transplanted chromosome. Most important, the host bacterium took on the molecular characteristics of the donor. “The entire protein repertoire changes,” Venter said at the press conference.

For Venter’s team, the genome transplant is a step toward engineering microbial machines to efficiently produce fuel. The researchers are currently trying to stitch together a synthetic version of the genome of Mycoplasma genitalium, a bacterium found in the human genital tract, which Venter’s group has been studying for more than a decade. By rearranging or deleting specific chunks of the synthetic genome and inserting it into a bacterial host, scientists should be able to figure out which genes are critical for the organism to function–in essence, the minimal genome. This minimal genome could then be modified to carry fuel-producing genes, and the entire string of DNA could be transplanted into a bacterial carrier.

In addition to the research at his institute, Venter has also founded a Maryland-based startup called Synthetic Genomics. (See “Building a Bug to Harvest Oil.”) The company, which is working with BP, hopes to commercialize bacteria for energy applications.

But some scientists question whether a minimal genome is necessary to engineer useful bacteria. “It’s not clear why a minimal cell or a cell engineered by whole genome transplantation would be more cost-effective than just inserting or changing a few genes in a more robust genome,” says George Church, a geneticist at Harvard Medical School, in Boston. He points out that synthesizing even the smallest genome would cost an estimated $10 million with today’s technology. In fact, other companies are tinkering with existing microbes to engineer biological fuel factories. (See “A Better Biofuel.”)

However, Venter said that his approach would eliminate inherent biological traits that make extensive biological engineering tricky. For example, a nonessential metabolic process could suck away a molecular precursor needed for fuel production. In addition, said Venter, “existing organisms have a rapid ability to evolve. In synthetic biology, you don’t want a system that will self-evolve into something else. We want to eliminate those elements from the cell from the beginning.”

The genomic transfer technique is similar to nuclear transfer–used to clone Dolly the sheep–in which the nucleus of an adult cell is transferred into an egg. But getting the process to work in bacteria has been trickier. Scientists speculate that nuclear proteins transferred along with the DNA during nuclear transfer may help the process. Bacteria do not have a nucleus, and in this experiment, only DNA was transferred into the host cell. Researchers did this on purpose to show that only DNA was needed to successfully reprogram the host bacterium–a property that will be necessary when scientists are ready to transplant entirely synthetic genomes.

Scientists don’t fully understand how the genome transfer worked, particularly how the host genome disappeared. And it’s not yet clear how well the technique will work in other bacteria or in more-complex organisms. Most bacteria have a defense mechanism that chops up any foreign DNA that enters the cell, so scientists would need to find a way to block the DNA-degrading enzymes in each different species before they could successfully transplant foreign genomes into them.

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