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Longest Piece of Synthetic DNA Yet

Scientists have created an entire bacterial genome with off-the-shelf chemicals



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Scientists today announced that they have crafted a bacterial genome from scratch, moving one step closer to creating entirely synthetic life forms--living cells designed and built by humans to carry out a diverse set of tasks ranging from manufacturing biofuels to sequestering carbon dioxide.

Researchers at the J. Craig Venter Institute (JCVI) in Rockville, Md., report in the online edition of Science that they pieced together the genes of Mycoplasma genitalium, the smallest free-living bacterium that can be grown in the laboratory and a common culprit in urinary tract infections.

"The 582,970 base pair M. genitalium bacterial genome is the largest chemically defined structure synthesized in the lab," lead author Daniel Gibson told ScientificAmerican.com via e-mail. (Base pairs are complementary linked nucleotide bases, such as adenine–thymine.)

"It's the first time a genome the size of a bacterium has chemically been synthesized that's about 20 times longer than [any DNA molecule] synthesized before," adds Christopher Voigt, an assistant professor of bioengineering at the University of California, San Francisco, who was not involved in the study.

The research team, led by Nobel laureate Hamilton Smith, ordered short strands of genetic code from commercial DNA synthesis companies in the U.S. and Germany and stitched them into longer and longer strands using standard molecular biology techniques. To assemble the largest pieces of DNA, they inserted them into yeast cells and exploited a natural process called "homologous recombination," which is used by yeast to repair damaged DNA. The experiment's final product is equivalent to the naturally occurring genetic code of M. genitalium, with two minor exceptions: The scientists disabled the gene that gave the bug power to infect human cells, and they added a few "watermarks," short strips of signature genetic code that identify the product as man-made.

"This completes the second step of a three-step process in creating a synthetic organism," Gibson says. The first step came last summer when JCVI scientists transformed one species of bacteria into another with a DNA transplant, switching the identity of one bug by impregnating it with another's genetic code. The second step, constructing a synthetic bacterial genome, has now been accomplished with this study. The final step will involve inserting the synthetic genome into a cell and bringing it to life; Gibson says experiments with this goal are currently underway.

"We want to emphasize that we have not yet booted up the synthetic chromosome," JCVI founder Craig Venter said in a conference call with journalists this morning. There are multiple steps that must be overcome, the biologist explained, but "we are confident that they can be overcome."

"The ultimate step is proving what they have synthesized is biologically active," says Eckard Wimmer, a molecular biologist at Stony Brook University in Long Island, N.Y., who led the effort to construct synthetic polio, the first synthetically built virus. "Unfortunately, this very critical point is missing here."

If the researchers succeed in creating their synthetic bacteria, they will be closer to conceiving artificial creatures that could be used to mitigate some of society's greatest problems, among them climate change and overdependence on fossil fuels. Venter's team belongs to a cadre of scientists practicing synthetic biology, a burgeoning discipline that aims to design and build living things from the raw materials of life (organic chemicals) and nature's blueprints (genetic codes). Synthetic biologists also draw up their own blueprints, designing genetic sequences that nature never  fathomed; the idea is to create novel functions for living things. Man-made microbes that manufacture pharmaceuticals, crank out cheap biofuels, mop up pollutants and oil spills or invade and destroy cancer cells may be just a decade or two away.

Venter's group is trying to create a completely synthetic bare-bones version of M. genitalium with a genome stripped of all but the most vital genes. The goal is to use this organism as chassis into which new genes can be added--perhaps ones that would give the germ the ability to spin silk, detect toxins or manufacture drugs. The possibilities seem endless, albeit not all rosy.

Critics have pointed out that the same synthetic biology know-how and technologies could be used by terrorists or rogue states to engineer a bacterium that churns out a neurotoxin or, perhaps, a deadly flu virus with resistance to vaccines and antiviral medications. Leaders in the field recognize the potential for misuse, both accidental and intentional, and have begun to address the issue. In October, members of JCVI, the Center for Strategic & International Studies and the Massachusetts Institute of Technology released a report offering policy options for oversight, and several leading synthetic biologists have published papers on the matter in peer-reviewed journals.

Looking at potential applications, not everyone agrees on the best strategy for manufacturing these promising organisms. The sleekest bug is not necessarily the best, points out George Church, a geneticist at the Harvard Medical School in Cambridge, Mass., and director of the Lipper Center for Computational Genetics. "Simplicity is overrated. E. Coli, with all its so-called junk DNA, is way more efficient than Mycoplasma," he says, noting that E. Coli's genome is about eight times bigger but grows about 50 times faster.

A company called LS9, Inc., in San Carlos, Calif., has already taken advantage of E. coli’s productivity, engineering the bug to churn out DesignerBiofuels, "a family of fuels that has properties indistinguishable from those of gasoline, diesel, and jet fuel," according to the company's Web site. Instead of rebuilding E. Coli from scratch, LS9 has taken the organism from nature and modified it by inserting fragments of synthetic DNA, an approach that, Church notes, is much less costly and easy to scale up for industrial purposes.

Regardless of what approach yields the most return, synthetic biology is, no doubt, racing forward. In the last few years DNA synthesis techniques have become faster, cheaper and accessible to more people. Ordering DNA from commercial outfits has become as easy as ordering pizza, according to Voigt, who projects that in upcoming decades scientists will be able to whip up much larger segments of DNA: synthetic genomes for yeast, animals--perhaps even humans.

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