Building a better genome?

In a major step toward the creation of artificial life, scientists are reporting today that they assembled the entire genetic code for a simple bacterium from scratch.

The technique used to duplicate a real organism's DNA could allow the fashioning of novel organisms designed to, say, pump out new biofuels or absorb carbon dioxide, the researchers said. And by exploring the boundaries between the living and inanimate worlds, the work may change our understanding of the nature of life itself.

"We started with four bottles of chemicals," said Craig Venter, a collaborator on the project, done at his institute in Rockville, Md. They ended up with the single chromosome that contains the genetic code for Mycoplasma genitalium.

The bacterial chromosome also represents the largest synthetic molecule of any kind. Its chemical structure took 147 pages to spell out.

The team's next goal, Venter said, will be to "boot" the chromosome in a donor bacterium whose own genetic code has been removed. If researchers succeed, the bacterium will begin to run using the new genetic instructions just as a computer might run on a new operating system.

"We're laying the foundation for a very powerful new technology where one can design bacterial genomes to do what you want," said Hamilton Smith, a Nobel Prize-winning biologist who worked on the project.

News of the first synthetic bug, like that of Dolly, the first cloned sheep, is likely to have a major psychological impact on the world, Art Caplan, a bioethicist at the University of Pennsylvania, said in an interview. "It's the symbolism of creating life."

Caplan anticipates the technological benefits will come faster than what has followed the much-ballyhooed sequencing of the human genome, since bacteria are relatively easy to manipulate compared with plants, animals or people.

"Things are going to come flying out of this work in synthetic biology," Caplan said. "It's where the impact of genetic knowledge is going to be felt first."

While the breakthrough, announced in today's issue of the journal Science, could theoretically give terrorists new bioweapons, Caplan said that synthetic biology was not inherently more dangerous than the genetic engineering that has been practiced for decades. Venter said he has worked closely with the scientific community and the government to address safety concerns.

Often called a maverick, Venter gained prominence in the 1990s for pioneering new ways to sequence the human genome - and nearly beating a $3 billion government-sponsored project with his own private venture.

In a teleconference with reporters yesterday, he said he had been working toward a synthetic organism since 1995.

In 2002, a rival group achieved a critical intermediate step by creating a synthetic virus first - a critical but intermediate step, since viruses, which must infect other organisms in order to reproduce, are not considered by biologists to be fully alive. That team, at the State University of New York at Stony Brook, built a replica of the polio virus from the basic DNA building blocks and then showed it could reproduce itself.

"We not only synthesized the DNA, but we booted it - meaning we brought it to life," said geneticist Eckert Wimmer, whose team hopes to eventually synthesize new vaccines.

Bacteria are considered fully alive. But they are also much more complex than viruses, with far longer strings of DNA making up their genetic codes. Venter's group chose M. genitalium (named for its tendency to infect human reproductive organs) because its genetic code is relatively short.

The researchers started building up small strands of DNA in a test tube, said Smith, and later injected them into yeast cells for final assembly.

Venter said he was confident that his team would successfully transplant their synthetic chromosome into a living bacterium. As a step in that direction, they transferred the genetic code from one bacterium to another last year.

The burgeoning field of synthetic biology isn't waiting for a complete artificial organism, said Rob Carlson, a physicist who works in synthetic biology through his Seattle company, Biodesic L.L.C. His group and a few others are already working on inserting synthetic DNA sequences into existing organisms, much like transistors in electronic circuits.

"It is already possible to design a new protein or genetic circuit at home on a laptop, send the sequence to a gene synthesis company, and get the DNA back by FedEx a few weeks later," he said.

He said he was optimistic that technology would soon lead to microbes that can produce new biofuels and much more.

Carlson also foresees the use of synthetic DNA in the manufacture of new vaccines. Synthetic DNA may prove critical for creating new vaccines quickly in the event of a pandemic flu or SARS-like outbreak, he said.

By creating genomes at will, engineers could potentially free themselves from the constraints of existing life, said Drew Endy, a biological engineer at MIT. Natural organisms are all capable of reproduction and evolution, for example, but artificial ones wouldn't have to be.

"We could make genomes that can't replicate, creating disposable biological systems," Endy said.

Smith, who has worked on the current project with Venter from the start, said his main interest was in understanding how life works. One of their goals is to pare it down to the simplest possible form, to figure out just how many genes are necessary for survival.

"That's a very fundamental thing to understand - what is the smallest number of genes necessary to support a cellular organism," he said, referring to the big question: What does it take to make something alive?