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Fast method to build genes found

Complete biological systems envisioned

A team of scientists announced yesterday it has found a fast and accurate way to build genes from scratch, a technique that could give scientists the practical tools to create life in a lab.

The researchers, at a Maryland lab led by geneticist J. Craig Venter, created a functional virus from basic chemical building blocks in just two weeks -- a feat that had previously taken three years to accomplish.

"This is a remarkable achievement," said Spencer Abraham, secretary of the Department of Energy, which sponsored the bulk of the research.

The technique is more flexible and accurate than anything previously available, meaning that it is now realistic to talk of building up the entire genetic code for a living organism, and possibly custom-building entirely new kinds of life with new abilities.

Though the work is likely to sharpen fears that biotechnology could put dangerous new tools in the hands of terrorists, its sponsors were quick to tout a more beneficial side.

"With this advance, it is easier to imagine, in the not-too-distant future, a colony of specially designed microbes living within the emission-control system of a coal-fired plant, consuming its pollution and its carbon dioxide, or employing microbes to radically reduce water pollution or to reduce the toxic effects of radioactive waste," said Abraham.

Before the work was publicized, officials at the Department of Energy consulted with the White House and the Department of Homeland Security to make sure there were no security concerns. And the paper describing the results, which will be published in the Proceedings of the National Academy of Sciences, was subjected to an extra level of scientific review, according to Venter, who heads the Institute for Biological Energy Alternatives in Rockville, Md., where the work was done.

After this review, the journal decided to make all the details of the technique freely available.

Most scientists consulted by the government believed that terrorists would be unlikely to use such a complex method to stage a biological attack when far simpler ones are available.

"I think the positive applications of this so outstrip the hypothetical negative ones that this will become a widely used technology," said Venter.

Yesterday's announcement is an outgrowth of a closely watched quest to understand the basic engineering of life. Every living thing has a set of genetic instructions, called a genome, which directs all its activities.

Venter, who was instrumental in sequencing the human genome, and his colleagues were working with a bacteria that has a very small genome when they started to wonder how small a genome could be and still function. What, they wanted to know, was the "minimum genome," the absolutely essential functions that life depends on?

To answer this question, which has enormous scientific and even philosophical implications, the team began looking for ways to build small genomes. That brought them into a burgeoning area of science known as "synthetic biology," where scientists hope to learn how to design and build biological systems the way they can now build machines.

Commercial companies can already produce small strands of DNA to order, matching any code that scientists want. But these strands, called oligonucleotides, cannot be longer than a few hundred letters of genetic code -- nowhere near the hundreds of thousands needed for even the simplest living thing.

Last year, a team of scientists at the State University of New York at Stony Brook announced that they had strung enough oligonucleotides together to build the genome of a polio virus. But the process took three years to complete and resulted in genetically weakened copies.

The advance reported yesterday relies on an ingenious series of tricks to coax small strands of DNA to assemble themselves quickly and in the correct order. Each oligonucleotide is built like a Lego block, with a unique series of bases at its end that will only connect to the next one in the series. Under the proper conditions, described in the journal article, all of the oligonucleotides will bump into each other and link up, forming the desired long piece.

The team proved that the technique is effective by synthesizing a virus known as "phi X174," which has a genome slightly shorter than the poliovirus.

The work was led by Dr. Hamilton O. Smith, scientific director of the lab, and Clyde A. Hutchison of the University of North Carolina at Chapel Hill. The two men, considered elder statesmen in the world of biology, spent long, exhilarating hours in the lab, pulling all-nighters and ordering pizzas as the work accelerated.

Yet the technical recipe they devised, scientists said, will be relatively easy to follow. "This is the enabling step for the field of synthetic biology," said Peter Sorger, associate professor of biology and biological engineering at MIT. The new process is so easy, he said, that "I could give this to undergraduates, and they could do it."

The next step for scientists is to synthesize the full genome of a microorganism, which is much longer than that of a virus. The new technique brings that goal closer, but does not solve all the problems researchers will face, scientists cautioned. The team has not yet tried it to build longer strands.

Even with strands of DNA as long as 5,000 base pairs, the approximate length of the synthetic virus's genome, the researchers will still need to find a way to join together about 60 of these long strands, at least, to form the genome of a living thing, Venter said.

Yet Venter said that he thinks his team could make such an artificial genome within a year of starting. The team has not yet begun this project, Venter said.

Then, if this is successful, the researchers would remove the natural DNA from a living cell and replace it with the synthetic DNA -- and pray that it works.

Last year, the Department of Energy announced a $3 million grant to Venter's team for the work. The department started the human genome project, so it has deep contacts in the community of gene researchers, and it has become increasingly interested in using microorganisms and genetic technology to solve energy-related problems.

The work has moved faster than anyone expected, Abraham said yesterday, and the department announced another $9 million grant to the Venter team last spring.

At yesterday's news conference, Abraham said the department was forming a new committee to look at ways of accelerating the research and find new applications for it in medicine, homeland security, and other areas.

The work also represents a legacy of the human genome project in another way, according to Dr. Leroy Hood, president of the Institute for Systems Biology in Seattle.

"It has us thinking about biology in big, bold ways that we didn't think about before," said Hood.

Gareth Cook can be reached at cook@globe.com.

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