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05 Nov 2002

Source: Washington Post, July 17, 2002.

Mail-Order Molecules Brew a Terrorism Debate

Virus Created in Lab Raises Questions of Scrutiny for DNA Suppliers

By Rick Weiss, Washington Post Staff Writer

The orders arrive by fax and e-mail 24 hours a day from pharmaceutical companies, government agencies and academic scientists. And every day at Integrated DNA Technologies, an army of machines responds by producing hundreds of batches of microscopic merchandise: custom-designed snippets of genetic material.

Until recently the Coralville, Iowa, company prospered in quiet anonymity, spewing out for scientists round the world various made-to-order pieces of DNA, the molecular code upon which so much biotechnology research depends today.

But last week's announcement that scientists in New York had used the company's mail-order molecules to make polioviruses from scratch has prompted questions about whether the DNA synthesis industry deserves closer scrutiny, and whether strategies for preventing the proliferation of biological weapons need to be rethought.

For decades the United States and other nations have sought to limit the risk of biological warfare and bioterrorism by placing controls on the cultivation and shipment of dangerous microbes. The new work threatens to undermine that approach by proving for the first time that potentially deadly viruses can be built from the ground up.

If infectious agents can be made from off-the-shelf smidgens of DNA that are individually benign, then government regulators, law enforcement agencies and even DNA synthesis companies may have no way of knowing when someone is building a biological bullet.

"The customer gets to design the sequence they want manufactured and there is a limited ability for us to know what people are going to do with it," said Roman Terrill, vice president of legal and regulatory affairs at Integrated DNA Technologies.

Indeed, Terrill said, with perhaps $10,000 and a few months time, motivated scientists could manufacture the genetic components of a deadly virus. "You could buy your own used DNA synthesizer," he said, "and make whatever you want in the comfort and privacy of your own garage."

Integrated DNA is one of about a half-dozen major U.S. manufacturers of small DNA strands, which are known in the trade as oligonucleotides or "oligos." The bigger companies, including Qiagen Operon of Alameda, Calif., Invitrogen of Carlsbad, Calif., and Sigma-Genosys of Woodlands, Tex., make thousands of customized oligos each day.

Each oligo typically consists of about 25 or 30 units of DNA, representing a tiny fraction of an organism's entire genome (a full viral genetic code can be tens of thousands of units long or more). Scientists generally use the oligos as molecular tools to help them find genes in various organisms or to trigger biological chain reactions that allow them to mass produce DNA strands in test tubes.

Because they are so small, most individual oligos lack any "fingerprint" that might identify them as part of something dangerous. But it was just such oligos that Eckard Wimmer and two colleagues at the State University of New York in Stony Brook painstakingly stitched together into a full length, 7,741-unit poliovirus genome, which spontaneously began making infectious polioviruses.

The feat arguably fell short of creating life from scratch because most scientists maintain that viruses are not truly alive. But the implications were clear.

"If you can go from a viral DNA sequence on paper to an infectious agent using things you can order out of catalogues, obviously that has big implications for bioterrorism," said Mildred Cho of the Center for Biomedical Ethics at Stanford. Two years ago Cho chaired an expert panel on the implications of creating novel life forms.

In fact, it was the Department of Defense that funded the three-year research effort as part of a program to devise protections against "unconventional pathogens." In a statement, the department said Friday it did not believe that the techniques could be used to build viruses with greater bioterror potential, such as smallpox. But others disagreed.

"With a little more advancement in technology you could probably make something more complex than polio," said Jim Cornette, a retired Air Force colonel with a doctorate in biochemistry who served in the Defense Intelligence Agency and was involved in biodefense planning during Operation Desert Storm. "Smallpox is probably just two or three years down the road, maybe less," said Cornette, who now lives in Florida. "Then what about the things that are 'none of the above?' Something dangerous but totally new?"

Several scientists said in interviews they would be reluctant to see new layers of oversight slapped on oligo makers, which have become to the biotechnology industry what silicon chip makers are to the computer industry. But many suggested the time was ripe for a public discussion about how best to prevent nefarious use of the science.

Today most biodefense efforts focus on disease-causing organisms themselves, rather than the genetic instructions for making them. Federal regulations restrict shipments of dangerous microbes and toxins listed by the government as "select agents," but those rules do not apply to shipments of their DNA components, at least within the United States.

DNA exports are more strictly regulated, with the Commerce Department requiring licenses for overseas shipments of DNA deemed a threat to national security. But those rules are open to interpretation and are easily flouted, scientists inside and outside the government said.

When Terrill of Integrated DNA wanted to learn more about the export rules last year, he went to the Commerce Department's Bureau of Exchange Administration (renamed in April the Bureau of Industry and Security), which oversees and enforces export rules for "dual-use" technologies, including microbial DNA strands. He learned that the bureau restricts exports of genetic sequences "associated with pathogenicity," which means the ability to cause disease.

"The problem is the bureau has not released those sequences, so ... we would have to decide for ourselves whether a sequence is associated with pathogenicity," Terrill said. "But how pathogenic? And what does 'associated' mean? The phrase is difficult to get a grasp on. It's not really a scientific term. It's a lawyer's term."

Moreover, Terrill learned, the 370-person agency has only one microbiologist on staff to deal with the hundreds of biological export applications the agency receives annually.

That employee was away and not available to be interviewed this week. But another Commerce Department official, speaking on condition of anonymity, confirmed that it is "the responsibility of the exporter" to determine if a genetic sequence falls under the bureau's rules.

The official said the bureau engages in "outreach activities" to educate academic and commercial scientists about the export restrictions. But the official also acknowledged that many scientists -- especially university-based researchers -- have a tradition of sharing DNA freely through the mail, making enforcement difficult.

In any case, scientists said, rules that focus on "pathogenic" DNA sequences are meaningless in an era when manufacturers can make pieces of DNA that are individually benign yet can pose a serious threat if properly assembled.

"I don't know how you could overcome that problem," the Commerce Department official said. "You could get one part [of the sequence] from one company and another part from another company and completely circumvent the law."

Some experts have begun to consider whether manufacturers themselves should be brought under some kind of oversight. "We propose that ... those companies that produce the oligos should be asked to routinely check the sequences against those of known pathogens," said Wimmer, the scientist who led the polio project.

Several computer programs, most notably one known as BLAST, can quickly scan the genetic sequence of a large piece of DNA and report whether it is similar to other known sequences, such as ones encoding parts of a virus or toxin. But company officials said they were not enthusiastic about taking on the cost or legal responsibility of fingering potential perpetrators.

In any case, said Garry Merry, corporate vice president of genomic services at Qiagen Operon, a scientist could evade BLAST's eyes simply by ordering DNA components small enough to be completely generic, then assembling them later. "You could do it," Merry said, "and we couldn't tell."

As an alternative, some are calling for extra layers of institutional review for researchers who, like Wimmer, propose combining genetic components to make viruses or other dangerous entities.

"I would argue there needs to be more oversight in terms of getting approval," said Arthur Caplan, a University of Pennsylvania ethicist who sat on Mildred Cho's expert panel. "Are we going to be seeing this kind of thing done in a science fair soon? I'm in favor of tighter controls."

Craig Venter, president of the Center for the Advancement of Genomics in Rockville who last week called the polio work "irresponsible science," said the nation might need a special advisory committee to publicly review all such studies in advance, just as a National Institutes of Health panel reviews proposed gene therapy experiments as a way of watching for trouble and reassuring the public. Without such openness, Venter said, "this kind of work can set science back in the public eye."

But while institutional or government review may bring more oversight to legitimate research, others said, it's unlikely to deter those who wish to keep their work secret. And with the biotech revolution now 30 years old -- and trade in aftermarket equipment burgeoning -- deterrence may be difficult.

"You can buy an old synthesizer and some raw ingredients and no one would have any idea what you're doing or what you're making," said Terrill of Integrated DNA. With an old machine, he said, "it might take you a week longer. They're big and clunky. But a week isn't that long."