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Playing God in the Lab

THE BALTIMORE SUN

Think of how the Internet changed communications, or how the assembly line revolutionized manufacturing. That's what scientists say is happening today in the life sciences, thanks to an emerging field called synthetic biology. The new field, they say, could finally make good on the promises of the 30-year-old genetics revolution and deliver a flood of new drugs, therapies and diagnostic techniques.

But many scientists and government officials also fear that in the next few years researchers working alone or in small groups will be able to manufacture hard-to-obtain germs, like the smallpox and ebola viruses, using only a few thousand dollars' worth of lab equipment and chemicals. It is already possible to manufacture some simple but dangerous viruses, including tick-borne encephalitis.

And some governments may be tempted to use the technology to develop new, more terrifying bioweapons - organisms that resist all known drugs and vaccines, say, or that shut down the immune system.

Scientists are now tinkering with life more quickly, cheaply and extensively than was possible just five years ago.

Biologists are using computers to design arrays of genes and making them with off-the-shelf chemicals in their own labs. Strands of manmade DNA also can be ordered online - and delivered by FedEx.

In 2002, Eckard Wimmer and his lab at the State University of New York at Stony Brook demonstrated some of the power and danger of this technology. They synthesized the complete genetic code of the polio virus using mail-order DNA and the microbe's genetic sequence, posted on the Internet.

Researchers at the U.S. Centers for Disease Control and Prevention last year used similar techniques to re-create the long-extinct Spanish flu virus, which killed up to 100 million people across the globe in 1918-1919. Scientists at the University of Wisconsin-Madison in April created a new form of the Escherichia coli bacterium, a major cause of diarrhea.

Until recent years, scientists were limited to cutting and pasting genes from one organism to another. In this way, they have made bacteria that produce insulin and human growth hormone, and have bred goats that produce human antithrombin - which regulates the coagulation of blood - in their milk.

Synthetic biology makes it possible, in theory, to do much more: to re-create whole genomes - an organism's complete genetic library - from scratch. One day, it may produce synthetic organisms never previously seen in nature.

The new approach in biology is the unforeseen result of the convergence of progress in several other fields, including computer and materials science. Because it has developed so rapidly, there are, researchers say, still significant gaps in regulation and oversight.

George M. Church of Harvard University says that synthetic biology is one of those rare disciplines with the power to "disrupt" the social, economic and cultural landscape. "Synthetic biology is growing exponentially," Church said, "and it's hard to be exponential without being disruptive."

Two years ago, Church started calling for the scientific community to push for voluntary and regulatory controls. The government, Church said, should monitor the sales of chemicals and lab equipment used to synthesize DNA.

Universities where young molecular biologists train should keep track of their alumni, he said, so no one "disappears" into the world of clandestine research, whether it is a government lab or a jihadist cell.

Scientists who conduct research that could be used to make bioweapons, Church said, "should be voluntarily or involuntarily under surveillance."

But Church and other scientists don't want strict rules that ban certain research outside federal labs, like those being built at the $1.2 billion National Interagency Biodefense Campus in Fort Detrick.

If that happened, Church said, only scientists who were interested in bioweapons research would wind up using the new technology. "You would end up exactly with the 10 people in the world working on it who you don't want working on it."

Some of Church's ideas were incorporated into a proposed voluntary code of conduct considered by researchers last month at a conference called Synthetic Biology 2.0 at the University of California, Berkeley.

Yet the idea of a voluntary code was rejected by the assembled scientists, after Greenpeace International, the United Kingdom-based GeneWatch and 36 others issued a letter that called for a "global societal debate" over the implications of the field and mandatory government rules.

A federal law requires universities and the National Institutes of Health to monitor research into 41 biological agents and toxins that pose a severe threat to public health and safety. But with synthetic biology, relatively harmless microbes may be rendered lethal.

"The Department of Health and Human Services is concerned about whether or not there may be additional need for oversight for this new technology," said Mark Hemphill of the Centers for Disease Control, part of Health and Human Services.

The department in November created a working group on the hazards of synthetic biology within the National Science Advisory Board for Biosecurity. The working group's recommendations are due in July.

The stakes are high. An article in the current edition of the journal The New Atlantis reported that synthetic biology could "bring about epochal changes in medicine, agriculture, industry, ethics, and politics, and ... may have a profound influence on the definition of life."

The field is already transforming the hunt for new medicines. The Bill and Melinda Gates Foundation in 2004 donated $42.6 million to the University of California, Berkeley, as part of a program to make a cheaper, synthetic form of the highly effective malaria drug artemisinin, now extracted from wormwood. To produce the compound, researchers plan to create a novel chain of interacting genes, called a gene circuit, to produce a precursor to the drug.

Scientists hope to use the new technology to make cells that fight cancer or regenerate tissue. They may one day manufacture genes or whole organisms to make new chemicals or fabrics, detect and neutralize pollutants or, perhaps, mass-produce hydrogen or ethanol fuel.

The technology for synthesizing large pieces of DNA has swiftly advanced. As a result, the cost of purchasing mail-order DNA has fallen 50 percent per year in each of the past three years.

Today, some companies are offering DNA at a cost of $1.25 for every nucleotide base pair - the chemical units that make up strands of DNA.

Drew Endy, a biological engineer at MIT, said the new technology coupled with the Internet will make it possible for scientists and students around the world to do advanced genetic research. "We're perhaps on the cusp of broader access to biological technology," he said.

Endy is president of the BioBricks Foundation, which has created a Web site where anyone with the proper training can design new circuits of genes from a selection of functional segments of DNA.

Scientists have used the BioBricks site to make genes that, when inserted into bacteria, make them flash on and off like marquee lights. Other bacteria have been engineered to record images like a photographic negative.

These are playful efforts, but some experts are nervous about making such potentially powerful tools so freely available.

Jonathan B. Tucker, a biological weapons expert at the Monterey Institute's Center for Nonproliferation Studies, called MIT's Endy "a bit naive" for his belief in sharing the technology as widely as possible. "He's very idealistic," Tucker said. "He thinks that if you make this technique open that people will use it for good purposes. I hope he's right."

In the March/April edition of MIT's Technology Review, author Mark Williams outlined a darker view of the new genetic technology. There was, he reported, a "consensus" among researchers that the field had "advanced to the point that terrorists and rogue states could engineer dangerous novel pathogens."

Williams cited the work of Mark Buller of Saint Louis University. In 2003, Buller announced he had created a highly lethal form of the mousepox virus by splicing in a gene that makes Interleukin-4, or IL-4. Mousepox, a relative of smallpox, can't harm humans but affects rodents. The modified virus, the scientist said, was unusually lethal - it killed 100 percent of the mice infected, even those treated with antiviral drugs and vaccines.

"What would happen if bioterrorists spliced IL-4 into chickenpox and released the hybrid into the population?" Williams wrote. Maybe nothing, he acknowledged. But it could turn chickenpox into a highly lethal disease. Modification of the virus, he wrote, could be done by a competent molecular biologist at a cost of about $10,000 in equipment and materials.

Despite the concern of many scientists, some bioweapons experts say the fears are overblown. In a book last year, Assessing the Biological Weapons and Bioterrorism Threat, Milton Leitenberg, a biowarfare expert at the University of Maryland, College Park, wrote that the threat of bioterror "has been systematically and deliberately exaggerated" by an "edifice" of government-funded institutes and experts who run programs and conferences.

Germ weapons need to be carefully cultured, transported, stored and effectively disseminated, said Raymond Zilinskas, a policy expert and biologist at the Center for Nonproliferation Studies. Groups like al-Qaida and Japan's Aum Shinrikyo attempted, and abandoned, efforts to make germ weapons because the task was too difficult.

National governments are far more likely to exploit synthetic biology for weapons production, many nonproliferation experts say.

According to the Web site of the Nuclear Threat Initiative, China, Iran, Syria, North Korea and Israel have all been accused by the U.S. government of secretly developing bioweapons. Moscow once had a massive biological weapons program, and may still have the capability to develop new agents.

A 2001 Pentagon report said "some elements" of the former Soviet bioweapons program "may remain intact and could support future agent production."

Synthetic biology could make such research much simpler, and "may have a significant impact on the future of bioweapons," said Alan Pearson, director of biological and chemical weapons control at the Center for Arms Control and Nonproliferation in Washington. "Whether it does or not is going to depend on how we handle it."

douglas.birch@baltsun.com

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