(© BRIAN STAUFFER) 

Seeking Security For Synthetic Genes

In the 6th century B.C., Assyrian warriors attacked their enemies by poisoning their wells with rye ergot, a fungal toxin. Today, thousands of years later, concerns about the destructive potential of biological
products fuel security discussions about a far more advanced technology: the creation of synthetic genes. As Ralf Wagner, chief executive officer of Geneart in Regensburg, Germany, explains, "The importance of gene synthesis in helping to tackle some of the world's most pressing issues—climate change, hunger, disease and even biosecurity itself—makes it critical for our industry to be completely secure." Concerns about the misuse of synthetic genes increased when the 9/11 attacks caused governments to evaluate emerging security threats, just as the commercial gene synthesis industry was developing.

Over the past decade, makers of synthetic genes have responded to these concerns with measures to screen both customer orders and the clients themselves. Although they generally have considered it unlikely that a terrorist could use their products in an attack, companies have always screened orders in some way, such as comparing ordered sequences against GenBank, the DNA-sequence database maintained by the U.S. National Institutes of Health. After linking an ordered sequence to a known gene, the company can then see if the gene's product shows up on, say, the Select Agents and Toxins List, which is curated by the U.S. Centers for Disease Control and Prevention and the U.S. Animal and Plant Health Inspection Service. Other procedures are used to screen customers, such as con rming a university affiliation or checking them against government export control lists.

Despite the fact that different companies could use different sequence screening techniques with equally safe results, industry leaders maintain that inconsistencies might raise public concerns. "It was clear from 2006 that the U.S. government had a mandate to take steps that would reduce the perceived risks created by synthetic genes," explains Damon Terrill, general counsel for international legal and regulatory affairs at Integrated DNA Technologies (IDT), headquartered in Coralville, Iowa. "We recognized that harmonizing customer and sequence screening approaches among the major genesynthesis companies would make that screening more effective, while at the same time providing the government with a better sense of how exactly the industry was working to reduce risk."

PILES OF PROTOCOLS

In November 2009, proposed screening protocols were presented by the International Association Synthetic iology (IASB), the International Gene Synthesis Consortium (IGSC)—made up of Blue Heron Biotechnology, Bothell, Wash.; DNA2.0, Menlo Park, Calif.; Geneart; Genscript, Piscataway, N.J.; and IDT—and the U.S. Department of Health and Human Services (HHS). In general, the protocols suggest similar guidelines: screen the sequences of allorders for double-stranded DNA composed of 200 or more base pairs, and screen the customers, as well.

Members of the IGSC—a group comprising the world's largest synthetic-gene makers—even expect their protocol to help the member companies. "We had already built a database in-house," says Claes Gustafsson, DNA2.0's vice president of sales and marketing, "and other companies have done so as well." Now, he continues, different ffrms can combine these internal databases so that "A couple genes that we missed can be incorporated from the databases of others, and they can incorporate [genes] from our database."

It sounds easy enough to keep a database updated, but special constraints arise when dealing with potential pathogens. Many toxin lists only give a gene's name, not its equence, Gustafsson explains, so someone must do extra work when relevant new information becomes available. "The sequence has to be created nd curated, so we can combine the efforts of the ffve companies to manage the database," he says.

Since the IGSC database is currently for members only, other companies will need access to a different
database—one that includes as many potentially hazardous sequences as possible. When asked how difficult t might be to keep such a database current, Peer Staehler, chief scientific officer of commercial sequencer febit, in Heidelberg, Germany, and a board member of IASB, quickly replies, "Very doable," but then adds, "it requires ome effort." For that effort, he and his colleagues in IASB envision an annual or biannual meeting. "It ould be government supported maybe," Staehler says. "Maybe a dozen people—pathogen experts and some embers of the scientific community—could get together and exchange thoughts and curate lists, maybe add  new virus or an additional strain of E. coli."

A Dialogue Among Stakeholders

In addressing the screening protocol suggested by HHS, Staehler says it is "a good step in the right direction." He goes on to stress that, "It should continue to evolve. It should be a discussion."

In fact, the discussion is underway. Some experts, for example, describe the U.S. government guidelines as too lax. In the January issue of Nature Biotechnology, Markus Fischer of Entelechon, in Regensburg, Germany, and Stephen Maurer, of the University of California, Berkeley, wrote: "[I]t seems strange for government to tell companies that current screening programs are in effect, too ambitious. Given that most companies have already volunteered for a high standard, government should do no less."

Although many experts in the industry think the U.S. government's suggestions for sequence screening
seem achievable, the same cannot always be said of customer screening. "There is no tool that makes customer screening easy," Staehler explains. "It's not clear, especially in the U.S., what customer information you can get and use in terms of privacy."

Further, instead of ordering a dangerous gene, a would-be bioterrorist might just make one. "My guess
is that 50 percent of synthetic genes are homemade by a graduate student in some lab," says Gustafsson. "It's not that complicated to make easy ones." As far as protocols are concerned, he continues, "You can put all the guidelines you want on industry, but if 'Mr. Evil' wants to do something stupid, he can make it in a high school lab." 

On the other hand, not everyone thinks that do-it-yourself gene-making is so easy. "It takes quite some effort to establish a lab for this," Staehler says. "It is doable, but requires some skill." With the right equipment, most anyone can make a short stretch of synthetic DNA, but the potential for errors increases with length. Consequently, Staehler concludes, "The risk here is medium to low."

Whatever the risk—from DIY gene makers or company customers—this discussion will continue. The ultimate control must find a balance between preventing bioterrorism while allowing legitimate scientists
to use genes to advance a range of biotech applications, from healthcare to energy and beyond.