Detecting Bioterrorism

Lives could be saved by sensors and therapies now under development-along with software that could help distinguish an anthrax assault from an outbreak of the flu.

As always for a presidential inaugural, security and surveillance were extremely tight in Washington, DC, last January. But as George W. Bush prepared to take the oath of office, security planners installed an extra layer of protection: a prototype software system to detect a biological attack. The U.S. Department of Defense, together with regional health and emergency-planning agencies, distributed a special patient-query sheet to military clinics, civilian hospitals and even aid stations along the parade route and at the inaugural balls. Software quickly analyzed complaints of seven key symptoms-from rashes to sore throats-for patterns that might indicate the early stages of a bio-attack. There was a brief scare: the system noticed a surge in flulike symptoms at military clinics. Thankfully, tests confirmed it was just that-the flu.

While the January monitoring revealed nothing unusual, the deployment was just one more indicator that, long before the September 11 attacks and subsequent letter-borne anthrax assaults, U.S. security experts were taking seriously the threat of a large-scale biological attack. And for good reason. Not only could bio-agents covertly released by terrorists potentially kill hundreds of thousands, but they are extremely difficult-with currently available technology-to detect in the environment. A successful attack with biological agents-anthrax, smallpox and bubonic plague top the most-feared list-might only become clear days later, when people became seriously ill and were beyond the help of available treatments. And unlike anthrax, many bio-agents are contagious, so in any time lapse before health officials recognized an attack, victims could multiply its effect by spreading disease to others.

Already, terrorists have shown they can obtain and deliver anthrax on a small scale, and experts believe a determined group could conceivably accomplish a much larger-scale bio-attack-though it wouldn’t be easy. “The level of sophistication that went into the World Trade Center attack, if applied to a chemical or biological attack, could produce an effective effort,” says George Whitesides, a Harvard University chemist researching treatments for anthrax. “It is technically feasible. Whether it is politically or operationally feasible, and at what scale, we don’t know. Nonetheless, we will have to prepare for the possibility, because we need an insurance policy.”

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That insurance policy will likely include a broad array of new technologies on at least three fronts: improved portable devices to detect and identify biological agents; new data-mining efforts to seek subtle bio-attack indicators like a spike in certain patient symptoms at emergency rooms; and improved therapies for victims. A number of these technologies have been under development for years, but in the aftermath of September 11, they’re getting a renewed burst of attention from government, academic and industrial researchers.

The urgency is felt because current technologies are not ideal for meeting the threat; for one thing, they can’t provide continuous air monitoring. Existing portable, briefcase-sized devices-including one from Sunnyvale, CA-based Cepheid that adapts established laboratory DNA tests-can identify pathogens in 15 to 20 minutes, and state and federal public-health laboratories are now widely using them for rapid, precise identification of suspected anthrax strains and other pathogens. But the devices only work with liquid samples-like water from a reservoir, or a sample swabbed from a solid surface-that generally take an hour or more to prepare. According to most experts, however, an airborne attack is more likely than a water-borne one and could be far more damaging.

In the coming months, the U.S. Department of Defense hopes to roll out a new truck- or ship-mounted system that continually samples and tests air for worrisome pathogens, says Calvin Chue, a microbiologist at the Center for Civilian Biodefense Studies at Johns Hopkins’s Bloomberg School of Public Health. The system, being manufactured by DeLand, FL-based Intellitec and Columbus, OH-based Battelle, uses a laser system and software developed at MIT’s Lincoln Laboratory to continually screen microscopic particles in the air. When something worrisome shows up, a detector mixes an air sample into a solution and tests for up to 10 pathogens using thin paper strips, each bearing antibodies for an anticipated biological agent. The device can operate autonomously, beaming results back to a base station; new cartridges can be inserted to test for different pathogens. In addition, Cepheid is adapting its detection system for use in the air sampler.

But existing antibody- and DNA-based detectors are limited in the number of pathogens they can identify. Future portable sensors are expected to use DNA chips that could screen for hundreds of possible threats. These chips carry small fragments of DNA from pathogens that could serve as bioweapons; the fragments bind to any complementary pathogen DNA that might be present. Using such chips to detect bio-agents is now possible but requires a lab full of equipment to prepare samples and analyze the results. “If we could shrink those down in a portable, fieldable unit,” Chue says, “you could look at hundreds of organisms, potentially in 10 to 15 minutes.” In the late 1990s, Affymetrix, a leading DNA chip maker, built a prototype system about the size of a large microwave oven. “There’s a fair bit of work needed” to turn it into a practical field device, says Robert Lipshutz, Affymetrix’s vice president for corporate development. “We’re not saying where that program is at this time.” Like the existing sensors, Affymetrix’s detector will only work on liquid samples, but Bill Altman, biosensor program manager for Battelle, says DNA chip systems could be adapted to work together with an air sampler, creating a powerful, versatile bioterrorism monitor.

Farther on the horizon are sensors that would harness the exquisite sensitivity of live cells to detect biological agents. While DNA arrays can only detect what they’ve been set up to find, whole-cell sensors could reveal unforeseen agents. These systems can also determine whether a pathogen is alive or dead-key to establishing its virulence-and eliminate the need to preprocess samples. Dozens of academic, corporate and federal labs are working on the technology. And while each version functions differently depending on the kind of cell being used-heart cells, neurons, white blood cells and liver cells are among those being tested-they operate on the same basic principles. When a pathogen invades a cell, the cell releases proteins, changes size or alters its metabolic rate; sensors can measure these changes electrically or optically.

But using cells as sensors is tricky; a detection device would require systems to keep cells alive and nourished. Although whole-cell sensors are probably two to five years away from field use, a clear sense of urgency has gripped the research community. “There is a palpable feeling that we need to bust ass and get this thing out,” says MIT chemical engineer Linda Griffith, who is developing a liver-cell-based sensor chip to detect bio-agents like aflatoxin, a compound produced by fungi, which attacks the liver.

With airborne-pathogen detectors  still in the lab, just realizing that an attack is under way could take precious time. So computer scientists are developing warning systems to spot early indicators of a biological attack, from troubling trends in patient symptoms to increases in school absenteeism. Known as bio-surveillance, the field aims to use data-mining techniques to recognize an epidemic days before the first cases are confirmed, says Kenneth Mandl, a pediatric emergency physician and informatics researcher at Children’s Hospital Boston.

Mandl and colleagues at MIT’s Laboratory for Computer Science have devised a computerized tracking system that uses emergency-room intake information to monitor the frequency of rashes, fevers, coughs and intestinal problems, symptoms associated with common ailments that would, however, appear in uncommonly large numbers in the event of a deadly biological attack. Effectively protecting a city or large population, however, requires linking reports from many medical facilities. Mandl and his counterparts at other hospitals are now working on a system that would do just that. It won’t be easy; hospitals use a hodgepodge of computer programs and don’t collect patient information in uniform ways. Still, Mandl says, “it’s an important public-health measure to take. Most likely, the way this will eventually happen on a large scale is when it becomes a mandated reporting obligation.”

It was just this type of system that the U.S. military tested at Bush’s inaugural. Its detection of a flu outbreak was an encouraging sign that such a system could sniff out-and make sense of-a particular pattern of symptoms. Now, efforts sponsored by the Department of Defense are under way to build a far more sophisticated early-warning system that would look beyond hospital information to include more subtle trends like hits on health-related Web sites, purchases at pharmacies and grocery stores (think orange juice and cough syrup), school attendance-even visits and inquiries at veterinary clinics and agriculture offices, since a bio-attack could affect animals and plants, too. Researchers at university, corporate and military labs are working on elements of this ultimate bio-surveillance tool; a prototype is due in 2004.

Even with early warning from bio-surveillance software and sensors, victims of a biological attack could face grim survival odds; 30 percent of smallpox sufferers die, as does nearly everyone who inhales or ingests anthrax and doesn’t quickly get antibiotics. To improve those odds, health officials are stockpiling vaccines; with smallpox inoculations discontinued in the 1970s, for example, and the vaccine effective for only about 10 years, the U.S. population is susceptible to infection. Last year, the U.S. Centers for Disease Control and Prevention contracted Cambridge, MA-based Acambis to provide 40 million doses of smallpox vaccine over 20 years. The vaccine could both protect the unaffected and save the lives of those already infected by decreasing the severity of the disease. And one month after the terror attacks, the Bush administration greatly accelerated this effort, asking Congress for $509 million to buy 300 million doses to be delivered in 2002.

Researchers are also developing treatments to combat other diseases caused by bio-agents. An anthrax antidote developed by Harvard’s Whitesides and Harvard Medical School microbiologist R. John Collier is in the pipeline. In early tests, the treatment has cured rats exposed to anthrax toxin. The anthrax bacterium produces both a deadly toxin and a protein that creates a donut-shaped channel in the wall of a target cell to let the toxin in. The potential drug consists of a molecule that acts like a strip of Velcro, binding to the donut and shutting out the toxin. Collier says he plans to further study this treatment using actual anthrax stored at military facilities. “There is a lot of activity right now in putting together a biotech company that will work closely with government agencies to develop this rapidly,” he says.

No level of preparedness-and no technological advances-can completely eliminate the threat of biowarfare. But as researchers at labs around the country begin delivering technology that sniffs the air and watches hospitals, that threat should become a whole lot smaller.

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