Attack of the Killer Microbes

There’s a new weapon in the war against bio-terrorism: biotechnology.

Dozens of companies, often working closely with university scientists, are developing novel ways to detect and block biological warfare agents, including microbe-killing skin lotions and an updated version of the gas mask.

The potential threats are as chilling as any biblical plague: anthrax spores that, when inhaled, are almost universally fatal; the smallpox virus, which can spread like a grass fire through a largely unvaccinated population; and even plague itself, the bug that changed the face of European history.

In theory, hostile countries, apocalyptic cults or roving terrorists could deploy these and other killer microbes, creating havoc on the battlefield or in cities.

The threat of bio-weaponry is being taken seriously, largely because of reports that several nations have stockpiles of biological agents. Among them are Iraq and Russia, both of which signed a 1972 treaty that called for a ban on biological weapons.

The fears took on a new urgency in 1995 when a Japanese religious cult released the deadly nerve gas sarin in the Tokyo subway system, killing 12 people. That attack reportedly came after a series of failed attempts to release deadly bacteria at different points around Tokyo.

The national Centers for Disease Control and Prevention in Atlanta reported a series of incidents late last year in four states, including California, where anthrax releases were threatened. All proved to be hoaxes. But the scares revealed how vulnerable the U.S. may be in the face of a genuine attack.

The federal government has dramatically increased spending in preparation for possible attacks on civilian populations and the panic that might follow. The military is playing a key role in developing vaccines and detection equipment to protect soldiers in the field.

Probably the most innovative responses are being underwritten by the Defense Advanced Research Projects Agency, a Defense Department branch that claims credit for such past advances as the Internet, stealth aircraft and the M-16 assault rifle.

One team funded by DARPA grants is working on a disinfectant made of microscopic droplets of soybean oil--a microbe-killing mayonnaise that should be harmless to humans and even edible. Another researcher has found a way of attaching antimicrobial agents to a person’s own red blood cells. It could help protect soldiers heading into a biological warfare zone or a cleanup crew responding to a terrorist attack.

One company has found a way to make antibodies out of plastic; they can be stored indefinitely and customized quickly in response to exotic diseases. Other researchers are designing protective gear, including a 21st century version of the gas mask, to trap bio-warfare agents and convert them to harmless carbon dioxide.

DARPA officials know that not all of these efforts are likely to succeed. The idea is to unleash brilliant minds on significant problems in the search for unconventional solutions, says Dr. Shaun B. Jones, a Navy Medical Corps commander who heads the agency’s unconventional pathogen countermeasures program.

The agency, says Jones, is looking for “extraordinary breakthroughs, and to achieve those we tolerate extraordinary failures.” Typical grants range from $1 million to $2 million a year.

The successes could be felt far beyond the world of bio-terrorism. All of society could benefit from new ways to detect epidemics and combat diseases.

The scientists themselves say at least some of their DARPA-financed work would never be funded by the relatively staid National Institutes of Health.

When the program was just gearing up two years ago, a headline in the journal Science advised grant-hungry scientists: “Too Radical for NIH? Try DARPA.”

The Pentagon likes what it’s seen so far. The Clinton administration is calling for a 70% increase in DARPA’s biological warfare research budget, to $146 million a year.

Nature has provided an abundance of deadly agents for would-be bio-terrorists and bio-warriors to choose from, including anthrax; smallpox; plague; and the Ebola and Marburg viruses, which cause hemorrhagic fever.

The attack scenarios are not pretty.

“The release would be silent and would almost certainly be undetected,” Dr. D.A. Henderson of the Johns Hopkins School of Public Health wrote in Science earlier this year. “The cloud would be invisible, odorless and tasteless. It would behave much like a gas in penetrating interior areas. No one would know until days or weeks later that anyone had been infected [depending on the microbe]. Then patients would begin appearing in emergency rooms and physician’s offices with symptoms of a strange disease that few physicians had ever seen.”

Some worry that genetic engineering could be applied to ordinary viruses and bacteria, making them more deadly and difficult to treat. But Henderson, who led the successful international program to eradicate smallpox, doubts that would happen.

“Anthrax and smallpox are pretty hard to improve on,” Henderson said in a recent interview. “They’re pretty lethal.”

Both Russia and the United States have kept limited stores of the smallpox virus under tight security for possible research use, but there’s concern that the virus could be in the hands of other nations as well. And without vaccination, the disease could spread through a population like wildfire in August. Current stores of vaccine are deteriorating and likely to be inadequate in the face of a terrorist-caused epidemic.

Anthrax, a disease of sheep and cattle that rarely infects humans, is considered a chief threat. The bacteria form spores, dry microscopic particles that are tough to destroy and can persist in the environment for decades. Disperse the spores in the air and they are easily inhaled, implanting themselves in the lungs like seeds. Days or weeks later, symptoms appear, starting like a cold but progressing to severe breathing problems and shock. Unless treatment begins early, antibiotics do not work and the person dies a few days after the first signs of infection.

Because no one is sure of what contagions to expect, DARPA is investing heavily in research to find defenses that will apply to a broad variety of infectious agents.

Dr. James R. Baker Jr. and his colleagues at the University of Michigan have discovered a simple way to kill anthrax and a variety of other disease-causing microbes on contact, using a solution of extremely tiny droplets of soy oil suspended in water. Baker compares the white concoction--called a nanoemulsion--to mayonnaise or, when it’s diluted, skim milk.

The uniform droplets in the mixture fuse with the outer coats of viruses or the walls of bacteria in an energy-releasing chemical reaction, destroying the microbes in a silent explosion.

The scientists have shown that their nanoemulsion can decontaminate surfaces and, when applied directly to wounds, speed healing. Yet it appears to be harmless to humans and other animals. The only damage to laboratory rats that were fed the stuff was weight gain from the added fat. Baker himself has tried a sample, flavored with peppermint chocolate, without ill effect.

“If someone throws [anthrax] into a New York subway, I believe in a couple of years we’ll be able to go in with an appropriate spraying mechanism and decontaminate the place,” he said. The only way to do that now is with powerful and highly toxic chemicals, bleach or formaldehyde.

The soy emulsion is so gentle that Baker’s team, which is working with biotech company Novavax in Columbia, Md., has proposed using it as a skin cream or nasal spray to block infections, reasoning that if it works for biological warfare agents, it could also work for the flu.

The defense agency is also funding efforts to manufacture artificial antibodies in large quantities to fight off or prevent infections in circumstances when it’s too late for a vaccine or no vaccine is available.

Chemical engineer David Soane, a UC Berkeley professor-turned-entrepreneur, is using technology he employed to manufacture plastic eyeglass lenses to make artificial antibodies out of plastic building blocks called monomers.

The monomers have heads that are attracted to the electrically charged surfaces of bacteria, spores and viruses. They converge on their targets the way sperm converge on an ovum, Soane said. Once in place, the monomer tails can be joined together. The resulting plastic antibody is like a tight-fitting rubber glove that retains its shape and is able to bind with the infectious agent but not anything else.

Soane hopes the artificial antibodies can be used in inhalers, creams and oral solutions to protect the lungs, skin or digestive tract--the usual entry points for bio-warfare agents. Unlike natural antibodies, which are hard to produce in needed quantities and difficult to store, these could be assembled and produced quickly from off-the-shelf components in response to a specific threat.

The bio-terrorism defense effort recognizes that it is vital to develop new kinds of antibiotics and antiviral agents because the current crop is useless against many of the killer microbes.

Scientists at Isis Pharmaceuticals in San Diego, for example, have a DARPA grant to develop a new class of antibiotics that stop bacteria by disabling their RNA, or ribonucleic acid, a natural substance vital to the health and maintenance of all living things.

Researchers at a smaller San Diego company, EPIcyte, are part of an effort to create a unique delivery system for powerful antibiotics--to get them to the linings of the lungs, nose and intestinal tract where bio-warfare agents are likely to enter the body.

The company is working with naturally occurring molecules that normally deliver antibodies to the body’s inner linings. The idea is to attach antibiotics to these molecules to deliver them where they can do the most good. “We’re the United Parcel Service of this project,” said EPIcyte President Mich B. Hein.

Essential to improving the response to biological agents is better protective gear for troops in the field and civilian cleanup crews.

Scientists at Caltech in Pasadena, Northrop Grumman in Long Island, N.Y., and Bell Sports in San Jose are developing what they describe as a revolutionary protective helmet--the first fundamental redesign of the military gas mask since World War I.

Caltech professor Michael Hoffmann has developed a filter made of tightly woven optical fibers that can trap particles and then disintegrate them after being activated by ultraviolet light--converting the microbes to harmless carbon dioxide gas.

Unlike existing gas masks, this one is designed to be comfortable to wear and easy to breathe through. “The prototype is similar to a NASCAR racer’s helmet,” Hoffmann said.

Another company, Molecular Geodesics in Cambridge, Mass., is developing “artificial smart skins,” comfortable fabrics that can be used in garments and that will trap and destroy biological warfare agents on contact.

One of the problems posed by bio-warfare is the difficulty in promptly spotting an attack and identifying the agent. A number of companies are working on highly automated, portable devices that the military or emergency workers could use in the field. One of the devices, developed by Cepheid in Sunnyvale, Calif., can detect the presence of pathogens in minutes. Away from the battlefield, the same technology could be used to detect salmonella in a food-processing plant or other disease-causing organisms in drinking water.

A Boston University biomedical engineer, Mark W. Bitensky, has an even more unconventional approach to detecting bio-warfare agents. He’s found a way to attach specially designed molecules to red blood cells that release a chemical signal into the bloodstream when a bio-warfare agent is present. The individual would know he’s been exposed because he could taste or smell the chemical signal. Because the modified red blood cells remain in the circulation for as long as 100 days, they would provide around-the-clock surveillance.

In a variation of the same approach, a small percentage of red blood cells would be outfitted with enzymes that could detoxify any bio-warfare agents they encountered. Bitensky’s ideas were ridiculed at first because there “was no scientific literature or basis for doing this,” said DARPA’s Jones. But early animal experiments show the approach may well work, Jones said.

The federal funding is of particular value to biotech companies that are hard-pressed these days to come up with dollars from the private sector for early-stage research. And it comes with remarkably few strings attached.

Unlike other defense research contracts, the scientists are encouraged to publish their results--secrecy and security are not issues.

While the Defense Department retains the right to develop the technology if the investigators do not, the companies are allowed to market any products that grow out of the research.

That could mean big profits for innovative approaches that pan out.

“If we meet all the criteria we want to achieve, we’ll have a blockbuster antibacterial drug,” said Isis Pharmaceuticals’ David Ecker. “Here we have commercial and military opportunities that are congruent.”

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Attacking Bio-Terrorism

To prepare for possible bio-terrorist attacks, the federal government is funding a variety of new approaches that make use of the latest advances in biotechnology. Some of the most innovative work is being underwritten by the Defense Advanced Research Projects Agency, a Pentagon branch that helped give birth to the Internet, the computer mouse and stealth aircraft technology. Among the bio-terrorism countermeasures being explored:

Disinfectants: Scientists are working on materials that would clean up a site after a bio-terrorism attack or after an enemy has delivered a biological warfare agent, destroying the microbes on contact without polluting the environment. They might also be used to protect the skin, lungs or nasal passages. One solution is a mayonnaise-like emulsion made of soy oil that would kill microbes but would be harmless--even edible.

Antibodies: One company is working on plastic antibodies that could be quickly manufactured on a mass scale from off-the-shelf components and deployed in response to a specific biological threat. Other biotech firms are working on antibodies produced in a special breed of mice to counter smallpox and other, more exotic viruses.

Antibiotics: Researchers are working on new classes of antibiotics and antiviral agents to fight diseases for which there is no cure or that have become resistant to drugs currently available.

Protective gear: University and company scientists have joined forces to produce a gas mask that traps bacteria, viruses and chemicals in a fiber-optic net. A pulse of light would turn the agents into harmless carbon dioxide gas. Other firms are working on protective skins and fabrics that would do the same thing, enabling soldiers on the battlefield or civilian cleanup crews to safely enter contaminated areas.

Detection systems: Biotech firms are working on portable systems that could quickly identify any one of a host of bio-terrorism agents, using the latest DNA technology. Similar devices, for detecting common disease microbes, could soon be coming to your physician’s office.