Biological warfare

Zipping up bio-war viruses
Viruses. Little more than capsules of genetic information inside a protein coat, they reproduce courtesy of the host's cellular machinery. Viruses -- including deadly influenza, HIV and ebola -- have earned their grim reputation as the ultimate biological weapons. Although the human body actually learns to accept or defeat most viruses, we respond too slowly to killer viruses, and we die.

a.An enzyme (red) loosens the virus's protein coat. The virus attaches to a port on the target cell's membrane and its genes enter the cell.

b.An inhibiting compound (black circle) blocks the enzyme so the protein coat stays closed. The viral genes cannot enter the target cell.



Those killers are something only a biological weaponeer could love. To counter the growing threat of biological weapons, the Defense Advanced Research Projects Agency (DARPA) is funding some blue-sky antiviral projects, to the tune of a projected $61.8 million during fiscal year 1998. Although designed for the military, the research could eventually have as many civilian benefits as DARPA's earlier investment in computer networks which spawned the Internet.

  Some of DARPA's money is going to a team led by Steven Kornguth, a molecular biologist at the University of Wisconsin-Madison, that is trying to freeze viral infections in their tracks. As Kornguth observes, viral exposure precedes disease symptoms. "We know there's a 24- to 72-hour window between being exposed through inhalation or ingestion and developing clinical symptoms."

Before it can cause disease, a virus must perform three steps:

  1. Travel from the site of initial infection (the nose, lung or stomach) to the site of secondary infection (perhaps the kidney, brain, liver or heart);
  2. Enter cells in the site of secondary infection; and
  3. Make copies of itself that can infect more cells (this is the step blocked by protease inhibitors in AIDS).

Kornguth's team is exploring how to interfere with each step in this process. The plan is to sustain patients long enough for natural immunity -- perhaps aided by a vaccine -- to arise and combat the virus.

To prevent viruses from entering target cells, Kornguth and associates are trying to interfere with an enzyme that prepares the virus for entry. They are working with a reovirus, a group that includes some biological weapons. All reoviruses require the enzyme cysteine proteinase to "unzip" their protein coat and expose their genes. Without the enzyme, the genes stay concealed and are unable to enter the cell. That halts the chain of infection.

Don't touch that zipper
Daniel Rich and Max Nibert, also of the University of Wisconsin-Madison, have built and tested a new cysteine proteinase inhibitor against a reovirus that normally infects livestock. Last December, the group found that the inhibitor prevented the virus from entering rat liver cells, keeping them alive and healthy.

Normally, this reovirus would kill those cells within 24 hours of entry. But for a yet-unknown reason, when the virus was allowed to enter the cells, the cells survived 8 to 10 weeks -- as long as the inhibitor was around.

Although both processes require the presence of the inhibitor, Kornguth is not aiming for a system that relies on a lifetime dose of the new chemical. He reasons that if the patient can be sustained long enough, the body's natural immunity, perhaps stimulated by a vaccine, could kill the virus.

The technique is about to be tested against some real biological weapons viruses. But Kornguth's method, like many other promising new biological weapons countermeasures, is highly specific: It only works against viruses that depend on cysteine proteinase. Thus the military would need a quick method for identifying biological warfare agents in the field. This is hard enough in laboratory-equipped hospitals; to do this delicate task in the middle of a battlefield, DARPA is funding a new generation of quick, hardy detectors.

In any event, Kornguth points out that the military would not rely on one countermeasure if it can mount a massive defensive attack on the killer agents. "If you know you've been hit [with a biological weapon] you'd use all of your ammunition at once."

Broken zippers. Red-blooded vacuum cleaners. Is this any way to battle biological weapons?

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