Biotech vs. Bioterror

New insights into molecular DNA, enzymes, and antibodies could lead to antidotes for a variety of biological agents -- but not soon

Think of it as the arms race of the 21st century -- only this time, it's a molecular arms race, and the weapons against terrorism will likely come from biological laboratories. "Developing a varied arsenal of countermeasures [against bioterrorism] is this country's best protection," says Floyd Taub, chairman of LifeTime Pharmaceuticals in College Park, Md., which is testing an immune-system booster called BetaLT.

Actually, efforts to protect an unsuspecting civilian population from bioterrorism have been under way since 1999. This year, the Defense, Energy, and Health & Human Services Depts. budgeted $1.2 billion for biodefense. Now, President Bush has vowed to pump an additional $1.5 billion into the effort.

That's a drop in the bucket compared with nation's total defense budget. But the mail-delivered anthrax incidents have given such research a new sense of urgency. Valuable new insights in how molecular DNA, enzymes, and antibodies work could provide emergency immunity for a variety of biowar agents, stop or slow the progression of disease in those already infected, and remove toxins from their bodies. "We must get beyond the one organism/one drug approach," says Donald A. Henderson of Johns Hopkins University.


  The Biotechnology Industry Organization, which recently formed a biodefense task force, estimates that nearly two dozen companies are involved in the development of biodefense vaccines and therapeutics. With new funding totaling $8.4 million, Advanced Biosystems, a subsidiary of Alexandria (Va.)-based Hadron Corp., is exploring ways to stimulate production of cellular secretions called cytokines, which form the body's first line of defense against invaders by kicking the immune system into a state of high alert.

The front line in bioterror defense also includes well known biotech companies such as Gilead Sciences in Foster City, Calif, which is developing treatments for viral diseases like AIDS; Isis Pharmaceutical in Carlsbad, Calif., which uses fragments of "antisense RNA" to interrupt the process that produces disease-causing proteins; and Seattle-based Corixa, which is developing a drug that boosts the immune system's response to vaccines. These companies are joined by a group of startups that are investigating novel ways to stop virulent diseases in their tracks.

Conventional vaccines aren't a practical solution for protecting civilian populations, experts say. Anthrax vaccine, for example, is administered in three injections at two-week intervals, followed by booster shots every six months. Immunity develops gradually. Says Stephen Sudovar, president of EluSys Therapeutics, a Pine Brook (N.J.) startup developing an anthrax antidote. "If you think of the logistics of tracking a five- or six-vaccination series and boosters for 280 million people for anthrax, you can easily visualize problems."


  The same goes for smallpox. Although the routine vaccination of children ceased after this disease was declared eradicated in nature in the '70s, the U.S. has a stockpile of about 15 million doses of smallpox vaccine. Last year, the government ordered 40 million additional doses, with initial deliveries scheduled for 2004.

Worse yet, smallpox vaccine is made from a live virus that is similar to smallpox -- and a small but significant number of those vaccinated could suffer serious complications. About one in a million who were vaccinated in the 1960s died or had brain damage. The vaccine caused severe infections in 1 of 18,000 Were a national immunization effort to be launched, the toll would far exceed deaths from the anthrax attacks so far.

A third problem: No one can guarantee that stockpiled vaccines will be effective against the particular strain that a terrorist chooses. At least 20 diseases have been the subject of biological warfare research, including botulism, tularemia, and bubonic plague. A study of bioterrorism by consultants Frost & Sullivan estimates that treating a single city with existing technology in the three weeks following an anthrax or smallpox attack would require $36.4 million in vaccines and $24.3 million worth of antibiotics.


  Medical experts see no way that the government could cope with such a crisis. "Remember the swine-flu program?" asks R. Stephen Porter, president of Virtual Drug Development (VDDI), a Brentwood (Tenn.) biopharma startup. Almost 1% of those given swine-flu vaccine in 1984 suffered from severe reactions. "The lawsuits almost destroyed our entire vaccine industry," says Porter. "If you want to immunize the entire U.S. population you'd better be very careful."

What to do? VDDI, EluSys, and others believe that advances in biotechnology hold the key. VDDI is working with scientists at the University of Alabama Center for Biophysical Sciences & Engineering to develop a custom-made drug that blocks the action of a key enzyme necessary for the reproduction of anthrax and other toxin-producing bacteria.

Taken as a once-a-day pill, these so-called NADS inhibitors (for nicotinamide adenine dinucleotide synthetase) prevent spores from growing into adult bacteria that release a lethal toxin into the bloodstream of infected individuals. Porter says it could be given to military personnel as a preventive measure and after exposure as a treatment.


  Another microbial enzyme, known as DNA adenine methylase (DAM), is the target of Remedyne Corp., a startup founded by scientists at the University of California, Santa Barbara. The researchers discovered that DAM is a "master switch" that controls more than 20 genes that are critical to many bacteria's ability to infect their hosts. When they engineered bacteria with a defective form of DAM, the virulent bugs turned into pussycats: They survived -- but they couldn't cause disease.

The disarmed bacteria turn out to be a powerful vaccine, invoking a robust and immediate immune response. In an early experiment, scientists administered a DAM-disabled bacterium to mice, then infected them with high doses of salmonella, which causes severe food poisoning. All the treated animals survived. All those in a control group died.

Remedyne, which has raised $3.4 million in venture capital, has submitted a proposal to the U.S. Army to develop a combined vaccine against both anthrax and bubonic plague. The company's goal, says President Krisztina M. Zsebo, is to produce inexpensive, fast-acting vaccines effective against a large number of dangerous bacteria. With additional funding and cooperation from the Food & Drug Administration, Zsebo believes "an oral pill could be ready for market within three years."


  Are live bacteria safe? Zsebo insists they are: "Our vaccine is based on a related organism which, in it's wild-type state, only causes a mild diarrhea in humans," she says. "With our technology, the organism is rendered completely harmless."

Other companies are taking a more cautious approach: injections of fragments of raw DNA that have no disease-causing capacity whatsoever. Darrell Galloway, a microbiologist at Ohio State University, and colleagues at the National Institutes of Health and the Naval Medical Research Center, isolated the DNA from three genes that work in concert to create the deadly cascade of toxins secreted by anthrax bacteria. Using viral carriers, called plasmids, they incorporated these genetic snippets into the cells of healthy mice.

When the treated mice were injected with five times the lethal dose of the anthrax bacterial toxin, those that received the plasmid injections were immune. Every animal in the control group died within hours. Moreover, the Ohio State team, in collaboration with scientists from researcher Battelle Group, have shown that the vaccine protects against aerosol-delivered anthrax -- the most deadly form -- more than a year later.


  Galloway, who says he has been approached by several drug companies, is expanding the research to include other pathogens. "In its present form, the vaccine is only effective against anthrax," he says. "But we are working on a form which would include other biothreats."

Antibodies are the key to a third strategy being developed by EluSys that sops up microorganisms or toxins and ferries them out of the body. The tricky molecules, which the company calls Heteropolymer (HP) technology, consist of two antibodies that are chemically bound together. One attaches the molecule to a red blood cell, the other is designed to bind to the biowar agent, such as the anthrax toxin. The immobilized biowar agents then get a ride on the red blood cells to the liver, where they are destroyed. "It's like two-sided sticky tape," explains George L. Spitalny, the company's vice-president for R&D.

Spitalny says the result is "instant immunity" that can sustain victims of attack until antibiotics take over. "This one-two punch should aid in helping to cure even symptomatic patients of the disease," he says. Moreover, by changing the active antibody, formulations can be rapidly produced that would target a wide range of bioterror bugs, including smallpox and deadly Ebola.

Like much of the new anti-terror technology, HP is a long way from the market -- so far it has been tested only on animals. But research funded for just three years has built the groundwork for a viable defense against bioterrorism. And additional funding should be the booster shot that will push new drugs and treatments into high-volume production. Clearly, pouring more funds into this research effort is a win-win enterprise.

Further Information:

The Center for Communicable Diseases

The Centers for Disease Control & Prevention

National Network for Immunization Information

Johns Hopkins Center for Civilian Biodefense Studies

By Alan Hall in New York

Edited by Douglas Harbrecht

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