DOCTORS LOOK FOR WAYS TO SPUR IMMUNE SYSTEM



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Last Updated

03 Nov 2002

Source: Wall Street Journal, September 24, 2002.

To Fight Bioterror, Doctors Look For Ways to Spur Immune System

By MARILYN CHASE Staff Reporter of THE WALL STREET JOURNAL

MANASSAS, Va. -- An audacious idea is captivating biologists: Could a simple inhaler or injection help the immune system fight off a wide variety of germs that might be used in a bioterror attack?

The notion defies longstanding dogma that immune-system boosters such as vaccines must be tailored for a specific disease, such as polio or a particular strain of flu. But a breakthrough in immunology has given life to the idea of revving up an early stage of the immune reaction that could help the body battle almost any invader. This approach would be a boon in a bioterror attack, where the germ's identity wasn't immediately clear.

Harnessing "innate immunity," as this early-stage immune reaction is called, is a long shot. Some scientists doubt it can be done. But it is given a chance of success by such medical authorities as Anthony Fauci of the National Institutes of Health. And one prominent bioweapons expert has established a company around the idea and gained substantial federal funding.

That scientist, in a twist worthy of a John Le Carre novel, is a man who once led the Soviet Union's secret production of vast quantities of smallpox, anthrax and other lethal bioweapons. Ken Alibek, since defecting to the U.S. a decade ago, has turned his skills to fighting the doomsday weapons he helped devise. As vice chairman and chief scientist of a Virginia company called Advanced Biosystems Inc., he is working on a cocktail of immune boosters that would be delivered through an inhaler. In studies he hopes to publish soon, he says, they helped protect mice against germs similar to both anthrax and smallpox.

Since last fall's anthrax attacks, more funding has become available for research on such remedies, and regulatory hurdles have fallen. Congress appropriated $4 billion for bioterror preparedness for the fiscal year that ends Sept. 30, and the Bush administration has another big request pending. The Food and Drug Administration has said it will approve bioterror remedies based on their efficacy in animal studies alone.

FBI Attention

The response to the anthrax attacks, which killed five, touched Dr. Alibek himself: He was among several hundred elite scientists interviewed by the Federal Bureau of Investigation. Dr. Alibek, 52 years old, says he has been told he was never a suspect or "person of interest." He also says he was recently granted FBI clearance to do certain sensitive work with the government. The FBI declined to comment.

Dr. Alibek has critics in the scientific world. Peter Jahrling, a smallpox researcher at the Army Medical Research Institute of Infectious Diseases, is highly skeptical of the notion of a universal immune booster that could help fight most any invader. "It's like cold fusion: a great idea, but where is the experimental basis?" Dr. Jahrling asks. But Dr. Alibek, he adds, "has a ton of U.S. government dollars to prove me wrong."

For decades, doctors have tried to treat illness by juicing up the body's immunity. It's been frustrating, and risky as well. A natural immune reaction such as inflammation or fever can get out of control if stimulated. Sometimes the effort triggers an auto-immune disease or a severe allergic reaction called anaphylaxis, which can shut down breathing. Doctors have had success only against specific diseases, such as hairy-cell leukemia, which they attack by spurring immunity with a form of interferon.

When a germ invades, the immune system responds within hours. It recognizes molecular patterns shared by the DNA of many microbes. An array of "first responders" rushes to the scene. Among them are macrophages -- literally, big eaters -- which engulf and gobble up germs. Natural killer cells also arrive, to slay the invaders. This phase is known as innate or nonspecific immunity.

During this phase, agents called dendritic cells help the body to identify the germ and mobilize the next, more-specific phase of immune response. That phase rallies cells that are tailored to fight a particular microbe. But this specific phase can take days or even weeks to develop, unlike the speedy reaction of innate immunity.

While lower forms of life rely on innate immunity, it wasn't known to play much of a role in man. But in 1997, Yale University scientist Charles Janeway Jr. found in humans a key agent of innate immunity: a family of receptors that detect and fight germs long before the body knows what the germ is. They are known as Toll-like receptors.

This landmark finding led others to unexpected moments of insight. For Arthur Krieg, a chance discovery from his days as a university researcher in the mid-1990s eventually made sense.

Dr. Krieg had stumbled on a DNA fragment in many viruses and bacteria that powerfully activated the immune system, but he didn't know why. The Janeway discovery suggested that a human receptor might be reacting to this particular sequence of DNA like a burglar alarm, setting off a cascade of immune reactions. Soon, a Japanese researcher named Shizuo Akira identified the receptor. Dr. Krieg, now at Coley Pharmaceutical Group in Wellesley, Mass., has won federal grants to test the DNA sequence, known as CpG, as a broad-scale immune-system booster.

His grants come from the Defense Advanced Research Projects Agency, which is often willing to go out on a limb. Darpa "makes high-risk investments, and many could fail," notes John Carney, the director of its biodefense grants program. His hope is that innate immune boosters could someday be given to soldiers entering battle zones where germ clouds might lurk, as well as to civilians exposed to a bioterror attack.

Dr. Alibek recalls that when he first approached grant-making agencies about innate immune boosters back in 1996, "nobody wanted to discuss it. They wanted to laugh." But in 1999, Darpa gave him the first of what eventually became $10 million in grants. Darpa helped "when no one else would give us the time of day," says Charles Bailey, a partner of Dr. Alibek at Advanced Biosystems. The Army later gave him $5 million of funding as well.

Academic labs are in this game too, seeded by grants from the National Institute of Allergy and Infectious Diseases. Alan Schreiber at the University of Pennsylvania Medical School has devised a technique that would draft cells of the lungs or liver to become germ-killing soldiers. The Army is testing it as a way to protect against inhaled anthrax .

Trying to spur innate immunity is "a hot area for research," says Mitchell Kronenberg of the La Jolla Institute of Allergy and Immunology in California. He is working on another way to ramp up innate immunity: using a substance that acts like a chemical alarm clock, activating white blood cells that form a bridge between early and later-stage immune responses.

At Advanced Biosystems, Dr. Alibek runs experiments using safer surrogates for the germs that cause anthrax and smallpox. Against them, he tests two prototype immune-boosters. Each contains a cytokine, or natural infection-fighting agent, such as an interferon or GM-CSF. Each also contains a chemical used to boost the power of vaccines, called muramyl dipeptide. The goal is to administer the chemicals in a device resembling an asthma inhaler.

"We realized the system we needed to protect is the respiratory tract, and the faster the better," Dr. Alibek says.

Test Results

Besides use by civilians right after a bioterror attack, the compounds might someday be given ahead of time, to troops heading into danger zones. In Dr. Alibek's tests, they've been given to mice both before and during exposure. In the studies he hopes to publish soon, he says, the mixtures protected 60% of mice against a nonlethal strain of anthrax and 96% of them against a virus related to smallpox. The next likely step will be treating animals shortly after exposure.

Scientists are divided on the odds of this working for humans. The NIH's Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases, sees a chance for innate immunity boosters. "It's a majestic leap between the concept and being able to do it," he says. "But it's not necessarily unattainable. That's why we welcome [such] research." His institute has given $1 million to support Dr. Alibek's efforts and has backed others as well.

But Phil Russell, former commanding general of the Army Medical Research and Development Command, warns that trying to regulate the immune system "is complex and fraught with risk. Turn it on, and it does things that can be detrimental as well as protective." The Army's Dr. Jahrling says that boosting immunity against bacteria might unwittingly help viruses do damage. That's because viruses, paradoxically, are believed to sometimes kill by unleashing a storm of natural infection fighters, in what's called a cytokine storm.

Dr. Alibek acknowledges the risks. He hopes that by spritzing the tissues of the respiratory tract instead of injecting his cocktail into the bloodstream, he could minimize the side effects. "We're not saying it would protect all people. There's nothing absolute in this world," he says. "But in the worst-case scenario, it would give people precious time."

The skeptical Dr. Russell calls Dr. Alibek "brilliant" but "a better theoretician than experimentalist." The former Soviet germ-warfare overseer, he adds, is "as much an enigma as a scientist as he is as an individual."

Tons of Anthrax

Born Kanatjan Alibekov in Kazakhstan, Dr. Alibek rose in the Soviet army to first deputy chief of Biopreparat, the Soviets' vast and clandestine germ-warfare program. He oversaw production of a staggering 4,500 metric tons of anthrax a year, among other germ products such as plague and smallpox.

Among his adversaries those days was Dr. Bailey, now his colleague at Advanced Biosystems. Dr. Bailey is a former top Army medical officer who in 1991 escorted Dr. Alibek and other Soviet scientists visiting the U.S. "I didn't care for him. I couldn't get him to respond," Dr. Bailey says now. For his part, Dr. Alibek recalls glowering as the amiable Bailey kept grinning at him. Dr. Alibek spoke no English and thought the American was mocking him.

Suspicion poisoned the atmosphere. While touring Fort Detrick, Md. -- which had been a bioweapons-development site before the U.S. voluntarily ended its own program in 1969 -- the Soviets spotted a strange conical structure filled with grayish-white crystals. Thinking they'd found evidence of continuing germ production, the Soviets approached the pile of granules. But finally one of them stuck his finger in the substance and tasted it. "It was road salt," says Dr. Bailey, laughing at the memory.

In 1992, after Soviet communism's collapse, Dr. Alibek defected to the U.S. He blew open the secret of the vast bioweapons program the Soviets had kept up, long after signing a treaty to end it. Dr. Alibek then went to work in an NIH biotechnology lab, where, in a measure of how far his status had fallen, he found he had to wash his own glassware.

When a later employer wanted to get into biodefense, it chose Dr. Alibek to start a subsidiary that became Advanced Biosystems. He soon recruited Dr. Bailey. The business is now owned by Analex Corp. in Alexandria, Va.

Dr. Alibek also gives courses on combating bioterrorism for the CIA. There's a simple explanation for the direction his career has taken since he left the Soviet Union, Dr. Alibek says. "It started as remorse."