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Last Updated

14 Oct 2002

Source: Washington Post, October 10, 2002.

The Biowarriors

Last Year's Anthrax Attacks Spurred Record Research Spending on Biodefenses, but Most Solutions Are Still Years Away

By Rob Terry, Washington Techway Staff Writer

Col. Erik Henchal regarded the envelope with a scientist's detachment but a citizen's dread. He had seen this day coming.

The letter, coated in white powder, was meant for U.S. Sen. Tom Daschle. It was now at Fort Detrick in Frederick, home of the U.S. Army Medical Research Institute of Infectious Diseases (known as USAMRIID, pronounced "you-SAM-rid"), carried by FBI escort. Last Oct. 15, as bioterrorism fears had started to sweep the nation, Henchal and John Ezzell, a senior anthrax researcher, knew pretty quickly that something they'd long feared - an attack on civilians with microscopic pathogens - had become reality.

The envelope held the same kinds of spores that would come to kill five people and infect 17 others, either through the skin or, worse yet, after being inhaled. There they would germinate, causing a fever, a cough, nausea and diarrhea. These flu-like symptoms masked a killer. Toxins would course through the body, attacking healthy tissues, vanquishing cells, giving way to respiratory failure and shock if left untreated.

"We knew pretty quickly we were dealing with an authentic threat," says Henchal. "This is the day that we had dreaded. We had been talking for a long time that it's not a question of whether but when."

A year later, the nation's top scientific minds are at work looking for ways to boost biodefense capabilities. But significant questions remain unanswered, questions as persistently complex as the bacillus anthracis spores that have long been the scourge of the world's livestock population, lying dormant in soil for years, waiting to be ingested and wiping out entire herds.

Since last October, scientists have learned that an aggressive course of antibiotics, given soon after exposure, works in staving off even inhalation anthrax, a particularly lethal form. They've discovered that new detection tools can yield faster and more accurate results. Anthrax's genetic blueprint has been sequenced, giving law enforcement officers clues to track the origin of strains. And a comprehensive sequencing database should help researchers develop new drugs and diagnostics.

But consider the unknowns. What's the minimum number of spores needed to infect humans? How long can they stay in the lungs before germinating into organisms, unleashing a toxic fury? Do antibiotics offer the best treatment? Are there effective ways to treat patients in later stages of anthrax infection? Can a new vaccine be made that requires fewer shots and has less severe side effects? Is there a way to accelerate the development and regulatory approval of new therapies?

"It's a vast problem ... that involves biology, epidemiology," says Pierre Noel, a physician and U.S. Air Force major who advises the Defense Department and other government agencies on biodefense issues and is a department head at the National Institutes of Health's Warren Grant Magnuson Clinical Center. "There's some politics involved. The important thing is there's good coordination of the effort."

Henchal says he's seeing "an improving situation every day" - but he also has concerns. Where's the blockbuster collaboration with the pharmaceutical industry and other strategic partners? Will a record level of research-and-development investment generate unrealistic expectations?

"Everybody wants us to have these products now, without due regard to the importance of basic research," he says. "A lot of the products we're transitioning to [advanced development programs] are products we did the basic research on five or 20 years ago. If people want us to have the products of the future, we have to have an appropriate investment in the basic science."

Strict regulatory guidelines mean that new vaccines under development won't be available for years. Cutting-edge, development-stage antibiotics are in short supply. USAMRIID has 14 potential vaccine products stuck in various investigation phases. It can't find takers to license the products because of their small market potential and a lack of clinical testing data. And testing potential vaccines for biowarfare agents in humans is an ethical no-go, since it would mean deliberately infecting a test patient with a deadly virus or bacteria.

"The biggest barriers now are regulatory," says David Franz, a former USAMRIID commander and United Nations biological weapons inspector who now heads the chemical and biological defense division of the Southern Research Institute, based in Frederick.

A whole new approach to biodefense needs to be considered, adds Ken Alibek, vice chairman and chief scientist of Alexandria-based Hadron Advanced Biosystems, which is working with USAMRIID and other Defense Department laboratories to develop drugs to treat late-stage infections and boost immune response.

Alibek is careful to praise the strides made in the last year. But the biowarfare veteran - he was the chief scientist in the former Soviet Union's massive program before defecting to the United States - knows last year's brush with bioterrorism could have been much worse.

"If you spend hundreds of millions of dollars developing new vaccines, you need to answer a very important question: What are you going to do next?" he says. "We need to do a very thorough analysis to develop a national understanding of these threats. We haven't done it yet."

Alibek says resources also are needed to study the immune system's defenses at each stage of infection from a biowarfare agent, finding better antibiotics and beating back the septic shock that shuts down the body's organs in the final stages of infection. But Hardon's products, expensive and time consuming to develop, remain years from clinical testing.

In 1984, followers of an Indian guru named Bhagwan Shree Rajneesh poisoned salad bars at 10 Oregon restaurants with salmonella. With county elections looming, cult members hoped to sicken enough voters so they'd be unable to make it to the polls, enabling their candidates to win. The scheme, a trial run for plans the group had to poison the water supply, sickened about 750 people. Only a year later did public health officials determine the salmonella was man-made and part of a deliberate attack.

"Today that would take 10 minutes [to pinpoint]," says Franz. "If you look at it like that, we've come a long way."

Indeed, new diagnostics offer the most immediate promise for boosting the nation's biodefense. Franz points to work done by Marti Jett, chief of the molecular pathology department at the Walter Reed Army Institute of Research in Silver Spring, as a promising new technology for confirming exposure. Jett's system samples blood cells for signs they've come into contact with pathogens. Because the symptoms resemble the flu, there's a chance a crucial early diagnosis could be missed.

But cells, when exposed to a pathogen, produce different levels of proteins coded by genes. Scientists call this a change in the gene expression profile, and it could tip doctors that they're seeing something other than flu. Jett's lab has catalogued blood cell responses to other agents like smallpox, anthrax and plague and is collaborating with the Institute of Human Virology in Baltimore to speed the application of the system, which is probably five years away.

Further along are next-generation environmental detection tests like those Gaithersburg-based Igen International is developing with USAMRIID and three other military partners. The tests are built around a process called electrochemiluminescence. Air or soil samples are electrochemically stimulated, and chemical compounds indicative of pathogens are rooted out because the process causes them to emit light. The instruments turn out results in about 30 minutes, according to Richard Massey, Igen's president and chief operating officer.

"The technology is there" for faster, cheaper and more reliable detection, he says. "The government has to figure out what instruments they're going to go with and how they're going to deploy them."

As one of the world's premier biodefense laboratories, USAMRIID is in many ways the fulcrum of much of this next-generation R&D. Since 1969, USAMRIID scientists have gone toe to toe with nature's deadliest viruses, working to unlock their secrets. At headquarters, winding corridors and a series of sophisticated identification scanners lead to suites of laboratories where scientists study anthrax, plague, botulism, tularemia and hemorrhagic fever viruses like Ebola and Marburg. There they develop vaccines, diagnostics and other countermeasures for the military.

USAMRIID's expertise is sought in quelling "hot zones," outbreaks of lethal viruses and bacteria, around the globe. Its research facility is the largest biocontainment lab in the country. To work with the most dangerous agents, like Ebola, scientists must wear a 12-pound "space suit," a pressurized and ventilated rubber suit with a spiral air hose attached to a filtering system.

To do their work - growing cell cultures, infecting them, injecting those into animals - scientists are subject to strict monitoring systems that track their comings and goings as well as their immunization records. An accidental exposure means a stay in a special patient containment ward known as the "slammer."

Henchal, a 22-year Army microbiologist, was named USAMRIID commander in June, and the flood of attention he's received has had little do with his arrival. His 656-person staff has been the focus of federal investigators who believe the perpetrator of last year's anthrax mail attacks may have ties to USAMRIID. The strain used in the attacks was developed there in the 1980s; a former scientist was identified by federal investigators as a "person of interest" but strongly denies any connection.

The pressure has been intense, enough to puncture the morale of a staff already working long hours. From last September through May, USAMRIID scientists, operating with a $50 million research-and-development budget, processed 31,000 specimens and performed 260,000 tests, more than any other government agency.

Its diagnostics staff numbered six last Sept. 10; six weeks later it had jumped to 85. In the past year, USAMRIID has handed 14 biological tests over to the Defense Department's advanced developer, to be used in the field and as part of a national laboratory response network coordinated by the Centers for Disease Control and Prevention in Atlanta.

Henchal believes staff morale at USAMRIID is improving, but scars remain. The FBI continues to scrutinize the lab's security measures and question staffers, Henchal included.

Henchal also says federal agents continue to give USAMRIID "real votes of confidence" and says they're moving closer to ruling out any lab personnel as the perpetrator. He's eager to put the suspicion behind USAMRIID, for its profile to once again be centered on being a leading center of biodefense research.

"I'd like to think we're past that and can now get back to business."

Robert Koch, a German physician, first confirmed the bacterial origin of anthrax in 1876, a discovery that would become a building block for the study of microbiology. As the world's economies transitioned from an agricultural to an industrial base an aerosol version of the bacteria emerged.

A vaccine was approved in the United States three decades ago for soldiers and "high-risk populations," such as animal product handlers. Troops fighting in the 1991 Persian Gulf War were vaccinated after evidence emerged showing Iraq had weaponized anthrax. The vaccine came under controversy after Desert Storm soldiers complained of lingering illnesses they attributed to the regimen of shots, which in some cases cause flu-like symptoms like nausea and fatigue.

One of USAMRIID's top anthrax hunters is Dr. Arthur Friedlander, a physician and infectious disease specialist. The Army veteran, now retired from the military, continues to work at USAMRIID developing a new anthrax vaccine.

The next-generation vaccine updates the original vaccine approved by the FDA in 1971. The new version uses a highly purified, genetically engineered protein technology called recombinant PA, which prevents the proteins in anthrax's lethal toxins from binding to cells and opening them up to infection. The hope is that the new vaccine can be administered with fewer shots - the current cycle requires six shots over 18 months - and with less severe side effects. The vaccine also shows promise boosting antibody strength. Special white blood cells that can ingest the spores will hopefully be coaxed out and sent to do battle. The new vaccine is still at least six months away from clinical tests, when Friedlander and colleagues will begin matching animal testing data showing its effectiveness with safety tests in humans.

"That's the best we can do right now," Friedlander says. "It's a very bizarre set of circumstances in which we're developing vaccines against a potential threat of someone using it, not the very existence of the disease."

Anthrax is only one of many challenges faced by government and industry scientists developing new drugs to combat bioterrorism and arm the nation's public health infrastructure should another attack occur. The threat of a smallpox outbreak tops the list.

Congress' Office of Technology Assessment estimates that the release of 100 kilograms of aerosolized anthrax over Washington, D.C., could kill anywhere from 130,000 to 3 million people; smaller quantities of weaponized smallpox would unleash a pandemic. The smallpox virus spreads among people through close contact - anthrax is not passed between people - causing a rash, high fever and fatigue. It kills up to a third of those infected.

Smallpox disease was eradicated in 1980, but samples of the virus remain. Some are kept in the CDC's maximum containment lab. It was also weaponized in the Soviet biowarfare program, and U.S. officials widely believe it's now in the hands of so-called rogue nations and possibly terrorist groups.

Federal officials are confident the nation's stockpile of smallpox vaccine could handle an outbreak. The government signed contracts with biotech company Acambis and pharmaceutical giant Baxter to produce new doses.

Studies conducted by the National Institute of Allergy and Infectious Diseases show that existing stockpiles of the vaccine could be diluted to provide 300 million doses, enough to inoculate every American.

New vaccines are needed not just for physically fit soldiers but for a civilian population that, with the scourge of the HIV virus, is more immunodeficient than when smallpox was eradicated. And there is still no treatment, beyond vaccines, for smallpox and other potential biowarfare agents.

One bright spot: USAMRIID scientists and colleagues at the University of California at San Diego have been able to stop the replication of the smallpox virus in laboratory cultures with a derivative of an antiviral medicine called cidofovir, used to treat AIDS complications. The drug has also shown promise in early tests on mice.

Five years ago, the Defense Department picked Frederick-based DynPort Vaccine to oversee the development, licensing and manufacture of new biodefense vaccines. With the 10-year, $322 million contract, DynPort today has six vaccines in its pipeline - for smallpox, anthrax, botulinum toxin, plague, Venezuelan equine encephalitis and tularemia. DynPort senior vice president and chief scientific officer Michael Langford says its smallpox vaccine is furthest along and should be ready for licensing in 2005.

He predicts that limited supplies of new vaccines - called investigational new drugs, or INDs - will be stockpiled for use over the next year. But the "conservative nature of the licensing process," due to regulatory guidelines governing drugs, will undercut opportunities to accelerate commercial development and will counter the impact of any pioneering discovery technologies that might emerge, many believe.

"The process of ensuring safety is time consuming," says Langford, a former USAMRIID virologist.

A recent survey by the Pharmaceutical Research and Manufacturers of America found that 256 drugs and vaccines targeting infectious diseases were in development. But, while companies like Eli Lilly and Aventis have given vaccine reserves to the government and started testing drugs for possible biodefense applications, blockbuster collaboration has yet to emerge.

In a nod to developers, the FDA passed a rule permitting them to work around efficacy restrictions. They'll be able to test potential biodefense drugs in animals for effectiveness, while demonstrating safety in humans.

Last Sept. 11, Dr. Anthony Fauci was in a taxi riding through the Queens Midtown Tunnel on his way to a morning meeting in Manhattan when a hijacked jet hit the first World Trade Center Tower. Fauci, director of the National Institute of Allergy and Infectious Diseases, watched events unfold on television until early evening.

Fauci walked 20 blocks down Broadway to Pennsylvania Station to catch an Amtrak home. As the train emerged across the river in New Jersey, Fauci turned for one last look at the New York skyline. Just then, Tower 7, a smaller building next to the two World Trade Center skyscrapers, crumbled to the ground. Fauci had trouble catching his breath as a dust cloud shrouded the skyline.

"I said, 'Uh oh, my world's going to change,'" Fauci remembers. "Because if that's happening with terrorism, bioterrorism's not far behind."

The federal government is set to channel $1.75 billion for biodefense R&D through NIAID, part of the National Institutes of Health. The bulk of that funding, $592 million, is slated for drug, vaccine and diagnostics development. More than $521 million will go to construction of new containment facilities like the one at Fort Detrick. And some of that money will go to institutions like The Institute for Genomic Research in Rockville for basic research.

After last fall's mail attacks, TIGR microbiologist Tim Read and scientists from Northern Arizona University compared the DNA of two anthrax strains - one the kind used to kill a Florida photo editor (case 5) - and found differences that might function as "genetic fingerprints," markers that could help law enforcement agencies pinpoint the origin of pathogens used in future attacks.

Read is leading a team now sequencing 14 other anthrax strains. The sequencing information will be compiled in a database that he believes will aid medicine as much as law enforcement. Armed with better bioinformatics tools, the research will yield new insights into the evolution and pathogenesis of anthrax, Read says, bolstering efforts to design new countermeasures.

Scientists like USAMRIID's Friedlander are already mining the data for clues in the sequence of chemical building blocks in anthrax's DNA that will lead to better diagnosis and treatment, much the way drug companies are using the human genome sequencing to find proteins involved with spurring or blocking disease.

Fauci's under pressure from the White House to deliver a return on investment, to make headway not only in basic research but to come up with "deliverables," applied research leading to the rapid development of new products.

"We need to cover a large waterfront," he says. "It's a challenge, but it's an exciting challenge."