Bioterrorism Research: New Money, New Anxieties

Ned Shaw US scientists have reason to feel both heady and scared. The federal government recently released unprecedented billions of dollars to fund bioterrorism research. Yet, the merits of this sudden shift in focus are being debated, and some worry that the money will be squandered or wasted. "I have been really very upset by the focus on bioterrorism," says Stanley Falkow, professor of microbiology and immunology and of medicine at Stanford University. "Everybody's talking about it, but there's really been no coordination. I'm really concerned." Bioterrorism fears moved the Bush administration to propose spending $5.2 billion (US) over the next three years to fund research into bioterrorism through the National Institute of Allergy and Infectious Diseases (NIAID). Congress recently authorized the FY 2003 installment, $1.5 to $1.75 billion, depending on how the institute allocates it, up from $270 million in FY 2002. Congress also authorized roughly $600 million in bioterrorism research for federal departments outside of the National Institutes of Health. President Bush also proposes to spend as much as $6 billion over the next 10 years for Project BioShield to buy new drugs, speed drug development, and allow emergency use of drugs that are not fully tested. The White House has not said whether the $6 billion will be appropriated with new funds or taken from other budgets. The centerpiece of the program is NIAID's charge to create all necessary vaccines, therapeutics, booster drugs, and diagnostics. Last October, Anthony Fauci, NIAID director, announced both his goal to complete that job by 2012 and the president's insistence that some of those products be ready in three years. These expectations are controversial. Senior scientists emphasize that they don't really know a straightforward way to create vaccines or antimicrobials, so they can't expect to find out soon. "We do not know the path for developing effective antimicrobial agents," Falkow says. "We just don't know what the right path is." Falkow recalls starting his career at Walter Reed Army Institute of Research in 1960 and working with a talented team that planned to create vaccines against bacillary dysentery, cholera, and typhoid within 10 years. Forty-three years later, they are still trying. Furthermore, scientists have not discovered a new family of antimicrobials in 30 years. "It's not for lack of trying on the part of the pharmaceutical industry," Falkow says. "The end result is that the disease process is complicated. ... It's not just focused on the infectious agent, it also has to do with the host. It's a complex interaction." According to Falkow, the problem is the unpredictability of basic research. NIAID's mission is a national priority, similar to the Manhattan Project during World War II. That earlier work began with proof of principle that fission existed, so it was mostly engineering, not basic research. But these vaccine studies begin with no proof of principle. Even Fauci agrees that time goals for antibioterrorism vaccines and drugs are impossible to guarantee. Meanwhile, the United States is left without protection: It has more than $5 billion of its eggs in one basket, and they might not hatch for decades. DOLLAR DEBATE Scientists sharply disagree about how much money is necessary to complete the NIAID program. Gigi Kwik, an immunologist at the Center for Civilian Biodefense Strategies at Johns Hopkins University and who trained at the US Army Medical Research Institute for Infectious Diseases (USAMRIID) at Fort Detrick, Md., thinks even megabillion dollar increases are not enough because the threat is much worse than most scientists understand. "We should spend more money on bioterrorism preparedness," than on next-generation fighter planes she reasons, "because biological agents can be a strategic threat to the US, for which we are more underprepared than [for] a dogfight in the air." Richard Ebright, professor of chemistry at Rutgers University, NJ, thinks the NIAID bio-terrorism budget is at least three times too large. He advocates a narrowly focused program that would make only three vaccines widely available--smallpox, anthrax, and plague--plus develop diagnostics, create some therapeutic agents, and pay to decontaminate poisoned sites. Ebright predicts that increasing any research agency's budget sixfold ensures that the extra funding will support unworthy research--adding that peer review panels have already winnowed out the best projects for funding, and what remains will probably not contribute enough to justify paying for it. "It's such a large sum that it can't be consumed even by completely removing all merit-based review of research, and funding every proposal that comes in the door," he says. NIAID is planning to build several more biosafety-level (BSL) 3 and 4 labs, designed to prevent the spreading of infectious diseases outside the lab. This is more than researchers need, Ebright says. Ironically, he asserts, those extra buildings increase security concerns needlessly as more people in more places gaining access to fatal pathogens increases the risk that someone will use them to kill Americans. That's a legitimate concern, says Michael Barletta, senior research associate, Monterey Institute of International Studies, Calif., because the anthrax in the letters from 2001 are thought to have came from a US biodefense community insider. If NIAID does have more money than it needs, other NIH institutes would like to get their hands on it. According to an analysis of the FY 2003 budget by the American Association for the Advancement of Science, NIAID received a big increase and the department-wide building budget was doubled, mostly to accommodate the NIAID increases, but the rest of NIH received only a 9.9% boost in funding for FY 2003.1 Many public health advocates would spend the extra money fighting the perennial worldwide killers: tuberculosis, malaria, hepatitis, HIV, measles, flu, pneumonia, and diarrheal disease. A Central Intelligence Agency (CIA) analysis estimates these diseases killed more than 12 million people in 1998 (the last year examined) while anthrax killed only five.2 By 2010, the CIA predicts that 80 to 110 million people with HIV/AIDS will live in Africa, China, India and Russia.3 Infectious diseases will likely aggravate or even cause "economic decay, social fragmentation, and political destabilization in the hardest hit countries ..." another CIA analysis says. BUTTON-DOWN BOMBS Barletta would like to see the government spend its funds destroying missiles and securing nuclear weapons in the former Soviet Union. Al Qaeda is trying its best to obtain a bomb or the fuel for one, he says, and argues that the US is not investing enough to safeguard the material. At current spending levels, it's "going to take a decade or more just to get basic controls," Barletta says. He also advocates raising the security level of labs in other countries and their shipment methods to that of US standards. What good does it do, he asks, for the United States to maintain high bio-security if terrorists can more easily steal bioweapons elsewhere? Stephen Morse, director of the Center for Public Health Preparedness at Columbia University, urges the scientific community to stop under-appreciating military biodefense labs. The majority of the nation's biodefense expertise "has been in the military or has come through the military," he says. Even so, "USAMRIID and the other military labs are really grossly underfunded," he insists. Fully funding them would cost only a few million dollars, he says, because they employ relatively few scientists. Some researchers find fault in the NIAID program's reliance on vaccines, not only because of the inability to create them all, but each vaccine takes as much as a decade to test. Vaccines for pathogens that rarely infect humans can never be fully tested, and vaccines might not work at all against bioengineered agents. Matthew Meselson, Thomas Dudley Cabot professor of the natural sciences at Harvard University, notes that the NATO threat list includes more than 30 diseases and toxins. "Are you going to vaccinate all the Americans against all these things?" he asks. "If public health officials vaccinate against only a few diseases, terrorists can just choose another one." Even when vaccines exist, they are not always available, says Stanford's Falkow. "In 2001 there were significant shortages of eight of the 11 vaccines against preventable childhood diseases," he adds. Meselson and Kwik point to a focus on fighting infection as a better approach. The US Defense Advanced Research Projects Agency (DARPA) is funding research that it hopes will lead to strengthening the immune system's innate response to infection. Another DARPA program is looking to create wide-spectrum antimicrobials using common pathogenic mechanisms. Kwik also contends that money should be spent training the public. "Planners have this idea that the public is going to collapse or rise up in revolutionary panic" during a bioattack, she complains. Meselson says bioterrorism threats will end only when people realize that these weapons are bad for everybody. Today's bioterrorists can easily become tomorrow's bio-victims. "It's not us against them," he reiterates. "It's bad for everybody." John Dudley Miller (johnmiller@nasw.org) is a freelance writer in Cleveland, Ohio. References 1. "FY 2003 Omnibus Bill completes NIH doubling plan; large increases for bioterrorism R&D and facilities," American Association for the Advancement of Science, Feb. 25, 2003, available online at usinfo.state.gov/topical/global/hiv/02100102.htm. 2. D.F. Gordon, "The global infectious disease threat and its implications for the United States," Central Intelligence Agency, January 2000, available online at www.cia.gov/cia/publications/nie/report/nie99-17d.html. 3. "The next wave of HIV/AIDS: Nigeria, Ethiopia, Russia, India, and China," National Intelligence Council, September 2002, available online at www.cia.gov/nic. DIAGNOSING BIOTERRORISM Agencies duplicate efforts to create microarrays One important near-term goal in the US war against bioterrorism is to develop DNA microarrays that can quickly and simultaneously test individuals for exposure to different biothreats such as plague, anthrax, and tularemia. At least seven federal agencies in four federal departments are funding or conducting research to design a device the size of a microscope slide that can turn anyone's blood sample into his definitive diagnosis within two hours. Although that final product sounds ideal, multiagency involvement is a big problem, according to microbiologist and immunologist Stanley Falkow from Stanford University. "Virtually each federal agency wants its own diagnostics," he says, which makes uniformity of detection impossible. "Clearly, there is no coordination or agreement about what would constitute a basic set of information that could be common and shared among all government agencies," he asserts. "It's almost as if they're competing with each other ... and it just leads to bad science." Most scientists won't discuss the problem publicly, Falkow explains, because they are "more or less held hostage to the government-granting agencies, and they are loathe to bite the hand that feeds them." One scientist who shares Falkow's concern and will speak out is Marti Jett, chief, department of molecular pathology, Walter Reed Army Institute of Research, Silver Spring, Md. She (and independently, professor David Relman, Stanford University) developed the information-rich strategy of detecting individuals' responses to infection over time rather than detecting the pathogens themselves. STREAMLINE EFFORT So much work needs to be done, she says, that duplication of efforts cannot be justified. For instance, in her group's research, chip-based diagnosis of a person's stage of infection and its probable future time frame necessitates first creating an archive of typical human gene-level responses to several different-sized doses of all important pathogens, measured every few hours. "It gets to be an awful lot of chips," she concludes. It is also a job that several coordinated labs using the same standards might complete much faster than any one of them using a proprietary design. A typical DNA microarray contains thousands of DNA or RNA fragments robotically arranged into a microscopic grid on a glass slide. Each short strand uniquely identifies a particular genetic strain of a pathogen (or in Jett's research, a unique human gene that upregulates in response to that pathogen). If that gene is active, its fluorescently labeled DNA or RNA poured over the slide will join with its complementary fragment on the array. The location and color of the light indicate which pathogen caused the infection. So far the main way these competing agencies interact is by sharing information, according to Maria Giovanni, assistant director, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Disease. She thinks cross-agency sharing on microarray research is common, as it has long been for genomics. One incipient sign she sees of possible future coordination is people in these agencies approaching the Food and Drug Administration for advice on microarray standards. "If it's a research tool and it has to become a clinical diagnostic tool, then the FDA needs to get involved," she says. Emilio Garcia, senior scientist, biology and biotechnology research program, Lawrence Livermore National Laboratory, Calif., believes competition is necessary at least to develop the best microarray technology, because no one can ever predict the winner in advance. He recalls that 15 years ago, the accepted sequencing method utilized radioactive tags, gel electrophoresis, and X-ray film. "The technology that finally won out" at professional meetings, Garcia says, "was the technology in the corner of the meeting, that was too expensive, too cumbersome, that nobody thought would ever pan out [automated PCR amplification, fluorescent base tags, laser base readers, and bioinformatics]." Several candidates are vying to become the next best microarray diagnostic technology. Nanogen utilizes electronics on its chips to concentrate DNA samples closer to the on-array gene probes, thus improving detection. Other researchers are developing chips that run DNA through micropores, identifying each gene passing through by changes in its electrical charge. DARPA is even funding research to put the patient on the chip, using living cells whose generalized infection response can detect airborne bioengineered strains that no DNA fragment recognizes. --John Dudley Miller

Bioterrorism Research: New Money, New Anxieties

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