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Has Biodefense Gone Overboard?

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Science  04 Mar 2005:
Vol. 307, Issue 5714, pp. 1396-1398
DOI: 10.1126/science.307.5714.1396

The 9/11 terrorist attacks and the anthrax letters triggered a vast program to protect the U.S. from bioterrorism. Three years later, some scientists complain that it is hurting basic microbiology—and ultimately, public health

Patricia Kiley is wondering whether to hop on the bandwagon.

As a young microbiologist at the University of Wisconsin, Madison, Kiley is making a name for herself studying some of the most basic life processes—for instance, how bacteria sense changing oxygen levels in their environment. But lately, she has felt the oxygen being sucked out of her own field, as funding has become increasingly scarce. Her dilemma: Should she trade her model organism, Escherichia coli, for a bioterrorism agent, to get a shot at the current U.S. biodefense bonanza? Scientifically speaking, switching would be “stupid,” Kiley says; progress is much easier in E. coli, a well-known lab workhorse. But she worries that she may have little choice.

Kiley is not the only one who's concerned. More than 750 U.S. microbiologists—including the president-elect of the American Society for Microbiology in Washington, D.C., Stanley Maloy of San Diego State University, and seven past ASM presidents—sent an open letter to National Institutes of Health (NIH) Director Elias Zerhouni this week, complaining that the current spending spree in biodefense is threatening the very foundation of microbiology. While budgets have skyrocketed for exotic agents such as plague, anthrax, and tularemia—each of them negligible as human health threats—research on widespread and perhaps mundane pathogens is falling by the wayside, the letter says, as is work with traditional model organisms such as Kiley's E. coli.

The letter by S. Altman et al., published in this issue, has circulated among more than 1100 reviewers for, and beneficiaries of, two NIH study sections for microbiology, and it has become a hot topic in recent weeks. “Researchers should never whine about a lack of funding for their research,” says David Walker of the University of Texas Medical Branch in Galveston, who did not sign it. “Biodefense is what Congress wants us to do,” adds Walker, whose university has thrived thanks to the new money. Walker also notes that the main organizer of the letter, molecular biologist Richard Ebright of Rutgers University in Piscataway, New Jersey, has an agenda that goes beyond advocating for microbiology; Ebright has been an outspoken critic of the biodefense buildup, arguing that it is creating new risks (see sidebar, p. 1397).

NIH officials, meanwhile, say the numbers cited in the letter are misleading. Biodefense research spending—some $1.7 billion this year in NIH funding alone, almost entirely at the National Institute of Allergy and Infectious Diseases (NIAID)—has come on top of existing budgets, says NIAID Director Anthony Fauci, and nonbiodefense microbiology has fared no worse than NIH-supported research in general. “I wish those who signed it would take a careful look at the data,” says Fauci. Moreover, studying biodefense agents is yielding valuable insights that will help fight other, more prominent diseases as well, Fauci says. Even among those who did sign, opinions vary widely. Whereas some believe that the massive biodefense effort is unnecessary or even dangerous, others agree that it can help the fight against infectious disease—they just think the balance is skewed. Windfall for science Just how much money would go to biodefense was decided in the frantic months that followed 9/11 and the anthrax letters in 2001. Among several other measures aimed at protecting the nation from bioterrorism, the Bush Administration decided to radically ramp up research on biodefense. NIAID staff added up rough costs for new labs, put together a strategic plan, and persuaded the White House to propose$1.5 billion in new money for biodefense research and labs in NIH's 2003 budget.

Congress agreed, and NIAID's overall budget rose 47% in 1 year, leaving it with a portfolio divided evenly among AIDS, biodefense, and other infectious diseases. Although the new money helped complete a plan to double the NIH budget over 5 years, many institutes other than NIAID saw their budgets rise only about 85% to 90%.

Fauci takes pride in having made sure the research money landed at his institute. If two other contenders—the Department of Homeland Security, formed in 2002, and the Pentagon—had gotten their hands on the money, it would have been directed toward more concrete countermeasures, such as vaccines, drugs, and diagnostics, he says—giving the research community much more to grumble about.

In a vigorous defense of the program during an interview last week, Fauci said he was able to strike a “deal” with the Administration that allows NIAID to spend about one-third of the money on basic research and so-called emerging infectious diseases. That includes components such as a genomics initiative and an \$85 million, 5-year program on innate immunity that “is totally non-organism specific,” Fauci says.

A large chunk of the money has gone to building 14 new biosafety level 3 and BSL-4 labs that can handle the most dangerous pathogens—a source of much debate in local communities. Fauci points out that these labs can also be used to study emerging diseases such as avian flu or severe acute respiratory syndrome. Broader than the Category A, B, and C list of biodefense pathogens of the Centers for Disease Control and Prevention, the NIH list includes agents such as dengue, influenza, West Nile virus, and drug-resistant tuberculosis.

Besides, Fauci contends, even work on a potential bioterrorism agent can have broad applications—for instance, in the February issue of the Journal of Clinical Investigation, researchers report that mice can be partially protected from a poxvirus infection by a drug that targets a cell-signaling pathway needed by the virus, findings that could yield a new approach for antiviral drugs.

Dueling data

The current brouhaha hinges on two different analyses: one, by the letter writers, that suggests a steady erosion in funding for microbiology, and one from NIAID that purports to show that such support hasn't changed.

Ebright and his colleagues have several gripes. One is that many of the biodefense grants were initially awarded through special competitions with pots of money set aside specifically for a handful of high-priority Category A or B agents. Unlike investigator-initiated grants, which are assigned to NIH-wide review panels by topic and receive funding only if they meet a certain quality level, the “requests for applications” are reviewed by panels created just for that competition, and proposals that fall below the usual quality standard may still receive funding. So, like other targeted research, these grants can be easier to get.

The letter asserts that this funding strategy resulted in a steep decline in awards funded by the two main NIH study sections evaluating nonbiodefense, basic microbiology grants: Microbial Physiology and Genetics, and Bacteriology and Mycology. These two sections constitute the bulk of funding for basic microbiology, says Ebright, and are supported mostly by NIAID and the National Institute of General Medical Sciences (NIGMS). Ebright and his colleagues contend that in these two sections, the number of awards has fallen from 1117 between 1996 and 2000 to 746 since then, a drop of 33%. (The numbers come from CRISP, NIH's grants database.) In the same period, the number of grants for six bacterial diseases that are on the priority bioweapons list but are extremely rare in humans—tularemia, anthrax, plague, glanders, melioidosis, and brucellosis—shot up from 33 to 497. (The letter does not address viruses, but the developments in virology are similar, says Ebright.)

Data on success rates (the fraction of applications funded) provided by NIAID support the critics' contention that it has been harder to get grants for nonbiodefense work than for biodefense work (see table, above), although projections for 2006 suggest that the difference will disappear as biodefense funds get shunted from new grants into paying for existing grants and contracts.

Not only is less money going to research on bacteria that cause thousands of infections each year, the protesters say, but fundamental research on model agents such as E. coli, Bacillus subtilis, and Salmonella is also in decline. Such basic work has led to vast advances in knowledge, paving the way for new antibiotics, says Stanley Falkow of Stanford University in California, who also signed the letter. “It will be very difficult to make the same basic discoveries working on the biothreat agents,” he says—not just because researchers barely know them, but also because studying them is restricted to high-containment labs subject to strict and cumbersome security measures.

But Fauci counters with a different set of numbers. NIAID's analysis of nonbiodefense bacterial physiology grants since 2000—defined more broadly, not limited to two study sections—finds that the number of awards has been stable, hovering between about 120 and 150 per year since 2000. It's possible that the number of grants has fallen at NIGMS, Fauci says, but that could reflect tighter budgets at that institute: “If there wasn't biodefense money, they [investigators] would be suffering anyway.” NIGMS program director James Anderson says the institute has not done an analysis of trends in microbiology funding, which are also affected by reviewers' own preferences; lately, they have preferred mechanistic studies, for example. But if the numbers of applications and awards have dropped, “NIGMS is interested in the reasons.”

The letter urges NIH to add basic microbial research to its biodefense program and to assess proposals for biodefense side by side with basic microbial research, which would give nonbiodefense researchers a better chance at competing.

An exaggerated risk?

The nitty-gritty of grant numbers aside, the letter does raise a broader issue: Does biodefense deserve all this money? Apart from the five anthrax deaths in 2001, there have been no known bioterrorism deaths in the United States. Natural deaths from many other biodefense agents—such as smallpox, tularemia, and plague—are also low if not zero. Is it worth spending billions of dollars on these agents, when flu alone causes more than 30,000 deaths a year in the United States and food poisoning some 5000?

Countries other than the United States don't seem to think so. Although many European nations have taken some basic precautions, for instance, such as stocking up on smallpox vaccine, there isn't anywhere near the funding avalanche—nor the meetings, journals, and businesses—that have sprung up in the United States.

But Fauci says he's seen intelligence that convinces him that the threat is all too real. Some researchers are worried too, even if they're not privy to secret information. “I'm personally very concerned,” says virologist Peter Palese of Mount Sinai School of Medicine in New York City, who considers the threat “underestimated.” If anything, he adds, more money should be going to biodefense.

But Milton Leitenberg, an arms-control expert at the University of Maryland, College Park, couldn't disagree more. No evidence suggests that any terrorist organization is able to produce an effective bioweapon, he says, and some of the grim scenarios outlining a bioterror attack appear primarily designed to scare people. As an example, he cites Atlantic Storm, a recent exercise in which politicians simulated an international smallpox attack that takes thousands of lives (Science, 28 January, p. 513) Many of its premises—for instance, that an Al Qaeda splinter group could produce a smallpox powder in a “small brewery in Klagenfurt, Austria”—are wrong, Leitenberg says.

Abigail Salyers of the University of Illinois, Urbana-Champaign, who presided over ASM when the anthrax attacks occurred in 2001, also believes that much of the fear—and much of the research—is unnecessary. Public health officials know how to respond to crises, she says; even in 1947, when a smallpox case surfaced in New York City, millions were vaccinated against the disease almost without a wrinkle. The lesson: Dealing with a bioterror attack isn't rocket science, she says, and a powerful public health system and an effective communication strategy are the best preparation.

Mark Wheelis, a biological arms-control specialist at the University of California, Davis, says he's delighted to see the discussions unfurl. A few people have been critical of the biodefense boom, he notes, but by and large, the three-and-a-half years since 9/11 have passed without an informed debate about exactly what's threatening the U.S. population and how much should be invested to avert those dangers. “This letter finally opens the debate,” he says. “We should welcome it.”

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