Dr. Marcus Horwitz, professor of medicine at the University of California, Los Angeles, has devoted most of his career to finding a vaccine for tuberculosis. Though the age-old killer is well controlled in the industrialized world, TB kills more than 2 million people each year among the global poor. It's not a sexy field: Compared with funding for heart-disease, HIV/AIDS or cancer research, National Institutes of Health money for TB research is a minor blip. Applied research into potential TB cures and vaccines is not a priority for the agency, or for drug companies, which see no profitable market among the poor. Still, after 15 years of research funded mainly by the NIH, Horwitz's lab has finally come up with what could be the first improvement in TB vaccination technology in nearly a century. His vaccine is being tested among a small group of patients, and a nonprofit drug development organization funded by the Bill and Melinda Gates Foundation is committed to sponsoring the full-blown efficacy trials if his early experiment proves successful.
So why, on the cusp of real progress, is Horwitz's lab phasing out its basic science research on TB in favor of studying tularemia, the bacterium spread by ticks and rodents that causes rabbit fever? Because tularemia is on the government's A-list of potential bioterrorism agents, put there because the United States and the former Soviet Union stockpiled it as a biological warfare agent during the Cold War. Today, Washington is throwing plenty of money at basic research of the pathogen even though it affects only a few hundred Americans a year, is relatively rare around the world and is easily treatable with common antibiotics. Even if it did fall into the hands of terrorists, the threat would hardly be grave: The disease is difficult to weaponize and, when treated, is fatal in fewer than 2 percent of cases. "Scientists call it money transferase," says Horwitz. In his case, the $200,000 he's received annually to study one of the globe's most virulent killers, TB, will now mainly go to study a disease whose significance is primarily symbolic in the war on terrorism.
It's a scenario that's being played out across the country. Since the 2001 attacks, Congress has poured billions into bioterrorism research aimed at developing vaccines and drugs to combat the most likely threat agents. Indeed, the amount of money being directed at bioterrorism defense will soon make it the second-largest (after cancer) results-oriented medical-research program of the post-Cold War era. And that has led the tiny fraternity of research scientists who've devoted their lives to studying infectious disease to expand or alter their research priorities in order to tap into the huge pot of money the government has set aside for bioterrorism research. Dr. Richard Guerrant, director of the Center for Global Health at the University of Virginia, for example, has tailored a few of his grants to win biodefense funding. "[Y]ou adopt what you do to attract the resources that are necessary," he said, adding that several of his colleagues at the center have shifted their "whole approach to tularemia and anthrax because of the availability of funding."
The drive to protect the nation against potential bioterrorism agents is having a major impact on the entire medical-research establishment. Direct spending on bioterrorism research and development by the National Institute of Allergy and Infectious Diseases (the lead NIH agency in bioterrorism defense research) and the Department of Defense soared from an annual $250 million pre-anthrax attacks to well over $2 billion this year, turning it almost overnight into a larger program than HIV/AIDS was in its heyday. By comparison, the NIH last year spent less than $200 million on tuberculosis and malaria combined. Meanwhile, the rest of the nation's medical-research budget is facing its first restrictive environment in decades. The NIH's overall research budget will rise only at the rate of inflation next year -- far below the double-digit increases of the Clinton years. The belt-tightening prompted virtually every medical school and patient-advocacy group in the country to sign full-page ads in The Washington Post last summer protesting the situation.
Meanwhile, Congress upped the ante this summer by quietly approving President George W. Bush's Project BioShield, a $5.6 billion fund to purchase the fruits of biodefense research. The bill gives the administration the power to negotiate a fair market price for the new drugs and vaccines once the Department of Health and Human Services secretary has determined that there's no commercial market. The price will presumably be based on what the drug companies invested in order to come up with the as-yet-undiscovered therapeutics, plus the industry's standard rate of return -- which, as Fortune magazine points out every year, ranks No. 1 among U.S. industries.
The idea behind BioShield is to entice for-profit pharmaceutical and biotech firms to invest in anti-terrorism therapeutics, as they've made it plain that they won't ride to the nation's rescue unless they're lured with a guaranteed payoff. Eli Lilly head Sidney Taurel, who recently drew fire from liberals on Capitol Hill for pushing for drug-industry liability exemptions from his perch atop the Homeland Security Advisory Council, indecorously encapsulated the industry's attitude in his public testimony last year. "Government is not going to get new miracle drugs for cost plus 10 percent," he said. Unlike run-of-the-mill defense contractors, the very profitable drug companies appear to have better uses for their capital.
Even with this pot of gold at the end of the research-and-development rainbow, the path to a payoff will be long and tortuous. The biggest problem is scientific. Finding antidotes to infectious disease isn't easy. It will take years, in some cases decades, to develop new or more effective vaccines and drugs to combat anthrax, botulism, smallpox, tularemia and the other pathogens on the government's list of agents likely to be weaponized by nations or groups hoping to wreak havoc on the United States. No wonder major pharmaceutical companies are reluctant to dive in. Why invest in risky biodefense products when there are more lucrative heartburn-, allergy- and pain-relief markets to pursue? Republicans in Congress seemed to recognize the flaw in relying on the market to protect the public against bioterrorism. During the bill's markup last June, they slipped in an amendment allowing the government to manufacture the drugs and vaccines directly if procuring them from private contractors proves too costly.
Another problem is that even if these drugs were developed quickly, the effectiveness of the new therapeutics would remain in doubt. Most anti-bioterrorism drugs would never get the extensive clinical trial testing usually demanded by the Food and Drug Administration because there is no naturally occurring patient population on which to test them. Special exemptions have been built into the laws that allow vaccines to gain approval with only limited safety testing. If the public's reluctance to line up for the smallpox vaccine is any guide, new biodefense vaccines would simply be put on the shelf for the day when a coordinated and large-scale bioterrorist attack makes the public receptive to mass inoculation. For many anti-bioterrorism agents, their first use would also be their first clinical trial.
Furthermore, a lot of the basic research money pouring into biodefense would be wasted on poor quality research. It's an inevitable outcome of the NIH peer-review process. Those familiar with the process say the closed-door panels divide applications into three piles: those that will get funded, those that will get funded if there's enough money and those in the "no way" pile. The sudden influx of funding inevitably means "you're reaching applications with less scientific merit," says Richard Ebright, who directs the chemistry lab at the Waksman Institute of Microbiology at Rutgers University. "There will be an enormous increase of people moving into bioterrorism, particularly people who have difficulty getting their grants funded." A similar process is under way in the private sector. Small biotechnology companies running out of venture capital are abandoning other projects to apply to the NIH for the small-business components of the anti-bioterrorism program.
Most disappointing of all, the majority of the applied research supported by the government -- the actual development of candidate drugs and vaccines for potential bioterrorism agents -- would have little effect on the diseases that pose the gravest threat to humankind. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) and a leading figure in the nation's biodefense effort, claims there will be many "spin-offs" from beefing up bioterrorism defense research. He argues on the agency's Web site that "NIAID research on organisms with bioterror potential will almost certainly lead to an enhanced understanding of other more common and naturally occurring infectious diseases that afflict people here and abroad," like TB and malaria. But enhanced understanding is not a cure. Vaccine research is almost always pathogen specific, as are most new drugs to combat viral diseases. And the number of people worldwide who suffer from smallpox, botulism, Ebola or anthrax in the absence of deliberate poisonings wouldn't fill up the tuberculosis ward in a small African city. "It's distracting from global health," said Dr. Carol Nacy, founder of the Sequella Global Tuberculosis Foundation (which will fund Horwitz's large-scale TB trial) and now head of a small biotech firm researching TB drugs. "We'll learn some things [from bioterrorism research] that are relevant, but not much."
So far, she seems to be right. Far from pursuing spinoff, many scientists are shifting their priorities to follow the money. Johnny Peterson, a professor of microbiology and immunology at the University of Texas Medical Branch in Galveston, has been studying cholera since his graduate-student days in the late 1960s. Periodic outbreaks of dehydrating diarrhoeal diseases like cholera and dysentery kill an estimated 2 million children around the world every year because their bodies are so severely weakened by a lack of fluids and undernourishment, according to the Population Resource Center. (While those numbers aren't relatively large, cholera is a serious problem because children who survive it almost always suffer long-term damage.) Peterson has spent decades looking for compounds that block the bacterium's toxin, which leads to diarrhea, dehydration and death, and he's come up with at least one. But last year he saw that the compound might also block the related anthrax toxin, so he applied for a grant to study that. "We're trying to make hay when the sun is out," Peterson said. While he's hiring more scientists and will continue studying the basic science of cholera, his plans to seek a grant to apply his work to potential cholera therapeutics have been put on hold. "Perhaps we can pursue it in the future," he said.
There will be some positive spinoffs from increased biodefense spending, to be sure. Money hopefully will get channeled into rebuilding the nation's network of public-health clinics, which were created to cope with the epidemics that ravaged America's cities over a century ago. The recent SARS outbreak reminded everyone of the importance of having an infrastructure able to rapidly diagnose and understand newly emerging diseases. There will also be a major hunt for new "broad spectrum" antibiotics -- drugs that are effective against a range of bacterial diseases including those that actually infect large numbers of people. There will be new research tools developed that can be deployed in the hunt for cures or vaccines for any infectious disease. This is especially important in an era when older antibiotics are rapidly becoming ineffective due to resistance brought on by over-prescription, improper use and the inevitable mutations of wily microbes.
But who will own these new antibiotics? And who will test them against diseases like multidrug resistant TB, a growing global threat? Unlike their use as anti-bioterrorism agents, these new drugs will have to be tested against each specific disease before regulators here or abroad allow them into widespread use. And the basic economics of who conducts such tests will not be changed by BioShield's purchasing of biodefense research: Only testing for use against potential terrorism agents will be funded; research into secondary uses will not. For their part, the biotechnology and pharmaceutical industries have not invested in developing drugs for the major infectious disease killers for the same reasons they under invest in rare diseases in the United States: there's no market. For diseases like malaria, leishmaniasis and cholera, the market's absence isn't defined by the small number of patients but by the fact that the millions of patients have no money. Testing a new antibiotic that is effective against anthrax to see if it is also effective against tuberculosis will require that it be tested against tuberculosis. And that will require money that no drug company wants to spend. It would be a terrible denouement for the spinoff promise if the new and untested anti-terrorism drugs get stockpiled in military warehouses while scientists who want to test them on sick populations can't because they don't have the rights or the money to conduct the tests.
One way to get around this problem would be for the government to earmark a good portion of the $2 billion-plus for anti-bioterrorism research -- say, one-quarter of it -- for targeted research and development toward new therapeutics to combat the great neglected diseases that kill millions each year. This will not detract from the war on bioterrorism; it will enhance it. How? Spinoff works in both directions. A new antibiotic that cures multidrug resistant TB may be just what we need for the day when a mad scientist-terrorist figures out a way to aerosolize tularemia over one of our cities. And unlike some new antibiotic developed with that remote bioterrorism threat in mind, the new antibiotic will have been tested in large clinical trials, so its side effects will be well characterized. And it's not only good science, it's good politics. As one scientist put it, by joining the fight against the infectious diseases ravaging the developing world, the United States can help drain the swamp that breeds terrorists. "[I]t is a very clear way to address ideologically the threat of bioterrorism," said Guerrant of the Center for Global Health. "If we can do something about diarrhea or malaria, that will affect my children's future security better than anything else we can do."
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