The Biodefense Enterprise

The national boom in biodefense research--a seldom-noted outcome of the Sept. 11 attacks and the anthrax letters of 2001--has been a particular bonanza for the academic science community. A massive influx of money--about $1.7 billion in 2005--is supporting construction of biosafety facilities and a huge increase in the number of grants to scientists willing to study highly dangerous, potential bioterrorism pathogens. Paralleling this growth in what might be called biodefense infrastructure is intensifying citizen opposition to the siting of such facilities and research in densely populated urban communities.

Ostensibly, this soaring funding for civilian biodefense--the federal government's response to the threat of terrorism--should make the U.S. safer. But critics of this expansion argue otherwise and contend that funding for biodefense could be better spent on more compelling public health needs.

As fodder for their argument, these critics point to the latest incident: three accidental infections that occurred last year in a laboratory at Boston University (BU). Researchers there were trying to develop a vaccine for tularemia under a grant from the National Institute of Allergy & Infectious Diseases (NIAID), which funds most of the nation's biodefense research. They thought they were working with an attenuated strain of the bacterium sent to them from the University of Nebraska and were conducting their research in a biosafety level 2 lab (BSL-2), the type of lab commonly found at universities.

They were, however, working with cultures tainted with the virulent strain of tularemia, which requires that work be carried out in a more secure BSL-3 lab. And they were doing this work without the approval of BU's biosafety committee.

BU officials say that working in the less secure lab and sloppy lab practices led to the researchers being infected. However, Donald A. Henderson, resident fellow at the Center for Biosecurity of the University of Pittsburgh Medical Center and formerly chief science adviser to the secretary of the Department of Health & Human Services, says, "I've not heard a plausible explanation for what happened; nothing I've heard makes sense."

The infected researchers were treated with antibiotics and have recovered. But state and national public health officials were not promptly informed of the infections--and neither was the public. The lead investigator has resigned from the university.

Critics say BU officials offered weak explanations for the delay in notifying state and local officials. And Thomas J. Moore, acting provost of BU's medical campus, concedes that poor lab practices were followed and says there was no need for public notification because the infected researchers posed no "public risk, since tularemia can't be passed from person to person."

Although tularemia is highly infectious but not contagious and Moore admits to inappropriate lab practices, he tells C&EN that "the reason people got sick was not due to human error. The reason they got sick was because they thought they were working with the vaccine strain of tularemia, which doesn't cause human illness." And, he adds, "They were working in a BSL-2 lab unknowingly with an agent that required BSL-3 precautions."

BUT RUTGERS University's Richard H. Ebright, a molecular biologist with NIH-funded research in microbial genetics, says that, if standard microbiological practices had been carried out, a single cell and its progeny would have been isolated and all subsequent research would have been performed on that homogenous, uncontaminated culture. If standard procedures had been followed, the researchers would have known that the sample they were working with was tainted. What happened in the BSL-2 lab "was human error, not a biocontainment problem," Ebright tells C&EN.

It is not yet known how or where the sample was contaminated. Because the Centers for Disease Control & Prevention is "a national reference library for tularemia," spokeswoman Jennifer Morcone says, both BU and Nebraska sent samples to CDC for molecular subtyping to determine the source of contamination. She says the "source stock sent from Nebraska had no wild [virulent]-type tularemia." But, she adds, "at this point, CDC has not been able to determine the source of contamination."

The Federal Bureau of Investigation and the Occupational Safety & Health Administration are also investigating the infections. The FBI was called in because tularemia could be used for terrorism.

In the meantime, Moore says the researchers who worked in the BSL-2 lab where the infections occurred will now be trained in proper BSL-2 and BSL-3 procedures. And soon, Moore says, the university plans to "initiate unannounced inspections in our many BSL-2 labs and our five BSL-3 labs on a monthly basis." Labs will be graded on performance; the results will be used for internal purposes and, "for some period of time," shared with the Boston public health division, he says.

LAST YEAR'S INFECTIONS might have gone unremarked outside the university except for the fact that BU has ambitious plans to build a highly secure BSL-4 facility for biodefense and emerging infectious disease research in Boston's poor, densely populated South End. Sometimes described as "submarines inside a bank vault," BSL-4 labs have redundant high-containment features that allow researchers to work with the most deadly of the deadly pathogens: anthrax, smallpox, and Ebola, for starters. Indeed, Moore contends that the safety features of a BSL-4 lab would have prevented the infections that occurred in the BSL-2 lab.

BU, along with the University of Texas Medical Branch, in Galveston, was awarded a $128 million construction grant from NIAID in 2003 to build a National Biocontainment Laboratory to include BSL-4 facilities for research on drugs and vaccines against infectious diseases and potential bioterrorism agents. BU matched the grant with $50 million of its own money and is expected to have to shell out annually about $70 million in operating costs.

BU's new lab is likely to bring prestige to an institution that has been overshadowed by its more stellar university neighbors, as well as billions of dollars in federal grants to the city and hundreds of permanent jobs at the new facility. But according to some critics, it could actually increase the threat of bioterrorism by increasing the ranks of people skilled in making and using bioweapons agents.

Despite criticism from some scientists, organized opposition from community activists, and increasing concern on the part of some local officials, construction of the BSL-4 lab in Boston's South End still appears likely to go forward.

Boston's mayor is a staunch supporter of the lab, and the city zoning commission has approved the site for the facility. The city council, however, has proposed an ordinance that would prohibit the BSL-4 lab.

The project received approval under the state environmental impact assessment process last November. But the federal environmental impact statement (EIS), which is required under the National Environmental Policy Act, is still in progress, so NIAID has not yet given its final approval for the project. NIAID's decision is not expected until this summer at the earliest.

In the state EIS and the draft federal EIS, Boston University touted an "excellent track record" of having no laboratory-acquired infections from research done in its BSL-2 and BSL-3 labs over the past 10 years. The revelation of last year's infections prompted a group of local residents calling themselves Safety Net to amend their lawsuit in Suffolk Superior Court to include the absence of public disclosure of those infections.

If Safety Net does not prevail in the state court, it is likely to file suit in a federal court once the federal EIS process is completed, says Tomas Aguilar, a community organizer with Alternatives for Community & Environment, Roxbury, Mass. Safety Net is affiliated with this group.

Aguilar believes several factors make it more likely than previously thought that the BSL-4 lab may not be built in the South End. "It's an election year, and there's a strong sense in the general public that BU is not being truthful with information regarding the handling of agents such as tularemia. If they can't properly handle tularemia, then what makes us have faith in their handling of the most dangerous pathogens like Ebola?" he asks.

The Conservation Law Foundation is also monitoring what it calls the biolab issue. Foundation attorney Carrie Schneider says her organization has "not yet decided to join Safety Net's state suit, though we are closely monitoring the federal EIS, and if that is not adequately completed, we will take legal action."

Philip Warburg, the foundation's president, is disturbed that the state approved the BSL-4 lab without doing an analysis of alternative sites, which state law mandates. "The project's proponents paint a picture of a world of science in which mistakes don't happen, but the recent tularemia exposures indicate that just isn't the case," he says. In fact, he adds, the exposures "raise the question of human fallibility and the impacts of that fallibility on the broader public."

If built, Boston's BSL-4 lab will become part of a growing nationwide network of highly secure facilities, according to Edward Hammond, director of the U.S. office of the Sunshine Project, a watchdog group tracking this growth. At present, there are four BSL-4 labs in the U.S., but six more, including those in Boston and Galveston, are on the drawing board. There are 50 BSL-3 labs currently operating in the U.S.; an additional 19 are planned to be built at government facilities and universities.

But the growth doesn't end with bricks and mortar. Some 235 laboratories nationwide have been fully certified, and another 82 have been given provisional approval by CDC to work with so-called select agents: pathogens with bioterrorism potential. More than 11,000 people have received FBI clearance to work with these dangerous agents.

The number of grants for biodefense research--primarily from NIAID, but also from the National Institute of General Medical Sciences (NIGMS), which funds a lot of chemists--tells an interesting tale. The number of NIAID grants for biodefense has soared 10-fold from 2001 to 2005, from 102 to an estimated 1,091. In dollar amounts, biodefense research has leaped 40-fold at NIAID, from $41.9 million to $1.66 billion over that same time frame. In fact, NIAID funds more biodefense research than HIV/AIDS research, which was once its largest category.

In 2002, NIAID focused its biodefense agenda on pathogens that cause tularemia, anthrax, plague, glanders, melioidosis, and brucellosis, noting, as Director Anthony S. Fauci did, that these agents could be used in a bioterrorist attack but otherwise had low scientific or public health significance. To encourage research on these agents, the institute established funding set-asides and special funding review panels and procedures. With NIH grants in general getting harder to obtain, institutions and researchers flocked to this new funding source.

According to compilations by Ebright and Hammond, from 1996 to 2000, NIAID awarded 33 grants to 15 principal investigators for those six agents, but in 2001 to 2005, the number of grants leapt to 497 awarded to 439 investigators. Nearly 97% of the investigators receiving grants after 2001 had never before received NIAID funding for research on the six agents.

Ebright contends that funding for biodefense research is sucking funding from nonbiodefense research that better serves the public health as well as the economy. NIAID's funding history alone doesn't support Ebright's thesis, however. Rona Hirschberg, a senior NIAID program officer, says NIAID's biodefense money "is entirely new money on top of the money we already had. There has been an increase in the biodefense part of NIAID's budget, but other parts of our budget have also increased, so we are not taking funding from other missions."

But Ebright's thesis gains support if both NIAID's and NIGMS's funding are considered. For example, the number of grants to study nonbiodefense-related microbial physiology and genetics--primarily awarded by NIGMS--dropped 41%, from 490 in 1996–2000 to 289 in 2001–January 2005, Ebright finds. From NIAID, the number of grants to study nonbiodefense-related microbial pathogenesis declined by 27%, from 627 in 1996–2000 to 457 in 2001–January 2005. These declines occurred while the number of NIAID grants for biodefense increased by 1,500%, he says.

When Ebright did an NIH grants database search for tularemia, he found that five grants had been awarded to three principal investigators from 1996 to 2000, but from 2001 to 2005, the number of grants referencing tularemia climbed to 93 awarded to 57 investigators. Ebright says his search revealed that 56 of the 57 investigators "had never previously been awarded a grant referencing tularemia."

At BU in 2003, five investigators received NIH funding for tularemia; one headed the lab in which the infections occurred. When Ebright searched the PubMed publication database, he found that none of the five had published any papers involving work on any bioweapons-related agent, let alone tularemia. Their work focused on sexually transmitted diseases.

BU's Moore confirms Ebright's findings, but points to the researchers' experience in working with bacteria and developing vaccines. "The focus of the research that they will be doing," he says, "is identical to one they have done for a long time. Only the organism has changed."

But Ebright's ultimate point is that NIH's biodefense thrust is making the nation less safe, not more. Directing resources to institutions and investigators who do not have experience in the safe handling of bioweapons agents will eventually increase the pool of people with experience with and access to bioweapons agents. This, he argues, increases "the likelihood of accidental or deliberate release of bioweapons agents."

Henderson concedes that risk increases when more labs work with potential bioweapons agents. But he believes additional highly secure labs with trained personnel are needed to study new and emerging infections like severe acute respiratory syndrome (SARS), and West Nile virus. Hirschberg agrees. "Bioterrorism research will spill over and aid us in combating emerging infectious diseases," she says.

Moreover, Henderson says that, given the stringent procedures and built-in redundancy of BSL-4 labs, increasing their numbers "will not augment the risk." He cites CDC's BSL-4 lab record: "It's in a densely populated area, and it has not had an infection that's escaped" the lab.

David M. Ozonoff, an environmental health scientist at BU and once a supporter of the BSL-4 lab, believes that more BSL-4 labs are not needed in the U.S. because much of the work on pathogens like the virus that causes avian flu can be done--and is now being done--in BSL-3 labs. Because Ozonoff believes that the work at BU's lab will focus on biodefense, not public health research, he's concerned that the BSL-4 lab will end up doing classified research, despite BU claims to the contrary. "There's no oversight and no set of independent scientists setting the research agenda, so we may end up with a situation I call scientific pornography: work that is secret and harmful."

Ozonoff raises yet another concern to add to his reasons for opposing the lab: the arms control issue. "This lab will have all the earmarks of looking from the outside like an offensive bioweapons facility and so could fuel the biological arms race."

Safety issues aside, Ozonoff also believes a BSL-4 lab at BU "is going to be a financial loser. It's a white elephant: You can't kill it, you can't give it away, and you have to keep feeding it."