| TH E N I H C A T A L Y S T | S E P T E M B E R – O C T O B E R 2008 |
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What's going on in 33? It may seem that only a select few can swipe their ID, pass through the series of security checks and measures, and enter into a world of high-containment research on infectious diseases.
Others need to identify themselves to the guards from the outside via a video intercom and then navigate the metal detector like a common airline passenger, surrender cell phones should they have a camera, trade in their official NIH badge for a visitor's tag, and await escort.
Why the beefed-up security on a campus already surrounded by a fence? What kinds of pathogens are housed in there and what do Building 33 scientists do with them?
Actually, there's nothing secret about the research in Building 33, and no research in the NIH intramural program is classified. What goes on in Building 33 is similar to what goes on in any NIH lab: world-class research with the ultimate goal of saving lives and improving the quality of life.
The presence of Building 33 on the NIH Bethesda campus serves two purposes. One purpose is to expand and consolidate NIAID's research programs on viruses and bacteria that can cause serious and potentially lethal diseases and are transmitted by the inhalation route or by insect vectors, mainly mosquitoes.
The other purpose for the facility, however, was to expand the NIH's basic research on infectious diseases of global importance—those that occur naturally or those that may be caused by agents intentionally released through an act of bioterrorism. The anthrax attacks on U.S. Senate offices and news media outlets in September and October of 2001 alerted the public to the country's vulnerability to intentional dissemination of such pathogens.
The level of security in Building 33, as in any government facility, is dictated by the most dangerous pathogen samples housed within—in this case, anthrax, tuberculosis and other biosafety level 3 (BSL-3) agents. Hence the need for the guards and various security protocols, which may seem imposing or intimidating to some at the NIH who are use to a more open environment. (See BSL table below.)
Although we cannot take you on a physical tour of Building 33, this article attempts to capture some of the intriguing research and facilities behind those closed doors.
Mycobacterium tuberculosis, it's back
Although the incidence rate of tuberculosis has been decreasing in high-income countries for decades, many African nations witnessed a tuberculosis epidemic in the 1990s, and the incidence rates have not decreased significantly. The disease is also prevalent in some Eastern European and Asian countries.
Especially worrisome is the fact that many of the new infections occur with bacteria that are resistant to the two main drugs used for tuberculosis treatment, accounting for over 20 percent of cases in some countries.
This problem is a major focus of Clifton Barry's research in Building 33. Because the emergence of multi-drug-resistant strains makes it important to develop new antibiotics, his group concentrates on the identification of cellular components that can be efficient targets for new drugs. A trained chemist, Barry works on all stages of drug development, from the initial discovery of the target and the synthesis of potential inhibitors to testing in animals and early-stage clinical trials.
Barry's laboratory contains a chemistry and a molecular biology section, in addition to a BSL-3 part with a robotic system to test drug candidates in a high-throughput setup. "This is the only such testing system in the world in a BSL-3 setting, as far as I know," Barry said.
Barry moved from the Rocky Mountain Labs in Hamilton, Mont., in 1997, camping out at a NIH Twinbrook lab for several years. Among the main advantages of the Bethesda location, he cites the integrated research environment at the NIH campus and the ease of travel from Washington, which he says is especially important for maintaining his international collaborations with Korea and China.
This integrated research environment was one of the main arguments for choosing to build Building 33 in Bethesda.
Flu Anew
The influenza virus poses a challenge for the development of seasonal influenza vaccines every year. The high mutation and reassortment rate of the virus makes it difficult to develop a universal vaccine. A new vaccine is developed every year to protect against strains that are anticipated to be prevalent the next winter.
Although this approach has been very successful for seasonal influenza, the recent spread of new subtypes, as well as the fear of an influenza pandemic, have made it necessary to develop a strategy to generate vaccines against novel influenza virus subtypes. Kanta Subbarao is working on this major public health issue.
It can take several years to develop a new vaccine, but a pandemic will require an immediate response. Subbarao's group works on generating and evaluating candidate vaccines for all 16 known subtypes of the influenza A virus. Even if those vaccines prove not to be an exact match for any given strain of the respective subtype, experience with these vaccines should provide valuable lessons and make it possible to significantly speed up the development of antigenically matched vaccines.
And Anthrax, of Course
Stephen Leppla's lab is performing major research on Bacillus anthracis, a.k.a. anthrax, the bacterium that prompted health authorities and politicians to expand the government's research on emerging bioterrorism threats.
Anthrax was one of the first biological weapons, developed by the U.S., the Soviet Union and other countries in the 1940s and 1950s. The potential dangers of anthrax were highlighted with the 2001 anthrax attacks.
Leppla's group researches the basic cell biology of the anthrax toxins. The group is especially interested in the receptors responsible for the uptake of the toxins and in how the processing of toxins by the cell contributes to their mechanism of action. His lab has generated mutants of one of the toxins for development of new and safer vaccines, which are now in clinical trials. (You may have noticed flyers on the NIH Bethesda campus asking for volunteers in an anthrax vaccine study).
While Leppla's research so far has had to rely on plasmids with single proteins or attenuated strains, moving into Building 33 will eventually provide him with lab space to perform experiments with virulent bacteria. Leppla is very conscious of the security requirements connected to working with potentially dangerous organisms. He especially stressed the importance of strict screening and training of personnel.
Animal Facilities
An essential part of the Building 33 resources is the integrated animal facility. Scientists can perform animal experiments under animal-BSL-3 conditions using "select agents," which are pathogens and toxins that the DHHS or USDA considers a serious threat to public health. (Refer to http://dohs.ors.od.nih.gov/select_agents_main.htm for the list.)
Staff in Building 33 are trained in animal care under ABSL-3 conditions. One assistant facility manager estimated that she had about nine months of specialized training. Standard procedures like infections or inoculations are often done by the animal technicians or research support specialists rather than the scientists themselves. Before being allowed to work with animals on their own, scientists are required to undergo additional training and have to have a proven record of animal handling.
Built to Last
Despite its light appearance with large windows and airy spaces, Building 33 was specifically planned with the possibility of a terrorist attack in mind. The building is set back from the surrounding streets, and physical barriers make it impossible to directly approach it with a vehicle. The construction included several different architectural features that protect the physical integrity of the building even under heavy impact or stress.
The design of BSL-3 laboratories themselves makes an unintentional release of bacteria and viruses extremely unlikely. Before reaching the actual laboratory one passes through two doors with an ante-room in-between. The microorganisms are handled in special biosafety cabinets that ensure product, personnel and environmental protection.
The laboratories are kept at a negative air pressure. This ensures that even in the unlikely event that pathogens are present in the laboratory air as aerosols, they are kept inside the confined laboratory area. All exhaust air is filtered through a series of High Efficiency Particulate Air Filters (HEPA) that remove more than 99.997 percent of all particles larger then 0.3 micrometers. The complexity of the air management can be appreciated by the fact that, despite its height, Building 33 has only three floors of laboratories. The interstitial space between the stories actually consists of maintenance floors that house the machinery for air pressure control and exhaust filtering.
Security Prior to Security
Although the engineering measures are essential they are far from sufficient. "The human factor is big," said Jeff Potts, the Safety and Occupational Health Manager in Building 33. And the "human factor" has two important sides.
One is the general reliability of the personnel working in the building. To avoid terrorists, criminals or emotionally unstable persons gaining access to highly dangerous pathogens, all employees have to undergo a background check by the Department of Health and Human Services (DHHS). Additional security clearance is needed to work with select agents.
In this case, both the FBI and DHHS conduct independent investigations into the personal history of each scientist. Even a bad college prank years ago can lead to a restriction of access to the microorganisms.
Equally important is that the day-to-day work is performed in a manner that guarantees optimal safety. Although an accidental release of pathogens to the environment is basically unheard of, accidental infection of scientists in the laboratory are very rare nationwide, but do happen. However, not a single incident of exposure of the people outside the lab was recorded in an internal review of more than 3 million hours of BSL-3 and -4 work at the NIH.
BSL-4 in the Offing
Prior to the construction of Building 33, NIAID did perform BSL-3 research on the Bethesda campus. The new facility has quadrupled its space of dedicated BSL-3 lab space, providing an additional 14,300 square feet.
NIAID remains committed to two BSL-3/BSL-4 facilities at Fort Detrick and Rocky Mountain Laboratories. Construction is now underway on the Fort Detrick Integrated Research Facility, a $105 million 100,000-gross-square-foot building to house laboratory space for animal research, radiology equipment, mechanical space and a waste-handling area. Construction is complete on the $66.5 million 47,000-net-square-foot BSL2, 3, 4 Integrated Research Facility at Rocky Mountain Laboratories.
In September and October of 2001, on the heals of the grief, confusion and fear brought upon the nation by the September 11 attacks, five news media outlets and two U.S. Senate offices received envelopes sent through the U.S. postal service containing anthrax spores. Five people died in the attacks, and 22 others were infected with anthrax.
In February 2002, NIAID convened a Blue Ribbon Panel on "Bioterrorism and its Implications for Biomedical Research" to map out strategies for an efficient response to the bioterrorism threat. The panel's final report concluded that a "serious shortage of high-containment laboratories in which to perform experiments using dangerous pathogens" existed in the United States. NIAID's subsequent Strategic Plan called for, among other things, an expansion of the NIH's basic research capabilities on bioterrorism agents. This led to the incorporation of funding for the construction of three new high security research facilities in the 2003 budget. One was to be constructed on the main NIH campus, one in Fort Detrick, and one in Hamilton, Mont., at the Rocky Mountain Laboratories.
Construction in Bethesda commenced in November 2003 and was completed two years later. In a dedication ceremony in May 2006 the building was named in honor of a Republican Congressman from Florida, Charles William "Bill" Young, a strong proponent of biomedical research during his more than three decades in the House of Representatives. As chairman of the House Appropriations Committee he oversaw the doubling of the NIH budget from 1999 to 2004.
By March 2006, scientists began setting up the laboratories. Today about 90 percent of the space is occupied. Research ranges from basic science and vaccine development of (re-)emerging pathogens such as influenza virus and tuberculosis bacteria, to potential bioterrorism threats such as Bacillus anthracis or pox viruses. For the cost of $182.6 million, Building 33 provides 84,000 square foot in laboratory space, animal care facilities, offices and conference rooms to the NIH community. Most important, it more than tripled the available BSL-3 space on the NIH campus that is necessary for the work on highly pathogenic organisms.
The scientific focus of Building 33 is the development of medical protection and countermeasures against not only potential bioweapons but also potential and emerging public health threats. The United States does not have an offensive bioweapons program. President Nixon renounced the development and production of offensive bioweapons in 1969, and Congress ratified the "Biological and Toxin Weapons Convention" in 1975, making such work illegal.