286 Hardiman: Role of research in developing anthrax countermeasures Hazard suits, biocontainment labs, and public controversy. Even though Dr. John Collier, Professor of Microbiology and Im- munobiology at Harvard University, has worked exhaustively on Bacillus anthracis, the causative agent of anthrax [1], one is hard pressed to find any of these in his lab. Dr. Collier has devoted much of his career to the study of bacterial toxins of diseases of great public health importance. Instead of being relegated to the bench, his work on how the anthrax toxin (AT†) is able to cause disease has yielded profound translational contributions. As such, his review of the field during his talk “Anthrax Toxin,” part of the Yale Microbiology Graduate Program Seminar Series on February 23, 2012, serves as a powerful case study of how basic re- search on biodefense agents can be an ef- fective approach to devising clinically relevant strategies to combat disease. How three individual components com- bine to form the AT has been an area of in- tense interest for Dr. Collier. Even though the B. anthracis bacterium is classified as a Category A Priority Pathogen by the Na- tional Institute for Allergy and Infectious Disease (NIAID) [2], Dr. Collier noted that his work is classified as biosafety level (BSL)-1. Because he works on individual components of the toxin, which are nontoxic until combined, he enjoys the relative ease of conducting research without the addi- tional regulation and resources required at higher BSL levels. This fact merits a closer inspection of why this claim is important. Indeed, this au- thor supports the implicit assertion that re- search on biodefense agents, even and especially at the BSL-1 level, can have pro- found translational consequences. Basic re- search on AT has led to the development of a more efficacious vaccine, the identifica- tion of cellular cofactors that may assist with toxin translocation, and the engineering of novel therapeutics that utilize AT as a plat- form for drug delivery. In light of the recent controversies and recalibrations over high- risk research, the importance and relevance of fundamental research becomes an espe- cially relevant issue. To x in -BASe D VACCin e De Ve l o PMe n T Although the bacterium cannot spread from human to human, B. anthracis is an at- tractive choice of bioweaponeers, due to its formation of hardy spores and relatively high morbidity and mortality rates [3,4]. Thus, countering a potential anthrax attack using vaccines and prophylactic counter- measures has been a biodefense priority for several decades [5,6]. In order to survive and replicate in an infected individual, B. an- thracis must evade host defenses. One mechanism is to selectively kill off cells of the innate immune system [7,8]. To accom- plish this, B. anthracis delivers components of the multimeric AT into the bloodstream, where they can encounter host immune cells [9]. AT is comprised of 83-kilodalton (kDa) Protective Antigen (PA), which serves as a pore [10,11] to translocate the other two components, 89-kDa Edema Factor (EF) and 90-kDa Lethal Factor (LF). Once deliv- ered to the cytosol, EF acts as an adenylate cyclase [12], adding a cyclic AMP (cAMP) molecule onto critical proteins in neu- trophils, leading to inactivation of these cells. The targeting of endothelial cells also results in fluid leakage and excess fluid build-up, known as edema. LF similarly in- activates host protein function via its pro- tease domain, which irreversibly cleaves members of the mitogen-activated protein kinase-kinase (MAPK-K) family [13,14]. The impaired immune response combined with edema promotes bacterial replication in the bloodstream, leading to septic shock and possibly death. The anthrax exotoxin is a critical viru- lence factor for B. anthracis pathogenesis [15,16]. Because of the requirement for the toxin in disease progression, developing a formulation targeting the toxin has been a priority for pharmaceutical companies inter- ested in a vaccine. The federal government established Project BioShield in 2004, which sought to invest in vaccines and pro- phylactic agents to employ for defensive purposes. BioShield contracted for 29 mil- lion doses of Anthrax Vaccine Absorbed