290 Hardiman: Role of research in developing anthrax countermeasures quences containing exclusively basic residues are competent for translocation, it is an attractive possibility that the adaptability of the PA translocon could be leveraged. Per- haps compounds of interest could hijack the AT translocation machine to gain access to cellular cytosolic compartments. In the fu- ture, AT will likely be engineered to both de- liver toxic molecules to pathogenic cells as well as deliver beneficial compounds to a broad range of human cells. Pe RSPe CTiVe S The cost and ease of research remain salient considerations as biomedical research budgets are stretched thin. These factors also represent a major difference between basic and applied research approaches. Although intrinsically valuable, live- pathogen work, often consisting of “ap- plied” research approaches, has limitations not observed in subunit research. According to a Sandia National Laboratories survey [55], 38 percent of investigators reported di- verting research funds to comply with secu- rity protocols. At the federal level, the estimated biodefense budget for the National Institutes of Health (NIH) in 2005 allocated 8.9 percent of total expenditures specifically for the construction of biosafety laboratories [56]. Further, as additional administrative re- sponsibilities accrue, the productive time that can be devoted to research is reduced. This effect can be quantified as a measure of publications produced in a given year nor- malized by the amount of federal funding in that year [57]. After select agent require- ments were enhanced in 2002, the number of B. anthracis publications per million dol- lars reduced 5-fold compared to the output before 2002 [57]. These indirect costs and consequences must be considered in the total cost effectiveness of live-pathogen, select agent research. Basic biodefense research, in contrast, is largely insulated from these accessory costs and loss of research efficiency. Indeed, the federal government continues to include basic research in its portfolio of biodefense research priorities. The 2005 NIH biode- fense budget provided for $550.2 million for basic research, representing almost one-third of total biodefense expenditures [56]. These resources appear to be a sound investment when basic anthrax toxin research, for ex- ample, provides a source for translational applications. Indeed, the elucidation of how sub- strates are recognized and translocated through the AT pore has achieved profound relevance to countermeasures for this dis- ease. Dr. Collier’s work has been, and will likely continue to be, leveraged in the de- velopment of efficacious vaccines and pro- phylactic compounds against anthrax infection. There are also new insights into repurposing AT as a molecular delivery sys- tem that will selectively target dysregulated cells in the context of overproliferation. When basic research is included in the portfolio of approaches against our most dan- gerous pathogens, it yields results while re- maining independent of the constraints of applied biodefense research. As such, basic biodefense research represents a lucrative area for discovering next-generation translational applications that are necessary for the contin- ued protection of the general population. Re Fe Re n Ce S 1. Koch R. Die Ätiologie der Milzbrand- Krankheit, begründet auf die Entwicklungs- geschichte des Bacillus anthracis. Cohns Beitrage zur Biologie der Pflanzen. 1876; 2(2): 277-310. 2. Biodefense Category A, B, C Pathogens, NIAID, NIH [Internet]. [cited 2012 Apr 10]. Available from: http://www.niaid.nih.gov/top- ics/biodefenserelated/biodefense/pages/cata.a spx 3. Henderson DA. The looming threat of bioter- rorism. Science. 1999;283(5406):1279-82. 4. Broussard LA. Biological agents: weapons of warfare and bioterrorism. Mol Diagn. 2001;6(4):323-33. 5. Ivins BE, Welkos SL. Recent advances in the development of an improved, human anthrax vaccine. Eur J Epidemiol. 1988;4(1):12-19. 6. Huxsoll DL. Narrowing the zone of uncer- tainty between research and development in biological warfare defense. Ann NY Acad Sci. 1992;666:177-90. 7. Tournier JN, Rossi Paccani S, Quesnel-Hell- mann A, Baldari CT. Anthrax toxins: a weapon to systematically dismantle the host immune defenses. Mol Aspects Med. 2009;30(6):456-66.