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Human and Agricultural Health Systems

INTRODUCTION

Biological pathogens (for example, anthrax bacteria or the smallpox virus) or toxins produced by biological organisms (for example, botulinus toxin or staph enterotoxin) that are released intentionally or accidentally—or that occur naturally—can result in disease, fear, disruption to society, economic harm, diminished confidence in public and private institutions, and large-scale loss of life.

People or livestock can be exposed to these agents from inhalation, through the skin, or by the ingestion of contaminated food, feed, or water. After exposure to a pathogen or toxin used as a biological weapon, physical symptoms can be delayed and prove difficult to distinguish from naturally occurring illnesses. Similarly, crops can be exposed to biological weapons in several ways—at the seed stage, in the field, or after harvest.

The deciphering of the human genome sequence and elucidation of the complete genomes of many pathogens, the rapidly increasing knowledge of the molecular mechanisms of pathogenesis and of immune responses, and the development of new strategies for designing drugs and vaccines offer unprecedented opportunities for using science to counter bioterrorist threats. But these advances also allow science to be misused to create new agents of mass destruction.

Two kinds of biological terrorist threats must be envisioned. The first is the release of communicable infectious agents—like smallpox, Ebola, or foot-and-mouth disease—that can spread rapidly within communities and farmland through contact and have the potential, as does influenza, to spread around the world and cause epidemics. The second kind of threat consists of biological agents that may cause disease or death in individuals but generally may not be transmitted between



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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism 3 Human and Agricultural Health Systems INTRODUCTION Biological pathogens (for example, anthrax bacteria or the smallpox virus) or toxins produced by biological organisms (for example, botulinus toxin or staph enterotoxin) that are released intentionally or accidentally—or that occur naturally—can result in disease, fear, disruption to society, economic harm, diminished confidence in public and private institutions, and large-scale loss of life. People or livestock can be exposed to these agents from inhalation, through the skin, or by the ingestion of contaminated food, feed, or water. After exposure to a pathogen or toxin used as a biological weapon, physical symptoms can be delayed and prove difficult to distinguish from naturally occurring illnesses. Similarly, crops can be exposed to biological weapons in several ways—at the seed stage, in the field, or after harvest. The deciphering of the human genome sequence and elucidation of the complete genomes of many pathogens, the rapidly increasing knowledge of the molecular mechanisms of pathogenesis and of immune responses, and the development of new strategies for designing drugs and vaccines offer unprecedented opportunities for using science to counter bioterrorist threats. But these advances also allow science to be misused to create new agents of mass destruction. Two kinds of biological terrorist threats must be envisioned. The first is the release of communicable infectious agents—like smallpox, Ebola, or foot-and-mouth disease—that can spread rapidly within communities and farmland through contact and have the potential, as does influenza, to spread around the world and cause epidemics. The second kind of threat consists of biological agents that may cause disease or death in individuals but generally may not be transmitted between

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism individuals—the most familiar example being anthrax. In either case, some agents may persist in the environment, as do anthrax spores, and continue to cause problems long after their release. In addition to naturally occurring pathogens, biological agents used offensively can be genetically engineered to resist current therapies and evade vaccine-induced immunity. Though it is vital that the molecular mechanisms by which classes of organisms cause disease (pathogenesis) be elucidated in order to understand and counter their effects, this is no simple matter. Preparedness for a biological attack against people, crops, or livestock is complicated by the large number of potential agents, the long incubation periods of some agents, and their potential for secondary transmission. Biological agents do not need to be weaponized for effective dissemination. Deliberate contamination of food looms as perhaps the easiest method, despite the recent focus on release of these agents as small-particle aerosols or volatile liquids. Moreover, because of its size and complexity, the U.S. food and agriculture system is vulnerable to deliberate attacks, particularly with foreign diseases that do not now occur domestically. Even without actual attack, plausible threats to infect populations or poison the food supply could, in and of themselves, damage the U.S. economy and reduce public confidence in the government’s ability to safeguard health and security. Recent experiences with the West Nile virus and anthrax spores in the United States, and with foot-and-mouth disease in the United Kingdom, offer practical lessons in human and agricultural outbreak detection, laboratory diagnosis, investigation, and response that might be useful in planning for future attacks involving biological terrorism (Fine and Layton, 2001). The experience with the West Nile virus outbreak highlighted the importance of communication and coordination between responding agencies (U.S. General Accounting Office, 2000). The GAO study noted that although the system worked, there were several obvious places for improvement. A single alert physician at a local hospital initiated the investigation early enough that an effective intervention was possible before the outbreak became widespread, but the investigation subsequently found many other cases, which were either not properly diagnosed or not reported to the health department. The GAO report concluded that much more systematic surveillance and reporting at the local level is needed. Similarly, improved communication among public health agencies, including those dealing with animal health, is needed. Increased laboratory capacity will also be important to an efficient and effective response to disease outbreaks (at first only one public health laboratory in the country was equipped to diagnose West Nile virus) (IOM, 2002). Moreover, these events raise vexing concerns about how many outbreaks could be managed at one time. The attacks of September 11, 2001, and the intentional release of anthrax spores shortly afterward also revealed vulnerabilities that are the results of long-term declines in the nation’s public health and agricultural infrastructures. The

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism decline in the U.S. public health system is the result of its systematic dismantling over time by Congress and the executive branch. In fact, the response of the Centers for Disease Control and Prevention (CDC) to the anthrax attacks was admirable given its limited resources and outdated communications system. CDC, together with state and local health departments, has provided this nation with an outstanding cadre of people who understand how to perform surveillance, prevention, and detection of infectious agents, whether they are endemic, emerging, or a result of bioterrorism. These agencies must be supplied with the tools and resources taken away from them in the past. Restoring the public health system of the United States should be the first order of business in the efforts to defend the nation against bioterrorism. The Need for Approaches with Multiple Benefits Bioterrorism poses a unique challenge to the security of the U.S. population. A state-sponsored enterprise, or just a few individuals with specialized scientific skills and access to a laboratory, could easily and inexpensively produce a panoply of lethal biological weapons, although it is no trivial matter to disseminate or disperse such agents across large populations. Such operations may be difficult to detect because, in contrast to nuclear weapons, biological agents can be manufactured with ordinary pieces of equipment that are listed in commercial catalogues and are legitimately purchased for producing such things as chemicals, pharmaceuticals, or even beer. Fortunately, investments made to protect the country against bioterrorism will help protect the public’s health and the U.S. food supply from naturally occurring threats as well. Although it may be difficult to distinguish an introduced infectious disease from a naturally occurring one, the strategies to protect against either—requiring preparation and new scientific and technological approaches to surveillance, prevention, response, recovery, decontamination, and forensics—must be the same. Similarly, investments made to protect the country’s food supply against bioterrorism have the potential, and are even necessary, to protect it from more routine threats as well. Because the most likely break-throughs will come from the study of both pathogenic and nonpathogenic bacteria and viruses, they should be studied together—indeed, the study of bioterrorism agents alone is likely to give a low return on investment. There are also indirect benefits associated with investments in protecting ourselves from bioterrorism. Money spent on research to develop new types of sensitive detectors and related monitors for biowarfare agents will almost certainly carry over to the public health sector in the form of rapid, improved diagnostics for disease. Money spent on coordinating and developing emergency response teams at the federal, state, and local levels will also bring better mechanisms for dealing with natural outbreaks of emerging diseases. Money spent on innovative surveillance approaches for detecting biowarfare attacks should improve

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism medical epidemiology. Money spent on vaccine research and delivery may help to buttress our limited capacity to protect civilian and military populations. Changing Research Paradigm While this report was being prepared, the National Institute for Allergy and Infectious Diseases (NIAID) released a bioterrorism research agenda for rapidly addressing the most threatening biological agents (NIAID, 2002).1 Though important and commendable, this agenda lacks several major components—such as surveillance strategies, epidemiology of transmission, and the entire range of agricultural threats—needed for a comprehensive plan to counter bioterrorism. Consideration must also be given to preparing for still-uncharacterized threats and to assuring investment in long-term, broad-range strategies. These gaps must be filled, where not appropriate for NIAID action, by other federal agencies. CDC is the logical place for surveillance efforts, given its expertise, and therefore it will require additional resources. NIAID’s expanded role in bioterrorism research demands a focused effort to coordinate activities with other agencies—CDC, the Department of Defense (DOD), the Department of Energy (DOE), the Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the very recently proposed new Department of Homeland Security, for example. All of the governmental entities must seek expertise from private organizations, such as industry and professional societies with relevant expertise, for example, the Infectious Diseases Society of America and the American Society for Microbiology. It also demands that NIAID’s parent, the National Institutes of Health (NIH), find new mechanisms to fund research in this area, particularly for taking on long-range, highly managed, higher-risk projects and for moving the research at a faster pace. Likewise, CDC’s role is critical to the nation’s preparedness, but it must have the resources to improve its focus, strengthen its extramural capacity, and extend its international collaborations. National security also depends on public-private sector cooperation and communication and on an increased willingness to collaborate. Organization of This Chapter This chapter is organized into three sections: (1) intelligence, surveillance, detection, and diagnosis; (2) prevention, response, and recovery; and (3) policy and implementation. Each section describes the desired capabilities that could soon exist through better application of existing science and technology (and that might therefore have a near-term payoff) as well as desired capabilities that 1   See March 14, 2002, press release “NIAID Unveils Counter-Bioterrorism Research Agenda” at <http://www.niaid.nih.gov/newsroom/releases/biotagenda.htm>.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism cannot now be provided through existing science and technology (S&T) but might be available in the future, given longer-term research and possibly more innovative funding and organizational approaches. The chapter focuses on research needs related to both human and agricultural health. Many of the recommendations apply equally to both areas while others are specific to one area or the other. In general, recommendations focus on R&D goals or organizational goals. The chapter concludes with recommendations about education and information dissemination, strengthening the public health and agriculture infrastructures, and organizing the research and development effort through improved policies, new funding models, and public–private partnerships. INTELLIGENCE, DETECTION, SURVEILLANCE, AND DIAGNOSIS A comprehensive approach to coping with bioterrorism must incorporate efforts to prevent the proliferation of biological weapons; methods for detecting covert biological weapons programs; strategies for deterring their use if biological weapons do proliferate; and mechanisms for protecting civilian and military populations if deterrence fails. The emphasis in this multitiered approach should be on defense, simply because the proliferation of biological weapons is difficult to control (biotechnology equipment and expertise are now available globally), covert biological weapons programs (e.g., those of the former Soviet Union and Iraq) are difficult to detect, and deterrence will likely be less effective against suicidal terrorist groups than against states. Consequently, in addition to improving intelligence and information management, the S&T community should be focused on improving defenses against biological weapons. The means to do so include environmental detection of biological agents together with preclinical, clinical, and agricultural surveillance and diagnosis. Intelligence and Information Management Increased awareness in the S&T community could reduce the inadvertent spread of knowledge that may aid terrorists, although there is a fine balance that must be achieved so as to not quash legitimate exchange of scientific information. Voluntary international and national efforts to share biotechnology information could improve security and safety in the handling, storage, and transport of sensitive biological material and equipment. Information technology could help monitor international trafficking in biotechnology products. Detection of covert programs will involve technical intelligence (e.g., remote sensing and environmental sampling) as well as human intelligence, which has special importance because it can distinguish the benevolent use of biotechnology from the malevolent. Understanding intent in the area of biotechnology, which requires familiarity with S&T culture, processes, and procedures, is an expertise that scientists and technologists can offer the intelligence community.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Meanwhile, there is a need to teach, reinforce, and strengthen ethical standards of the S&T community against the production and use of biological weapons; this will reduce the likelihood of scientists working in covert programs and increase the chance of them helping to abort malevolent efforts. Although much has been written about the potential efficacy (or inefficacy) of ways to deter biological attacks, the S&T community has yet to fully explore means for strengthening deterrence. An obvious option is biological forensics (discussed later), because without reliable attribution, most deterrence strategies are likely to fail. Nucleic acid sequence databases for pathogen strain types and advances in chemical-trace analysis and the use of taggants will help the process of attribution, thus discouraging terrorism, but they will by no means guarantee that perpetrators can be identified. The greatest potential benefit of a counterterrorism strategy might derive from preemptive efforts at earlier points in the bioterrorism-attack timeline—that is, the evolution of a bioweapons program from inception through weapon deployment, before any biological agent is released. The S&T communities have had relatively little input into detection and characterization of terrorist activities during this early stage, yet they could offer significant untapped resources. Opportunities for their involvement in the area of human intelligence should be explored (see Box 3.1). BOX 3.1 Opportunities for Integrating the Intelligence and S&T Communities Short Term Recruit members of the S&T community for assistance and advice on the collection and early analysis of relevant human intelligence in bioterrorism activities. Promote collaborative research programs that enhance contact between members of the S&T community and scientists from former or current biowarfare or bioterrorism research programs (e.g., cooperative research programs). Develop a database for locating bioterrorism or related expertise in academic and industrial laboratories. Long Term Recruit and train intelligence analysts in state-of-the-art biology, microbiology, and bioinformatics. Train or sensitize working scientists to recognize malevolent intent, as well as signatures of offensive bioweapons programs, and develop a plan for sharing this information with appropriate parties. Facilitate the development of tools for aiding in the recognition of such signatures.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Recommendation 3.1: All agencies with responsibility for homeland security should work together to establish stronger and more meaningful working ties between the intelligence, S&T, and public health communities. Identification of Biological Agents in the Environment At the present time, efforts to identify biological agents in air, soil, and water samples have had only limited success. Ideally, one would hope to be able to collect air samples, for example, and identify a pathogen in those samples in near real time, allowing the population to be warned of the pathogen’s presence. However, existing technologies for rapid and reliable detection (collection and identification) of bioagents have not been widely evaluated or well validated in real-world settings. Much greater attention must therefore be given to the transition between basic laboratory research and field application. Traditional laboratory approaches include microbial cultivation, immunological (e.g., antibody-based) assays, and nucleic acid detection schemes, especially amplification methods such as the polymerase chain reaction (PCR). The last two approaches seek molecular evidence of agent components, such as characteristic immunological markers and genome sequences. A fourth broad approach relies upon the response of a surrogate host—such as cultivated cells from humans, animals, or plants. Each of the four approaches has its advantages and disadvantages. It is important to note, however, that even though cultivation is slow, limited in scope (by ignorance of appropriate growth conditions in the test tube and in human tissues for many pathogens), and the least technologically sophisticated approach, it provides the most ready assessment of complex microbial phenotypes (behaviors), such as drug resistance. It also is the most widely used approach in laboratories throughout the world, especially in developing nations, and hence is currently the most common identification method for international surveillance. A number of challenges must be addressed in order to develop and implement effective methods of environmental identification. An improved understanding of natural background is needed, regarding both the agent (including genetic, antigenic, geographical, and temporal variations) and the setting (including related agents and inhibitors). Additionally, standards must be established by which sampling and detection methods can be rigorously evaluated, validated, and standardized (see Recommendation 3.16 and surrounding discussions). Centralized repositories of diverse, high-affinity binding and detection reagents (e.g., antibodies, peptides, oligonucleotides) should be established, as well as repositories of genomic material and control samples. There are dozens of ways to identify bioterrorism agents that are sensitive and accurate. However, agreement on how a few well-developed platforms are implemented would allow the data to be broadly understood and make the limitations of the test used apparent to all.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism For example, whether one is identifying anthrax on the farm, from the environment, or in a patient’s blood stream, the identification can be quickly made using a fairly easily agreed upon set of standard genomic and immunological reagents. Subsequently, there must be cultures of microorganisms grown in the laboratory using agreed upon standard methods. The identification should be based on uniform standards and not a free-for-all depending on program officers or agencies with differing views. To date, a disproportionate amount of the effort in the bioagent detection arena has been focused on the development of technology platforms. Efforts on standardization or validation of sample collection and sample processing procedures, as well as on test validation in a real-world setting, have had much lower priority. But the use of genomic and proteomic information, as well as the development of robotic sensing devices that can communicate signals from many environmental sites, offers new possibilities for the early detection of biologic agents in the environment. It also increases the risk of false alarms when sophisticated analysis and decision-making systems are lacking. Another challenge involves creating broad-spectrum detection tools and methods. Currently a large number of tests rely on a small number of specific antibodies or microbial genomic sequences. This reliance creates vulnerabilities—for example, with respect to bioagents having modified antibody epitopes (binding sites) or sequences. Rather than relying on methods that target specific, known organisms, one would like to have detection methods that target groups of organisms (i.e., all members of these groups) and that can identify specific members of the group, including recognition of those that may not yet have been characterized. Although there are experimental challenges, the expertise exists to immediately begin addressing these problems (Cummings 2000, 2002; Nikkari et al., 2002). A further challenge is the need for highly sensitive systems, as some highly infectious pathogens require the inhalation of only 1 to 10 organisms to cause disease. In general, much greater attention is needed to translate basic laboratory research into field applications and clinical validation (standards will play an important role; see Recommendation 3.16 and surrounding discussion). Finally, because no test is perfect, it is important to be able to anticipate false-positive test results in a reliable and quantitative fashion. One potential strategy for minimizing the impact of false-positive test results is to create a system of multiple, parallel, independent technical platforms so as to avoid dependence on any one testing procedure. This requires crosscutting, interdisciplinary science (e.g., combining environmental microbiology, cell biology, biophysics, electronics, materials science and microfabrication, microfluidics, and bioinformatics/statistics) and would require collaboration between several federal agencies and industry. However, even the currently available tests could be made significantly more useful by adopting a quality assurance index that would be applied to any positive test result. For example, single positives in tests with high false-positive rates, such

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism as ELISA, would receive a low ranking, whereas successful culture of a known biological agent from a sample would receive the highest ranking. Informed decisions on public action could be made based on the quality of the result rather than simply on the presence of a positive result. Recommendation 3.2: Federal agencies should work cooperatively and in collaboration with industry to develop and evaluate rapid, sensitive, and specific early-detection technologies. The types of identification systems needed are likely to be developed by industry, not in an academic laboratory. Federal funding agencies can speed this process by supporting the early stages of the work. The same kind of milestones should be applied to this kind of work as are used in industry to ensure that the technology is valid and meets the expected specifications. There is a role for the mobilization of established detection procedures and for those that might be second-generation detecting devices sometime in the future. The immediate need is acute and very attainable. Surveillance and Diagnosis of Infection and Disease Early diagnosis of patients infected with potential biological warfare (BW) agents is complicated by the lack of relevant medical experience with most of these agents in the United States and by the nonspecific symptoms of their associated diseases (e.g., many cause flulike symptoms in the early stages). Systems for effective surveillance and diagnosis of biothreat agents, as well as of many naturally occurring and emerging pathogens, are either unavailable at present or inadequate. Many of the current challenges in surveillance and diagnosis are quite similar to those described above for identification of pathogens. Surveillance and diagnosis must also address the important distinction between infection and disease—that is, between the colonization or contamination of a host with a potential biothreat agent and the actual manifestation of pathology (disease). Sensitive and specific diagnostic tests are important adjuncts to clinical diagnosis; however, such tests cannot substitute for astute clinical recognition of symptoms to raise the suspicion of a particular diagnosis. Equally vital is the role of classical epidemiological analysis in assessment and recognition of human- and animal-disease patterns. Preclinical Surveillance and Diagnosis It would be critical, in the event of a biothreat agent attack, to be able to recognize or identify infected persons, animals, or plants before they develop overt disease. Great benefit could be achieved by rapid intervention in those persons, animals, or plants known to be infected, while avoiding unnecessary

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism intervention in those who are not. It is at this stage that the difficulties and challenges of diagnosis are greatest as well. In recent years, novel biotechnological and biological approaches have opened up new opportunities in this area. In the interim, while new approaches are developed and refined, assessment of white blood count, fever, and relatively simple observations will remain the first line of defense in protecting human health. A primary focus of diagnostic strategy will continue to be the continuing education of physicians and health-care workers. An example of a plausible new technological approach is the host-genome-wide gene-expression profile. The availability of a nearly complete human-genome sequence and the power of DNA microarray technology have been harnessed to create an approach for surveying the responses of nearly all known human genes to various infectious agents. Cells are programmed to recognize pathogenic agents and foreign life forms, and they respond with changes in hostgene expression; microbial agents, meanwhile, have evolved strategies for manipulating and subverting these programmed responses. The result is an intricate, choreographed, and time-dependent set of induced and repressed gene-expression patterns that can be detected in small blood samples (Cummings and Relman, 2000). Although the dominant features of these patterns are common to virtually all infections, regardless of the particular infectious agent, other features may be more specific to the agent or disease. With further research and refinement, one might actually be able to distinguish infections by different pathogens and generate signatures that allow early identification. These patterns reflect how the host “sees” the pathogen, and they also reflect (and perhaps predict) the outcome of the host-pathogen interaction. Research exploring the potential usefulness of this approach is still in its early phases, however. Host-gene expression patterns are just one complex biological pattern that might lend itself to this kind of diagnostic and prognostic approach. Others include patterns of secreted proteins in host fluids, volatile compounds in breath (analyzed, for example, with mass spectroscopy), and spectral features of host cells and fluids (studied using spectrometers and hyperspectral analysis). The enormous advantage of such technology, should it be able to fulfill researchers’ expectations, is that it could distinguish genuine infection from hysteria or terror, either at the emergency room or in the clinic. Human Disease Surveillance and Diagnosis In this country and elsewhere, the recognition of almost all emerging infectious diseases—both naturally occurring and intentional—has depended on an astute clinician contacting a public health agency after suspecting an unusual serious illness (e.g., hantavirus in the Southwest or anthrax in Florida). This traditional system of notifiable human disease surveillance depends on the train-

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism ing of physicians and other health care providers, in terms of both disease awareness and their responsibilities to public health. In addition, the important systems linking hospitals around the country with CDC, known as sentinel surveillance systems, need to be enhanced; they can establish whether a common cause of disease is being seen simultaneously in multiple regions. Research should be conducted on the strategies likely to be most useful in enhancing the notifiable human disease reporting system for the broad range of potential threat agents (strategies such as education, animal sentinels, changes to the surveillance systems, and the use of infection control specialists). Mathematical models of disease transmission and distribution using simulations of a covert release of various agents could be helpful in assessing the potential and relative value of different surveillance systems. An integrated national system that can report diseases electronically in real time is needed to support these networks. Information technology advances should be explored both to automate required reporting (e.g., laboratory reporting of pathogens) and to develop new surveillance tools (e.g., the automated scanning of electronic media, such as that utilized by the Global Public Health Information Network). Systems of syndrome surveillance—that is, screening for changes in the frequency of cases of flulike illness seen in hospital emergency rooms across a city or town—should be developed to identify outbreak patterns. Relevant computer programs are being developed, but there are known fluctuations in emergency room admissions from season to season and day to day, and it will be important to determine their potential predictive value, specificity, and usefulness. Syndrome surveillance has allowed early recognition of some respiratory and diarrheal disease outbreaks, but it is not clear whether it will be useful for early detection of key threat agents such as smallpox, anthrax, and tularemia. Because infectious diseases do not respect national borders, international cooperation is vital in the sharing of epidemiological and clinical data, both on emerging infectious diseases and on outbreaks caused by potential bioterror agents. A global network for surveillance of infectious diseases in humans and animals would be strengthened by augmenting the numbers and capabilities of U.S. overseas laboratories and by providing enhanced support for current initiatives on international surveillance (e.g., DOD’s Global Emerging Infectious Diseases program and corresponding Department of Health and Human Services (HHS) initiatives). Increased support for the development and expansion of public health and agricultural laboratories in other countries, particularly in their capacity to diagnose threat agents, would yield dividends for recipient and donor alike. This means that CDC and other agencies must reach out to educate, train, and collaborate with scientists from many countries on aspects of surveillance and identification of threats. The World Health Organization could play a critical role in building and strengthening international capabilities.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism sible by fumigation with appropriate chemicals, but this is costly, from both an economic and environmental perspective. Eradication, especially of soil-borne spores of plant pathogens, is virtually impossible. Methyl bromide, one of the few standard chemicals used for fumigation of soil and containers, will be banned after 2005 in developed countries and 2010 in developing countries as the result of an international agreement made in response to evidence that the chemical depletes the ozone layer. Live steam can be used to clean up facilities and handling equipment, but its cost and damage to the equipment can make this method unappealing. Alternative methods for decontamination and eradication of biological threats to plants are needed (NRC, 2002). Recommendation 3.14: Develop methods and standards for decontamination. Develop standards for levels of decontamination and certification of products to ensure safety. Research is needed on chemical fumigation and irradiation as methods for decontamination of buildings and mail; development and evaluation of novel decontaminants; disposal of crops and livestock carcasses; and decontamination of trucks, railroad cars, container ships, and warehouses used to transport and store contaminated crops, livestock, food, and feed. This effort will require collaboration among all agencies with expertise and a mission in this area, including HHS, EPA, USDA, the Coast Guard, and DOD. Because cross-agency collaboration is often challenging, the Office of Homeland Security should designate a lead agency on these issues and ensure that collaborating agencies provide the necessary resources to identify and support research efforts in this area. POLICY AND IMPLEMENTATION Effective preparedness for countering bioterrorism will not only require focused and sustained efforts to build the nation’s public and agricultural health infrastructures (including the training of health care professionals in detection, surveillance, prevention, and response); it will also require substantial changes in the way government-supported research is executed. Several overarching strategies are needed to provide the necessary funding for research and development (R&D), mechanisms for response, integration of efforts, and translation of findings into application. The recommendations listed below, which support and facilitate the R&D priorities outlined in previous sections of this chapter, are offered in that spirit. Develop Scientific and Technological Human Resources The public and private sectors should explore new funding mechanisms that select for the best ideas and the most productive scientists, that offer great flexibility, and that provide the freedom to pursue bioterrorism-related research in a

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism protected environment (i.e., not subject to 1- or 2-year budget fluctuations or constraints). The traditional system of reviewing and funding grants and contracts can be lengthy and averse to highly focused, highly managed research initiatives. Although basic and discovery science will continue to be a critical underpinning of all research in countering bioterrorism, a more focused, outcomes-based approach is also warranted. Balance between basic and applied research approaches will be crucial. One model worth considering is a central organization that directs R&D projects whose risks and payoffs are very high—that is, whose successes may provide dramatic advances—and that pursues these projects with both flexibility and speed. There is a real need for NIH, particularly NIAID, to adopt an approach like this for funding the kinds of high-payoff, high-risk projects that might create innovative scientific tools for addressing bioterror threats. Recommendation 3.15: Create special research organizations to build expertise in countermeasures to bioterrorism. Federal agencies must build human resources in threat-agent characteristics, pathogenic mechanisms, and responses to bioterrorism-induced disease. Protected environments that foster innovation must be developed to support a cadre of leaders, scientists, engineers, policy experts, and strategic thinkers. These designated research organizations should address both classified and unclassified issues, and special mechanisms for rapid funding should be created to support external research efforts as the needs and opportunities emerge. New mechanisms for funding high-risk, long-term, high-payoff projects should be created in NIH. Ideally, the new organizations recommended above would be small but have strong interactions with universities and government agencies. They would work in basic and applied science—specifically, to understand pathogenic (virulence) factors at the molecular level and how they affect mammalian systems. And they would also work in product development—specifically, in diagnostics, antiviral and antibacterial drugs, and all stages of vaccine manufacture, from development to pilot production. Clearly, drugs and diagnostics should have dual use, and the range of pathogens studied will inevitably have dual-use spinoffs. As a companion to this initiative, a mechanism for rapid funding should be established for bioterrorism-related research conducted extramurally; this mechanism would select for creative ideas quickly, with a minimum of bureaucracy. Need for Standards and Standardization The goals for research on surveillance and clinical diagnostics include rapid diagnostic assays for common pathogens and biological warfare agents. These assays could be used in primary-care settings (point of care) as well as referral laboratories. But standards are needed by which they may be rigorously evalu-

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism ated and validated, and centralized repositories of standardized reagents and samples are needed as well. Because the development and evaluation of diagnostics require interdisciplinary applied research, however, it is currently difficult to find targeted funding sources and mechanisms. Recommendation 3.16: Establish laboratory standards. Set up an oversight standards laboratory to evaluate diagnostic and detection tools; to ensure the availability of standard reagents for academia, industry, and government; and to develop appropriate standards on a continuing basis. The National Institute of Standards and Technology (NIST) is one agency where these sorts of efforts might appropriately be undertaken. It is to be expected that many new products will be introduced for detecting and responding to bioterrorist threats, but no mechanism currently exists for evaluating them and comparing their effectiveness. An oversight standards laboratory would have the capacity to evaluate biosensors and diagnostic systems for infectious diseases, develop taxonomies of syndromes and data classifications, improve the quality of the expanding DNA and protein databases, validate methods, develop reagents, create internal standards for diagnostic comparisons for the scientific community, and evaluate methods and standards for personal protective equipment and decontamination. Facilitate Development of Therapeutics and Vaccines: Engagement of Industry Government has a vital role to play in basic research on countering biological warfare agents through its own institutions, many of which have enormous expertise that has long been brought to bear in the fight against infectious diseases. It would be inefficient, however—and ultimately ineffective—for government to go it alone, without actively engaging private industry in the race to deploy needed biomedical countermeasures. Indeed, the greatest efficiency in this urgent effort is likely to come from working the broadest possible network of synergy among all institutions of established expertise—public sector entities, academic laboratories, private research institutes, biotechnology start-up ventures, and pharmaceutical companies. The fight is big enough and difficult enough to demand that the entire spectrum of available talent and resources be productively engaged. To build this network, a new partnership model for industry and government is needed that goes beyond the current models of government contracting. Existing mechanisms for government interactions with the private sector cover a wide range: from simply acting as a customer in the marketplace, through NIH grants, to the comprehensive R&D contracting done by DOD. There seems to be no one best way among these mechanisms, nor any clearly better way

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism beyond them. They all have valid applications, and, in practice, different cases will probably require different solutions. However, there is one principle that must serve as the foundation for any partnership aimed at developing countermeasures for bioterrorism. It is the principle of risk sharing. Drug and vaccine development is an incredibly high-risk business. Front-end costs start big and grow bigger as development proceeds. The total is often something like $800 million by the time a successful drug is launched—10 years or more from the day it was discovered. The odds against success are long—one compound in 5,000 makes it all the way from the test tube to the pharmacy shelf. And even among newly launched products, only one in three earns back its development costs. Public policy makers must consider whether drugs and vaccines could be developed more cheaply, given the compounds that are languishing in the developmental pipeline because bioterrorism is a small and uncertain market. At the front end, government could help defray some of the costs associated with discovery and early-stage development. Grants and other forms of direct investment might help, especially with smaller organizations. But given the current needs related to antibiotic resistance in naturally occurring pathogens and to the decline of innovation in antibiotic-drug discovery, risk sharing may need to be considered more broadly. Government could further reduce the risk to industry by providing some form of legal relief from the product-liability issues associated with new countermeasures. Risk sharing could also help to lower the costs of purchasing and storing biodefense drugs—whether existing or to be developed. The government’s current practice is to determine what quantity of a given material it may need, issue a contract to purchase that quantity, and then stockpile it until needed. This process works well for some products, but it is a very expensive way to purchase pharmaceuticals. A more cost-effective approach would be to contract with drug manufacturers for assured access to the necessary quantities. The manufacturers would have to be able to prove beyond doubt that they could deliver the requisite quantities within the needed time frame. It is essential that production capability occurs at more than one facility and that these facilities be based within the United States. The government would reimburse the cost, build and maintain the inventory, and add a modest profit. In the event of an attack, the government would take control of the inventory at no additional cost. Meanwhile, responsibility for addressing such additional risks as unforeseen spoilage would rest with the manufacturers. Recommendation 3.17: Facilitate vaccine and therapeutics production. Through public-private partnerships, create research, development, and manufacturing capacities to produce diagnostics, therapeutics, vaccines, and devices to counter terrorism and an oversight laboratory to evaluate, prepare, and standardize methodologies.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Traditional market mechanisms for the development of new diagnostics and vaccines are failing with regard to pubic health generally and response to bioterrorism in particular, where the principal market is likely to be federal and state governments. National orphan vaccine centers, perhaps created as government-owned, contractor-operated (GOCO) facilities, are needed to help bring vaccines for otherwise rare diseases to the stages of mass manufacture. Such centers could help coordinate extramural R&D activities in the public and private sectors as well as perform critical research. In particular, national orphan vaccine centers could coordinate the clinical trials and studies with animals on which licensing would be based, and could serve as conduits for production at industrial facilities (including development of surge vaccine-manufacturing capacity and the training of personnel to produce vaccines that meet FDA standards). Such collaboration would require the establishment of new relationships between the public and private sectors. For development of broad-spectrum antibiotics and antivirals, federal funding should encourage the large pharmaceutical and biotechnology companies to enter the field with the expectation that at least some drugs developed for bioterrorist threats will have dual use—that is, they may be applicable to common infectious diseases as well. Such encouragement for undertaking R&D on new drugs against bioterrorism agents could take the form of streamlined grant mechanisms, financial incentives, and regulatory changes. Regulatory Reform Maintaining public confidence in vaccines, and in medical products in general, is critical to assuring overall confidence in the nation’s public health programs. But bioterrorism is a moving target, not a single disease of predictable epidemiology, and all potential product uses may not be anticipated. This complicates many decisions about product use. Current biodefense-related activities at the FDA include meeting with sponsors and sister agencies to encourage interest in developing safe and effective new products, performing research that ultimately facilitates the development of these products, and intensively interacting with product sponsors to expedite availability. Other steps that the FDA has employed in an attempt to safely speed up the licensure process include the following: Emergency use under investigational new drug (IND) status allows rapid access to products that have not yet completed requirements for licensure. While IND status makes available potentially lifesaving items, a disadvantage of emergency use under this rule is that the product is not licensed, which not only reflects the true scientific limitations of the data but also raises important issues about public perception.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Fast-track processes can speed up the review procedure so that the FDA can evaluate information as it becomes available and as soon as the sponsor submits it. Accelerated approval uses surrogate end points to demonstrate benefit. For bioterrorism agents, this might include protective-antibody levels for vaccines. The use of CD4 cells for assessment of antiviral treatment for HIV was one of the first surrogates to be approved under this rule. The “Animal Rule”5 is extremely important with respect to bioterror agents. It states that where human efficacy trials are not feasible or are unethical, the use of animal-efficacy data may be accepted as they relate to the desired benefit in humans—usually a significant outcome such as mortality or major morbidity. Clinical studies are still required for establishing pharmacokinetics and for assessing safety. The Animal Rule has postmarketing and labeling restrictions, however, and it does not apply if the product could be approved on the basis of any other standard under the FDA’s regulation. Much more research is needed to establish acceptable criteria for reduction in morbidity and mortality. Human diseases caused by many of the CDC Category A agents are so poorly understood at present that meaningfully defining such criteria for the Animal Rule will be difficult. For some agents—for example, smallpox—appropriate animal models are lacking, and many existing animal models are poorly characterized with respect to lesion character and disease progression. Animal models (with the exception of those for anthrax) remain poorly characterized with respect to aerosol challenge and disease characteristics in animals receiving sublethal challenge doses. Criteria need to be established with respect to end points that will be acceptable to the FDA for reduction in morbidity and mortality and similarity to human disease—i.e., route of inoculation, challenge doses and strains of organisms to be used, strain and species of animals, and duration of observation periods for reduction in morbidity according the FDA’s Animal Rule regardless of route of challenge. Recommendation 3.18: Allow regulatory exceptions for development of therapeutics and vaccines against bioterrorism threats. The FDA should convene a broadly based conference to consider options and plausible mechanisms for expedited approvals under specific emergency conditions. In addition, for new drugs and vaccines that cannot be tested in humans, mechanisms for indemnification in the case of adverse effects will need to be 5   The Animal Rule is Code of Federal Regulation (CFR) Title 21, Parts 314 and 601: “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs when Human Efficacy Studies Are Not Ethical or Feasible.” The final version of this rule was published in the Federal Register on May 31, 2002, and will take effect June 30, 2002. The final rule can be viewed at <http://www.fda.gov/OHRMS/DOCKETS/98fr/98n-0237-nfr0001-vol1.pdf>

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism developed. The possibility of encouraging collaboration between pharmaceutical companies in this area by waiving antitrust restrictions—in specific cases justified by the national interest—must also be considered. Thus, in addition to the FDA, the Departments of Commerce, Treasury, and Justice should also be involved in these discussions. Clearly, in an emergency, someone or some agency has to be authorized to decide, for example, that INDs may not be required, that the informed consent process can be modified, that companies might have to be indemnified, or that companies might have to exchange information or work together, which would require a waiver of antitrust law. The factors that go into such decisions should be discussed by government and industry, and possible approaches recommended to federal agencies. CONCLUDING REMARKS Understanding of biological agents as threats to human, livestock, and crop health, as well as to the U.S. economy, must be improved. Special emphasis might be placed on an urgent short list of recognized agents, including Bacillus anthracis (the agent responsible for anthrax), variola virus (which causes smallpox), and a few others, for obvious reasons; but much of the preparation should target a broader list and effectively prepare the nation for the unknown. Appropriate government agencies and scientific organizations must evaluate emerging viruses and the genetic modification of existing viruses. Similarly, they need to consider the impact of genetic manipulations of pathogenic bacteria that enhance their virulence, particularly manipulations that render them resistant to the available antibiotics. Although there are gaps in the scientific understanding of many potentially deadly biological agents and in the technological advances needed to anticipate and respond to their release, reliance on purely scientific or technological solutions is misguided. A much more inclusive effort is needed to build a seamless system of preparedness and response—one that can exercise the best available tools to counter biological threats. This task depends first and foremost on rebuilding the public health infrastructure of the United States, which has been allowed to decay as the nation conquered some of the more common infectious and other disease challenges of the past century. The terrorist events of September and October 2001 should serve as a wake-up call to those in the position of setting science and health policies in the United States. Many of the scientific goals described in this chapter cannot be achieved in the absence of trained and well-equipped public health officers, educated and prepared first responders, and clear communication among leaders, the medical community, and the public. HHS, CDC, and other federal agencies, along with state departments of

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism health, have begun to consider the best ways to educate health care professionals for effectively responding to bioterrorism. This country’s public health schools and professional societies have a major role to play both in training individuals and in researching ways to build a more responsive public health system. Various entities with some knowledge of bioterrorism, such as medical associations, have already prepared educational materials. The American Medical Association, for example, has produced an excellent primer to help physicians recognize and treat diseases likely to be caused by acts of bioterrorism. Regular updating of physicians and other health care professionals, perhaps through mandatory continuing education courses on the agents that pose the greatest threats, would be prudent. Meanwhile, training in this area should be part of the basic curricula for all aspiring health care professionals. Agencies and other institutions also face a major challenge in training first responders, such as firefighters and police, as well as in educating leaders and influential nonhealth professionals, such as teachers, on the realistic threats of bioterrorism and the ways in which they can be empowered to protect themselves and their communities. But countering terrorism is not the only incentive for such actions. In 1992, the Institute of Medicine published a groundbreaking report, Emerging Infections: Microbial Threats to Health in the United States (IOM, 1992). It pointed out that “pathogenic microbes can be resilient, dangerous foes. Although it is impossible to predict their individual emergence in time and place, we can be confident that new microbial diseases will emerge” (p. 32). Thus, preparedness is essential not only for countering bioterrorism but also for facing the constantly evolving threat of infectious diseases, particularly the widespread escalation of bacterial pathogens resistant to all known antibiotics. In reality, humans and the livestock and crops that sustain them are in a perpetual contest with microorganisms and the diseases that they cause—a contest that requires an armamentarium of knowledge gained from research, surveillance, and improved health practices. Humans and animals are not immune to the threat of infectious diseases just because they have been immunized or eat food and drink water that is regulated and evaluated for their safety. Serious, sometimes deadly, outbreaks of infectious diseases continue to occur naturally around the world. Even when they are treatable, these diseases take their toll in pain and suffering, inconvenience, disability, lost time from work and lost wages, and cost to the health-care system and the economy. But preparing for the once unthinkable—a biological attack—should also prepare the U.S. population for the inevitable: the natural occurrence (or recurrence) of diseases that can affect all living things. Efforts that protect humans, animals, and plants from bioterrorism will also help us prevail in that never-ending contest with natural threats. The reader is referred to Box 3.2 for Web sites with additional information on bioterrorism.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism BOX 3.2 Resources on the Internet with Bioterrorism Information (Accessed May 2002) Centers for Disease Control and Prevention: <http://www.bt.cdc.gov/> U.S. Army Medical Research Institute of Infectious Diseases: <http://www.usamriid.army.mil/education/bluebook.html> Johns Hopkins Center for Civilian Biodefense: <http://hopkins-biodefense.org/> New York City Department of Health: <http://NYC.gov/html/doh/html/alerts/wtc8.html> American Medical Association: <http://pubs.ama-assn.org/bioterr.html> National Institute of Allergy and Infectious Diseases, NIH: <http://www.niaid.nih.gov/publications/bioterrorism.htm> International Society for Infectious Diseases: <http://www.promedmail.org/> Biohazard News: <http://biohazardnews.net/> American Society for Microbiology: <http://www.asmusa.org/pcsrc/bioprep.htm> Wake Forest University Baptist Medical Center: <http://wfubmc.edu/intmed/id/links_biot.html> National Academy Press Web resources for first responders on bioterrorism and public safety: <http://www.nap.edu/shelves/first/index.html> REFERENCES Anderson, R.M. 2001. “The Application of Mathematical Models in Infectious Disease Research,” Firepower in the Lab: Automation in the Fight Against Infectious Diseases and Bioterrorism, S.P. Layne, T.J. Beugelsdijk, and C.K.N. Patel, eds., Joseph Henry Press, Washington, D.C. Barbera, J., L. Gostin, T. Inglesby, T. O’Toole, C. DeAtley, K. Tonat, and M. Layton. 2001. “Large-Scale Quarantine Following Bioterrorism in the United States,” JAMA, Vol. 286, pp. 2711-2717. Bradley, R.N. 2000. “Health Care Facility Preparation for Weapons of Mass Destruction,” Prehospital Emergency Care, Vol. 4, pp. 261-269. Brinsfield, K.H., J.E. Gunn, M.A. Barry, V. McKenna, K.S. Dyer, and C. Sulis. 2001. “Using Volume-Based Surveillance for an Outbreak Early Warning System,” Academic Emergency Medicine, Vol. 8, p. 492. Centers for Disease Control and Prevention (CDC). 2001. “Updated Guidelines for Evaluating Public Health Surveillance Systems: Recommendations from the Guidelines Working Group,” Morbidity and Mortality Weekly Report, Vol. 50, No. RR-13, pp. 1-35. CDC. 2000. “Biological and Chemical Terrorism: Strategic Plan for Preparedness and Response, Recommendations of the CDC Strategic Planning Working Group, Morbidity and Mortality Weekly Report, Vol. 49, No. RR04, pp. 1-14. Committee on Emerging Microbial Threats to Health, Institute of Medicine, National Research Council. 1992. Emerging Infections: Microbial Threats to Health in the United States, Joshua Lederberg, Robert E. Shope, and Stanley C. Oaks, Jr., eds., National Academy Press, Washington, D.C.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Cox, N.J., and K. Subbarao. 2000. “Global Epidemiology of Influenza: Past and Present,” Annual Review of Medicine, Vol. 51, pp. 407-421. Cummings, C.A., and D.A. Relman. 2000. “Using DNA Microarrays to Study Host-Microbe Interactions,” Emerging Infectious Diseases, Vol. 6, No. 5, pp. 513-525. Cummings, C.A., and D.A. Relman. 2002. “Microbial Forensics—When Pathogens Are “Cross-Examined,” Science, May 9. Defense Threat Reduction Agency. 2001. Human Behavior and WMD Crisis/Risk Communication—Final Report from a Workshop, March. Available online at <http://www.dtra.mil/about/organization/finalreport.pdf>. Fine, A., and M. Layton. 2001. “Lessons from the West Nile Viral Encephalitis Outbreak in New York City, 1999: Implications for Bioterrorism Preparedness,” Clinical Infectious Diseases, Vol. 32, pp. 277-282. Gust, I.D., A.W Hampson, and D. Lavanchy. 2001. “Planning for the Next Pandemic of Influenza,” Reviews in Medicine Virology 2001, Vol. 11, pp. 59-70. Hilleman, M.R. 2001. “Current Overview of the Pathogenesis and Prophylaxis of Measles with Focus on Practical Implications,” Vaccine, Vol. 20, pp. 651-665. Institute of Medicine. 1992. Emerging Infections: Microbial Threats to Human Health, National Academy Press, Washington, D.C. Institute of Medicine. 1999. Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical Response, National Academy Press, Washington, D.C. Institute of Medicine. 2002. Preparing for Terrorism: Tools for Evaluating the Metropolitan Medical Response System Program, National Academy Press, Washington, D.C. Interagency Task Force on Antimicrobial Resistance. 2000. A Public Health Action Plan to Combat Antimicrobial Resistance. Available online at <http://www.cdc.gov/drugresistance/actionplan/html/index.htm>. Layne, S.P., and T.J. Beugelsdijk. 1998. “Laboratory Firepower for Infectious Disease Research,” Nature Biotechnology, Vol. 16, No. 9, pp. 825-829. Layne, S.P., T.J. Beugelsdijk, and C.K.N. Patel, eds. 2001. Firepower in the Lab: Automation in the Fight Against Infectious Diseases and Bioterrorism, Joseph Henry Press, Washington, D.C. Layne, S.P., T.J. Beugelsdijk, J.K. Taubenberger, N.J. Cox, I.D. Gust, A.J. Hay, M. Tashiro, and D. Lavanchy. 2001. “Global Laboratory Against Influenza,” Science, Vol. 293, p. 1729. MacDonald, J.M., M.E. Ollinger, K.E. Nelson, and C.R. Handy. 1999. “Consolidation in U.S. Meatpacking,” Agricultural Economics Report, No. 785. Available at USDA-ERS Web site. Murch, R.S. 2001. “Forensic Perspective on Bioterrorism and the Proliferation of Bioweapons,” Firepower in the Lab: Automation in the Fight Against Infectious Diseases and Bioterrorism, S.P. Layne, T.J. Beugelsdijk, and C.K.N. Patel, eds., Joseph Henry Press, Washington, D.C. National Institute of Allergy and Infectious Diseases. 2002. NIAID Biodefense Research Agenda for CDC Category A Agents: Responding Through Research, National Institutes of Health, February. Available online at <http://www.niaid.nih.gov/dmid/pdf/biotresearchagenda.pdf>. National Research Council. 2002. Countering Agricultural Bioterrorism (in press). Nikkari, S., Lopez, F.A., Lepp, P.W., Cieslak, P.R., Ladd-Wilson, S., Passaro, D., Danila, R., Relman, D.A. 2000. “Broad-Range Bacterial Detection and the Analysis of Unexplained Death and Critical Illness,” Emerging Infectious Diseases, Vol. 8, No. 2, pp. 188-194. Peters, C.J. 2002. “Many Viruses Are Potential Agents of Bioterrorism,” ASM News, Vol. 68, pp. 168-173. Pizza, Mariagrazia, et al. 2000. “Identification of Vaccine Candidates Against Serogroup B Meningococcus by Whole-Genome Sequencing,” Science, Vol. 287, pp. 1816-1820. Raber, E., A. Jin, K. Noonan, R. McGuire, and R.D. Kirvel. 2001. “Decontamination Issues for Chemical and Biological Warfare Agents: How Clean Is Clean Enough?” International Journal of Environmental Health Research, Vol. 11, pp. 128-148.

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Making the Nation Safer: The Role of Science and Technology in Countering Terrorism Taubenberger, J.K., A.H. Reid, and T.G. Fanning. 2000. “The 1918 Influenza Virus: A Killer Comes Into View,” Virology, Vol. 274, pp. 241-245. U.S. General Accounting Office. 2000. West Nile Virus Outbreak: Lessons for Public Health Preparedness, HEHS-00-180, Washington, D.C. Von Bredow, J., M. Myers, D. Wagner, J.J. Valdes, L. Loomis, and K. Zamani. 1999. “Agricultural Infrastructure Vulnerability,” Annals of the New York Academy of Sciences, p. 894.