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4

Research Directions

The grand challenges and specific challenges (barriers) posed in prior chapters should be met as quickly as possible to ensure the safety of the United States and its populace. Chemists and chemical engineers can help the nation by working together with other scientists to address questions relevant to national security and homeland defense in their own research programs if they recognize the need for multidisciplinary collaboration in research and in education.

THREAT REDUCTION

The actions that can be taken to reduce terrorist threats are many and varied. From increased energy independence to chemical transportation safety, from new methods of detection to intrinsically secure chemistry in production and processing, much of the research required for improvements in threat reduction technologies is similar to research needed for the other grand challenges. Synthesis of new molecules, synthesis of new materials, new synthetic methods, and new methods of sample collection and preparation could ultimately yield more highly selective sensors; more robust detectors; lighter, more portable detectors; more efficient energy conversion or storage; and manufacturing that is cleaner and safer. This could decrease the probability of attack on a chemical processing plant or allow the detection of illegal trafficking of weapons from stockpiles, among other possibilities. Because this research is so closely related to research in other areas, detailed discussion of research directions for threat reduction is included in the other sections of this chapter.



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Page 26 4 Research Directions The grand challenges and specific challenges (barriers) posed in prior chapters should be met as quickly as possible to ensure the safety of the United States and its populace. Chemists and chemical engineers can help the nation by working together with other scientists to address questions relevant to national security and homeland defense in their own research programs if they recognize the need for multidisciplinary collaboration in research and in education. THREAT REDUCTION The actions that can be taken to reduce terrorist threats are many and varied. From increased energy independence to chemical transportation safety, from new methods of detection to intrinsically secure chemistry in production and processing, much of the research required for improvements in threat reduction technologies is similar to research needed for the other grand challenges. Synthesis of new molecules, synthesis of new materials, new synthetic methods, and new methods of sample collection and preparation could ultimately yield more highly selective sensors; more robust detectors; lighter, more portable detectors; more efficient energy conversion or storage; and manufacturing that is cleaner and safer. This could decrease the probability of attack on a chemical processing plant or allow the detection of illegal trafficking of weapons from stockpiles, among other possibilities. Because this research is so closely related to research in other areas, detailed discussion of research directions for threat reduction is included in the other sections of this chapter.

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Page 27 PREPARATION The workshop identified the area of preparation, or pre-response, in terms of the following question: What can be done prior to a terrorist event to improve our capability to limit the effects of a disaster? The answers to this question encompass an enormous range of activities relevant to the chemical sciences. These challenges have been grouped into two subcategories: process engineering and chemical synthesis. Several issues that can be broadly classified under “infrastructure” also emerged in our discussions. These are treated separately below. Process Engineering Successful scaling up of chemical or biochemical reactors for rapid production of decontaminating chemicals or pharmaceutical products such as vaccines and antibiotics requires comprehensive understanding of scaling effects on the performance of a reactor. Quantifying reactor conversion and product selectivity requires knowledge concerning reaction pathways and reaction kinetics for the chemical or biological syntheses and rate processes of momentum, heat, and mass transfer for the specific types of reactors employed. The scale-up of the reactor often also necessitates the scale-up of other manufacturing process units. Given the need for reducing time from discovery to manufacturing, research into process intensification (reducing the physical scale of unit operations by orders of magnitude) should be pursued. For pharmaceutical processing, other important unit operations include powder dissolution, crystallization and precipitation, drying, milling, blending, granulation, agglomeration, deagglomeration, compaction, lubrication, fluidization, encapsulation, tableting, and coating. These subjects are sparsely taught and inadequately researched in academe. Drug manufacturing and drug delivery systems need to be effective so that user safety is ensured in terms of therapeutic dosage applied and dosage effectiveness. Therefore, process control for each of the unit operations as well as quality control involved in the scale-up of the drug manufacturing process is of great importance for a reliable manufacturing process. For pharmaceutical products, extensive knowledge of particle technology is necessary for the optimal design, operation, and synthesis of drug manufacturing units. The scale-up of these units has traditionally largely relied on empirical approaches due to complex powder or fluid-powder flow mechanics involved in a vessel of complicated geometry. More mechanistic approaches based on, for example, the similarity rule of dimensionless groups, leads to a very limited applicability with operation conditions restricted to only physical operation. A mechanistic scaling law verified under commercial-scale operating conditions for powder and fluid-powder reaction systems to be used with confidence for commercial unit scale-up purposes is currently not available. Replicating the units to increase production is the common viable alternative.

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Page 28 The volume of chemical components used for full-scale production of pharmaceuticals or other products and processes can be surprisingly large. Maintaining large stockpiles of toxic or otherwise hazardous materials is dangerous and inefficient. With the added risk of sabotage or intentional contamination, such practices are not prudent. The development of synthesis and fabrication processes that minimize the use or storage of large amounts of chemicals is a clear challenge to the chemical industry. Scaling up solids processing systems is often more challenging than scaling up fluid processing systems, because fundamental understanding of particle technology for processing cohesive powders for pharmaceuticals is needed. For example, in powder blending (a critical unit operation in the drug manufacturing process) formation phenomena for a binary mixture of powders in a simple rotating cylinder are not yet understood. The more challenging problem of predicting powder-mixing patterns in complex geometric blenders also needs to be addressed. Computational fluid dynamics in the simulation of fluid or solids flows in reactive and nonreactive environments in various process systems could provide a useful alternative to the rapid system scale-up strategy. Computational code development, however, requires experimental verification to ensure its reliability. Of course, the pharmaceutical industry is not the only sector in which process engineering is needed to enhance national security and homeland defense. Also, other areas of process engineering such as model development, optimization schemes, on-line control, catalyst development, new separation methods, biomass conversion, and models using multiple length scales are equally important to include in research efforts. Chemical Synthesis Many drugs are produced by either chemical synthesis or biosynthetic processes. Recent advances in synthetic organic chemistry, catalysis, biotechnology, and combinatorial chemistry have made it possible to synthesize many chemicals that are not found in nature or have heretofore been difficult to produce. Current chemical drugs, such as antibiotics, used to combat infectious diseases are threatened by bacterial abilities to quickly mutate into a drug-resistant form. Concern also exists for purposefully genetically modified organisms used for terrorist attacks. Consequently, there is a need to constantly develop new chemical drugs for fighting infectious diseases caused by new biological agents. As we know more about human genomics, many new drugs, whether small-molecule chemicals or large proteins, can be developed to better target the diseases. Rapid production of small-molecule drugs will require the development of new organic reactions that maximally increase chemical complexity and that are highly selective. Advances in automation and miniaturization will be required to expedite discovery of synthesis sequences for large-scale drug preparation.

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Page 29 Synthetic Organic Chemistry Mauricio Futran Bristol-Myers Squibb Even though synthetic organic chemistry is a very old scientific pursuit, I believe that today most medications needed for homeland defense will be created by means of synthetic organic chemistry. This type of research and development is done by industrial organic chemists and chemical engineers, and there are many opportunities to involve academic scientists to increase the speed of development. Discovery of new biotransformations and improvements in separations and reactor design are also required. Developing a scalable high-efficiency separation process for separating and purifying chemical isomers, such as chiral compounds, would be useful for many chemical syntheses. In addition, the development of new drugs is dependent on new technologies for fast screening and testing. Fundamental understanding of biosynthetic pathways in cells, the structure-function relationship of biological molecules, antibody-antigen interactions, signal transduction on the cell surface, and the mechanism of toxicity are important. The ability to generate a mass library of chemical compounds and screen them for their biological activities or functions also remains a challenge to industry. Genomics, proteomics, rational drug design based on structure-functional information, and knowledge in metabolic pathways and immunology also require further research and development. Development of new bioprocesses with a high yield, high product specificity, and high production rate remains a challenge that requires an interdisciplinary approach and collaborative effort among chemical scientists and engineers, biologists, and other scientists. Of course, offering a new drug to the public is dependent on more than the synthesis. Preclinical trials, clinical trials, and regulatory approval tend to be rate-limiting steps for bringing a drug to market. In an attack, all of these processes may need to be streamlined and expedited through the use of new technologies, in addition to the use of more efficient drug development. Materials synthesis is a necessary component in the development of advanced technologies for national security and homeland defense. For instance, new composites, nanoscale molecules and compounds, and polymers are needed for tougher, explosion- or puncture-resistant materials that can be employed in buildings, garments, bridges, and other products and structures. Personal protective materials could be enhanced with new chemical adsorbents; filter materials, impermeable membranes, artificial sutures, and improved energetic materials for

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Page 30 Enzyme Production for Natural Products Biosynthesis C. Richard Hutchinson Kosan Biosciences Natural products biosynthesis relies on enzymes to create the final product. Production of these enzymes is in itself quite a process. Traditionally, the microorganism with the engineered gene that produces the enzyme undergoes random mutagenesis. The mutagenesis products are then screened for organisms that produce increasingly larger amounts of enzymes. In today's laboratories, enzymes are produced by a more efficient process. Engineered genes are removed from the original microorganism and through DNA cloning methods are placed into a host that already contains abundant substrates from which the enzyme is made. This process may produce enzymes that do not function as well as science desires or as well as the native enzyme, but they do function. The overwhelming benefit of this process is that it requires 6 months of work, compared to 10 years of mutation and screening by the traditional method. munitions and rocket motors could be developed. Simultaneously, new methods for tagging, tracking, and sensing precursors and other agents for explosives and nuclear, chemical, or biological weapons should be developed. New types of electrode and electrolyte materials, including biomaterials, are needed for high energy density batteries and fuel cells. The ability to respond effectively to an event will require first responders and HAZMAT teams to coordinate thousands of details. Development of new materials for advanced telecommunications and radar could greatly improve the current response standard. Materials that can lead to faster computers, higher-density storage, and more efficient telecommunications are vital. One example of a basic area of research that could have an impact on our ability to respond to a threat is wide bandgap semiconductors, used, for instance, in phased-array radars. The development of shipboard phased-array radar systems over the past few decades has provided the military with a very high degree of situational awareness with respect to airborne targets. Infrastructure The need for a central laboratory or test facility to validate new detection, detoxification, remediation, and medical countermeasure technologies was

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Page 31 repeatedly articulated at the workshop. Possibly, this can be expressed as a need for a central clearinghouse and also a need for a test facility (or facilities). The Soldier Biological and Chemical Defense Command (SBCCOM) is located at the Edgewood Arsenal (Aberdeen Proving Ground) in rural Maryland, north of Baltimore. The SBCCOM is the Army's principal research and development center for chemical and biological defense technology and has an extensive complement of skilled professionals in this field. This program could easily be expanded for civilian defense needs. Testing facilities for chemical and biological materials are expensive and complicated. Some exist in the private domain, for example, Battelle Memorial Institute. The Army's Dugway Proving Ground, located in an isolated area of Utah, provides tens of thousands of square feet of biological and chemical testing laboratories (40,000 instrumented square feet for biotesting; 35,000 square feet for chemical testing including 40 separate certified chemistry laboratories; and two 30,000-cubic-foot testing chambers). These facilities are available for private use on a contract basis and could be put to work on the demands of a civilian program. Expansion, however, may be required if civilian defense needs grow and cannot be reasonably accommodated in existing facilities. New and improved instrumentation is also a necessary component of infrastructure. Single-user and multiuser instrumentation is needed to support research at testing facilities; obsolete equipment also needs to be replaced. SITUATIONAL AWARENESS Research needs for situational awareness stems from a number of chemical disciplines and other sources as seen below. Dispersion, Collection, and Concentration Atmospheric chemists and other scientists who have focused on pollution and global climate change have much to contribute to national security and homeland defense. These scientists have developed computational methods to accurately model and in many cases predict the transport of pollutants and particles in air or water. These same tools can be used to predict the effect of release of a chemical agent in an urban area so that appropriate emergency response plans can be developed. Generally considered the “gold standard” in rapidly identifying small molecules such as chemical warfare agents, mass spectrometric techniques have been developed by analytical chemists that allow the identification of larger bio-molecules. This work should prove important in identifying biological warfare agents including proteins such as botulinum toxin and viruses. Recent work has also focused on concentrating and identifying bacterial pathogens such as anthrax spores from air and water based on protein biomarkers. Finally, the development

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Page 32of miniaturization technologies by engineers to allow the manufacture of low-power, compact (portable) devices to perform these and other types of analyses is already a robust area of research in the United States. The number of particles that can cause infection is often very small; hence, the amount of agent used in an attack can also be relatively small. Agent dispersion and sample collection, concentration, and preparation are all crucial issues for detection of biological warfare agents, chemical warfare agents, and explosives threats. The environmental sampling community (environmental chemists, atmospheric chemists) has been addressing the problem of sample collection and concentration for some time, although the need for real-time collection and analysis, though important in the national security and homeland defense arena, has not been particularly urgent. The medical diagnostics community has been actively engaged in developing methodologies for rapidly collecting, processing, and identifying disease in samples from patients, and recent efforts have focused on mechanical devices that can be used to provide a more active means of sample concentration and presentation to a sensor. For example, new microfluidics technologies allow us to install “plumbing” on a small (millimeter-scale) device. The ability to accurately control the flow of liquids in miniaturized systems using current chip fabrication technology has been key to the development of the “lab on a chip,” a low-cost, portable package that can be used by first responders, emergency medical personnel, and HAZMAT teams to analyze very small samples very rapidly. To extend miniaturization to the sampling and concentrating of aerosols and airborne particles, advances are needed in flow and handling of small volumes of gases. Temperature Control in Microfluidic Devices Andrea W. Chow Caliper Technologies One method of amplifying DNA in a polymerase chain reaction is through temperature cycling. The double-stranded DNA is denatured between 90°C and 100°C, while the annealing and extension demands lower temperatures. Sufficient amplification of the DNA occurs only after many cycles of temperature change. DNA amplification can be achieved very effectively on a chip through Joule heating, heating due to energy loss from electrical currents. In some microfluidic devices, there are electrodes in the reagent wells to promote the flow of ionic liquids. Although the energy loss from these electrodes is often viewed as problematic, by varying the current to the electrode the temperature of the microfluidic device can easily be controlled.

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Page 33 Our ability to detect, identify, and track a plume of a chemical or biological agent in air or water is not adequate, and the capability to track long-range transport and to better understand survivability of bacteria and viruses over long distances is in great need. We also need to more completely characterize the natural background of spores and other bioagents in the 1 to 10 mm (respirable) range as it varies from place to place, seasonally, and temporally. An efficient approach to collect, separate, concentrate, and process samples has not emerged, and remains the significant challenge in this area. Real-Time Detection—Sensors and Diagnostics Identification of a radiological, chemical, biological, or explosive threat is achieved with a sensor. Diagnosis of disease is also often achieved with some sort of sensor, in the form of a medical test. Sensors can be remote, such as a satellite-borne camera, or they can be localized, such as a smoke detector or home pregnancy test. The chemical sciences have contributed significantly to the development of accurate and sensitive sensors for a variety of medical, pollutant detection, and industrial monitoring applications, and this robust area of research will continue to contribute in the national security and homeland defense arena. The challenge in this area is to develop specific, sensitive, low-power, fast, and robust portable devices that will detect radiological, chemical, biological, or explosive threats in the environment and that will rapidly diagnose disease. Chemical Detectors Mass spectrometry and ion mobility spectrometry are well-established analytical techniques that are heavily used by the DOD. These devices are used as detectors of chemical agents and explosives; in fact, ion mobility spectrometry is currently being used in most U.S. airports for explosives detection. Mass spectrometry is simultaneously broadband and specific—molecular masses provide exquisitely specific identification of chemical agents, precursors, trace explosives, and such materials. Of course, established methods can and should always be improved. Improved detectors for conventional chemical warfare agents such as blood, nerve, and blister agents are desired. In addition, new methods to detect explosives and toxic industrial chemicals are needed. In general, the detection problem can be broken into two parts: chemical identification and signal transduction. The chemical identification issue involves some specific or nonspecific chemical recognition element that displays a unique response to the analyte of interest. Three general schemes for providing chemical specificity or identification were discussed by workshop participants: methods based on spectroscopy, cross-reactive arrays, and specific molecular recognition. Spectroscopic methods involve measurement of characteristic “fingerprint”

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Page 34 regions of the vibrational, mass, or electronic spectrum of the analyte of interest. There are many good examples of diagnostic spectroscopic tools that reside on a laboratory benchtop; chemists and chemical engineers are challenged to develop tools to enable the miniaturization and portability of such devices. Although mass spectrometers are not considered to be spectroscopic devices, small mass spectrometers are offered as an example of the concept of miniaturization in the Appendix. 1 A cross-reactive array, or “electronic nose,” behaves like the mammalian olfactory system: the response from an array of hundreds or thousands of individual sensor elements is combined to form a response pattern characteristic of the analyte of interest. 2 Various implementations of this basic concept have been developed, using solvatochromic dyes or electronic polymers as detection elements, for example. 3 – 5 Work in this field has established how multiple redundant sensor elements can be used to improve the signal-to-noise ratio of such an experiment, making analyte identification easier and clearer, and similar highly parallel assays have been applied industrially for the identification of proteins and sequencing the human genome. 6 , 7 Although the usual implementation of an “electronic nose” targets chemicals in the gas phase, this technique is equally applicable to detection of species in water or from blood or urine samples. Nature provides many examples of how the specific binding of two complementary molecules can be used to achieve molecular recognition, such as an antigen-antibody pair or the DNA duplex. Indeed, many of the workshop presenters showed transduction schemes that incorporated biological molecules. This approach has the advantage that the sensor designers can rely on two billion years of evolution to design their recognition elements; this biological scheme works particularly well for detection of biologically derived molecules. If there are no naturally occurring molecules to be used as sensors, researchers can resort to chemical synthesis. Several molecules have already been constructed to specifically sense toxins, biological hazards, and explosives. 1K. A. Prather. 2002, Overview of Real-Time Single Particle Mass Spectrometry Methods. Presentation, Workshop on National Security and Homeland Defense, Irvine, CA. (See Appendix D.) 2T. A. Dickinson, J. White, J. S. Kauer, and D. R. Walt. 1996. A Chemical-Detecting System Based on a Cross-Reactive Optical Sensor Array. Nature 382: 697-700. 3J. W. Gardner and P. N. Bartlett (eds.). 1992. Sensors and Sensory Systems for an Electronic Nose. NATO ASI Series: Applied Science 212, 327. Dordrecht: Kluwer Academic Publishers. 4M. S. Freund and N. S. Lewis. 1995. A Chemically Diverse Conducting Polymer-Based Electronic Nose. Proceedings of the National Academy of Sciences U.S.A. 92: 2652-2656. 5N. A. Rakow and K. S. Suslick. 2000. A Colorimetric Sensor Array for Odour Visualization. Nature 406: 710. 6J. A. Ferguson, T. C. Boles, C. P. Adams, and D. R. Walt. 1996. A Fiber Optic DNA Biosensor Microarray for the Analysis of Gene Expression. Nature Biotechnology 14: 1681-1684. 7A. Lueking, M. Horn, H. Eickhoff, K. Bussow, H. Lehrach, and G. Walter. 1999. Protein Microarrays for Gene Expression and Antibody Screening. Analytical Biochemistry 270: 103-111.

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Page 35 For any of the recognition schemes described above, a quantifiable signal must ultimately be generated. This process is referred to as signal transduction. Participants in the workshop identified a variety of optical or electrical methods of signal transduction using a wide range of physical, spectroscopic, and materials tools. This is also a robust area of research in the United States that should play a key role in chemical agent detection. The challenges in this field rest on improving sensitivity and specificity, and reducing the power drain to allow the manufacture of palmtop, wristwatch-size, or even smaller sensors. Advances in microelectronics have enabled the fabrication of compact, portable, low-power devices, and advances in power sources, miniaturization techniques, nanofabrication tools, and fundamental materials chemistry should allow this trend to continue. Biological Detectors A variety of detection methodologies that were either inspired by or derived directly from biological systems were discussed at the workshop. These have been used to detect conventional chemical as well as biological agents. Biologically derived systems may use just a small component of a living system, such as an antibody, or an entire live cell to achieve detection. For example, detection assays based on single cells or arrays of cells are now being used for diagnostics, in rapid drug discovery applications, and to sense toxins in water. Single components of biological systems, such as an antibody or a biomimetic membrane, have been incorporated into nonbiological systems to provide sensors for biological or chemical toxins. Chemical biomarkers released by the host in response to invasion and infection could provide a target for antibody arrays, mass spectrometry, and other analytical techniques to diagnose infection. In spite of these advances, general research into the biochemistry of agents and the rapid identification of pathogenicity of agents is still needed. This is particularly important if we are to develop the ability to respond to new threats such as artificially bioengineered diseases and agents. The challenges in detection of biological agents are similar to those facing chemical agent detection. However, biological toxins can be much more toxic on a per-molecule basis than chemical agents and in some cases can be transmitted and amplified from one individual to the next. In addition, it is very difficult to distinguish toxic biological agents from the harmless biological compounds ubiquitous in our environment or from naturally occurring toxic biological agents that are present. As with chemical agent detection, significant challenges in this field involve improving sensitivity, specificity, and power requirements of devices. There are also opportunities for reduction of solutions and fluidics to create more robust, unattended, biologically based sensors. This area could benefit substantially from efforts to improve the response time and portability of medical diagnostic equipment. Advances in the medical field to improve our capability to

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Page 36 identify pathogenicity by class or function as opposed to specific gene sequence will improve our ability to respond to unknown or emerging threats. Other Detection and Identification Issues Early detection and identification of nuclear, biological, chemical, and explosive warfare agents is essential for the timely deployment of preventive and defensive measures. One of the first steps involves constant surveillance of transportation in high-security areas such as airports and national borders. This can be achieved by using noninvasive sensors alone or in conjunction with imaging techniques capable of detecting and identifying sealed containers with chemicals or explosive materials inside, or items such as knives or guns on the body. These techniques include the use of ultrasound, optical waves, and nuclear radiation that are based on the interactions of acoustic or electromagnetic waves with matter. Ultrasonic and optical sensors detect reflected (or transmitted-through-and-reflected) waves. For nuclear materials, the detection and monitoring is primarily based on (isotopic) neutron and gamma ray detectors. Long-range detection of nuclear material is also necessary to prevent illegal trafficking from known stockpiles around the world. As mentioned earlier, chemicals and explosives are usually detected spectroscopically. Fiber-optic-based chemical sensors have application in the real-time tracking of rapidly changing chemical environments. These sensors provide rapid The Difficulty of Water Supply Contamination Rolf A. Deininger University of Michigan Although worries abound over contamination of the water supply, in reality, the task is quite difficult to accomplish. For example, a contaminant can be dumped into a reservoir, but studies show that the chemical does not mix throughout the entire body of water, even after many hours. There are multitudes of chemical and biological agents that can be used to contaminate the water supply, but all contaminants do not behave similarly. Not all contaminants are threats—some become unstable in water, while others require such large quantities to do harm that they could never be dumped without being noticed. Additionally, if a disinfectant residual is maintained in the water distribution system, that residual will react with the contaminant, and the populace will remain relatively safe. It will be extremely difficult for terrorists to successfully contaminate the water supply.

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Page 37 and reversible response to a variety of chemicals at trace concentrations. Flow injection analysis on a microelectromechanical system (MEMS) microlab platform provides high sensitivity and selectivity within a matter of hundreds of seconds from a small sample volume. Micromachined gas chromatography sensors aid in on-the-spot, real-time chemical sensing of toxic gases. Further variations of miniaturized devices might include a tongue-on-a-chip that can identify water pollutants through colorimetric chemical reactions. The main mode of proliferation of biological warfare agents is through the use of aerosols. Ultraviolet and laser-induced fluorescence techniques are under development for the remote sensing and detection of man-made aerosol clouds containing biological agents. The challenge extends to the detection of such agents that contaminate water and food supply lines, particularly close to end-users. For contamination of the water supply, the distribution system is the most likely candidate for an attack. An effective contaminant will be tasteless, odorless, and colorless, otherwise consumers will recognize the problem themselves without additional detection technology. 8 New detection technologies are needed for the in situ monitoring of biological warfare agents inside “suicide attackers” to curb the spread of contagious diseases, including smallpox. Chemical biomarkers released by the host in response to invasion and infection could provide a target for antibody arrays, mass spectrometry, and other analytical techniques to diagnose infection. There is also a growing need to detect mutagenic strains of existing agents and to render them harmless. Detection of these agents involves real-time size and number classification followed by multiple analyses to identify the virulence of the organism. Research efforts are underway in the government and private sector to develop bioMEMS devices for multiple purposes such as drug delivery, microsurgery, and implants. Lab-on-a-chip platforms carry out the reactions involved in the detection and identification of DNA and protein sequences from minute sample sizes of biological warfare agents. The detection is achieved on a CD-sized device by chemical analysis of DNA/protein fragments released from the cell. These portable devices are engineered by using a combination of micropumps and valves. Mass-scale production of these devices usually involves a combination of techniques such as photolithography and electroplating on one hand and surface machining, atomic force microscopy-indentation, differential etching, self-assembly, and X-ray lithography on the other. Devices that can be used by an individual without medical supervision (for example, biosensors incorporated in a bandage) need to be developed to detect and identify human exposure to chemical and biological agents. Current methods used to counteract human exposure to pathogens involve needle-based drug 8R. I. Deininger. 2002, Vulnerability of Public Water Supplies. Presentation, Workshop on National Security and Homeland Defense, Irvine, CA. (See Appendix D.)

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Page 38 delivery by trained personnel. Self-administration of required dosage (tens of milligrams) could be achieved by improved aerosol-based drug delivery devices, thereby eliminating the need for intervention by medical personnel. Prevention of human exposure to chemical and biological agents must be achieved. On a large scale, this can be accomplished by maintaining the integrity of indoor air quality. Applying heat and temperature to the air that is taken in can change the physical characteristics of carrier aerosols and can lead to their aggregation and consequent removal by standard particulate filtration devices. At a more individual level, a rapid breath or urine test for appropriate biomarkers would be useful to identify carriers of communicable diseases (for example, small pox) before they have the opportunity to infect multiple people through actions such as boarding an airplane. Miniature devices that work under ambient conditions (rather than at cryogenic temperatures) need to be developed to improve their portability. A biological aerosol sentry system developed to analyze data from numerous sensors can be used to detect the release of biological agents at public gathering arenas and closed spaces such as subways. Systems monitoring water, fuel, and food supplies would be necessary to prevent mass human exposure to chemical and biological agents. It is equally imperative to identify new strains of biological agents that are resistive to current medications. Further aerosol science research is needed to understand the fundamental mechanism of aerosol agglomeration processes to develop more effective preventive measures. More fundamental study of the interactions of acoustic or electromagnetic waves with matter is needed. Information on Biological and Chemical Threats For many of the currently available antibody and nucleic acid-based detection systems, identification takes advantage of unique characteristics of the pathogenic organisms in order to distinguish harmful from harmless species. However, discussion at the workshop pointed to a lack of knowledge and understanding of many of the characteristics of pathogenic or toxic agents. Some unique characteristic of pathogens may allow their selective collection or concentration out of complex air, soil, or biological matrices. To encourage and enable innovations in this area, workshop participants discussed potential advantages of an extensive database on the properties of pathogens that could be readily available to researchers considering solutions to the problem. A central, unclassified, Web-based repository for all the properties of pathogens and toxins could be developed. Table 4.1 below shows an example of some of the properties that could be listed using anthrax as an example. The table is broken into properties of the agent itself and properties of any of the known biological targets. The database would present all known protein sequences and structures; nucleic acid sequences; exosporium structure; metric parameters such as mean density and size; spectral properties such as the fluorescence, fluorescence

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Page 39 TABLE 4.1 Sample Entry in a Chemical and Biological Agent Database Anthrax Spores Biochemical Properties DNA sequence Whole organism Specific toxin plasmids Proteins sequence and structure Exosporium Spore internal Toxins Physical Properties * Density average and standard deviation Size average and standard deviation Fluorescence Fluorescence excitation spectrum Scattered light spectrum Absorption spectrum (from microwave to UV) Raman spectrum Electrical conductivity, impedance Acoustic properties *Note some of these properties may be highly variable and dependent on specifics of sample preparation. excitation, scattered light, absorption (from microwave to UV), and Raman spectra; and electrical and acoustic signatures. This database would focus on properties and would not contain information on the preparation or delivery mechanisms of agents. Thus, the information contained may not need to be sensitive or classified. Much of the biological data already exists on the Web and could be linked to the biowarfare database. For example, The Institute for Genomic Research maintains an on-line database of known bacterial DNA sequences. 9 Limited databases on these properties are already in existence, although they are not readily available. In addition, extensive information about and knowledge of chemical and biological agents is maintained at the Chemical and Biological Information Analysis Center (CBIAC) at Aberdeen Proving 9< http://www.tigr.org/tdb/mdb/mdb.html>.

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Page 40 Ground in Edgewood, Maryland. “The CBIAC generates, acquires, processes, analyzes, and disseminates CB [Chemical and Biological] Science and Technology Information. . . .” 10 The agency also maintains a hotline on epidemiological and medical treatment data for first responders. Maintaining a Web-based database would lower the barrier for researchers who may be thinking of proposing new and novel ideas for detection of biological and chemical agents. THREAT NEUTRALIZATION AND REMEDIATION In the case of exposure to chemical and biological agents, mitigation and neutralization efforts need to be immediate. The effective decontamination process requires decontamination techniques and equipment that are readily available or can be easily deployed. Prior to the actual application, it is necessary to secure proof of the decontamination process's efficacy by testing live agents, to demonstrate its versatility for a variety of surface structures, and to ensure that it is environmentally benign (possessing nontoxic and noncorrosive properties). It is clear that the decontamination agents need to be sensitive to the material surface, whether it is building material or human skin. For selection or development of decontamination equipment, it is necessary to consider the capability and throughput, effectiveness, set-up time, power capability, durability, and operational conditions. The decontamination processes could include physical processes (using solvents, sorbents, or filtration operation), chemical processes (reactive chemicals) and thermal processes (vaporization, for instance). Decontamination of human skin requires immediate action after exposure, using chemical, biological, or physical means with attendance to safety throughout the application. Information on common chemical agents and biological agents and their respective decontamination equipment is available in the Guide for the Selection of Chemical and Biological Decontamination Equipment for Emergency First Responders, published by the National Institute of Justice. 11 The challenges in decontamination include the logistics of providing materials in a timely manner, the development of effective multifunctional decontamination agents that are able to neutralize a variety of chemical or biological contaminants of diverse properties, and the development of low-toxicity decontamination agents that can be applied to such sensitive surfaces as human skin. More importantly, agreement by regulating agencies must be reached as to what defines “clean”, and a protocol for determining whether a facility is “clean” needs to be clearly outlined. Agreement between civilian and defense agencies as to what is 10< http://www.cbiac.apgea.army.mil/about_us/general.html>. 11National Institute of Justice. 2001. Guide for the Selection of Chemical and Biological Decontamination Equipment for Emergency First Responders. Guide no. 103-00. See also < http://www.ojp.usdoj.gov/nij/pubs.htm>.

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Page 41 “clean” would speed the development of disinfectants and their testing. Also, a method for transferring information from classified programs to civilian programs regarding methods for decontamination, results from decontamination tests, and how to best test a decontaminant would be useful.