Biological Warfare Defense 1. Overview of the Biological Warfare Defense (BWD) program at DARPA. Dr. Jane (Xan) Alexander, Deputy Director of DARPA, in her presentation, introduced the programs and discussed why BWD is a very high priority for DARPA. She also discussed a number of our program thrusts in nonmedical BWD, such as Sensors and Accelerated Consequence Management. I will be discussing the medical areas and external protection. 2. The ultimate Goal of the DARPA BWD program is to remove the incentives for developing or using biological agents, by making the agents ineffectual, for example. In addition to the current known threats, there is also the potential of novel threats, such as newly recognized natural infections that might be adopted by potential adversaries, and of bioengineered agents, for which we need to be prepared. 3. Because the threat profile is complex and changeable, we are emphasizing approaches that are broadly applicable -- targeting the fundamental mechanisms of disease, for example -- rather than targeting individual agents. Many of these targets may also apply to infections of broad medical interest, helping with commercial development of promising products. 4. We also look for demonstration programs that show biologically meaningful results in appropriate live model systems -- such as relevant animal models -- with significant pathogens, not simulants. 5. Here are the various program thrusts in the DARPA BWD program: Sensors, External Protection, Consequence Management, Advanced Diagnostics, Medical Countermeasures, and a new thrust, Genomic Sequencing. The timeline shows how they fit together: Sensors are most critical pre-event and early in an attack. External Protection is most important in the first few minutes to hours after an attack, and so on. Genomic Sequencing provides information useful for a variety of applications, including sensors, diagnostics and medical measures. 6. Here are the current DARPA program thrusts, with the names of the responsible Program Managers. There are additional supporting technologies being pursued in other offices. For example, microelectromechanical systems and microfluidic devices, which may impact the development of both sensors and diagnostics, which are major program thrusts of the Electronics Technology Office. 7. First, I will discuss our thrust in external protection. 8. Two examples of DARPA’s projects in external protection. On the left, a gasmask “filter” that sterilizes the incoming air using a miniature thermocatalytic device. On the right, artificial polymer “skins” for making protective suits. The fabrics are made by a novel process that allows natural-like give, with embedded enzymes to make them self- decontaminating. 9. DARPA has a small, but growing effort in decontamination. One of our first projects in this area involves “Novasomes” developed at the University of Michigan. Novasomes are a nanomolecular formulation of lipid and detergent. The formulations are nontoxic to us, but rapidly kill a wide range of gram positive bacteria and envelope viruses. The results here show killing of anthrax spores. 10. Next, our thrust in Advanced Diagnostics will be discussed. 11. The goals of the Advanced Diagnostics program. One important objective is to be able to identify those who have been exposed as soon as possible after exposure, and to be able to triage them -- separate them from the “worried well.” 12. Why do we need an Advanced Diagnostics program? Here are some of the reasons. 13. Our approach is threefold: In addition to leveraging cutting-edge developments in biotechnology, and developing new technologies for diagnostics, there is an essential need to identify the targets, or markers of disease -- to know what signals we should look for. 14. As an example, white blood cells rapidly respond to infection by making the gas nitric oxide. A DARPA funded group tested whether it was a good marker for infection, testing in emergency room patients and schoolchildren. Their data indicate that it shows great promise as an early marker, for triage. They have also developed a prototype miniature sensor for further testing. 15. We are also interested in developing revolutionary new technologies, such as a new approach for sequencing DNA by passing it through a pore and reading off the changes in electrical signal as each DNA base blocks the pore in turn. This would make it possible to sequence DNA at a rate order of magnitude faster than the best methods available today, and at a much lower cost. This could allow us to diagnose a wide variety of diseases very rapidly. 16. Earlier, Dr. Alexander spoke about our program thrust in Sensors. A relatively new component of the Sensors thrust is “Tissue-Based Biosensors”, using cells to detect harmful agents -- like the proverbial “miner’s canary”, only on a chip. These cell or tissue-based systems may also be used for diagnostic purposes. 17. For example, B cells are the cells in our body’s immune system that produce antibodies in response to foreign antigens. They can do this with exquisite sensitivity. This project, called “CANARY”, is engineering B cells to light up when they bind a particular antigen; the event can then be detected optically. A panel of B cells, engineered to detect a variety of pathogens, can then be integrated into a microfluidic chip. Preliminary results in a model system, with several prototype microfluidic chip designs, demonstrated high specificity and rapid response. 18. The next major thrust that I will discuss is medical countermeasures. 19. The goal is to target the fundamental mechanisms of disease, the features that are unique to pathogens, and to find ways to shift the host-pathogen balance in our favor. 20. Immunization is one way to shift the balance. Current vaccines take time to make, are slow to take effect, and cover one pathogen at a time. DARPA projects in this area are looking at new ways to speed up the process -- for example, by targeting more effectively to the antigen presenting cells that start the immune response -- and to develop new vaccines rapidly by DNA technology. 21. As I mentioned earlier, a key strategy is to target functions that are essential for the pathogen, and that are shared by many different pathogens. 22. Here are some examples. This project, at SmithKline Beecham, looked for unique bacterial genes turned on early during the infection process (using several animal models). They found a number of genes that had never before been identified. Several are very widely conserved genes in pathogenic bacteria, including a number of 2-component signal transduction systems -- functions used by bacteria to sense their environment. Using this knowledge, they are now developing drug candidates to block key genes -- to “turn off the lights” on the pathogen. 23. Some functions are also essential to pathogen reproduction and survival. This project at Stanford University is targeting an important housekeeping gene, found in the BW threat agent Brucella and a number of other pathogens. These bacteria need the right amount of the protein at the right time in order to survive and reproduce -- block this, and they die. The researchers are now testing candidate compounds to block this protein. These compounds would represent an entirely new class of antibiotics. To give you some indication of the significance of a new class of antibiotics: Until very recently, there had not been a single new class of antimicrobial drugs since 1976. 24. Our newest thrust is Genomic Sequencing. 25. Libraries of DNA sequences of important pathogens are under development in a number of places. It is important to make sure that we have a sufficient database, with both depth and breadth, for the threat organisms that most concern us. In addition, genomic data provide a rich storehouse of information for analysis. Genome sequences are needed for sensors and diagnostics, for organism identification, and to identify potential new targets for therapeutics. By comparing sequences of pathogens and closely related nonpathogens, we can learn a lot about what makes a pathogen a pathogen. 26. This shows some of the specific objectives of the genome sequencing program. 27. In this half-hour, I’ve tried to give you a flavor of our BWD program, especially in the medical areas. Much more detailed information can be found on the DARPA Website. This URL will provide you with more detailed information on the BWD programs you’ve heard about today. New solicitations are anticipated this fall -- stay tuned!