REVIEWS A GENOMICS-BASED APPROACH TO BIODEFENCE PREPAREDNESS Claire M. Fraser The anthrax letter attacks in October 2001, followed by the SARS outbreak in early 2003, dramatically illustrated our vulnerability to both deliberate and natural outbreaks of infectious disease. The availability of pathogen genome sequences and high-throughput methods for studying the biology of both pathogens and their hosts have provided new insights into the mechanisms of pathogenesis and host defence. As infectious disease research expands to include major bioterror agents, genomics-based approaches will provide one of the cornerstones of efforts to develop more accurate diagnostics, new therapeutics and vaccines, and further capabilities for microbial forensics. CATEGORY A AGENTS Since the anthrax letter attacks in October 2001, the US bioterror agents; develop new vaccines, antimicrobial Organisms that pose a risk to federal government has placed a premium on homeland and antiviral therapeutics, and diagnostic tools against national security because they: security, with research and development considered to the most threatening diseases, such as smallpox, anthrax, can be easily transmitted from be a key component of an integrated and unified biode- and plague; and to develop research resources such as person to person; result in high mortality rates and have the fence strategy. For fiscal year 2003, President Bush pro- BSL3 and BSL4 LABORATORY containment facilities to allow potential for major public health posed a $1.75 billion budget for biodefence research, to more work on category A–C agents than is possible at impact; might cause public be administered primarily through the National present. Ultimately, the expectation is that these new panic and social disruption; and Institutes of Allergy and Infectious Diseases (NIAID) at research activities will increase our level of prepared- require special action for public the National Institutes of Health (NIH). As summarized ness so that we might better respond to, and protect the health preparedness. on the NIAID web site (see online links box), the pro- world’s population against, bioterrorism. CATEGORY B AGENTS posed new biodefence research agenda will broadly Much needs to be done to realize the ambitious goals Organisms that are moderately focus on studies of CATEGORY A, CATEGORY B and CATEGORY C of the NIAID Strategic Plan for Biodefense Research — easy to disseminate, result in BIOTERROR AGENTS (for more information, see online links this includes not only an expanded research portfolio moderate morbidity rates and low mortality rates. They require box). These potential bioterror agents share several fea- and the development of new tools and reagents, but also specific enhancements of the tures, including a high morbidity or mortality that is the creation of new research facilities and the recruit- Center for Disease Control and associated with infection, a high likelihood of person- ment of new investigators into the area of infectious dis- Prevention’s diagnostic capacity to-person spread, the ability to be made into a weapon ease research. On 4 September 2003, the US Department and enhanced disease and spread by aerosols or food and water supplies, and of Health and Human Services announced the creation surveillance. the potential to cause widespread panic in the public if of eight Regional Centers of Excellence for Biodefense released into the environment. The goals of this acceler- and Emerging Diseases (RCEs). The aim of the RCEs is ated research and development agenda are to: understand to bring together investigators from several disciplines better the molecular mechanisms that are responsible for and public and private institutions to tackle the most pathogen transmission, virulence and invasion; develop compelling research questions that are relevant to The Institute for Genomic new animal models of disease that can be used in the bioterror agents, particularly anthrax and smallpox, in Research, 9712 Medical study of potential bioterror agents; elucidate host large, comprehensive programmes (for more informa- Center Drive, Rockville, Maryland 20850, USA. responses to microbes to understand better the complex tion on RCEs, see online links box). Collectively, what e-mail: [email protected] parameters of innate and acquired immunity, and how sets this new research agenda apart from previous doi:10.1038/nrg1245 they might be manipulated after exposure to potential efforts on the study of infectious disease agents is the NATURE REVIEWS | GENETICS VOLUME 5 | JANUARY 2004 | 23 REVIEWS expectation that in a relatively short period of time information derived would be available to all scientists these expanded research activities must achieve several for all time. We could then think about a new post- key objectives that can provide immediate benefits in genomic era of microbe biology.” (REF.1).As genomics, the public health arena. It is also anticipated that one of proteomics and bioinformatics are considered to be key the other positive spin-offs of the new bioterrorism enabling technologies in the development of new meth- research agenda will most certainly be a better under- ods to deal with potential bioterror agents and emerging standing of other more common and naturally occur- infectious diseases, this review summarizes the status of ring infectious agents. This is an important goal because pathogen genome sequencing and analysis at present we are at least as vulnerable to emerging infectious dis- and discusses how these approaches might best be eases as we are to deliberate attacks. The recent severe applied to biodefence preparedness. acute respiratory syndrome (SARS) epidemic that in 9 months killed over 900 people in 31 countries illus- Vulnerabilities and assessment of needs trates just how devastating a new disease can be, and The intentional spread of disease during war (biowar- how quickly it can spread around the world (for more fare) has a long history that dates back to the ancient information on SARS, see online links box). Greeks and Romans (BOX 1).Bioterrorism, by contrast, Barry Bloom, the present Director of the Harvard has a much shorter history. Recent events, in particular School of Public Health, summarized the potential of the anthrax letter attacks of 2001, have exposed our vul- genomics-based approaches to expand our understand- nerabilities in the area of BIOPREPAREDNESS against both ing of the biology of pathogens in 1995 (REF.1) after the natural and deliberate outbreaks of infectious disease. publication of the second complete microbial genome As there is a dearth of investigators who study biowar- sequence. He stated that “The power and cost effective- fare pathogens and only a few specialized facilities for ness of modern genome sequencing technology mean carrying out such research, we only have a rudimentary CATEGORY C AGENTS These third highest priority that complete genome sequences of 25 of the major understanding of the mechanisms of pathogenesis for agents include emerging bacterial and parasitic pathogens could be available most of these agents. We also lack rapid and precise pathogens that could be within 5 years. For about $100 million we could buy the diagnostic assays for identifying most of these species. engineered for mass sequence of every virulence determinant, every protein The deliberate release of microbial pathogens can be dissemination in the future antigen, and every drug target. It would represent for done, for the most part, without being noticed, until sig- because of their availability, ease of production and each pathogen a one-time investment from which the nificant numbers of symptomatic patients appear at dissemination, and their potential for high morbidity and mortality rates and major health Box 1 | History of biowarfare and bioterrorism impact. Biological warfare began with the ancient Greeks and Romans, who used toxic plants and human and animal corpses to BSL3 LABORATORY poison drinking-water wells. More recently (in the fourteenth century) the Tartars catapulted bodies of plague victims Laboratory facilities for work on over the city walls to infect the Genoese inhabitants of Caffa, a trade centre on the Black Sea. The Genoese took to their biological agents that might boats to escape, spreading the Black Death along shipping routes throughout Europe. In just a few years the plague killed cause serious or potentially lethal disease as a result of approximately one-third of Europe’s population. exposure by the inhalation The seventeenth and eighteenth centuries saw French and British soldiers intentionally infect native Americans with route. European diseases. For example, Sir Jeffrey Amherst ordered that smallpox be spread as a way “…to inoculate the Indians by means of blankets … to extirpate this execrable race…”63. BSL4 LABORATORY During the First World War, Germany had plans to conduct covert operations in the United States with the intent to Laboratory facilities for work infect horses and cattle that were destined for service in Europe with GLANDERS and anthrax. During the Second World with dangerous and exotic biological agents that pose War, bioweapons programmes were initiated in every major participating country. The Japanese military practiced a high individual risk of biowarfare on a large scale against the Chinese in Manchuria during the 1940s, infecting the population with various aerosol-transmitted laboratory disease agents including anthrax, cholera and plague. The Cold War brought about