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In cases of bioterrorist attack such as the recent anthrax outbreaks, decision makers and law enforcement officials need to understand the situation quickly. Early detection and identification of the biological organism and its source are crucial for minimizing the potentially catastrophic human and economic costs of such an attack.
Clues may lie hidden in the weapon itself. Does the bacterium or virus harbor information in its DNA that could lead to its source? Is it resistant or vulnerable to vaccines and antibiotics?
To find answers to these questions, revolutionary new approaches, including many at the national laboratories, are being developed with DOE funding. These strategies combine the knowledge and tools generated in genome programs with advanced computation and microfabrication.
Many projects are funded through DOEs Chemical and Biological National Security Program of the National Nuclear Security Administration (NNSA). NNSAs mission is to develop, demonstrate, and deliver technologies and systems to prevent the spread of chemical and biological weapons. This article describes some examples of the new techniques.
Intensive research at DOE laboratories concerning Bacillus anthracis, Yersinia pestis (causes of anthrax and plague, respectively), and many other causative agents has led to a wealth of genetic information and unique technologies for detecting and identifying the genetic strains of these organisms down to their precise DNA fingerprints. The laboratories have focused on tracking selected, highly variable, or very specific DNA signatures in the microbial genomes. In some cases, these analyses offer clues to the agents genetic identity, geographic origin, and genetic modification to enhance its resistance to antibiotics and vaccines.
Researchers at Lawrence Livermore National Laboratory (LLNL) have developed unique reagents for rapid identification of target genome fragments using polymerase chain reaction. The test also may enable the tracking of bacterial infections. In October 2001, researchers Peter Agron and Gary Andersen reported success with a technique to identify a strain known as Salmonella enteriditis, which is commonly associated with food poisoning. Their paper appeared in the November 1, 2001, issue of Applied & Environmental Microbiology. The successful Salmonella testing follows an achievement in May 2001, when unique Y. pestis DNA signatures identified by LLNL researchers were used to confirm quickly a naturally occurring outbreak of plague. Made available to federal agencies, this technique may soon lead to identification of some bacteria in hours rather than days or sometimes weeks. These groups are working with the Centers for Disease Control and Prevention to validate assays for distribution to the U.S. public health network.
Researchers at Pacific Northwest National Laboratory and Washington State University are improving microarray sensors that speed the detection of such pathogens as anthrax and smallpox. The new sensors allow direct detection of RNA or DNA from multiple pathogens at improved sensitivity and are expected to make the technology less expensive and more readily available for routine use.
Los Alamos National Laboratory (LANL) researchers developed an amplified fragment length polymorphism tool to analyze B. anthracis from naturally occurring anthrax outbreaks around the world. This method uses small DNA fragments to establish a fingerprint that is added to a database where it can be read and interpreted by comparison to others. In recent work on the anthrax threat, researchers analyzed B. anthracis strains found in the attack and compared them with a library of more than 1200 different strains. The group continues to work on the rapid identification of drug-resistant strains.
At Sandia National Laboratories, a project is under way to help doctors quickly identify and contain disease outbreaks, especially infectious diseases. The Rapid Syndromic Validation Project (RSVP) is a full-time medical database used to report and give early warning of disease outbreaks. RSVP tracks syndromes (signs and symptoms) rather than positive diagnoses of specific diseases. Real-time syndromic and epidemiological surveillance could significantly speed the process of determining whether a novel disease was introduced naturally or intentionally, where the disease first appeared, how it spread, and the pathogen's origin. A version of RSVP also is being developed for livestock surveillance.
Other genomic technologies developed with DOE funding include multiple-locus variable number of tandem repeat analysis (MLVA) and single nucleotide polymorphism (SNP) analysis. Through the recognition of repeated DNA sequences in the genome, MLVA provides a very high resolution DNA fingerprint of a suspected agent. SNP analysis uses a flexible microsphere array that can target potential antibiotic-resistant genes, toxin genes, and genome sites that may have undergone deliberate genetic modification. Also being used for strain identification, SNP detection eventually may supplant MLVA when enough sequences are available.
Toward a Greater Understanding
A vital next step toward realizing the full potential of genomic advances to neutralize biothreats is to translate their genetic codes into a deeper understanding of how these organisms infect and survive in the host and how they cause toxic effects. This information is needed to understand fully what makes a biological agent a threat and how it can best be found and counteracted.
Exploring the critical life functions of microbes is a goal of the new DOE Genomes to Life (GTL) program (http://genomicsgtl.energy.gov), whose findings will have applications in biothreat research. A brochure by Jill Trewhella (LANL) and Bert Weinstein (LLNL) highlighting GTL contributions in this area can be accessed via the Web site.
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v12n1-2).
The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.