In the wake of the Sept. 11 attacks and subsequent Anthrax scares, scientific researchers worldwide are working to expand the ability to rapidly assess what poses a terrorism threat to the public at large. The Institute of Human Virology, in collaboration with the Walter Reed Army Institute for Research (WRAIR) and the University of Maryland School of Medicine, is working to develop diagnostic tools that can distinguish common flu-like viruses from biochemical warfare pathogens.
"The symptoms for both the common flu and biowarfare agents can be near identical," explains Dr. Maria Salvato, a researcher and professor at the Institute of Human Virology, a center of the University of Maryland Biotechnology Institute and affiliated with the University of Maryland School of Medicine. "By identifying the gene expression that corresponds to the most common strains of flu, we can more quickly discriminate a relatively common viral infection from a more serious threat."
Jennie Hunter-Cevera, the president of UMBI, emphasizes the critical need for diagnostic capabilities from the public health perspective. "Should there be a terrorist event using biochemical warfare, emergency rooms would be ill-equipped to make a quick assessment. Our diagnostics," she adds, "seek to detect the earliest stages of exposure to a pathogen or toxin."
The Walter Reed Army Institute for Research has long been working toward ways to more quickly identify agents of biochemical warfare. For the last 10 years, Dr. Marti Jett's laboratory at the WRAIR has monitored blood cell responses to smallpox, anthrax, cholera, plague, endotoxin, and many other lethal agents. By analyzing mRNA changes that occur in the blood cells after they have been exposed to a pathogen or toxin, Dr. Jett's lab has been able to catalog those gene expression responses indicative of the presence of toxins.
At the IHV, Dr. Salvato's lab will expose blood cell cultures to five different viruses that cause flu-like symptoms (influenza, respiratory syncytial virus, parainfluenza virus, rhinovirus, and arenavirus) to determine which genes can discriminate between natural disease and biowarfare agents.
In the aftermath of the Sept. 11 attacks, there is a heightened public awareness of potential pitfalls in emergency response efforts and, given the difficulty of both diagnosing the common flu and distinguishing it from the more serious threats posed by agents of biochemical warfare, researchers are pooling resources to develop rapid diagnostics that can be used globally toward this goal.
The science boils down to a process of elimination.
Each human cell contains 40,000 genes and only expresses 1-10 percent of those genes in the form of messenger RNA (mRNA). When blood cells come in contact with a pathogen or toxin, they change the spectrum of genes they express which means they change the spectrum of mRNA they produce. Changes in blood cell mRNA can be detected by hybridizing the mRNA to microarrays. Microarrays are glass slides or membranes covered with thousands of spots, each spot containing fragments of genes (DNA fragments) that will bind to probes made from the mRNA. Indicator dyes are used to light up spots on the microarray and to indicate changes in the expression of blood cell genes.
Drs. Salvato and Jett hope to narrow the list down to about 50 genes per virus that have been chosen for their diagnostic pathogen-specific potential.
Those genes determined to have the ability to discriminate between natural disease and biowarfare agents will be printed on a limited microarray called a "Select Chip" that will be used to rapidly determine whether blood cells have been exposed to a dangerous agent. The diagnostic tool, which could be available in as little as two years, would allow physicians the ability to determine within hours -- potentially minutes -- whether a person has a common flu or has been exposed to more serious agents.
To validate these laboratory findings, blood and nose-wash samples from patients with flu-like symptoms will be taken while ill and after recovery for correlation with clinical diagnoses. Researchers at the University of Maryland School of Medicine and the leadership team of the University of Maryland Medical Center's Emergency Medicine Division are collaborating with the Institute in this endeavor. A preliminary report is due this fall.
"Though it would have been beneficial earlier to have a test that diagnosed flu, it wasn't critical based on the fact that the severity of the illness was relatively mild and treatment protocols typically resorted to simple prescriptions such as antibiotics and rest," says Dr. Brian Browne, head of emergency medicine at the University of Maryland Medical Center and professor of surgery at the University of Maryland School of Medicine.
"Post 9/11, however, the reality that flu-like illness might be something more severe prompts us to reconsider the value of a diagnostic tool that could 1) confirm a case of flu and 2) simultaneously distinguish it from what could easily become a crisis. Because, in fact, it's extremely hard to tell the difference," says Dr. Browne. "Having something more definitive -- and so quickly available -- would be very reassuring to doctors everywhere."
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