The TIGER Biosensor System Stalks Pathogens
The TIGER biosensor system, which SAIC helped develop with a San Diego pharmaceutical company, was honored with an R&D 100 Award for 2005. Often called the Oscars® of invention, R&D 100 Awards have recognized innovative products such as the automated teller machine (1973), the fax machine (1975), the liquid crystal display (1980), and HDTV (1998). Below is an example of TIGER’s innovation.
Late in 2002, recruits at San Diego's Marine Corps Recruit Depot (MCRD) experienced one of the most severe outbreaks of pneumonia in decades.
To help contain the epidemic, its cause had to be quickly identified. With standard techniques — such as culturing — identifying a particular bacteria or virus can take weeks. (Culturing helps determine the cause of infectious disease by letting the agent reproduce in a certain media.)
However, Navy researchers enlisted the aid of SAIC and Ibis Technologies (a division of ISIS Pharmaceuticals), which together have developed the TIGER (triangulation identification for genetic evaluation of risks) biosensor system under a contract with the Defense Advanced Research Projects Agency — Special Projects Office.
Identification without culturing
Using TIGER, which combines advanced genomic and signal-processing techniques to identify known, newly emergent, and bioengineered pathogens, researchers quickly identified the bacteria responsible for the infections and were able to monitor the epidemic. (Not only does TIGER identify and quantify bacteria, viruses, fungi, and protozoa, it does so directly from their genomic DNA or RNA without culturing.)
"The unique thing about TIGER is that it can detect and classify nearly any bacterial pathogen with a single assay," said SAIC's David Robbins, who manages the Sensor Technology Division in Jurgen Gobien's Technology Research and Integration Business Unit. "The classical approach for identifying pathogens requires a specific assay for each pathogen you're looking for."
The bacteria infecting most of the recruits turned out to be group A streptococci (GAS), also known as Streptococcus pyogenes. Especially virulent because it's encased in a carbohydrate capsule, GAS causes mild to severe respiratory infections, with complications such as acute rheumatic fever.
"The majority of infections were caused by the emm3 genotype of group A strep, a genotype previously associated with high respiratory virulence. Recruits are deployed to other locations after completion of training, so there was concern that the virulent strain might spread to these locations. As a result, the team also surveyed respiratory outbreaks at other military facilities," said Robbins. "In this case, we found that while one or two samples from each location had an emm3 genotype, the highly virulent strain was not dominating the GAS population at other locations. Group A strep is a big issue (at MCRD and throughout the military)." This is probably because military recruits gather from across the country and are subject to intense physical and psychological stress as a normal part of training, according to medical literature.
In addition, TIGER simultaneously identified other pathogenic organisms, including N. meningitidis-which can cause meningitis. (The ability to simultaneously identify GAS and other bacteria and viruses in large numbers of samples could greatly facilitate an understanding of respiratory epidemics, according to experts.)
Containing outbreaks
Another key impact of TIGER was that it helped with the epidemiology of the disease. "Our team was able to show that it wasn't passed around to other places after that," said Robbins. "(TIGER helped the Navy) understand how it spread, which can help them take preventative action in the future."
Because TIGER can determine a particular strain of an infectious agent, you can use TIGER to monitor the spread of an epidemic in real-time, thus facilitating rapid intervention to help contain the outbreak.
In fact, the SAIC/Ibis team, a subcontractor to SAIC on TIGER, has delivered systems to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) for detection and analysis of emerging infectious diseases and to the Department of Homeland Security for microbial forensics. The team also plans to soon deliver a TIGER biosensor system to the Naval Health Research Center in San Diego for respiratory pathogen surveillance. Systems are also slated for delivery to the Centers for Disease Control and Prevention for epidemiological surveillance and to the National Institute for Allergy and Infectious Disease (NIAID) for detection of viral and bacterial contaminants of vaccines.
TIGER Checks a Pathogen's “Signature”
Besides helping health care workers determine the causes of many illnesses, a TIGER biosensor system could help detect biological warfare attacks on high-value installations.
This is especially important as biological terrorism ranks as a strategic threat to the U.S. Not only do biological agents represent the highest lethality density of any of the major weapons of mass destruction, they are fairly simple to produce and can be deadly at doses as small as .00000001 milligrams (a paper clip weighs about 500 milligrams).
"A TIGER biosensor system has been shipped to the United States Army Medical Research Institute for Infectious Disease (USAMRIID), which will use the system to identify infectious agents for biowarfare defense," said David Robbins. In addition, the Department of Homeland Security's National Bioforensics Analysis Center will use TIGER for microbial forensics to investigate crimes involving infectious organisms.
TIGER amplifies genomic DNA (the genetic blueprint of living things) or RNA sequences in samples using a technique called "broad range PCR." (RNA plays several roles in determining the synthesis of proteins.) TIGER then analyzes the PCR products with mass spectrometry and signal processing to develop mass or base composition signatures (i.e., the number of As, Ts, Cs, and Gs — chemical "building blocks" — in the PCR products). Because it is difficult to distinguish genetic material from pathogens from the many other background organisms that may be present in complex samples — such as a throat swab, surface swab or air sample — TIGER uses SAIC-developed signal processing algorithms to detect and interpret a pathogen's genetic mass "signature."
TIGER checks the pathogen's mass against the masses of known pathogens in its database. If there is no match — because it is a newly evolved strain or it has been bioengineered — TIGER can tell researchers if the pathogen is similar to any known pathogen. (In fact, TIGER can identify any of hundreds of pathogens that might be present in a single sample.)
SAIC's system differs in this regard from most biosensors, which use antibody-based or pathogen-specific PCR components that cannot detect unknown or bioengineered pathogens. In addition, TIGER has a fast turnaround — it can analyze 200 samples in less than 24 hours — and has extremely low false positive rate. This is important to avoid a false alarm and prevent putting the population on antibiotics unnecessarily.