Chance is often the best inventor. Isis Pharmaceuticals never set out to become a maker of sensors for biological weapons. The company, based in Carlsbad, Calif., is best known for its work in developing antisense therapies, the use of small pieces of DNA-like molecules that bind to messenger RNA (a copy of a gene) to block synthesis of an encoded protein. Its research led to the formation of a division called Ibis Therapeutics, which develops chemicals other than DNA that would interfere with RNA.

Along the way, Ibis discovered a method of screening pathogens that might lead to a universal detector for biological weapons--even perhaps nefarious, as yet to be invented bioengineered strains of pathogens. The road to a universal biosensor began in the mid-1990s, when Ibis started looking for chemicals with a low molecular weight that would bind to and block the activity of RNA, the same mechanism used by many antibiotics. The Defense Advanced Research Projects Agency (DARPA) funded some of the research because of its interest in finding new drugs to counter the microorganisms used in biowarfare. Conventional high-throughput screening--conducting a multitude of tests to measure the interaction of drug candidates with different enzymes--is ineffective for drugs that would work by binding to RNA. So Ibis began to explore the possibility of using mass spectrometry to determine when a small molecule binds to RNA.

The company refined a technique called electrospray ionization, as well as mass spectrometry, to extract RNA and the bound drug candidate from an aqueous solution intact and then suspend those molecules in a vacuum, where they can be weighed. As the methods proved themselves, Ibis president David J. Ecker came to the realization that pulling out the RNA alone, without the bound molecule, would provide the makings of an extraordinary sensing system.

After RNA from a cell is weighed with the spectrometer--each cell has multiple types of the molecule--these very precise measurements, accurate down to the mass of a few electrons, can be correlated with a database that contains information about RNA weights for a given pathogen. Each weight in the database table corresponds to the weight of the exact number of letters, or nucleotides, for a particular RNA. As long as information about the nucleotide composition is in the database, the system, called TIGER (triangulation identification for genetic evaluation of risks), can identify any bacterium, virus, fungus or protozoan. Before the RNA is weighed, another critical step is necessary: the polymerase chain reaction must make copies of stretches of DNA or RNA that are found in all cellular organisms (or, for viruses, in whole families of them).

Six months before last year's anthrax attacks, Ibis and partner SAIC, a contract research house, received a $10-million DARPA grant extending over two years to do a feasibility study for TIGER. The goal of the program is to develop a system that can detect the 1,500 or so agents known to infect humans. This approach differs fundamentally from the way other biodetectors are designed. Most systems use an antibody or a piece of DNA as a probe to bind to a protein or nucleic acid in a pathogen. These tests are limited to detecting a small subset of the universe of pathogenic agents. And an antibody probe for, say, anthrax needs to make a match with the exact strain of the specific bacterium it is targeting.

With TIGER, if information about a pathogen is not in its database--because it is a newly evolved strain or a specially bioengineered bug--the software can flag any genetic likeness it has with other microorganisms. "The database will say, 'I've never seen this before, but it's very similar to Yersinia pestis [plague],'" Ecker says. The detector would not, however, be able to pick up some genetic alterations of a microorganism--for instance, a gene for a toxin put in an otherwise harmless microbe.

Although biosensors were never part of Ibis's business plan, about half of its 35 employees are now on the TIGER team. Work at the company continues on sequencing the relevant genes to extract the needed RNA signatures for populating the databases--or obtaining this information from sequencing efforts under way worldwide. One of the biggest challenges the researchers still face is how to tell one piece of RNA from among thousands of specimens in a complex sample, such as a ball of dirt. "That requires very complex signal processing," Ecker says. The problem that Ibis had encountered was one that radar engineers deal with constantly. In fact, this was the reason behind the collaboration with SAIC, which produced culture shock when Ibis's molecular biologists began to work with SAIC's radar engineers. "We spent the better part of a whole year figuring out how to communicate with each other," Ecker remarks.

   
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