Mimicking Natural Sensors, Scientists Create Highly Precise Biosensors

Based on strategies that organisms have evolved over billions of years for monitoring their surroundings, chemists at UC Santa Barbara and the University of Rome Tor Vergata have developed a DNA-detecting biosensor that could eventually help improve medical diagnostic applications, such as HIV or cancer tests. The researchers' work is presented in the Journal of the American Chemical Society.

Despite their positive attributes, biosensors are limited in their precision, which is confined to a fixed, well-defined dynamic range of target concentrations, according to Kevin W. Plaxco, professor of chemistry at UCSB and leader of the group that carried out this research. In fact, the useful dynamic range of typical biomolecule binding events spans an 81-fold range of target concentrations.

"This fixed dynamic range complicates--or even precludes--the use of biosensors in many applications," Plaxco comments. "To monitor HIV progression and provide the appropriate medication, for example, physicians need to measure the levels of viruses over five orders of magnitude. Likewise, the two orders-of-magnitude range displayed by most biosensors is too broad to precisely monitor the concentrations of the highly toxic drugs used to treat many cancers." Consequently, the scientists' goal was to create sensors with an extended dynamic range--for applications requiring a broad dynamic range--or a narrowed range--for applications requiring high measurement precision.

The researchers' key breakthrough stemmed from the understanding that all living organisms monitor their environments in an optimized way by using sensing molecules that respond to either wide or narrow changes in target concentrations, according to Alexis Vallée-Bélisle, a postdoctoral fellow and the lead author of the study. "Nature does so by combining in a very elegant way multiple receptors, each displaying a different affinity for their common target."

Inspired by the optimized behaviors of natural sensors, the UCSB research group teamed up with Francesco Ricci, professor at the University of Rome Tor Vergata, to mix and max biomolecules to manipulate biosensors' dynamic ranges. They validated their approach using a DNA-based biosensor--called a 'molecular beacon'--that is commonly employed for detecting mutations in DNA.

By combining sets of molecular beacons all binding the same target molecule but with differing affinities, the team created sensors with rationally tuned dynamic ranges. For example, in one case, they developed a sensor that monitors DNA concentrations over a six-orders-of-magnitude range. In another case, they developed an ultrasensitive sensor that precisely detects small changes in target concentration over only a five-fold dynamic range. They also built sensors with complex dynamic ranges in which the sensor is insensitive within a window of desired concentrations--the clinically 'normal' concentration range of a drug--and very sensitive above or below this range.

In principle, the researchers believe that these strategies can be applied to a wide range of biosensor applications, which may significantly impact efforts to build better point-of-care biosensors for the detection of disease biomarkers.