Jonathan Carlson MD, PhD
One of the outstanding challenges in clinical medicine is the accurate detection of diseases at the earliest stages of their natural history. This work requires resolutions far below what is currently achievable, on the millimeter rather than the centimeter or multicentimeter scale. Indeed, it is at the sub-cubic millimeter scale that cancers are least likely to have metastasized and thus are most curable by resection; just as pivotally, occult metastatic disease, hiding below the limit of detection, is the central player in both adjuvant therapy and late relapse. Recognizing this critical biological threshold, the NIH has highlighted the need for new detection technology as one of its provocative challenges. New molecular and physical methods will be required to meet this goal—to increase signal strength and sensitivity, to enhance biological contrast (i.e., to identify and exploit molecular characteristics that distinguish normal tissue from abnormal tissue), and to enhance spatial resolution. We have recently described a set of fluorescent dyes that combines exceptionally efficient on/off switching capabilities, becoming more than 1,500-fold brighter on activation, with the ability to chemically react with a labeled target molecule in vivo. These probes harness “click” chemistry, through the exceptionally rapid and specific reactivity of a class of molecules known as “tetrazines,” for superb target-to background ratios, and they open the door to new mechanisms for molecular imaging and intravital diagnostics.
