The major focus of Dr. Kool's laboratory is the design, synthesis and study of unnatural DNA and RNA bases. These are used as tools for basic study of biochemical and biological mechanisms (see our work with "hydrophobic isosteres"), and as the basis for a new genetic system design (see "xDNA").

The lab has been developing a new, functional genetic set that is orthogonal to the natural DNA system. The design is based on expanded size (expanded DNA, or "xDNA"). They have shown that xDNA assembles into helices selectively, much like DNA, except that it is more stable and is also highly fluorescent. We have found polymerase enzymes that can copy bases of xDNA, and have shown that E. coli replication machinery can read the genetic information stored in xDNA. Very recently, we have begun to synthesize and study xRNA as well.

The group also has an ongoing interest in finding simple and rapid ways to detect the cellular genetic mutations that cause cancer and drug resistance. The approach is to use RNA-templated chemistry, in which chemically modified probes perform a fluorogenic reaction when they hybridize to their genetic target. The laboratory was the first to use nucleic acid templated chemistry for detection of genetic sequences in solution, and the first to apply it in intact bacterial and human cells. New ways to improve this chemistry and monitor the output signal of these sensor molecules are under research. They are collaborating with clinical laboratories and physicians to test these molecules for applications in identifying pathogenic bacteria and in monitoring genetic changes in cells from patients with leukemias.