The chemistry of the genome is far more complex than the base pairing recognition of A-T and G-C. For example, small modifications to each base (e.g., DNA damage and epigenetic marks) profoundly impact a cell's ability to proliferate and produce secondary metabolites. On the other hand, direct binding of small molecules to DNA or RNA can be used to regulate biosynthetic pathways. Our research bridges the chemistry of the genome to natural product production and clinical diagnostics for new applications in green chemistry and cancer therapeutics.

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Controlling Cells with Functional Nucleic Acids

We are developing “RNA switches” that can precisely control cell fate. These switches are composed of nucleic acid aptamers that bind to a variety of molecules from small molecule drugs to proteins. The RNA switches can be encoded into the genomes of bacteria, cells, and even whole animals allowing non-invasive tuning of specific genes. The successful application of RNA switches in these complex systems depends on their molecular orthogonality, specificity, and small genetic footprint. As such we are designing and characterizing new aptamers and switches. Furthermore, our lab leverages these switches to improve biochemical pathways, to monitor cell stress and toxicity, and to probe complex pathways involved in development and regeneration.

Aptamer-Based Biosensing

Detecting drug metabolism and biomarkers helps clinicians determine and adjust optimal treatment for each patient while reducing unwanted side effects. Sophisticated analytical methods have enabled detection of some pharmaceuticals and health markers; however, low cost and sensitive detection is needed to improve the efficiency and accessibility of safe treatment. An emerging technology for detecting molecules involves the use of aptamers. Our lab selects new aptamers to important targets. We also include unique chemistry to improve their stability and function. Finally, we measure aptamer kinetics, thermodynamics, binding specificity, and structure to enable the development of aptamer biosensors for use in the environment and in medicine.

Nucleic Acid Therapeutics for Leukemia

Despite advancements in cancer treatment, Acute Myeloid Leukemia (AML) remains challenging to treat effectively. Tailoring therapies based on the unique genomic profile of individual or subset of patients has the potential to maximize treatment efficacy while minimizing adverse effects. Therefore, our lab is harnessing the power of nucleic acid therapies such as small interfering RNAs (siRNAs), small activating RNAs (saRNAs), aptamers, and antisense oligonucleotides (ASOs) to target aberrant gene expression patterns in specific patients. Nucleic acid therapeutics offer flexibility in targeting a wide range of disease-causing factors, including proteins, enzymes and specific “undruggable” genetic sequences.


The McKeague lab is grateful to the following agencies and groups for funding our research.