What is Chemical Biology?
At its heart, the discipline of chemical biology uses the power of chemistry to ask and answer questions of biological significance. Often this involves the use of molecular tools designed to inhibit, activate, or report on the function of biomolecules. Increasingly, these tools are being applied to probe and perturb biological functions in the complex environment of live cells and animals.
Some chemical biology labs primarily focus on the chemical side of tool development, where the emphasis is on the design and synthesis of molecular structures with the desired properties for querying biological systems. Other labs primarily focus on one or more biological problems, but make frequent use of chemical tools to help understand particular biological functions on a molecular level. At UMass Medical School, the highly collaborative and collegial environment is ideally suited to embrace the entire spectrum of chemical biology, from basic tool development to rigorous application in animal models.
Our research in the area of Chemical Biology
The sheer breadth of chemical biology research at UMass Medical School is impressive. Gang Han’s lab develops novel nanomaterials for imaging and drug delivery. The Kobertz lab designs and uses chemical biology tools to probe the function of ion channels. Bob Matthews’ lab studies the protein folding problem and its importance in neurodegenerative disease. Stephen Miller’s lab uses the bioluminescent light of the firefly to probe gene expression and enzyme function in live cells and animals. Celia Schiffer’s lab focuses on the rational design of HIV protease inhibitors to ameliorate drug resistance. Paul Thompson’s lab studies the post-translational modification of arginine and its role in disease. Jon Watts’ lab develops synthetic RNA analogs with promise for use in RNAi-based therapies. All of these labs also collaborate extensively with colleagues at UMass Medical School, as a part of our Chemical Biology Program, and beyond to further leverage the impact of their chemical biology research.
Our breakthrough discoveries
The power of chemical biology to advance biomedical research and reveal molecular mechanisms is perhaps best illustrated by specific examples:
In Vivo Imaging. Gang Han’s lab has developed upconverting (anti-Stokes) nanoparticles that allow optical imaging in deep tissues, free from the autofluorescence background of conventional ‘downconverting’ fluorophores. Related nanomaterials developed in the Han lab also have powerful potential applications for optogenetics and persistent luminescence imaging. Meanwhile, Stephen Miller’s lab has developed synthetic luciferin analogs and firefly luciferase mutants that allow highly sensitive and selective bioluminescence imaging in live mice. Based on molecular insight into the chemistry of luciferins and enzymology of luciferases, the Miller lab further developed specific bioluminescent reporters of the enzyme fatty acid amide hydrolase (FAAH), which allow noninvasive detection of FAAH activity and inhibition in the brain.
Drug Design. Celia Schiffer’s lab put forward the “substrate-envelope hypothesis” to explain how the drug resistance that rapidly evolves against many HIV protease inhibitors can be avoided. Extending this approach to other targets such as Hepatitis C NS3 protease, the Schiffer lab has created potent inhibitors that confine their interactions to the substrate binding pocket, limiting the ability for drug resistance to develop. Appreciation for the details of how enzymes function was also important for Paul Thompson’s lab in their development of mechanism-based inhibitors of protein arginine deiminases (PADs). These tools helped elucidate the importance of the arginine-to-citrulline post-translational modification, and are also quite promising as therapeutics for the treatment of inflammatory diseases.
Answering Challenging Questions. The Kobertz lab studies voltage-gated potassium ion channels, which are membrane-embedded protein complexes critical for regulating the heartbeat and maintaining proper cellular ion balance. The exact composition of the ion channel and its regulatory units has long been unclear. Using an iterative ligand-based subunit labeling approach, the Kobertz lab determined the stoichiometry of the functional KCNQ-KCNE complex, an unanswered question that was intractable using standard methodologies.