Jeff Vieregg
Research Interests: Understanding the modern RNA world
The ‘RNA World’ hypothesis suggests that, billions of years ago, RNA was the original living molecule. Uniquely among biomolecules, RNA can store genetic information, form complex structures, and catalyze chemical reactions, including replication of more RNA. In the eons that followed, DNA and proteins largely supplanted RNA as the primary materials for information storage and enzymatic catalysis, but RNA is arguably still the most dynamic type of molecule in the living world. RNA is at the core of essential cellular machinery such as the ribosome, and viruses both annoying (rhinoviruses, which cause the common cold) and deadly (HIV) rely on RNA genomes. Additionally, recent years have seen an explosion in our appreciation of RNA’s many roles in regulating gene expression, both normally and in disease states. RNA (and DNA) are also exciting materials for construction at the nano-scale, as their programmable interactions allow precise control of molecular interactions and dynamics. My research focuses on learning how nucleic acids work in the natural world and applying that knowledge to design new molecules for useful applications.
RNA folding: Structure and function from sequence
Like all biomolecules, RNA molecules’ functions are determined by their three-dimensional folded structures. How RNA, with only four similar chemical building blocks, can perform its marvelous variety of roles is one of the central questions of biochemistry. It is also a fascinating physical problem, as RNA folding involves a balance of strong attractive and repulsive forces, high charge densities, and strong interactions with the environment. As a grad student in Nacho Tinoco and Carlos Bustamante’s labs at Berkeley, I used optical trapping to fold and unfold individual RNA molecules and study their response to external forces. By applying mathematical methods from non-equilibrium statistical mechanics, we were able to measure thermodynamic parameters for folding and unfolding reactions far from equilibrium and inaccessible to traditional ensemble techniques. I am currently working on methods to chemically interrogate the structure and binding partners of long RNA molecules in vitro and in the cell, with a goal of learning how their sequence determines their structure and biological function.
Nucleic acid nanotechnology: Making molecules that work
Richard Feynman famously wrote “What I cannot create, I do not understand.” Our knowledge of DNA and RNA folding is imperfect, but it is good enough to create useful things. In particular, the Watson-Crick hybridization rules (G pairs with C, A with T/U) form the basis of a programmable assembly language for matter at the nano-scale. As a postdoc in Niles Pierce’s lab at Caltech, I developed nucleic acids that predictably change their shape in response to environmental changes (i.e. presence or absence of a target molecule) and react in useful ways, such as covalently capturing the target. We are currently leveraging these tools to study how RNA and DNA molecules interact with other molecules in the cell, as well as developing new techniques for research and therapeutic interventions. For the latter goal, developing better ways to get synthetic nucleic acids into living cells is essential. I am working with the Tirrell lab in the Institute for Molecular Engineering to develop self-assembling complex coacervate micelles for nucleic acid delivery.