Synthesis of Artificial Cells and Membranes
Natural cells have a number of mechanisms to organize biochemical pathways, one of the most prominent being membrane compartmentalization. All living cells utilize membranes to define physical boundaries, control transport, and perform signal transduction. We are developing and exploring novel reactions that can trigger de novo vesicle formation and reproduction. While many of the reactions we study are not prebiotically plausible, we believe such studies could reveal some of the fundamental chemical principles that led to the origin of life. Furthermore, we are studying how such reactions could improve our ability to study membrane localized structures and processes.
We are also creating hybrid synthetic cells that are composed of artificial components (for instance synthetic membrane/hydrogel nucleus) and can perform biological functions such as gene expression. These cell-mimics are capable of communication using diffusive protein signals. We aim to develop hybrid systems that combine the control and stability achievable through synthetic chemistry with the highly evolved complex functionality of biology.
Tools for Detecting and Labeling RNA
One of the major revelations of the Human Genome Project was that protein coding genes comprise only 1.2% of the 3 billion base pairs of the human genome. In contrast, 75% of the genome is transcribed, and most of these transcripts do not code for proteins and are thus classified as noncoding RNAs (ncRNAs). Improved tools for the isolation and imaging of endogenous RNA, and associated protein partners, have the potential to illuminate the various functions and mechanisms of RNA, particularly the vast repertoire of ncRNA elements. Our lab at UCSD has begun developing chemical tools to aid in the imaging and manipulation of RNA. We are approaching this problem by exploiting novel enzymatic and non-enzymatic bioconjugation chemistries.
Tetrazine Bioorthogonal Reactions
We have had a long-standing interest in the advancement and application of tetrazine cycloadditions, a form of next generation “click” chemistry, to bioconjugation problems. Our goal is to advance the synthetic knowledge related to this unique class of inverse electron demand Diels-Alder cycloadditions to create novel tools for chemical biology research. Tetrazine reactions are attractive because they proceed in the absence of catalysts, have rapid reaction kinetics, and are compatible with fluorogenic probes for live cell imaging. At UCSD, we are tackling many of the challenges in the field. For instance, we are expanding the synthetic methods available to generate tetrazines and are exploring new dienophiles such as cyclopropenes and benzonorbornadienes. We are actively translating our chemical advances to applications in imaging and diagnostics.