Synthetic chemistry, protein engineering, and molecular evolution to create molecules that measure and control biological systems.
Research Interests:
The Dickinson Group employs synthetic organic chemistry, molecular evolution, and protein design to develop molecular technologies to study and control chemistry in living systems. The group's current primary research interests include: 1) developing new evolution technologies to reprogram and control biomolecular interactions, 2) engineering RNA-targeting biotechnologies as new therapeutic platforms, and 3) developing novel proximity-labeling chemistries to study biomolecular interactions. The motivating principle of the Dickinson Group is that our ability as chemists to create functional molecules through both rational and evolutionary approaches will lead to new breakthroughs in biology and biotechnology.
Evolution technologies:
Proteins that selectively bind to a target protein of interest are foundational components of research pipelines, diagnostics, and therapeutics. However, current immunization-based, display-based, and computational approaches for discovering binders are laborious and time-consuming, suffer from high false positives, and have a high failure rate. Moreover, converting binders into bifunctional recruiters to reprogram interactions results in molecular with suboptimal properties, such as a “hook-effect”. To address these issues, we are developing rapid selection and evolution/based technologies to create peptide- and protein-based molecules the bind-to, inhibitor, or glue target proteins.
RNA-targeting therapeutics:
In mammalian systems, post-transcriptional gene expression regulatory processes at the RNA level are a key determinant of genetic information flow. Our group has developed several new molecular technologies to exploit these RNA regulatory mechanisms for therapeutic purposes. We developed programmable RNA reader proteins by engineering RNA-targeting Cas systems with effector domains from RNA regulatory proteins in order to study the role(s) of individual regulatory sites in the transcriptome. We developed an entirely human protein-based programmable RNA delivery systems, called CIRTS, which is smaller than the current RNA-targeting Cas systems and can avoid immune reactivity, providing us with a powerful new approach to probe transcriptome regulation and also providing a path toward clinical applications of programmed epitranscriptome regulatory systems. Finally, we developed "taRNAs", engineered bifunctional RNAs that recruit key translational intiatoris to target mRNAs to boost gene expression, as a step toward an oligo-based technology for correcting gene deficiency disorders. Overall, this research area is focused on addressing key unmet medical needs of patients through molecular engineering.
Spatial biology:
RNA localization is highly regulated, with subcellular organization driving context-dependent cell physiology. Although proximity-based labelling technologies that use highly reactive radicals or carbenes provide a powerful method for unbiased mapping of protein organization within a cell, methods for unbiased RNA mapping are scarce and comparably less robust. Therefore, we developed α-alkoxy thioenol and chloroenol esters that function as potent acylating agents upon controlled ester unmasking. We paired these probes with subcellular-localized expression of a bioorthogonal esterase (BS2) to establish a new platform for spatial analysis of RNA: bioorthogonal acylating agents for proximity labelling and sequencing (BAP-seq). By selectively unmasking the enol probe in a locale of interest, we can map RNA distribution in membrane-bound and membrane-less organelles. The controlled-release acylating agent chemistry and corresponding BAP-seq method expand the scope of proximity labelling technologies and provide a powerful approach to interrogate the cellular organization of RNAs. Currently we are interested in both using BAP-seq to map the dynamic interactome during stress responses, as well as pushing the technology toward new systems and molecules to expand the scope of biology we study at the molecular level.
Selected Publications
Pani, S.; Qiu, T.; Kentala, K.; Azizi, S.-A., Dickinson, B.C. “Biorthogonal masked acylating agents for proximity-dependent RNA labeling.” Nat. Chem., 16, 717-726 (2024). ChemRxiv link
Cao, Y.; Liu, H.; Lu, S.S.; Jones, K.A.; Govind, A.P.; Jeyifous, O.; Simmons, C.Q.; Tabatabaei, N.; Green, W.N.; Holder, J.L; Tahmasebi, S.; George, A.L.; Dickinson, B.C. “RNA-based translational activators for targeted gene upregulation.” Nat. Commun., 14, 6827 (2023). link
Cochran Xie, V.; Pu, J.; Metzger, B.; Thornton, J.; Dickinson, B.C. “Contingency and chance erase necessity in the experimental evolution of ancestral proteins.” eLife, 10:e67336 (2021). BioRxiv link
Dewey, J.D.; Azizi, S.-A.; Lu, V.; Dickinson, B.C. “A system for the evolution of protein-protein interaction inducers.” ACS Syn. Biol. 10, 2096-2110 (2021). ChemRxiv link
Rauch, S.; He., E.; Srienc, M.; Zhou, H.; Zhang, Z.; Dickinson, B.C. “Programmable RNA-guided RNA effector proteins built from human parts.” Cell 178, 122-134 (2019). link
Zinkus-Boltz, J.; DeValk, C.; Dickinson, B.C. “A phage-assisted continuous selection approach for deep mutational scanning of protein-protein interactions.” ACS Chem. Biol. 14, 2757-2767 (2019). ChemRxiv link
Pu, J.; Zinkus-Boltz, J.; Dickinson, B.C. “Evolution of a split RNA polymerase as a versatile biosensor platform.” Nat. Chem. Biol. 13, 432-438 (2017). link
