Antibodies protect us from infections, and eliciting potent neutralizing antibody responses is a core goal of most vaccination programs. We have extensively characterized the breadth and potency of SARS-CoV-2-directed antibodies elicited by COVID-19 vaccines and infections (1, 2, 3, 4, 5, 6, 7) using BSL-2-rated pseudovirus neutralization assays, human cohort studies, mouse models, and related specialized techniques. We have also isolated, engineered, and characterized a variety of monoclonal SARS-CoV-2-neutralizing antibodies. Scientifically, this work has dissected the impacts of immune imprinting on adaptive immune responses to evolving pathogens. Translationally, these studies have been important in vaccine development and regulatory decision-making, with some of our work featured in CDC scientists’ presentation at a VRBPAC meeting. We are pursuing projects about vaccine development, monoclonal antibody development, and more.

Viruses evolve under a variety of selective pressures, and predicting evolutionary trajectories is a major goal in the field. We are most interested in how viruses balance the trade-offs associated with mutation-induced evasion of existing adaptive immune responses and changes to critical host cell entry mechanisms, most recently explored in the context of SARS-CoV-2 (8, 9, 10, 11, 12). We use rapid engineering of BSL-2-rated pseudoviruses combined with epidemiological data mining, phylogenetic analysis, and biophysical modeling to predict near-term evolutionary trajectories and dynamics. We are pursuing projects related to predicting the evolution of SARS-CoV-2 and other pathogens, engineering immune-evasive gene therapy vectors, and more.

Diverse forms of gene regulation underpin genotype-to-phenotype maps. We aim to discover mechanisms of gene regulation and harness them for genetic engineering and gene therapy applications, developing experimental and computational methods along the way. In Ian’s PhD thesis, he invented a single-molecule RNA FISH-based tool for visualizing and quantifying RNA editing with sub-single-cell resolution and he contributed to the development of other specialized RNA FISH-based methods for amplifying RNA FISH signal and for visualizing allelic expression in tissues. More recently, we published a study about transcriptional adaptation, a gene regulatory phenomenon that allows organisms to compensate for mutations. We are pursuing projects related to modeling gene regulatory networks and leveraging transcriptional adaptation for genetic engineering.

Complex cellular interactions and gene regulatory patterns shape the emergence and long-term functioning of the many different cell types in the human body. We are interested in developing and applying quantitative models of the regulation of cellular identity (a.k.a. cell type) at a molecular level. Relatedly, we are interested in designing protocols for reprogramming and transdifferentiation (directing cells to progenitor or other differentiated types, respectively). We made progress toward this goal for more efficient fibroblast-to-iPSC reprogramming by suppressing genes that may be needed to maintain fibroblast identity. Currently, we are pursing theoretical and experimental projects about how cells make tradeoffs in single-cell gene expression patterns to balance regulation of their diverse functions, mapping pre-manipulation cell states to cell engineering protocol outcomes, and how to use our insights to improve cell therapies for cancers, autoimmune disorders, and regenerative applications.