Our laboratory uses the tools of biomolecular engineering, synthetic biology, and systems biology to understand fundamental biological design principles and to design new molecular and cellular therapeutics for applications in cancer, diabetes, and infectious diseases. Current research areas of interest include:
Multivalent protein design
Multivalency involves the binding of multiple domains within a given molecule to multiple domains on a given target, such as the binding of an antibody to two antigens on the surface of a cell or virus. Moreover, multivalent proteins can achieve binding dynamics and selectivities that are not possible with monovalent binding, making them attractive options for therapeutic protein design. However, the multiplicity of binding states makes multivalency combinatorially complex and non-intuitive to study and engineer.
We have established a new computational framework that enables predictive modeling of multivalent protein-protein interactions by taking into account both the spatial presentation and combinatorics of binding configurations. Advances to this framework have enabled us to analyze protein logic gates, uncover hidden dynamics in the SARS-CoV-2 spike protein, and optimize the design of multivalent therapeutics. It has also underscored the importance of specific, low-affinity binders as building blocks for constructing selective multivalent proteins, and we have developed an experimental method for extracting such low-affinity binders using cell-free directed evolution.
Cellular therapeutics and diagnostics
The significant promise of cellular therapeutics that can be reprogrammed to sense and respond to their local environment has led to a proliferation of immunoengineering approaches to combat diseases such as cancer. We are interested in elucidating principles of therapeutic cell proliferation, differentiation, and engagement with target cells to better inform cell designs.
Furthermore, we are developing new classes of bacteria to be used as therapeutics and diagnostics. We have engineered Escherichia coli with the ability to sense and respond to cell-impermeable proteins in their environment. We have also evolved E. coli strains that are more resistant to acid and bile for oral drug delivery applications. In addition to their potential use as therapeutic agents, E. coli biosensors are inexpensive to manufacture and distribute, so they can be used as cheap diagnostics in low-resource settings.
We have also had a longstanding interest in rationally tuning cellular response dynamics. Recent research includes model-guided approaches to quantifying cell identity, understanding cell-fate decisions, and tuning DNA recombination rates for cell engineering.
Drug delivery across cellular barriers
We are building stem cell-based models of various cellular barriers in the body, including the intestinal epithelium, the blood-brain barrier, and the placenta. We use these in vitro models to study healthy barrier function as well as barrier dysregulation in the context of diseases such as diabetes and Alzheimer’s disease. We are particularly interested in developing new strategies for selective drug delivery across these physiological barriers.
Improving food security
With the growing impacts of climate change, food insecurity and malnutrition will have increasingly adverse effects on human health. In parallel with our efforts to engineer therapeutic proteins and cells for human disease applications, we are also elucidating the molecular determinants of pathogen-plant interactions and using protein engineering methodologies to create more durable crops in the face of significant threats to the global food supply.