Engineering the Cell Surface
The cell surface is the central hub of biological processes, transducing information from the cell’s surroundings to enable dynamic and specific responses to their local environment. Myriad human diseases result from the dysregulation of extracellular and membrane signal perception and regulation. Our research bridges the disciplines of biomolecular engineering, chemical biology, cancer biology, and immunology to understand how different cell signaling components are precisely regulated at the cell surface and coordinated in space and time to achieve functional specificity, and how these processes are altered in diseases. By studying cancer and immune cells through a protein engineering and synthetic biology lens, our research facilitates the construction of precise spatiotemporal maps of cell signaling pathways in living cells, and establishes new pharmacological methods for therapeutic control of cell function and fate.
Context-Dependent Protein Switch
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Precise molecular sensing is the key to the development of highly specific diagnostics and treatments. To this end, one central goal of our lab is to design and build novel functional proteins capable of sensing and responding to environmental cues and exogenous signals. These signals include protein post-translational modifications, conformations, interactions, disease-specific mutations, and soluble ligands.
To engineer these proteins, we have established recombinant antibody and protein libraries, phage display and yeast display platforms, directed-evolution strategies, and structure-guided computational protein design technologies. By creating Darwinian selections in a test tube and modeling proteins in silico, we envision the development of a versatile panel of biomolecules with fascinating new features to modulate biology.
Cell Surface Signaling Engineering
In addition to applying the engineered proteins directly to manipulating cell activities, our interests also lie in the incorporation of these proteins into cellular pathways as novel signaling components. The new signaling proteins would allow the cells to harness desired functionalities, such as converting an inhibitory PD-1 signal to a stimulatory response to enhance T cell activity, recognizing the excess amount of VEGF in the tumor microenvironment to initiate cancer-killing, binding a target of interest only in the low-pH environment for cancer-specific targeting, or responding to a pulse of light for spatiotemporally restricted activation.
By incorporating newly designed protein into synthetic cells, we aim to engineer a new generation of cell-based technologies for specific recording and manipulation of the dynamic interaction between the diseased cells, immune cells, and the surrounding microenvironment.
Novel Biotherapeutic Modalities
Key challenges remain for therapeutic targeting of disease-driven signaling mechanisms. Systemic inhibition, such as kinase inhibitors, immune checkpoint blockers, or receptor traps, has been successfully applied in various malignancies. However, the specificity of these treatments remains low, leading to toxicity issues, resistance, and low response rate. In addition, direct blockade of protein activities can be challenging. More than 85% of the human proteome has been deemed “undruggable” with traditional pharmacological approaches.
To enhance disease-targeting specificity and effectiveness, and to target these “yet-to-be-drugged” protein groups, the Zhou lab harnesses principles in chemical biology and protein design to develop new biologics-based therapeutic modalities. We build multi-functional antibodies and antibody conjugates, signaling engagers, and protein degraders to functionally manipulate proteins through novel mechanisms.