Research
Our research focuses on two high-level questions: (1) How are molecules and signaling networks spatiotemporally regulated within the tumor microenvironment and (2) What designs of biosensors and biomedicines can provide more precise reporting and perturbation of disease-specific signaling. The lab currently works on three interrelated research topics: (1) Building artificial kinases and signaling cascades by evolving phosphotyrosine recognition, (2) Engineering single-domain antibody (sdAb)-based biosensors to interrogate disease signaling dynamics, and (3) Building multi-specific biomolecules that modulate membrane proteins in a different way than current immunotherapy strategies. Our ultimate goal is to leverage molecular engineering to gain a deeper fundamental understanding of malignancies and to discover new avenues for therapeutic intervention.
Designing and Evolving Novel Protein Sensors and 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 highly diverse recombinant antibody/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.
Engineering Cell Signaling Pathways to Build Molecular Sensors and Recorders and Enhance Cell Therapy
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 and therapies for specific recording and manipulation of the dynamic interaction between the diseased cells, immune cells, and the surrounding microenvironment.
Development of New 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.
If you are also excited about protein engineering, molecular technology, and new biomedicine designs, send inquiries to Dr. Xin Zhou about joining the lab. We are keen on building a positive, caring, and inclusive laboratory environment, and are committed to training and supporting a new generation of scientists.
To learn more about our previous work, please refer to the following papers: (1) optogenetic switches and light-activated kinases (Science, 2012; Science, 2017), (2) antibodies recognizing tyrosine phosphorylation (JACS, 2018; JACS, 2020), and (3) luminescent biosensors for point-of-care detection of SARS-CoV-2 patient antibodies (Nature Biotechnology, 2021).