Lab of the Month – The Schepartz Lab
Who We Are
The Schepartz Lab at UC Berkeley is a powerhouse of discovery at the intersection of chemistry and synthetic biology. Led by Professor Alanna Schepartz, we explore the potential of molecular machines—biological nanostructures that drive fundamental processes in life. Our research is not just about understanding these systems, but about harnessing them to build new materials, therapeutics, and tools that redefine what’s possible in molecular science.
As the leading force behind the NSF Center for Genetically Encoded Materials (C-GEM), our lab is pioneering efforts to expand the genetic code and engineer novel sequence-defined polymers. We also develop molecular carriers that cross cell membranes with ease, and we create super-resolution imaging probes that allow scientists to see deep into the intricate world of living cells.
Driven by bold ideas, rigorous science, and a passion for innovation, the Schepartz Lab is pushing boundaries in molecular engineering to unlock new frontiers in biology, medicine, and materials science.
Our Lab
At its core, the Schepartz Lab is a place where cutting-edge science and creative problem-solving converge. We employ a diverse set of techniques—including peptide synthesis, genetic code expansion, and high-resolution mass spectrometry—to tackle complex biological questions with precision and ingenuity.
Our current research spans multiple key areas: engineering new molecular delivery platforms, expanding the scope of ribosomal synthesis, and designing innovative fluorescent probes for real-time cellular imaging. By challenging the traditional boundaries of chemistry and biology, we are creating tools that will shape the future of molecular science.
This is not just a lab—it’s an incubator of discovery, where collaboration and curiosity fuel groundbreaking research.
Our People
The Schepartz Lab is more than a research group—it’s a community. Graduate students, postdocs, and undergraduates come together in an environment where deep scientific discussions and camaraderie go hand in hand. It’s a place where collaboration thrives, and where curiosity drives scientific breakthroughs.
And while science is serious business, we never forget to celebrate our successes. From cupcakes and champagne for qualifying exam passes to homemade banana bread from Alanna herself, the lab’s culture is one of support, shared enthusiasm, and an occasional sugar rush.
NSF Center for Genetically Encoded Materials
As the home of C-GEM, the Schepartz Lab is leading a multi-institutional effort to revolutionize synthetic biology. C-GEM isn’t just about discovery—it’s about rewriting the rules of molecular construction. By reprogramming the ribosome to build new classes of polymers, we are expanding the fundamental building blocks of life.
Our lab has demonstrated the direct translation of non-natural monomers, including beta-3-hydroxy acids, into functional proteins inside living cells. We’ve also pioneered new analytical tools to track acyl-tRNA intermediates, revealing mechanistic insights into how the translational machinery can be repurposed.
Beyond translation, our team is developing post-translational modifications that open new doors in protein engineering. With strategies for backbone macrocyclization and selective C–C bond formation, we are designing molecules with unprecedented structural and functional diversity.
At C-GEM, we’re not just studying biology—we’re teaching it new tricks.
Super-Resolution Microscopy
Seeing is believing, and in the Schepartz Lab, we’re pushing the limits of what’s visible with super-resolution microscopy. Our lab develops cutting-edge small-molecule fluorophores that transform how scientists visualize living cells.
We’ve engineered highly photostable fluorophores that can embed directly into organelle membranes, enabling long-term imaging beyond the diffraction limit. Our innovations have also led to the creation of pH-sensitive dyes that allow researchers to track the dynamic behavior of acidic organelles in real time.
Most recently, we have optimized click chemistry-based fluorophore modifications to extend imaging capabilities even further, allowing simultaneous visualization of multiple organelles with a single dye set. These advances aren’t just making microscopy better—they’re reshaping how we study the molecular machinery of life.
Alanna Schepartz
Professor Alanna Schepartz holds the T.Z. and Irmgard Chu Distinguished Chair in Chemistry at the University of California, Berkeley, with joint appointments in the Departments of Chemistry and Molecular and Cell Biology. She earned her B.S. in Chemistry from the State University of New York at Albany in 1982 and her Ph.D. in Organic Chemistry from Columbia University in 1987, under the guidance of Ronald Breslow. Following a postdoctoral fellowship with Peter Dervan at the California Institute of Technology, she began her independent academic career at Yale University in 1988, where she was later named Sterling Professor of Chemistry. In 2019, she joined UC Berkeley, where her research continues to explore the interface of chemistry and biology, focusing on the design and application of molecules to probe and manipulate complex cellular processes.
Question: Your research has significantly advanced our understanding of protein-DNA interactions. Could you elaborate on the chemical principles underlying this specificity?
Answer: Our investigations into protein-DNA recognition have revealed that specificity is governed by a combination of direct readout, involving specific hydrogen bonds and van der Waals contacts between amino acid side chains and DNA bases, and indirect readout, which pertains to the DNA’s conformational flexibility and its ability to adopt shapes complementary to the protein surface. By dissecting these interactions, we’ve been able to design synthetic molecules that can mimic or disrupt these contacts, providing tools to modulate gene expression.
Q: The development of β-peptide bundles is a pioneering achievement in your lab. What challenges did you encounter in designing these non-natural protein architectures?
A: Designing β-peptide bundles required us to venture beyond the canonical α-amino acid framework. One significant challenge was achieving the precise folding necessary for a stable tertiary structure, as β-peptides have different propensities compared to α-peptides. We employed principles of stereochemistry and side-chain functionality to promote desired folding patterns, ultimately creating bundles that mimic natural protein architectures despite lacking α-amino acids.
Q: Your lab has repurposed the ribosome to synthesize non-natural polymers. How does this approach expand the scope of synthetic biology?
A: By engineering the ribosomal machinery to incorporate non-canonical monomers into nascent chains, we’ve expanded the genetic code to include a broader spectrum of chemical functionalities. This allows for the biosynthesis of sequence-defined polymers with properties distinct from natural proteins, opening avenues for creating novel materials and therapeutics with enhanced stability, functionality, and specificity.
Q: Your group’s latest paper describes a strategy for site-selective C–C bond formation within peptide backbones, something traditionally difficult to achieve. Can you explain the significance of this breakthrough?
A: Peptides and proteins have traditionally been constrained to forming C–N, C–O, and C–S bonds within their backbones, limiting the structural and functional diversity available to biomolecular engineers. Our recent work leverages a spontaneous acyl shift mechanism to enable backbone C–C bond formation, effectively bridging the gap between peptides and polyketide-like scaffolds. By incorporating dehydrolactic acid, DHL, into ribosomally synthesized or synthetically derived peptides, we trigger a cascade of acyl shifts that generate α,γ-diketoamide motifs, which can then be diversified into heterocycles. This transformation provides a genetically programmable route to peptide modification, significantly expanding the chemical space available for peptide-based therapeutics and biomaterials.
Q: The concept of miniature proteins has been a recurring theme in your work. How do these constructs contribute to our understanding of protein-protein interactions?
A: Miniature proteins, due to their reduced size and simplified structures, serve as excellent models to dissect the fundamental principles governing protein-protein interactions. They allow us to systematically study the roles of specific residues and structural motifs in binding affinity and specificity. Moreover, their small size facilitates cellular uptake, enabling studies within the cellular context and the development of potential therapeutic agents that can modulate intracellular interactions.
Q: Your research delves into the mechanisms of chemical information transfer across cellular membranes. What insights have emerged from these studies?
A: We’ve discovered that certain peptides and their mimetics can traverse cellular membranes by engaging specific transport mechanisms or by modulating membrane dynamics. Understanding these pathways has led us to design molecules capable of delivering therapeutic cargos directly into cells, thereby overcoming one of the significant barriers in drug development. These findings have profound implications for targeted therapy and the delivery of biomolecules into specific cellular compartments.
Q: Fluorogenic probes have become vital tools in biological imaging. How has your work contributed to advancements in this area?
A: We’ve developed a series of fluorogenic probes that become fluorescent upon binding to their target or undergoing specific chemical reactions. These probes have been instrumental in visualizing dynamic processes within live cells with high spatial and temporal resolution. For instance, our HIDE, Hydrophobic Interaction-Dependent Emission, probes allow for prolonged super-resolution imaging of organelles in multiple colors, providing deeper insights into cellular dynamics and function.
Q: Looking ahead, what are the future directions and potential applications of your research in chemical and synthetic biology?
A: We aim to further expand the capabilities of the ribosome to synthesize a wider array of non-natural polymers, thereby creating materials with unprecedented properties. Additionally, we’re exploring the therapeutic potential of miniature proteins and β-peptide bundles in modulating disease-related protein-protein interactions. Our ongoing efforts to elucidate membrane translocation mechanisms will continue to inform the design of more efficient delivery systems for therapeutics. Ultimately, we strive to develop innovative chemical tools that can both answer fundamental biological questions and lead to novel therapeutic strategies.
