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“Academia is about knowing when to walk and when to run.” Imposter Syndrome and Finding Your Place Ben shares the moment he realized he mattered, when he was A Final Aha Moment: Try the Crazy Idea When a collaborator offered a neuroma model (one where opioids

Some breakthroughs don’t start with a hypothesis. They start with a sentence that freezes the room. I can image the whole islet. Not a single cell, not a cropped region, not a patch of fluorescence — the entire pancreatic islet , 100–200 microns across, lighting up in real time. That moment didn’t just validate a probe. It opened a new window into GPCR imaging in native tissue, and reshaped what this collaboration between a chemist and a biologist could make possible. The Moment GPCR Imaging Became a Turning Point Before the islet lit up, the collaboration wasn’t even aimed at imaging. Johannes “JB” Broichhagen trained as a synthetic chemist — someone who trusted carbon–carbon bonds far more than live-cell behavior. Yet curiosity and chemistry pulled him into the world of GLP-1R, pancreatic β-cells, and the biological questions David Hodson had been exploring for years. The call from David — the glowing islet — created a pivot the team couldn’t ignore. A fluorescent peptide probe binding with clarity and specificity was exciting enough. Seeing that probe expose receptor distribution across an entire native islet changed what they believed was possible. This was more than data. It was ignition. A single successful GPCR imaging experiment can transform a project’s trajectory. From that moment, imaging wasn’t an add-on. It became the center of gravity. How a Chemical Design Sparked a GPCR Imaging Breakthrough The concept was elegant: antibodies weren’t delivering reliable GLP-1R visualization. A ligand-based peptide probe could, offer the consistency and surface selectivity GPCR imaging demands. One issue: JB had never made peptides Solution: collaborate. Working with a peptide specialist at the Max Planck Institute, the team moved quickly from concept to synthesis. What emerged was more than a ligand — it was a tool that enabled reproducible, stable, and high-contrast GPCR imaging across cells and tissue. Once the first images came in, the scientific questions multiplied: Could the probe support super-resolution GPCR imaging? Could they map receptor heterogeneity across the islet? Could they quantify plasma membrane vs. intracellular receptor pools? Could these tools scale to multiple GPCRs? The design didn't just work — it revealed. Interdisciplinary design isn’t optional in GPCR imaging. It’s the catalyst. The breakthrough didn’t happen because the chemistry was perfect. It happened because the chemistry and the biology met in the right way. The Human Reaction Behind a GPCR Imaging Milestone Scientists rarely talk about the emotional side of discovery — the instant where the experiment stops being data and starts being meaning. JB describes early experiences vividly: Seeing calcium waves flicker in cells. Realizing tissue is alive, unpredictable, and full of hidden structure. Feeling the urge to take phone pictures of super-resolution data and send them to collaborators because he couldn’t keep the excitement to himself. That same emotional imprint hit with the whole-islet image. It wasn’t just successful GPCR imaging — it was proof that receptors could be seen as they truly exist in native tissue, not simplified models. GPCR imaging doesn’t just visualize receptors. It gives scientists a way to feel the biology. This emotional spark carried the team through the next steps — validation, iteration, and expanding the scope of what these probes could do. Why Chemical Probes Shift the GPCR Imaging Landscape Chemical probes don’t replace antibodies outright — but they excel where antibodies struggle. For GPCR imaging, their strengths are practical and decisive: Consistency from batch to batch Long-term stability Compatibility with live cells and intact tissue Surface-receptor specificity A compact footprint that fits sub-10 nm resolution techniques These attributes enable experiments that previously required compromise. And the most striking validation came from in vivo GPCR imaging. Two-photon microscopy revealed a glowing islet in a living mouse — a moment JB calls the “Holy Grail” of chemical biology. Better GPCR imaging doesn’t just capture biology — it expands the biological questions the field can ask. The tools didn’t simply visualize receptors. They unlocked pharmacologically relevant insights that were previously inaccessible. The Collaboration Model That Makes GPCR Imaging Possible Behind every technical advance in this story sits something less tangible but equally decisive: a collaboration grounded in trust and fun. That’s how JB describes it — and it’s exactly why the work moved quickly. He learned tissue complexity from David; David picked up the quirks of acetonitrile. They exchanged instincts as much as data, and built a shared rhythm of problem-solving. Strong GPCR imaging tools come from strong interdisciplinary relationships. Good collaborations share protocols. Great collaborations share momentum. The trust between chemistry and biology drove the project forward faster than either discipline could have moved alone. Where GPCR Imaging Goes Next Once the breakthrough happened, the horizon widened dramatically. JB’s team now moves GPCR imaging toward: New fluorophores engineered for deep-tissue clarity Multi-color strategies for parallel receptor mapping Super-resolution imaging of receptor nanodomains AI-assisted probe design Multi-receptor visualization in complex tissue The dream is ambitious and increasingly feasible: A catalog where scientists choose a receptor, choose a color, and visualize biology exactly as it exists — in cells, in tissue, in living organisms. Not one receptor at a time. Not one color. Not one imaging depth. The islet lighting up wasn’t the pinnacle. It was the proof of concept. GPCR imaging is evolving from a specialized technique into a foundational method for receptor biology. And this breakthrough became one of the stepping-stones. This conversation is part of a three episode series produced in collaboration with our partners at Celtarys Research . If this behind-the-scenes story resonated, you’ll love the full conversation.  🎧 Listen to the full episode https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/chemical-probes-for-gpcr-imaging-and-internalization If JB's story resonates 🎧 Listen to part 1 of this series with Dr. David Hodson

But everything changed when his recurring pain — and the rigid protocols around opioid prescription — "When you talk to patients that have an unmet need, you learn things that no one is thinking about in

functional micro-domains” and the “helix movement model of receptor activation” were confirmed later when Recently, Tom’s lab discovered, along with Yu Chen and Ping Chi , that a mutant of CYSLTR2 is a driver

New cryo-EM structures from Chen et al. New cryo-EM structures from Chen et al.

of AGPCRs in the periphery ADGRG1/GPR56 regulates survival of terminally differentiated CD8+ T cells Cheng-Chih and disease Douglas Tilley ADGRG1/GPR56 regulates survival of terminally differentiated CD8+ T cells Cheng-Chih Hsiao Abstract Only available for AGPCR 24 Attendees Authors & Affiliations "Cheng-Chih Hsiao1,2, Hendrik Departments of Neurology and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands" About Cheng-Chih Netherlands Institute for Neuroscience; 2022 - present: Researcher associate, Netherlands Brain Bank" Cheng-Chih