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Explore GPCR signaling kinetics and temporal drug action mechanisms with Sam Hoare. Clinical insights on tachyphylaxis, tolerance, and kinetic-based therapeutics. < Back How Signaling Kinetics Shapes GPCR Drug Action May 14, 2026 10 AM - 11:30 AM EST 🔒 Watch Recordings - Join Premium Access the full library of recorded Masterclass sessions. Get Live Updates Be notified when new live Masterclasses are scheduled. Introduction GPCR signaling kinetics, the temporal dynamics of receptor activation and downstream signaling, directly influence therapeutic outcomes from beta-agonist tachyphylaxis to opioid tolerance. This session addresses the clinical landscape of kinetic-dependent drug action, biosensor-based measurement of signaling over time, and analytical approaches for extracting actionable kinetic parameters in drug discovery. Coverage spans tachyphylaxis mechanisms in beta-agonist therapy, tolerance development with opioid agonists, and therapeutic desensitization strategies at S1P1 and GnRH receptors. Designed for pharmacologists, drug discovery scientists, and translational researchers working on temporal aspects of GPCR therapeutics. Instructor Sam Hoare is a drug discovery consultant and founder of Pharmechanics LLC, specializing in kinetic analysis of drug action and the application of binding and signaling kinetics to therapeutic development. After completing his Ph.D. in biochemistry studying allosteric modulation of dopamine receptors at the University of Kent and postdoctoral training on Class B GPCRs at the National Institute of Mental Health, he spent 15 years as a pharmacology leader at Neurocrine Biosciences, guiding in vitro biology for numerous drug discovery campaigns. Sam is an editor at the NIH Assay Guidance Manual and regularly teaches advanced pharmacology and experimental design. His expertise in translating kinetic data from bench to bedside directly informs this Masterclass. Upcoming Live Sessions

Explore detailed information about our GPCR-focused University Courses. Learn about course content, instructors, and how to advance your expertise in drug discovery. Empower. Connect. Transform. Become part of the Dr. GPCR University Instructor community—where teaching is more than sharing knowledge; it’s about uplifting scientists and advancing GPCR discovery, together. Connecting scientists through knowledge, passion, and purpose. About Dr. GPCR University Dr. GPCR University is a global platform where scientists share their knowledge, inspire discovery, and advance GPCR research together. Our on-demand courses connect experts, students, and industry professionals through authentic, instructor-led learning—built by scientists, for scientists. Each contribution brings new perspectives and tools to advance the field. Instructors are recognized and compensated for their work, ensuring that every shared insight creates impact, visibility, and lasting value across the GPCR community. Course Formats You Can Teach At Dr. GPCR University , every instructor brings a unique voice, style, and rhythm to teaching. Our flexible course formats are designed to fit your time, depth, and teaching goals — whether you’re sharing a focused insight or leading a full exploration of GPCR science. You can also co-lead Full-Length Courses with up to three fellow instructors to share the workload and enrich the learning experience. 🧭 Full-Length Course Structure: 4 × 1-hour sessions Purpose: Deep, multi-session learning experience Best for: Comprehensive topics that require exploration and discussion ⚡ Short Course Structure: 1 session (2–4 hours of content) Purpose: Concise yet thorough coverage of key concepts Best for: Core methods, applied principles, or emerging topics 🔍 Mini Course Structure: 1 short lesson (1–2 hours of content) Purpose: Focused insights into a single theme Best for: Quick takeaways or specialized topics No matter the format, your course helps scientists learn, connect, and keep GPCR science moving forward — one discovery at a time. Instructor Benefits At Dr. GPCR University , we believe those who teach move science forward. As an instructor, you’re not just sharing knowledge — you’re shaping the next generation of GPCR scientists. We make sure your time, expertise, and contribution are recognized and supported every step of the way. 🌟 By teaching with us, you gain: ✔ Premium Membership for you and your team for one year (no credit card required) ✔ A global platform to share your expertise and reach scientists worldwide ✔ Full support with technical setup, editing, and course promotion — so you can focus on teaching We handle logistics so you can focus on what truly matters: delivering meaningful, high-quality education. To ensure lasting impact, each course becomes part of the Dr. GPCR University ecosystem — maintained, updated, and accessible to learners in the long term. Your name and expertise remain at the heart of the course, continuing to inspire scientists long after the sessions end. Together, we’re shaping the future of GPCR education — one course, one scientist, one discovery at a time. What You’ll Need to Provide to Teach a Course Welcome — we’re thrilled to have you join Dr. GPCR University . You bring the expertise; we’ll handle the setup, editing, and promotion. Here’s everything you’ll prepare to bring your course to life: 🧩 Step 1: Email us Start by emailing it us at Hello@DrGPCR.org . We will then have a short call and send you the our Instructor Intake Form — it’s how we build your profile and course page. You’ll be asked for: Instructor info – name, email, affiliation, short bio, photo, and optional social media handles. Course details – title, format (short talk / mini-course / series), audience, main objectives, expected learning outcomes, key topics (≈ 250 words), recommended readings, and any co-instructors. Preferences & agreement – communication style, access to the Premium area, and acknowledgment of the instructor agreement (you’ll receive the full version right after submission). 🧱 Step 2: Plan Your Course Structure Decide how your course will flow — number of modules, duration, and teaching style. (See Course Formats above for ideas.) 🕙 Scheduling note: Courses are typically hosted Thursdays at 10 AM EST — a sweet spot for our global community. We’ll confirm your date together once your proposal is approved. 📝 Step 3: Prepare Your Content Create your teaching materials — slides, visuals, readings, or anything that helps learners grasp your message. Don’t worry — we’ll support you with templates and review tips along the way. 🎥 Step 4: Record a Short Video Chat You’ll have a quick recorded conversation with Dr. Yamina Berchiche about your course — what it covers, why it matters, and what students can expect. It’s relaxed, engaging, and helps introduce you to the community. 💬 Step 5: Join Your Private Course Group Once live, you’ll connect with your students in a private discussion space — perfect for questions, insights, and follow-ups. 💫 Step 6: Teach & Inspire Share your expertise with scientists around the world. Enjoy the experience, the visibility, and the impact — and receive recognition and compensation for your contribution. (See Instructor Benefits for details.) ✨ Your ideas, your voice, and your course will help shape the next chapter of GPCR discovery. Share Your Expertise with the World We’re here to support you from idea to impact. Start your journey as a Dr. GPCR University Instructor and help move GPCR science forward. Email us at Hello@DrGPCR.org Live Masterclass Sessions Previous Instructors Dr. Matteo Pavan Dr. Terry Kenakin Dr. Kenneth Jacobson Dr. Yamina Berchiche Dr. Sam Hoare Dr. GPCR Courses Reviews Dr. Hoare is very experienced in the field. What came as a pleasant surprise was how didactical and well-thought-out his course was—highly recommended. The really unexpected was that the Q&A sessions reached the highest level—beyond excellent. I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere GPCR researcher Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field GPCR researcher The content had enough depth to satisfy the hunger for theory while being full of practical knowledge GPCR researcher The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology GPCR researcher Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him GPCR researcher Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator. GPCR researcher The course was very practical and easily translatable to experiments that we could do in our own labs. It was clear that Dr. Hoare is very in touch with the technical and human challenges we encounter in our work GPCR researcher Contact Contact us First name* Last name Email* Write a message Submit

Advance your GPCR research career with Dr. GPCR University. Access 20+ on-demand GPCR courses, 200+ expert talks, weekly news, and a global scientist network. Join Premium today. Dr. GPCR University Your professional home in GPCR science. University is your professional home in GPCR science — premium intelligence, live Masterclasses, job listings, events, and a community of scientists who have your back. Everything you need, in one place. See what it feels like — $50 for 14 days Already know this is home? Join University — $499/year 1,400+ GPCR scientists reached 200+ Expert talks available $499 Per year — less than $10/week What's inside? The rooms in your professional home University isn't a bundle of features — it's a place where your GPCR professional life is supported. Here's what's waiting for you inside. Live Masterclass Live scientific exchanges with leading GPCR experts. You're in the room with the scientist, asking your question — not watching from the audience. Explore Live Masterclass → Job Listings GPCR-specific job opportunities curated for the community. Your next role is already here — opportunities find you when you're inside the ecosystem. Masterclass On Demand Full recordings of every session, available anytime. Revisit the science at your pace — over 200 expert talks in the library and growing. Explore Masterclass on Demand → GPCR Events A calendar of relevant conferences, meetings, and events in the GPCR field. Your next conference is already here. Premium Weekly News The complete GPCR intelligence — classified publications, industry news, job listings, and events calendar. Know what's coming before it becomes consensus. See Weekly News → Ask the Ecosystem The question you've been sitting on — someone in this ecosystem has the answer. A discussion forum where members share insights and get answers from the community. Live Masterclass In the room with the scientist, not watching from the audience Live scientific exchanges where you engage directly with leading GPCR experts. The question you've been holding — this is where you ask it. Dr. Andrew Tobin | Glasgow University How to Build Breakthrough GPCR Programs Research Strategy June 4, 2026 Dr. Sam Hoare | Pharmechanics How Signaling Kinetics Shapes GPCR Drug Action Translational Pharmacology & Disease Models May 14, 2026 Dr. Marsha Pierce | Midewestern University Introduction to GLP-1 pharmacology October 8, 2026 Dr. Sudarshan Rajagopal | Duke University The Spatiotemporal Revolution in GPCR Biology Biased Signaling & Allosteric Modulation May 21, 2026 Dr. Jakob Höppner | Harvard University | MGH Subcellular Regulation of PTH1R Signaling June 11, 2026 Explore Live Masterclasses → Who it's for? Whether you're just starting out or 20 years in — this is your place University is designed for GPCR scientists at every career stage who want to stay sharp, connected, and supported. 🎓 Early-career researchers Find your footing in the field. Access the experts, the intelligence, and the community that accelerates your growth. 🔬 Discovery scientists Stay at the frontier. Live Masterclasses and Premium Weekly News keep you ahead of the field — not chasing it. 🏆 Senior investigators Your career stage doesn't matter. Your commitment to the science does. Connect, contribute, and stay current. Explore the Masterclass On Demand Watch Now Structure-Based Design of Modulators of Purinergic GPCRs Kenneth A. Jacobson, Matteo Pavan Watch Now The Allosteric Advantage Terry Kenakin Watch Now CRC Super-User: Your Data Advantage Sam Hoare Explore Masterclasses On Demand → The comparison A society membership costs more and gives you less Most GPCR scientists belong to at least one scientific society. Here's how that compares to University. Typical Scientific Society $150 – $500+/year A journal subscription A conference discount A newsletter Occasional networking events Dr. GPCR University $499/year — less than $10 a week Live Masterclasses with leading GPCR scientists 200+ on-demand expert sessions Premium Weekly News intelligence GPCR job board and events calendar Community forum & ecosystem access Intelligence Hub dashboard Grandfather guarantee — your rate never increases "The one membership that has your back." $50 for 14 days - Strat Now What others are saying Scientists inside the ecosystem Dr. Hoare is very experienced in the field. What came as a pleasant surprise was how didactical and well-thought-out his course was—highly recommended. The really unexpected was that the Q&A sessions reached the highest level—beyond excellent. I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere GPCR researcher The content had enough depth to satisfy the hunger for theory while being full of practical knowledge GPCR researcher Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him GPCR researcher The course was very practical and easily translatable to experiments that we could do in our own labs. It was clear that Dr. Hoare is very in touch with the technical and human challenges we encounter in our work GPCR researcher Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field GPCR researcher The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology GPCR researcher Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator. GPCR researcher Common questions Thinking it over? Fair enough. Here are the concerns we hear most — and honest answers. "It's too expensive." At less than $10 a week, University gives you live access to leading GPCR scientists, 200+ on-demand talks, premium intelligence, a job board, events calendar, and a global community of peers. One insight, one connection, one 'aha' moment — can save months of research time. "I'm not sure I'll use it often." Even one Masterclass or one new collaboration can make a difference. Members often find value in ways they didn't expect — from expert feedback to career-changing introductions. That's why we offer a 14-day trial, so you can experience it first. "I already get what I need from papers." Papers inform. University helps you understand and apply that knowledge — through expert context, structured scientific exchanges, and real interaction with peers from academia and industry. "Will this really help my career?" Yes. Members grow visibility, confidence, and connections that open doors. It’s not just about learning — it’s about being seen, supported, and part of something bigger . There was a technical issue on our end. Try again or refresh. Move in. Look around. See if it's home. For 14 days, this is what it feels like to have everything in one place — intelligence, learning, community, and opportunities. Your first Masterclass is waiting. See what it feels like Already know this is home? Join University — $499/year Your 14-day trial is $50. If University feels like home, it's $499/year — less than $10 a week. Grandfather guarantee: your rate never increases. No surprise charges.

Explore upcoming GPCR Masterclass live sessions featuring expert discussions on GPCR pharmacology, receptor biology, and drug discovery. University / Live Masterclass Sessions In the room with the scientist, not watching from the audience. Live scientific exchanges with leading GPCR experts. Interactive, question-driven, frontier science. This isn't a lecture — it's a conversation with the people shaping GPCR discovery. Masterclass is included inDr. GPCR University Try it for 14 days Upcoming live sessions Your next Live Masterclass Session is waiting Each session focuses on a specific pharmacology or GPCR discovery topic, led by a recognized expert. Live Q&A means your questions get real answers. May 14, 2026 Dr. Sam Hoare | Pharmechanics How Signaling Kinetics Shapes GPCR Drug Action Translational Pharmacology & Disease Models Details June 4, 2026 Dr. Andrew Tobin | Glasgow University How to Build Breakthrough GPCR Programs Research Strategy Details May 21, 2026 Dr. Sudarshan Rajagopal | Duke University The Spatiotemporal Revolution in GPCR Biology Biased Signaling & Allosteric Modulation Details June 11, 2026 Dr. Jakob Höppner | Harvard University | MGH Subcellular Regulation of PTH1R Signaling Details 1 2 1 ... 1 2 ... 2 What makes this different? Not a lecture. Not a webinar. A scientific exchange. The Masterclass was created because the most valuable insights in GPCR science aren't captured in papers or conference talks. Scientist-to-scientist discussion Extended Q&A allows deeper exploration than typical presentations. You're engaging directly with the expert — not submitting a question to a moderator. Beyond conference time limits Topics are explored in greater depth than standard conference talks allow. Sessions focus on scientific reasoning, data interpretation, and real discovery problems. Focused audience of specialists Sessions bring together GPCR researchers, pharmacologists, and discovery scientists. The conversation stays at the right level because everyone in the room speaks the same scientific language. Every session recorded Can't make it live? Every Masterclass is recorded and available on demand in the library. Revisit the science anytime — over 200 sessions and growing. On-demand library 200+ expert sessions, available anytime Full recordings of every Masterclass session. Revisit the science at your pace — filter by category, level, or instructor. Kenneth A. Jacobson, Matteo Pavan Structure-Based Design of Modulators of Purinergic GPCRs Terry Kenakin Assessing Bias: The Practical Approach Terry Kenakin Unconventional GPCR Ligands Explore all Recorded Masterclasses → The scientists Learn directly from world leaders in GPCR research Dr. Matteo Pavan Dr. Terry Kenakin Dr. Kenneth Jacobson Dr. Yamina Berchiche Dr. Sam Hoare What scientists say? From the people in the room Dr. Hoare is very experienced in the field. What came as a pleasant surprise was how didactical and well-thought-out his course was—highly recommended. The really unexpected was that the Q&A sessions reached the highest level—beyond excellent. I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere GPCR researcher Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field GPCR researcher The content had enough depth to satisfy the hunger for theory while being full of practical knowledge GPCR researcher The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology GPCR researcher Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him GPCR researcher Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator. GPCR researcher The course was very practical and easily translatable to experiments that we could do in our own labs. It was clear that Dr. Hoare is very in touch with the technical and human challenges we encounter in our work GPCR researcher There was a technical issue on our end. Try again or refresh. Masterclass is included in Dr. GPCR University Live sessions, 200+ on-demand recordings, plus premium intelligence, jobs, events, and a community of GPCR scientists — all in one place. See what it feels like for 14 days. Try University for 14 days — $50 Your professional home in GPCR science. $499/year after trial.

Strategic approaches to building GPCR research programs that translate fundamental discoveries into clinical impact and drug development. < Back How to Build Breakthrough GPCR Programs June 4, 2026 10 AM - 11:30 AM EST 🔒 Watch Recordings - Join Premium Access the full library of recorded Masterclass sessions. Get Live Updates Be notified when new live Masterclasses are scheduled. Introduction Building GPCR research programs that achieve both fundamental discovery and clinical translation requires strategic thinking from day one. This session addresses the structural and strategic decisions that determine whether breakthrough science reaches patients: securing funding aligned with translational potential, defining research directions that balance risk and impact, identifying discoveries worth pursuing to clinical endpoints, and navigating the pathway from academic research to drug development and spin-out companies. Andrew Tobin draws from his experience leading translational GPCR programs and co-founding Keltic Pharma to illustrate each strategic element. Intended for GPCR scientists, postdocs, and research leaders planning translational research programs. Instructor Andrew Tobin directs translational GPCR research focused on generating new medicines for brain disorders, severe asthma, and inflammatory gut disease. As co-founder and CEO of Keltic Pharma Therapeutics, he leads a biotechnology company developing a novel drug-discovery platform and working toward a radical cure for malaria. He also serves as Director of the Advanced Research Centre at the University of Glasgow, a £130M collaborative initiative housing over 550 researchers designed to redefine interdisciplinary research. His recent work on muscarinic acetylcholine receptor modulation and structure-guided design of M1 receptor agonists exemplifies the strategic approach to translational GPCR science that defines this Masterclass session. Upcoming Live Sessions

Explore how subcellular location and temporal dynamics revolutionize GPCR signaling through nanodomains, endosomal compartments, and phase separation mechanisms. < Back The Spatiotemporal Revolution in GPCR Biology May 21, 2026 10:00 AM - 11:30 AM EST 🔒 Watch Recordings - Join Premium Access the full library of recorded Masterclass sessions. Get Live Updates Be notified when new live Masterclasses are scheduled. Introduction Classical GPCR signaling models assumed uniform receptor distribution and immediate signal termination upon ligand dissociation. Contemporary research reveals that subcellular location and temporal dynamics fundamentally determine signaling outcomes. This session examines how receptor nanodomains, endosomal signaling compartments, and biomolecular condensates create distinct signaling environments that prevent crosstalk and enable pathway specificity. The discussion spans location bias mechanisms that drive differential G protein versus arrestin activation, advanced imaging techniques that visualize these spatiotemporal processes, and the emerging role of liquid-liquid phase separation in organizing signaling complexes. Designed for structural pharmacologists, cell biologists, and drug discovery scientists working on GPCR systems where spatial organization influences therapeutic outcomes. Instructor Sudarshan Rajagopal is Associate Professor of Medicine in the Division of Cardiology at Duke University School of Medicine and Co-Director of the Duke Pulmonary Vascular Disease Center. His research has fundamentally advanced understanding of receptor regulatory mechanisms underlying cardiovascular and inflammatory diseases, particularly pulmonary hypertension. Since establishing his independent laboratory, his group has made defining contributions to biased agonism mechanisms and chemokine system signaling, with particular expertise in how spatial organization influences GPCR function in disease contexts. His work on spatiotemporal GPCR regulation directly informs the mechanistic framework addressed in this Masterclass. Upcoming Live Sessions

Discover the Dr. GPCR Ecosystem – the ultimate hub for GPCR professionals to connect, collaborate, and advance drug discovery. Home: About The global hub for GPCR science Accelerating GPCR drug discovery, together Where academia and industry meet to advance GPCR research, share knowledge, and foster collaboration across the entire ecosystem. For scientists University Your professional home in GPCR science. Live masterclasses, curated research intelligence, and a community that keeps you connected and ahead. ➔Live masterclasses with leading researchers ➔Weekly GPCR research intelligence ➔Members-only networking & AMAs Explore University For industry Foundry Reach the GPCR research community where they already learn and collaborate. Strategic partnerships, visibility programs, and curated service directories. ➔Yearly Glow strategic media partnerships ➔CRO Bank curated service directory ➔Direct access to 1,400+ GPCR scientists Explore Foundry 1,400+ GPCR scientists reached 200+ Expert talks & masterclasses 25–50% Newsletter open rate Strategic Partner(s) Closing the gap between academia and industry Dr. GPCR is a 501(c)(3) nonprofit empowering the GPCR field through shared knowledge, collaboration, and open access to tools that accelerate drug discovery. 🤝 Support the Mission

Explore the world of GPCRs with Dr. GPCR Podcast! Join industry leaders as they share insights, stories, and groundbreaking discoveries, enriching our understanding of GPCRs. Delve into the science behind these vital components shaping our collective knowledge. Welcome to the Dr. GPCR Podcast - The Voice of the Community Conversations with the world’s leading GPCR scientists. Exploring discoveries, careers, and ideas shaping human health. In each episode, we sit down with leading experts to explore their career journeys, groundbreaking discoveries, and the impact of their research on our shared understanding of GPCR biology. Launched at the height of the pandemic, the Dr. GPCR Podcast was created with three goals: Share discoveries – Highlight the latest advances in the GPCR field. Amplify voices – Provide scientists a platform to showcase their work. Inspire the future – Motivate the next generation to pursue GPCR research. At its core, Dr. GPCR’s mission is simple yet ambitious: to bring the GPCR community together - across borders and disciplines - to connect, exchange, and collaborate in order to improve human health through a deeper understanding of GPCR biology. Latest Podcast Episodes More podcast episodes Dr. GPCR Podcast Audience Survey We are currently planning our next season and need your help. This short survey will help us understand your needs to bring you exciting and informative content. We also know that you are busy, which is why we designed this short survey that should take you 5 minutes. Fill out this form Be our Guest In each episode, we chat with an expert about their career trajectory, discoveries, and how their research contributed to the shared pool of knowledge about GPCR biology. We’d love to have you on our podcast. To be a guest, fill out the form below, and we’ll be in touch in 48 hours. Fill out this form What others are saying about this podcast "You made it a very comfortable and engaging experience, and it felt like we were chatting over coffee — Yamina thoughtfully guided our chat throughout." Anita Nivedha I think it's really well done. I'm genuinely interested to see how it evolves and grows over time, as I feel it has the potential to develop into something even more impactful. Anonymous This came at just the most perfect time. I hadn't heard a scientific talk outside my lab since February and was starved to hear someone else talk passionately about GPCRs. I've listened to the episodes multiple times and it's just like being at a conference getting new ideas. I just couldn't be happier y'all created this podcast. Anonymous Great initiative, thanks. Carrier paths, choosing research topics, switching fields, late start, failures and successes. Anonymous I enjoy the breadth of questioning that goes beyond just the science, and reveals a bit about the scientists as individuals/mentors/people. Anonymous Really enjoyable science podcast! Dr. Yamina Berchiche interviews leading GPCR scientists on this vibrant, entertaining podcast. I really appreciate the way the podcast educates and mentors, particularly towards junior scientists but also to the community as a wholen Yamina is a great interviewer, getting insight and personal history from her guests. Am very grateful for Dr GPCR livening up the week in these difficult times! Sam @Pharmamechanic Listen and subscribe where you get your podcasts

A conversation with Dr. Tore Bengtsson on β₂-adrenergic receptor signaling, muscle metabolism, and how GPCR pharmacology can lead to new therapies for metabolic disease. << Back to podcast list Strategic Partner(s) Dr. Tore Bengtsson: Rethinking β₂-Adrenergic Signaling in Metabolic Disease Scientific Abstract This conversation with Dr. Tore Bengtsson , professor of physiology at Stockholm University, explores how β-adrenergic receptor signaling can be reimagined to address metabolic disease, muscle physiology, and energy balance. Dr. Bengtsson’s research spans sympathetic nervous system signaling, brown adipose tissue biology, and skeletal muscle metabolism—fields deeply connected to obesity, type 2 diabetes, and metabolic health. A central theme of the discussion is the pharmacology of the β₂-adrenergic receptor , a GPCR traditionally associated with bronchodilation but increasingly recognized for its broader physiological roles. Dr. Bengtsson describes how classical β₂ agonists stimulate muscle growth and metabolic changes but are limited by receptor desensitization. His work focuses on developing novel β₂-adrenergic ligands that selectively engage signaling pathways without triggering rapid desensitization, enabling sustained metabolic effects. The conversation also examines how GPCR signaling is far more complex than a single downstream pathway. Instead, receptors integrate multiple signaling outputs, temporal dynamics, and interactions with other pathways to shape physiological outcomes. Dr. Bengtsson discusses how understanding this signaling complexity opens opportunities to design drugs that promote beneficial metabolic responses such as muscle growth and increased energy expenditure. Listeners gain insight into how basic GPCR pharmacology can translate into therapeutic strategies targeting metabolism, aging, and metabolic disease. About the Guest Dr. Tore Bengtsson is a professor of physiology at Stockholm University whose research focuses on sympathetic nervous system signaling, metabolic regulation, and skeletal muscle physiology. His work investigates how β-adrenergic receptors regulate energy metabolism, muscle growth, and glucose homeostasis. Dr. Bengtsson began his research career studying brown adipose tissue under the mentorship of Dr. Barbara Cannon and Dr. Jan Nedergaard, pioneers in thermogenesis research. His laboratory now explores how β₂-adrenergic receptor signaling can be manipulated to influence metabolism and muscle physiology. He is also an entrepreneur and founder of biotechnology companies translating GPCR pharmacology into therapeutic development. Scientific Themes of the Conversation β-adrenergic receptor pharmacology and signaling bias Sympathetic nervous system control of metabolism Brown adipose tissue and thermogenesis Skeletal muscle metabolism and glucose homeostasis GPCR signaling complexity and pathway selectivity Translating receptor pharmacology into metabolic therapeutics Key Insights from the Conversation A Childhood Physiological Experiment Sparked a Scientific Career Dr. Bengtsson recounts a formative experience when his father pushed him into icy water as a child to demonstrate survival in cold conditions. The intense physiological response—an adrenaline surge and rapid adaptation to cold—sparked his lifelong fascination with sympathetic nervous system signaling and stress physiology. Stress Is Not Always Negative A recurring theme in the discussion is that physiological stress is often misunderstood. Short bursts of stress—whether exercise, cold exposure, or sympathetic activation—can trigger adaptive responses that improve metabolic function and resilience. Muscle Is Central to Metabolic Health While brown fat has received considerable attention, Dr. Bengtsson emphasizes the dominant role of skeletal muscle in metabolic regulation. Approximately 75% of glucose disposal occurs in muscle, making muscle physiology central to metabolic diseases such as type 2 diabetes. Classical β₂ Agonists Have a Fundamental Limitation Traditional β₂-adrenergic agonists can stimulate muscle growth and fat loss but lose effectiveness over time due to receptor desensitization. This pharmacological limitation prevents their long-term use for metabolic therapies. GPCRs Do Not Produce a Single Signal Dr. Bengtsson highlights that GPCR signaling is inherently multidimensional. Activation of a receptor can generate multiple signaling pathways, and different ligands can bias signaling toward specific outcomes. Understanding this complexity is essential for modern drug discovery. Absence of a Signal Can Be a Discovery One of Dr. Bengtsson’s key scientific breakthroughs came from an unexpected experimental result: glucose uptake without detectable cAMP signaling. Rather than dismissing the result as an error, this observation led to the realization that β₂ signaling could be separated into distinct pathways. Scientific Discovery Requires Intellectual Independence Dr. Bengtsson advises young scientists to shift from passively following instructions to actively questioning experiments and interpretations. True scientific thinking begins when researchers take intellectual ownership of the questions they pursue. Episode Timeline 00:00 Introduction and research focus of Dr. Bengtsson 03:00 A childhood experiment that sparked interest in physiology 07:00 Cold exposure, sympathetic signaling, and brown fat research 10:00 β₂-adrenergic receptors and muscle physiology 15:00 Exercise, metabolism, and pharmacological modulation of muscle growth 17:30 Early research on brown adipose tissue and thermogenesis 22:30 Translating academic discoveries into biotech companies 25:00 GPCR signaling complexity and biased signaling 36:00 A key experimental observation leading to a new drug concept 38:30 Advice for young scientists and intellectual independence Selected Quotes “You will not know what happens before you do the experiment.” “People think a receptor produces one signal. In reality, a receptor produces many signals.” “Sometimes the most important discovery is when a signal is missing.” “You have to move from being told what to do to thinking for yourself.” Full Transcript (Formatted for readability — full transcript preserved) Yamina Berchiche: Hello, everyone. This is Yamina from Dr. GPCR. And today I'm very excited to have with me Dr. Tore Bengtsson. Dr. Bengtsson: Tore Bengtsson. And you got it right. Yamina Berchiche: I'm happy to have you on. For those who don't know, we've been chasing each other and postponing this conversation several times. I'm very excited that we're finally able to do it today. Dr. Bengtsson: Thank you. I'm very happy to be here. Yamina Berchiche: Let's start at the beginning. Could you introduce yourself and tell us about your research? Dr. Bengtsson: I'm a professor in physiology at Stockholm University. I've been working with pre-diabetes, type 2 diabetes, obesity, and the mechanisms behind these diseases for about 25 years. I'm especially interested in β-adrenergic receptors because I believe they regulate far more physiological processes than people typically assume. I'm also an entrepreneur. I've started several companies. One is Sigrid Therapeutics, which focuses on digestion and metabolic regulation. Another company, Atrogi, is based on our research on β₂-adrenergic receptors and the development of new drugs. We’ve already completed Phase I clinical trials and are preparing for Phase II. Yamina Berchiche: If you were not a scientist, what would you be doing? Dr. Bengtsson: I think I might have been a historian or a writer. I like storytelling. I'm very interested in Viking runes and ancient rune stones in Scandinavia. I can actually read runic inscriptions, and I find it fascinating to interpret what these stones tell us about history. Yamina Berchiche: How did you become a scientist? Dr. Bengtsson: I'll tell you a story I don't share very often. When I was about ten years old, I lived on an island in the Stockholm archipelago. My father and I went ice skating frequently during the winter. One summer he asked me: “What happens if you fall through the ice?” I said I didn't know. He replied: “We should test it.” Months later, during winter, he cut a hole in the ice. I asked what he was doing. He said he was catching a big fish. Suddenly he pushed me into the icy water. I went under, looked up at the hole in the ice, and quickly swam out. I remember the intense adrenaline surge. My body reacted instantly. I wasn't even cold at first. Walking home later I started to freeze, but in that moment I experienced a powerful physiological response. That event sparked my lifelong fascination with sympathetic nervous system activation. Yamina Berchiche: So your father pushed you into science quite literally. Dr. Bengtsson: Yes — and into physiology. Yamina Berchiche: And that connects directly to your later work on brown fat and sympathetic signaling. Dr. Bengtsson: Exactly. I've spent many years studying brown adipose tissue and how sympathetic activation stimulates thermogenesis. Later I became increasingly interested in skeletal muscle metabolism and how β₂-adrenergic signaling affects muscle growth and glucose metabolism. Yamina Berchiche: Could you talk about how β₂-adrenergic signaling relates to muscle growth? Dr. Bengtsson: For many years it's been known that β₂ agonists can stimulate muscle growth and reduce fat. This has been observed in athletes and even in livestock production. But traditional β₂ agonists lose effectiveness over time because the receptor becomes desensitized. The body adapts, requiring higher doses. That makes them unsuitable as long-term therapeutic drugs. So about 15–20 years ago I began working on the idea that we need a new type of β₂ agonist—one that activates the receptor differently and avoids desensitization. That’s what we’ve now achieved with new compounds that stimulate the receptor in a novel way. Yamina Berchiche: You mentioned something very important earlier: GPCRs don’t produce a single signal. Dr. Bengtsson: Yes. Traditionally people thought receptor activation leads to one downstream pathway. But GPCRs activate multiple signaling pathways simultaneously. Different ligands can bias signaling toward different pathways. That means we can design compounds that favor beneficial physiological responses while avoiding unwanted effects. That is exactly what makes GPCR pharmacology so fascinating and powerful. Yamina Berchiche: You mentioned an important experimental moment that led to your drug concept. Dr. Bengtsson: Yes. A doctoral student ran an experiment measuring glucose uptake. The compound produced strong glucose uptake but almost no cAMP signaling. She thought the experiment had failed. But I realized this might be something important: glucose uptake without cAMP. And that turned out to be correct. That observation opened the door to separating signaling pathways and designing new β₂ ligands. Yamina Berchiche: What advice would you give to young scientists? Dr. Bengtsson: Young scientists often follow instructions without asking why. Real science begins when you take control of the question. You must move from being told what to do to thinking independently. You have to be in the driver's seat of your own thinking. Yamina Berchiche: That’s a powerful message. Dr. Bengtsson: And another lesson I learned from my wife: success often depends not just on knowledge but on understanding how other people think. Science is not just experiments. It's communication, persuasion, and collaboration. Yamina Berchiche: Dr. Bengtsson, thank you very much for the conversation. Dr. Bengtsson: Thank you. This was great. Yamina Berchiche: Bye. Dr. Bengtsson: Bye-bye. Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. 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Dr. Jennifer Pluznick explains why olfactory receptors in the kidney are more than curiosities — they sense gut-microbe metabolites, modulate blood pressure, and are forcing a rethink of what "smell" actually means. << Back to podcast list Strategic Partner(s) Dr. Jennifer Pluznick: Olfactory Receptors in the Kidney and the Gut-Microbe Signal Olfactory receptors are known by a single address — the nose. But a microarray Dr. Jennifer Pluznick ran as a postdoctoral fellow placed them, surprisingly, at the top of a kidney gene expression list. She almost dismissed the result as an artifact. Instead, she followed it, and the decision has shaped the direction of her lab at Johns Hopkins ever since. In this conversation, Dr. Pluznick explores what changes when olfactory receptors are treated not as smell receptors but as general-purpose chemosensors — scattered across the body and tuned to ligands circulating in the blood. She walks through the kidney ORs her group has connected to renin release, to proximal tubule glucose handling, and to blood pressure regulation. One of those receptors is activated by small-molecule metabolites produced by gut microbes, a finding she still calls mind-blowing and that she continues to unpack. The conversation also surfaces the field's quiet bottlenecks: the trafficking problem that traps ORs in the ER, the orthology gap between 1,000 mouse receptors and 350 human ones, and the reagents — antibodies, agonists, antagonists — that the community still does not have. About the Guest Dr. Jennifer Pluznick is Associate Professor of Physiology at Johns Hopkins University School of Medicine. Her lab studies the role of understudied GPCRs — olfactory receptors, taste receptors, and orphan GPRs — in kidney physiology. Her group has linked specific kidney olfactory receptors to blood pressure regulation via the renin-angiotensin pathway, to glucose handling in the proximal tubule, and to circulating metabolites generated by the gut microbiota. She first encountered olfactory receptors in the kidney during her postdoctoral training, and her lab continues to deorphanize and functionally characterize them today. Scientific Themes of the Conversation Olfactory receptors as general-purpose chemosensors outside the nose Deorphanization strategies for kidney-expressed GPCRs The renin-angiotensin axis and OR-mediated blood pressure control Gut microbiota metabolites as endogenous GPCR ligands Receptor trafficking and the ER-retention problem for ectopically expressed ORs Mouse-to-human orthology in a highly expanded receptor family Key Insights from the Conversation A surprise at the top of a microarray. When Dr. Pluznick's postdoc screen flagged olfactory receptors as top hits in a kidney disease cell line, her first instinct was to distrust the data. A single comment from her advisor — olfactory receptors in the kidney could actually be really cool — reframed a possible artifact as a research program. Reframing olfactory receptors as chemosensors. The name "olfactory receptor" narrows the imagination. Dr. Pluznick argues they are better understood as chemical sensors that happen to dominate the nose. Once reframed that way, ectopic expression in tissues like the kidney stops seeming strange and starts making sense. Two kidney ORs with physiology attached. One OR her lab has studied modulates renin release and therefore blood pressure; another regulates glucose handling through a transporter family that includes a validated type 2 diabetes target. Both started as receptors with no known ligand, no known localization, and no reason to expect physiological relevance. Gut microbes at the other end of the signal. The OR linked to blood pressure is activated by small-molecule metabolites produced by gut bacteria at low millimolar circulating concentrations. That makes blood pressure regulation, in part, a readout of microbial metabolism — a connection Dr. Pluznick describes as something that still blows her mind. Trafficking as a field-wide bottleneck. Exogenously expressed ORs tend to get stuck in the ER. Matsunami's RTP1S chaperone, the Rho tag, and the Pluznick lab's Lucy tag — a cleavable leucine-rich signal sequence developed by a rotation student — each help, but no combination fully solves the problem for every OR. The trafficking failure itself may encode something about how tightly ORs are regulated in olfactory sensory neurons. The orthology gap. Mice have ~1,000 olfactory receptors; humans have ~350. Sequence-based orthology calls are often ambiguous, and in the Pluznick lab's hands, putative orthologs frequently fail to share ligand profiles. Finding functional orthologs — not just sequence matches — is non-trivial, and it matters for anyone hoping to translate kidney OR biology into a human drug. Follow the data that surprises you. Dr. Pluznick's advice to early-career scientists is shaped by her own near-dismissal of an inconvenient microarray result. Established assumptions about where a receptor "belongs" are often what stop a discovery from being recognized as one. Episode Timeline Timestamps were generated using AI for readability. 00:00 Opening: newsletter, season close, and welcome 02:13 Becoming a scientist as a first-gen college student 04:17 The case for chasing understudied GPCRs in the kidney 06:18 "Olfactory receptors will always be my first love" 08:45 Renin, blood pressure, and a glucose-handling receptor 12:14 Localization and ligand screening when there's no antibody 17:06 What happens to OR expression in a disease kidney 19:56 The orthology problem: 1,000 mouse ORs, 350 human ones 23:08 RTP1S, the Rho tag, and the Lucy tag 29:20 One-neuron-one-receptor and the tight regulation of smell 36:57 The aha moment: gut microbes, a GPCR, and blood pressure 39:58 Diversity as everyone's responsibility Selected Quotes "I famously said that I wasn't sure I could really trust the data because these crazy receptors came out as the top hits. But my postdoc advisor, who's much wiser than I, said, 'olfactory receptors in the kidney, though — that could be really cool.' And somehow when he said it, it sounded like a much better idea." "Olfactory receptors as a class will always be my first love in terms of GPCRs." "Your blood pressure regulation is somehow tied to the activity of your gut microbes. And that is something that still kind of blows my mind." "You need to follow your data, even when it surprises you, even when it might go against what you assumed to be true before you started the experiment." About this episode Dr. Pluznick discovered that olfactory receptors in mice are also expressed in their kidneys and blood vessels. Her research is focused on the role of chemosensory GPCRs in regulating renal and cardiovascular function, and identifying renal/cardiovascular olfactory receptor ligands, and relating them to whole-animal physiology. This work contributes to a better understanding of how the kidney helps maintain homeostasis in humans. Jennifer is currently an assistant professor of physiology at the Johns Hopkins School of Medicine. She received her undergraduate degree in biology from Truman State University and earned her Ph.D. in renal physiology from the University of Nebraska Medical Center. She then spent five years training as a postdoctoral fellow in the laboratory of Michael Caplan at Yale University, where she studied both renal physiology and sensory biology systems and focused on olfaction. Dr. Jennifer Pluznick on the web John Hopkins Pluznick Lab Pubmed Ted Talk Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Fiona Marshall on structure-based GPCR drug discovery, the GABA-B heterodimer, the acetate that rewrote a receptor family, and why the same names keep filling GPCR conference agendas. << Back to podcast list Strategic Partner(s) Dr. Fiona Marshall: Three Decades Inside GPCR Drug Discovery This conversation traces how structure-based GPCR drug discovery moved from a stubborn crystallography problem to a generative platform — through the career of a scientist who helped engineer that shift. Dr. Fiona Marshall walks through the decade when membrane proteins kept failing to crystallize in detergent, and how Chris Tate's thermostabilization strategy finally made GPCR structures routine, the insight that seeded Heptares Therapeutics. The conversation moves across discoveries that shaped a generation of GPCR pharmacology: the GABA-B heterodimer, the free fatty acid receptors, the unexpected allosteric pockets that emerged once structures became available. It also confronts where the field still struggles — translating biased agonism from cell line to clinic, drugging orphan receptors without obvious phenotypes, and expanding the voices that define the field's agenda. For Dr. Marshall, the throughline is personal: she remembers the exact lecture at Bath where she first heard about the β-adrenergic receptor, and has spent three decades inside the rooms where GPCR drug discovery actually changed. About the Guest Dr. Fiona Marshall is VP and Head of Neuroscience Discovery at MSD, leading teams in West Point, Boston, and London. She co-founded Heptares Therapeutics and served as Chief Scientific Officer for twelve years, through the company's acquisition by Sosei, helping establish structure-based drug design as a productive strategy across GPCR families. Earlier, at GSK, she contributed to the identification of RAMP proteins, the GABA-B heterodimer, and ligands for orphan receptors including what are now known as FFA2 and FFA3. Her work spans GPCR structural biology, membrane protein stabilization, allosteric modulation, and the pharmacology of receptor families implicated in neuroscience, immunology, and metabolism. Scientific Themes of the Conversation Structure-based GPCR drug design and the thermostabilization breakthrough GPCR heterodimerization and the logic of accessory proteins (RAMPs, GABA-B1/B2) Allosteric modulation and non-orthosteric binding sites on GPCRs Biased agonism, target validation, and animal-to-human translation failure Orphan GPCRs and the missing pharmacology of ~100 unassigned receptors GPCRs in oncology, immunology, and microbiome-host signaling Key Insights from the Conversation Why Membrane Proteins Wouldn't Crystallize The bottleneck wasn't expression level, as most groups had assumed — it was the instability of the receptor in detergent. Chris Tate's thermostabilization strategy, which introduced stabilizing mutations selected by thermal assay, reframed the problem and opened the door to routine GPCR crystallography. Dr. Marshall is clear that the conceptual reframing, not a brute-force technical push, is what unlocked the field. The GABA-B Heterodimer Was Hiding in Plain Sight Dr. Marshall's team at GSK cloned GABA-B1, tried to get it to signal, and couldn't. A screen run to find an intracellular scaffolding partner pulled up something unexpected: a second GABA-B receptor. The moment baclofen activated ion channels in Xenopus oocytes expressing both — with Dr. Marshall in the room — a new category of GPCR biology opened, with heterodimers as obligate signaling units. The Ligand That Wasn't the Ligand Screening orphan receptors in yeast, the team chased peptide hits that made no SAR sense. The realization — triggered by Andrew Brown sitting with a table of actives and inactives — was that the active condition was the acetate buffer, not the peptide. The orphan was a free fatty acid receptor. Years of assumed peptide biology dissolved into a simpler truth hidden in the solvent. Structures Reveal Pockets the Field Didn't Know Existed Once GPCR structures became routine, unexpected binding sites emerged: extra-helical pockets on the glucagon receptor, intracellular sites for C5a antagonists, allosteric modulators bound far outside canonical regions. These discoveries rewrote what counts as "druggable" on receptors once considered fully mapped. Biased Agonism Needs Human Biology, Not Just Pathway Dials The promise of biased ligands — pulling one signaling arm while sparing another — only survives translation if the coupling profile in the relevant human cells matches the cell-line model. Dr. Marshall's caution is hard-won: many animal-model-validated GPCR drugs have failed in the clinic precisely because this step was skipped. Oncology Ignored GPCRs for Decades — and Is Paying Attention Now Twenty years ago, cancer biologists dismissed GPCRs: they weren't oncogenic and didn't kill tumor cells directly. The shift came through the tumor microenvironment — immune cells, chemokine receptors, adenosine signaling — where GPCRs now sit at the center of immuno-oncology strategies that tumor-intrinsic target lists missed. Thirty Years, and the Same Names Keep the Mic One of Dr. Marshall's most pointed observations: the people speaking at GPCR conferences today are, in large part, the people who were speaking at them twenty-five years ago. She frames this as a scientific problem — a narrowing of perspectives on hard problems — not only a social one, and argues the old guard should actively make room for the next cohort. Episode Timeline Timestamps were generated using AI for readability. 00:00 Welcome and guest introduction 02:32 How an undergraduate lecture on β-adrenergic signaling set a career in motion 07:07 A venture capital visit to the LMB and the founding of Heptares 11:28 Building a membrane protein team from scratch 15:29 Unexpected allosteric pockets and the next wave of GPCR drug design 18:47 Which GPCR families pharma is chasing now — and why 21:23 Why animal model validation keeps breaking in clinical trials 27:33 How oncology finally stopped ignoring GPCRs 36:39 The GABA-B heterodimer — the moment baclofen finally worked 40:06 The acetate-in-the-buffer discovery 41:47 Thirty years in, and the same speakers keep getting the mic Selected Quotes "We did the classic experiment in Xenopus oocytes, where you inject the cDNA of both the receptors together. And I was in the room when we then added on baclofen, the agonist, and we could see the ion channel activation." "He just sat down with a table of what was active or inactive. And then he realized the peptides that had been dissolved in acetic acid or acetate were the ones that were active... So it turned out that the ligands were not the peptides at all." "Having worked in GPCRs for 30 years and I look at the conferences, the same people are speaking now as was speaking 25 years ago. So can we now try and encourage the next cohort of people to be the main speakers at conferences?" "We had this really cool room where you could see — you put on 3D glasses and see the receptor in three dimensions sort of floating in the room and moving around." About this episode Fiona Marshall got fascinated with GPCRs after attending a lecture on how the beta-adrenergic receptor in the heart is activated by adrenaline, during her undergraduate studies at Bath University. She then pursued her Ph.D. in neuroscience at Cambridge University. An expert in GPCR biology, Fiona published the first description of the cloning and structural requirements of the GABAB receptor. One of her career path-defining moments came when she visited Dr. Chris Tate and Dr. Richard Henderson at the Laboratory of Molecular Biology in Cambridge, UK. As a co-founder of Heptares Therapeutics , now called Sosei Heptares , a GPCR-focused drug discovery and development biotechnology company, Fiona and her team made considerable breakthroughs in the field of GPCR stabilization and structure-based drug design. Today, Dr. Marshall is the VP Head of Neuroscience Discovery and Head of Discovery UK, Global Head of Neuroscience discovery research leading teams in West Point, Boston, and London at MSD. Join me and learn more about her fascinating career trajectory. Dr. Fiona Marshall on the web LinkedIn Twitter Google Scholar MSD UK Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) EARNEST Panel: Can AI Accelerate GPCR Drug Discovery? In October 2020, five scientists gathered virtually at the 3rd EARNEST meeting to debate a question that has only grown more urgent: can artificial intelligence actually accelerate GPCR drug discovery, or is it mostly a rebranding of methods the field has used for decades? Panelists from InterAx Biotech, Rockefeller University, and the University of New Mexico — computational chemists, systems biologists, structural biologists, and drug-discovery veterans — drew on their combined experience to separate what machine learning can credibly do for GPCR research from what still depends on pharmacological judgment. The conversation moves from definitional clarity (AI is not machine learning, and neither is simple computational modeling) to the practical realities of building usable datasets, deorphanizing receptors, handling generative models, and confronting the true-negatives problem that quietly breaks so many published models. For any scientist whose grant proposal now contains the phrase "machine learning" whether they fully believe in it or not, this panel is an honest audit of what the technology can deliver today and where it still falls short. About the Panelists Dr. Maria Waldhoer is Chief Scientific Officer at InterAx Biotech in Switzerland. A pharmacologist by training, she spent more than six years in early R&D at Novo Nordisk before turning to systems biology approaches for connecting in vitro signaling data to in vivo drug behavior. Dr. Aurélien Rizk is Chief Technology Officer at InterAx Biotech. Trained as a mathematician and computer scientist, his doctoral work focused on developing new methods for modeling GPCR signaling pathways. Dr. Yaroslav Nikolaev is a scientist at InterAx Biotech with a dual background in biology and computation. His research combines biomolecular NMR, structural biology, and machine learning to study how GPCRs function dynamically. Dr. Thomas Sakmar has run a laboratory at Rockefeller University for roughly thirty years. His group contributed to the early cloning of GPCRs in the mid-1980s and has since pushed the boundaries of GPCR biochemistry — including early homology modeling, coarse-grained molecular dynamics, and genetic code expansion for site-specific chemistry on receptors. Dr. Tudor Oprea is Principal Investigator at the University of New Mexico and coordinator of the Illuminating the Druggable Genome Knowledge Management Center. An MD-PhD who has practiced machine learning since 1989, he built Pharos, the public-facing data platform for the IDG program, and co-developed G1, the first agonist for GPR30, which reached an IND for melanoma. Scientific Themes of the Conversation The definitional boundary between AI, machine learning, and computational modeling Data quality as the rate-limiting step for machine learning in GPCR pharmacology Orphan receptor deorphanization and the limits of learning from known peptides Generative models, scoring functions, and the role of molecular dynamics in ligand design The true-negatives problem and how it distorts biological models The hybrid future: chemical intuition, experimental judgment, and where computation still falls short Key Insights from the Conversation AI and machine learning are not the same thing, and the difference matters. Machine learning finds patterns in defined datasets; AI aims to substitute for human reasoning more broadly. Using the terms interchangeably blurs what each approach can realistically deliver in a pharmacology workflow. The barrier isn't messy data — it's missing metadata. Most pharmacology datasets aren't useless for ML; they're incomplete. Buffers, incubation temperatures, time points, co-expression conditions, the specific Emax reference — these are the details that determine whether a dataset can be pooled with others or must stand alone. Deorphanization via AI is possible, but constrained by what we already know. Random-forest classifiers trained on known peptide ligands can find new orphan-receptor pairings. But the remaining orphans may be orphans precisely because they don't resemble anything we've characterized — which caps what this class of model can find. The bottleneck in structure-guided ML isn't the algorithm. The panel agreed that the real limits are the availability of high-resolution GPCR structures and the computational cost of molecular dynamics simulations needed to capture the dynamic conformations behind signaling. True negatives quietly wreck biological models. Most published models rely on inferred negatives — genes or molecules assumed inactive by convenience. When one panelist replaced inferred negatives in an autophagy model with CRISPR-validated true negatives, the model's predictions changed radically. Chemical intuition has no AI equivalent yet — and won't soon. The experience of a seasoned medicinal chemist mentally docking a molecule from a 2D structure is not a skill current models replicate. The panel expects a hybrid future, not a replacement one, for the next five to ten years. Olfactory GPCRs remain a trillion-dollar opportunity the field has largely ignored. GPCR-targeting drugs represent roughly 0.9 trillion dollars in global sales across 75 countries. Olfactory GPCRs — which account for a large fraction of the receptor class — have been systematically sidestepped for lack of tractable in vitro screening methods. Episode Timeline 00:00 Welcome from Yamina Berchiche 01:36 Panelist introductions 11:41 AI vs machine learning — the definitions that matter 15:21 The undrugged majority: 400 non-olfactory GPCRs, only 160 drugged 20:12 What makes a pharmacology dataset usable for machine learning 24:41 Advice for small academic labs entering the field 30:34 Can AI help deorphanize understudied receptors? 37:01 Reading GPCR signaling dynamics with computational models 39:53 Generative models, scoring functions, and molecular dynamics 50:32 The true-negatives problem and the limits of inferred datasets 52:30 Hype vs reality in AI drug discovery 55:05 Where the GPCR field goes in the next five years Timestamps were generated using AI for readability. Selected Quotes "My computational team told me, 'this receptor is not using arrestin to internalize. There has to be an arrestin-independent thing there.' And I'm like, that's rubbish. Never picked it up. Complete rubbish. And then a year later or so, I get a call from a colleague who said, 'oh, we've tested this compound as a negative control because we thought it doesn't need arrestin to internalize. And now we put it in this CRISPR knockout cell and — it does.'" — Dr. Maria Waldhoer "In 1989, as a med student in Romania, I used BASIC to model the variation in heart rate and blood pressure for 11 patients. I wrote an 11 polynomial that fit everything, so I thought I had solved the problem with drug discovery. I have learned a lot since." — Dr. Tudor Oprea "Dan Rich worked on HIV protease inhibitors. He would look at the 2D structure and basically mentally do a docking and tell you whether that's a good protease inhibitor or not. I think there are people who have worked in the GPCR field that can do a similar exercise." — Dr. Tudor Oprea "If you only make big enough numbers, big enough networks, big enough algorithms, suddenly intelligence pops out on the other side. [Roger Penrose] said, well, it's simply because they cannot think of anything else to do yet." — Dr. Maria Waldhoer About this episode Listen to this fantastic round table discussion that I had the privilege to moderate with Alexander Hauser . Our guests were Maria Waldhoer , Tudor I. Oprea , Thomas Sakmar , Aurelien Rizk & Yaroslav Nikolaev . The explosion of biomedical data such as in genomics, structural biology, and pharmacology can provide new opportunities to improve our understanding of human physiology and disease. In recent years, machine learning (ML) and artificial intelligence (AI) methods have received a significant boost in attention. ML/AI can be powerful for identifying abstract patterns within large data where traditional methods would be oblivious to. This comes without the need for manual feature engineering as systems can learn through implicit rules from the data provided. G protein-coupled receptors (GPCRs) mediate a vast variety of critical biological processes and provide an ideal case study for quantitative, and multi‐scale integration of these amounts of data to gain novel insights into receptor biology. How can we best leverage these exciting new techniques in areas such as protein structure prediction, bioactive ligand discovery, in-vivo translation ability, or in our understanding of signaling determinants? Here, we would like to discuss the opportunities, weaknesses, and advantages of these new technologies, which may contribute to probe our favorite targets at all scales. For more information on the ERNEST network, visit https://ernest-gpcr.eu/ . Dr. Yamina Berchiche on the web Website LinkedIn Publications Twitter Facebook Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

From chemokine receptors at Rockefeller to founding Dr. GPCR during COVID — the career arc behind the ecosystem built for the field's unreached receptors. << Back to podcast list Strategic Partner(s) Dr. Yamina Berchiche: Beyond the Lab — From Chemokine Receptors to the Dr. GPCR Ecosystem Dr. Yamina Berchiche spent two decades working on G protein-coupled receptors at the bench — training that spanned chemokine receptor conformational dynamics at the Université de Montréal, CXCR3 splice-variant signaling at Rockefeller University in Dr. Tom Sakmar's lab, CRISPR knockout generation at NIAID, and class B peptide receptor work at Generate Biomedicines. Across those stops, one observation kept resurfacing: the GPCR field is enormous — roughly 400 non-olfactory receptors — but clinical drug discovery has reached only about 166 of them, leaving more than 250 receptors unstudied at anything close to therapeutic depth. This conversation traces the scientific arc that led Dr. Berchiche to leave the bench after a COVID-era redundancy, and examines the motivation behind founding Dr. GPCR — an ecosystem of podcasts, newsletters, summits, and working spaces designed to give the field connective tissue it has historically lacked. For Dr. Berchiche, this work is personal: the receptors she helped characterize for years belong to a family she believes has been collectively underserved by the infrastructure around it, and building that infrastructure has become a full-time scientific question in its own right. About the Guest Dr. Yamina Berchiche is the founder of the Dr. GPCR ecosystem and the host of the Dr. GPCR Podcast. She holds a PhD in Biochemistry from the Université de Montréal, where she trained in Dr. Nikolaus Heveker's lab at the CHU Sainte-Justine Research Center on chemokine receptor structure–function relationships, with extensive collaborative work in Dr. Michel Bouvier's lab on BRET-based conformational readouts. She completed postdoctoral training at Rockefeller University in Dr. Tom Sakmar's lab, where she characterized the signaling diversity of three alternative splice variants of CXCR3. Her career has moved through academic pharmacology, a research fellowship in B-cell molecular immunology at NIAID, and a senior scientist role at Generate Biomedicines, where she worked on class B peptide receptor engineering using AI-driven protein design. She now builds scientific community infrastructure for the GPCR field. Scientific Themes of the Conversation Chemokine receptor redundancy and the shift toward functional selectivity as a framework Splice variants as signaling variants — CXCR3 as a case study for transcript-level diversity The orphan-majority problem in GPCR drug discovery — why ~250 non-olfactory receptors remain outside clinical attention Career architecture for bench pharmacologists moving beyond academia and biotech Scientific community as infrastructure — what connective tissue a 400-receptor field actually needs Assay design as the lever that shifts conceptual frameworks Key Insights from the Conversation Rejection as redirection. The summer placement Dr. Berchiche didn't get in Michel Bouvier's lab led her to Nikolaus Heveker's newly opened lab at CHU Sainte-Justine, where she was the first student. The lab had no equipment, only stacks of bills on every bench — and a research program on chemokines and chemokine receptors that would define her career. The redundancy assumption crumbled under better assays. The chemokine system — roughly 50 ligands for 20 receptors — was framed for decades as redundant because multiple chemokines bind multiple receptors. Dr. Berchiche's thesis work on CXCR4 mutants and her PhD characterization of natural chemokines binding CCR2B showed the opposite: distinct ligands activate distinct signaling outputs, and functional selectivity was quietly hiding inside what had been called promiscuity. Splice variants aren't just structural — they signal differently. Her Rockefeller work on the three alternative splice variants of CXCR3, initially prompted by a simple question from Tom Sakmar, demonstrated that variants encoded by the same gene can recruit different signaling outputs in response to the same ligands. The implication: transcript-level diversity is itself a signaling mechanism, not a cloning artifact to be collapsed away. The 250-receptor problem sits in plain sight. Of roughly 400 non-olfactory GPCRs, only about 166 are being targeted or studied for clinical application. The remaining 250+ are not obscure — they are simply not connected to drug-discovery momentum. This gap, visible in the 2017 mapping work by Dr. Alexander Hauser and colleagues, is the motivating tension behind Dr. GPCR. The 30,000-foot view requires leaving the bench. After nearly two decades in the lab, Dr. Berchiche found that deep focus on one project was no longer fulfilling. The bench scientist's perspective — which she explicitly values — comes at the cost of the field-level view that ecosystem-building requires, and choosing between them turned out to be a real career architecture decision rather than a detour. Community is scientific infrastructure, not marketing. A podcast, a monthly newsletter, and a virtual summit are not promotional surfaces. They are the connective tissue a 400-receptor field uses to exchange techniques, ideas, and trust across institutional boundaries. Without that tissue, GPCRs stay siloed by receptor family and by lab. Building during a pandemic is a design constraint, not a footnote. Dr. GPCR was founded in March 2020 after a COVID-era redundancy at Generate Biomedicines. Early episodes were recorded in a Toyota Prius parked outside a gym with public Wi-Fi, and then in a closet studio her husband built so she could keep the AC running without bleeding background noise into the audio. The ecosystem's physical origins are inseparable from its founding conviction. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 02:25 The closet studio and what's in the talk 04:00 From Oradea to Montreal — the geography of a GPCR career 06:30 An empty lab and the chemokine redundancy problem 09:00 A master's, old-school molecular biology, and an accelerated JBC paper 11:00 CCR2B, functional selectivity, and a stellar reviewer moment 14:00 Rockefeller, CXCR3, and three splice variants that weren't the same 17:00 NIH and the pull toward a 30,000-foot view of the field 21:00 COVID, redundancy, and the 250 GPCRs nobody studies 23:08 Building the Dr. GPCR ecosystem 32:28 Q&A — preparing an episode, funding, and what's next 46:53 Recording Brian Roth from a Prius — the closet-studio origin story Selected Quotes "You have 400 non-olfactory GPCRs. Only about 166 of them are being targeted and studied for clinical applications. But you have 250-plus receptors that are not well characterized enough and are not considered for the treatment of any diseases." "If you want to advance the field and you want to drug GPCRs better, the point is not to show that you can pipette, but the point is to get to that result." "At NIH, I decided that I wanted to go what you'd call the dark side, which I don't think it's the dark side." "Brian throughout his career was told so many times that he should quit science. And thank God he did not quit science. That's the kind of story that I like to share in the podcast." About this episode GPCRs have played a central role in my scientific career ever since I took Dr. Michel Bouvier’s class as an undergraduate student at the University of Montreal in early 2000. During the past 2 decades, my research mainly focused on chemokine receptor structure/function relationships. For the purposes of this presentation, I will walk you through my various career experiences and include the skills I learned during each experience, which ultimately led me to found Dr. GPCR. Last, I will give an overview of the various programs we established at Dr. GPCR, present our team as well as provide you with a sneak peek of our future podcast guests and more. I gave a talk on October 12th at the 3rd ERNEST meeting about the Dr.GPCR Ecosystem . I want to say thank you to the ERNEST meeting organizers for the invitation with special thanks to Dr. Martha Summer and Dr. Alexander Hauser , and Luise Wagner . For more information about the ERNEST network, visit https://ernest-gpcr.eu/ . Dr. Yamina Berchiche on the web D r. GPCR Ecosystem Member Website LinkedIn Publications Twitter Facebook Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Aaron Sato on building the synthetic antibody library that finally makes GPCRs tractable — and the greenfield strategy that led him there. << Back to podcast list Strategic Partner(s) Dr. Aaron Sato: Synthetic Antibody Libraries for the Hardest GPCR Targets GPCRs account for a substantial fraction of validated drug targets, yet most are drugged by small molecules — antibodies against GPCRs remain notoriously difficult to discover. This conversation explores how synthetic antibody phage display libraries, built on silicon-based DNA synthesis, are rewriting that constraint. Dr. Aaron Sato, CSO of Twist Biopharma, describes the motif-directed library his team developed by collecting known GPCR-binding sequences from protein, peptide, and antibody ligands and seeding them into the heavy chain CDR3 of a fully human synthetic library. The discussion covers why degenerate oligos had been the bottleneck for library quality, how a "library of libraries" strategy sidesteps the ten-billion-variant ceiling that caps any single phage library, and why the team can now move from a GPCR target to a bivalent IgG ready for functional assays in eight to ten weeks. For Aaron, this work is personal: he has built his career hunting greenfield targets where others had failed — and GPCRs were the greenfield he had been waiting for. About the Guest Dr. Aaron Sato is the Chief Scientific Officer and VP of Protein Engineering at Twist Biopharma, the biologics division of Twist Bioscience. He earned his PhD at MIT in the laboratory of Lawrence Stern, where he studied structure-function relationships of MHC class II proteins by X-ray crystallography. His career has traced the evolution of antibody engineering, with leadership roles at DIAX, Oncomed, Sutro Biopharma, and Lake Pharma before joining Twist. His current focus is building synthetic phage display libraries that drug targets the field has long treated as intractable — GPCRs chief among them. Scientific Themes of the Conversation Silicon-based DNA synthesis and the end of degenerate oligos in library design Motif-directed library design — encoding ligand-binding sequences into CDR3 architecture The library of libraries as an answer to the diversity ceiling of single phage libraries Greenfield target selection as a drug discovery strategy Family-level cross-reactivity as an advantage, not an obstacle, in GPCR antibody discovery Timelines, automation, and the industrialization of antibody workflows Key Insights from the Conversation Silicon DNA synthesis removes the degenerate oligo bottleneck. Traditional synthetic libraries rely on degenerate or trinucleotide mixtures to encode CDR diversity, which limits control over which variants actually appear. Twist's silicon platform produces pools of discrete, designed sequences — a shift in how synthetic libraries are composed. The motif-directed library encodes prior biological knowledge directly into CDR3. By curating protein, peptide, and antibody motifs known to bind GPCRs and inserting them at the top of the heavy chain CDR3, the library enters each panning campaign already biased toward the target class. The design decision is the library's main differentiator. A motif-directed library reaches targets its motifs weren't designed for. The same library has produced antibodies against orphan GPCRs and receptors without peptide ligands, because the surrounding CDR diversity provides enough variation to find binders outside the seeded motif content. Phage display's ~10¹⁰ variant ceiling can be broken by stacking libraries. Any single phage library is capped near ten billion variants. Running multiple libraries in parallel moves the effective diversity toward 10¹² — the idea Aaron calls his library of libraries. Eight to ten weeks from a GPCR target to a functional IgG is the platform's working tempo, not a best case. By skipping fragment-based screening and going directly to full bivalent IgG, the team hands functional biology teams a molecule that is ready for flow cytometry and receptor assays almost immediately. Aaron's strategy is deliberately greenfield. He looks for target classes where existing platforms have already failed — not because the biology is easier, but because new technology is rewarded most where the incumbents have stalled. GPCR family architecture is a discovery advantage. Receptors within a family share sequence and surface topography, so an antibody recovered against one member is often a legitimate starting point for discovery across the family. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction and sponsor acknowledgment 01:53 The conversation begins 02:29 From MIT crystallography to leading Twist Biopharma 04:21 Twist Bioscience, Twist Biopharma, and the silicon DNA platform 08:12 Using DNA for long-term data storage — a parallel vertical 09:17 Why antibodies to GPCRs have stayed so intractable 09:29 The motif-directed library — encoding receptor motifs into CDR3 12:34 Why one antibody can open up a whole receptor family 14:36 Eight to ten weeks from target to tested bivalent IgG 17:21 The library of libraries — scaling past 10 billion 18:42 Who partners with Twist Biopharma today 22:45 Beyond oncology — inflammation, metabolism, cardiovascular 24:55 Running a protein engineering team through a pandemic Selected Quotes "Synthetic antibody phage display libraries are actually best used for really difficult to drug targets." "I often love to look for my greenfield areas, where there's not a lot of competition because there's just really no technology that enables you to drug specific targets." "In phage display, you're oftentimes kind of capped out around 10 billion different antibodies per library. One way around that limited diversity is to actually have multiple libraries." "GPCR antibodies are just so intractable oftentimes." About this episode In this episode of the Dr. GPCR Podcast , I spoke to Dr. Aaron Sato from Twist Biopharma , a vertical within Twist Bioscience . Aaron is currently the Chief Scientific Officer and VP of Protein Engineering. He earned his Ph.D. at the Massachusetts Institute of Technology, where he studied MHC class II structure-function relationships. His path led him to work in an industry where he assumed various responsibilities and roles in the antibody space. Aaron has a proven track record as a biologics leader as he led teams to discover and develop novel first-in-class antibody therapeutics. Dr. Sato published over 30 peer-reviewed papers and contributed to 40 issued patents in the antibody space. During our time together, Aaron and I discussed how using Twist Bioscience’s proprietary technology to manufacture DNA at a scale, the team saw an opportunity to tackle the challenge of identifying novel functional antibodies targeting GPCRs by incorporating these natural binding partners into Twist’s antibody library design. We’d like to extend a special thanks to Twist Biopharma for sponsoring this episode of the Dr. GPCR podcast. Dr. Aaron Sato on the web LinkedIn Twitter Google Scholar Twist Bioscience Twist Biopharma Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Amynah Pradhan on why mu opioids worsen migraine, why delta agonists may relieve it, and how chronic disease states rewrite drug discovery. << Back to podcast list Strategic Partner(s) Dr. Amynah Pradhan: The Delta Opioid Receptor and the Migraine Paradox Chronic migraine sits at a peculiar crossroads in opioid pharmacology: sustained mu opioid receptor activation is a well-documented driver of medication-overuse headache, while preclinical evidence points to delta opioid receptor agonism as a candidate to relieve the same disorder. Dr. Amynah Pradhan's lab at the University of Illinois at Chicago has spent years pulling apart that asymmetry — combining mouse models of chronic migraine, cortical spreading depression, and opioid-induced hyperalgesia with peptidomic screens and conditional genetics to ask where the two receptors diverge anatomically, pharmacologically, and in the chronic disease state. The work sits inside a larger argument Dr. Pradhan returns to often: that organisms in chronic pain are fundamentally different biological systems than naïve ones, and that drug discovery fails when it pretends otherwise. For her, this line of work is also personal — the delta opioid receptor has been her scientific focus for nearly two decades, through failed clinical trials in depression and pain, and migraine may finally be where it finds a clinical home. About the Guest Dr. Amynah Pradhan is Associate Professor of Psychiatry at the University of Illinois at Chicago, where her lab studies opioid receptor biology in the context of headache disorders, chronic pain, and their comorbid emotional states. She trained in pharmacology at McGill University with Paul Clarke and completed postdoctoral work at AstraZeneca, with Brigitte Kieffer in Strasbourg, and with Chris Evans at UCLA. Her research integrates behavioral pharmacology, ligand-directed signaling, and mouse models of migraine, and has become central to the small community of basic pharmacologists working inside the headache field. Scientific Themes of the Conversation The mu/delta asymmetry in migraine — why two receptors in the same family produce opposite clinical outcomes Chronic disease states as fundamentally altered biological systems — and what that means for drug discovery Ligand-directed signaling and receptor trafficking — how internalization shapes tolerance and adverse effects The emotional circuitry of chronic pain — and the kappa opioid / dynorphin link The unfinished GPCR frontier — PACAP, CGRP, and the persistent antibody problem Career mobility through collaboration — how a headache neurologist redirected two decades of work Key Insights from the Conversation The yin-yang that organizes the lab. Mu opioid agonists, in chronic use, exacerbate migraine and drive medication-overuse headache. Delta opioid agonists appear to relieve the same symptoms — pain, negative affect, and aura-related signs in preclinical models. Dr. Pradhan treats the contrast not as a side story but as the organizing question of her work. Chronic states are not scaled-up acute states. One of Dr. Pradhan's recurring arguments is that the organism in a chronic disease state is fundamentally altered, and that drug candidates fail in clinical trials partly because they are validated in naïve animals that do not resemble the patients they will eventually treat. Internalization is a design choice, not a side effect. Earlier work in her career showed that high-internalizing delta agonists drive receptor downregulation and tolerance, while low-internalizing agonists uncouple the receptor from ion channels without losing it. The ideal delta agonist, by her account, would be non-internalizing, brain-penetrant, long-half-life, and directed at forebrain circuits where emotional salience of pain lives. Delta agonists may finally have a disease. After failed trials in depression and pain, Dr. Pradhan argues that migraine — with its emotional comorbidity, its anatomical overlap with delta receptor expression, and its distinctive pain mechanisms — may be the clinical home the compound class has been looking for. The conviction is quiet but deeply held. The antibody problem is keeping a field from basic answers. Her "bugaboo": we still do not know reliably where many GPCRs live — which cell type, which compartment, surface versus intracellular — because antibodies for the family are widely unreliable. For a pharmacologist, the resolution problem sits upstream of every other question. A single collaboration can redirect a career. Her move from pure opioid pharmacology into migraine came from sharing a building with neurologist Andrew Charles at UCLA. She treats this as a generalizable lesson for junior scientists: openness to collaboration is not decorative — it is how fields get rewired. The invisible labor of being the only one in the room. Toward the end of the conversation, Dr. Pradhan turns to the structural weight carried by women and scientists of color in academia — the cumulative load of committee service, mentorship, and representation — and argues that real support requires institutions to account for it, not just request it. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 01:13 From McGill to migraine — a path through four labs 04:19 Why mu worsens migraine and delta relieves it 09:27 What chronic dosing does to the receptor — tolerance, internalization, downregulation 14:17 Designing the delta agonist she wants 17:30 The emotional circuitry of chronic pain — and the kappa link 22:22 CGRP, PACAP, and why GPCR drug discovery is not out of runway 28:54 Biased ligands after the hype cooled 34:08 How you measure migraine in a mouse 40:44 Three aha moments — and why delta agonists may finally have a home 43:28 The hidden cost of being the only one in the room 57:05 What the pandemic did to a mouse colony Selected Quotes "The delta opioid receptor is my baby. I've been working on it for almost 20 years under lots of different contexts." "The organism is fundamentally altered in a chronic disease state. They're not in the same state as they were if they were naïve. Patients didn't come to the doctor to look for drugs because they were feeling fine." "Every person I know who studies G-protein coupled receptors will tell you — the antibodies suck. We're still arguing about where the receptor is. What cell type it's on. Is it on the cell surface? Is it inside the cell? The fact that we can't say that is kind of crazy to me." "Maybe the disease state where delta ligands would really be effective would be in headache disorders — in migraines specifically. Maybe this is where it all comes together." About this episode In this episode of the Dr. GPCR podcast , we meet with Dr. Amynah Pradhan. She is an Associate Professor of Psychiatry at the University of Illinois at Chicago. Amynah did her undergrad research measuring IP3 in airway smooth muscle cells and completed a Ph.D. at McGill University in Canada with Dr. Paul Clarck , where she studied opioid receptors. Her next career step took her to AstraZeneca as a postdoctoral trainee, where she studied animal models of pain and sensory neuron sensitive-receptor. She then returned to academia and worked on opioids as a postdoctoral trainee with Dr. Brigitte Kieffer , where she studied ligand-directed signaling at the delta-opioid receptor. Her career path-defining moment came from a third postdoctoral experience with Dr. Chris Evans at UCLA. Amynah studied how arrestins regulate ligand-directed signaling at delta-opioid receptors, and it is their collaboration with a headache physician-scientist Dr. Andrew Charles that who specialized in animal models of migraine and delta-opioid receptors as a therapeutic target to treat headache. Dr. Amynah Pradhan on the web Lab page LinkedIn Twitter Google Scholar PubMed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Antonella Di Pizio on building computational models for GPCRs with almost no crystal structures and almost no ligands — bitter taste receptors, odorant receptors, and the trace amine-associated receptors that may one day treat depression. << Back to podcast list Strategic Partner(s) Dr. Antonella Di Pizio: Computational Pharmacology of Taste and Olfactory Receptors Chemosensory receptors — bitter taste receptors (TAS2Rs), odorant receptors, and trace amine-associated receptors (TAARs) — sit among the most structurally underserved families of class A GPCRs. No crystal structures exist for most of them, sequence identity within the TAS2R family hovers between 15% and 19%, and several members are effectively orphans with only a handful of known ligands. Yet these receptors appear to govern far more than flavor and smell. Bitter taste receptors have been identified in the heart and intestine, olfactory receptors in the brain, and the TAARs sit at the interface between neurotransmission and chemoreception — with clinical interest emerging in schizophrenia, neurodegeneration, depression, and anxiety. In this conversation, Dr. Antonella Di Pizio — who leads the computational pharmacology group at the Leibniz Institute for Food Systems Biology at the Technical University of Munich — describes how she uses homology modeling, docking, molecular dynamics, and iterative mutagenesis to probe these systems. For her, the work isn't abstract: she spent five months staring at empty protein crystals during her PhD, and learned that the distance between giving up and seeing a ligand inside a binding pocket can be measured in weeks. About the Guest Dr. Antonella Di Pizio is an independent research group leader in computational pharmacology at the Leibniz Institute for Food Systems Biology at the Technical University of Munich, where she was the first group leader appointed to the institute's newly-formed in-silico department. Trained as a medicinal chemist at the University of Chieti in Italy, she completed her PhD in computational medicinal chemistry before spending a formative period in Gerhard Klebe's structural biology lab in Marburg. Her postdoctoral training in Masha Niv's lab in Israel marked her first work on GPCRs, specifically the bitter taste receptors (TAS2Rs). Her group now studies taste receptors, odorant receptors, and trace amine-associated receptors using a combination of homology modeling, docking, molecular dynamics, and virtual screening — tightly integrated with experimental mutagenesis and functional assays through collaborations. Scientific Themes of the Conversation Chemosensory receptors as a frontier for GPCR drug discovery Trace amine-associated receptors (TAARs) and their neurological relevance Promiscuity and selectivity within the bitter taste receptor family Iterative integration of computational modeling with experimental mutagenesis Ectopic expression of taste and odorant receptors beyond their namesake tissues Persistence, career building, and what it means to lead a first-generation computational group Key Insights from the Conversation The first in-silico group inside a food biology institute. When Dr. Di Pizio arrived in October 2018, she founded the first computational group in an institute whose original identity had been food chemistry. Her job description — computational pharmacology — was itself an attempt to name a new interface between food chemistry and receptor pharmacology. TAARs look more classical than most chemosensory GPCRs — and that matters for modeling. Unlike bitter taste receptors, which share only 5–10% sequence identity with available structural templates, the TAARs share roughly 30% identity with the β2-adrenergic receptor. That proximity transforms what's computationally tractable, making homology modeling genuinely predictive rather than speculative. TAAR5 is effectively orphan — and may be a new kind of antidepressant target. With only about five known agonists, TAAR5 sits in a pharmacological twilight. Yet knockout mice show anti-anxiety, anti-depressant phenotypes, and expression of the receptor in the brain alters serotonin levels. An antagonist of TAAR5 could, in principle, seed a new class of psychiatric therapy. Bitter is not only about taste. TAS2Rs have been identified in the heart and intestine; olfactory receptors in the brain. What they do there remains largely unknown. But evidence is accumulating that bitter taste receptors participate in innate immunity, recognizing bacterial secretions that happen to register as bitter on the tongue. A bitter receptor is already in phase 2 clinical trials. Isohumulones — the hop-derived bitter compounds that give beer its characteristic flavor — have shown anti-diabetic activity in clinical development. The receptor responsible, TAS2R1, is expressed in the intestine. The drug candidate was never designed as a bitter receptor ligand; the receptor was identified post-hoc. Computational pharmacology is not a downstream silo. Dr. Di Pizio's workflow is deliberately iterative: build the model, predict binding-site residues, send them out for mutagenesis, fold the experimental results back into the model, rebuild. Collaborators are not recipients of finished predictions — they are partners embedded in the modeling loop itself. Five months of empty crystals, then a ligand. During her PhD, Dr. Di Pizio spent five months crystallizing carbonic anhydrase 2 with small molecules and seeing only empty proteins at the synchrotron. Two weeks before her internship ended, after changing every parameter she could think of, she finally saw her ligand inside the binding pocket. She describes it as the happiest moment of her scientific life — and, for a computational chemist, a lasting lesson in what sits behind every coordinate file. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 01:46 Computational pharmacology inside a food systems institute 03:13 From medicinal chemistry to bitter taste receptors 05:44 Trace amine-associated receptors on the edge of neuroscience 12:34 Anosmia and viruses of the olfactory system 19:03 Inside a computational workflow for orphan receptors 29:14 Bitter receptors in the heart and gut 30:43 A bitter receptor in phase 2 clinical trials 43:40 Five months of empty crystals 55:56 Rebuilding a research group during lockdown Selected Quotes "We don't have any crystal structures. So the research is more food-oriented and food-chemistry-oriented — this is why we have knowledge about compounds, but we don't have a lot of knowledge about quantitative structure-activity relations based on the structure of the receptor." "For five months, my protein was always empty at the X-ray. And two weeks before I had to leave, I finally saw my ligand inside the pocket. For me, I think that was my happiest moment in my life." "You share your research goal with your collaborators. They are more partners than collaborators." "Think of being an investor of yourself. Read, study, do the most as you can to learn as much as you can — not only scientifically, but also networking. Be passionate on exactly the field that you work on, because this will be extremely useful later." About this episode In this episode of the Dr. GPCR podcast , we meet with Dr. Antonella Di Pizio, an independent research group leader at the Leibniz Institute for Food Systems Biology at the Technical University of Munich. Antonella trained as a medicinal chemist in Italy, followed by a Ph.D. in computational medicinal chemistry, during which she developed a taste for structural biology. Antonella then moved to Israel, where she first started working on bitter taste GPCRs in Dr. Masha Niv's lab . Today, Antonella has expanded her research to olfactory GPCRs and trace amine receptors. Join us to learn more about chemosensory GPCRs and how computational pharmacology can help better understand their function. Dr. Antonella Di Pizio on the web Leibniz-Institute for Food Systems Biology at the Technical University of Munich Google Scholar PubMed LinkedIn Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

GPCRs drive cancer more often than the textbooks say. Dr. Silvio Gutkind on G protein hotspot mutations, why the canonical GαQ pathway fails in uveal melanoma, and how CXCR3 may gate immunotherapy response. << Back to podcast list Strategic Partner(s) Dr. J. Silvio Gutkind: When GPCRs Drive Cancer GPCRs are the most drugged protein family in medicine, but until recently their role in cancer was treated as marginal — a few curiosities around mas and muscarinic receptors, overshadowed by kinases and Ras. The emergence of cancer genomics has dismantled that framing. Roughly 20% of tumors now show mutations in GPCRs or their coupled G proteins, and specific cancers — uveal melanoma above all — are understood to be driven almost entirely by single hotspot mutations in GαQ. For Dr. J. Silvio Gutkind, who has spent more than three decades pushing GPCRs as oncogenic signaling systems, the shift has concrete stakes: uveal melanoma patients who metastasize to the liver live six to twelve months, and every pathway his lab has opened — from TRIO and Rho to YAP and FAK — has been an attempt to give those patients something the canonical PLC pathway could not. In this conversation, Dr. Gutkind traces how GPCRs moved from a side project nobody believed in to a recognized driver class in oncology, and explains why chemokine receptors like CXCR3 may be the next frontier for understanding immunotherapy response. About the Guest Dr. J. Silvio Gutkind is Professor of Pharmacology and Associate Director of Basic Science at the UC San Diego Moores Cancer Center. His training began at the University of Buenos Aires on alpha-2 adrenergic receptors, continued at the NIH across neurobiology and oncogenes, and grew into a multi-decade program on GPCR signaling in cancer — first as NIH branch chief at NIDCR, then as head of a team that moved cross-country with him to UCSD in 2015. His lab combines classical pharmacology with cancer genomics, bioinformatics, and synthetic lethality approaches to identify druggable nodes downstream of G protein mutations. Current focuses include GαQ-driven uveal melanoma, GαS mutations across pancreatic, colon, and appendix cancers, and chemokine receptor biology in cancer immunotherapy. Scientific Themes of the Conversation GPCRs as oncogenes without mutations — aberrant expression and "oncocrine" autocrine/paracrine signaling The cancer genomics revolution and the rise of G protein hotspot mutations (GαQ Q209, GαS, Gα13) GαQ-driven uveal melanoma and the limits of the canonical PLC pathway Non-canonical GαQ signaling through TRIO, Rho, YAP, and the druggable FAK node CXCR3 and the chemokine axis that gates immunotherapy response Structural biology, machine learning, and team science in GPCR pharmacology Key Insights from the Conversation 1. GPCRs don't need mutations to drive cancer. Aberrant expression — a receptor in the wrong place at the wrong time, paired with autocrine or paracrine ligand — is sufficient to transform cells. Early focus-formation assays using muscarinic receptors and carbachol produced transforming efficiencies comparable to Ras, and the community largely looked away because the biology didn't fit the prevailing mutation-centric frame. 2. Cancer genomics rewrote the role of G proteins. Roughly 20% of tumors carry mutations in GPCRs or G proteins, with striking hotspots in GαQ, GαS, and Gα13. Most large cancer sequencing panels now include these genes — though most oncologists are still unsure what the results mean clinically, leaving a gap between the genomic data and how it's acted upon. 3. The uveal melanoma driver is almost monogenic. Nearly 93% of uveal melanomas carry a single GαQ Q209 activating mutation that blocks GTPase activity. Beyond this driver, the tumor has only a handful of additional mutations — more like a pediatric cancer than an adult one. The canonical assumption that targeting PLC would be therapeutic has failed in the clinic, and patients with liver metastases still have six to twelve months to live. 4. Non-canonical signaling opened a new drug target. A synthetic lethality analysis performed entirely in silico revealed that GαQ tumors depend not only on PLC but on a TRIO → Rho → YAP axis, with FAK emerging as a druggable downstream node. That insight is now powering focal adhesion kinase–directed clinical trials, including one Dr. Gutkind's team is launching. 5. CXCR3 may be the hidden gatekeeper of immunotherapy response. CXCL9, CXCL10, and CXCL11 are among the most robust predictive signatures for checkpoint inhibitor response — and all three are ligands for CXCR3. In knockout mice, loss of CXCR3 abolishes response to both anti-PD-1 and anti-CTLA-4, reframing the receptor as something to activate, not block. 6. "What the heck" moments define real discoveries. Two of Dr. Gutkind's most cited papers came from results that directly contradicted the textbook: βγ subunits (not α) activating ERK through Gi-coupled receptors, and Rho GTPases (not Ras) driving JNK activation. Both required trusting the data when the conceptual framework was telling the team they must be wrong. Both landed in Nature and Cell respectively. 7. Team science is structural, not decorative. The 2020 Cell paper on G protein coupling specificity came from a Gordon Conference hallway conversation, combining bioinformatics from Europe, high-throughput screens from Japan, and biology from UCSD. And the 12 people who moved cross-country from NIH to UCSD did so because of relationships built over years — a retention outcome Dr. Gutkind attributes to the team, not the weather. Selected Quotes "The very simple concept is that GPCRs do not need to be mutated to be oncogenic." "There are cancers that are driven by G proteins. That changed the landscape in terms of understanding and appreciation." "What the heck — this doesn't make sense. And that was our first Cell paper. Still our most cited paper." "Don't be afraid to send emails." Episode Timeline 00:00 Introduction 02:09 From Buenos Aires to NIH: a career that followed the science, not the field 06:19 Operation Exodus — the team that moved cross-country 07:35 The muscarinic focus assay and a side project no one believed in 10:52 The cancer genomics result that reframed GPCRs as drivers 16:45 Why CXCR3 may decide who responds to checkpoint inhibitors 20:28 GαQ, uveal melanoma, and the failure of the textbook pathway 41:27 Structural biology, machine learning, and the coupling problem 45:31 Two "what the heck" moments that became Nature and Cell papers 50:48 Advice for young scientists — read, think, question the dogma 56:33 Why small conferences produce the best collaborations Timestamps were generated using AI for readability. About this episode Have you had moments that defined your scientific tastes? For Dr. J Silvio Gutkind, a class on oncogenes and his interests for GPCRs helped shape his scientific interests. These took him from the University of Buenos Aires in Argentina to UC San Diego and through the National Institutes of Health in Bethesda, Maryland. In this episode, Silvio discusses G protein signaling in the context of cancer, immunotherapies, and combination therapies that could help improve patients’ lives. Dr. J. Silvio Gutkind on the web Dr. J Silvio Gutkind on LinkedIn Gutkind Lab – UC San Diego Moores Cancer Center Gutkind Lab publications Gutkind Lab on Pubmed Gutkind Lab on Twitter UCSD Moores Cancer Center Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Graciela Piñeyro on what happened when her lab tested biased agonism at the μ-opioid receptor across 25 ligands, why δ-opioid receptors recycle from the lysosome, and the quantitative pharmacology that turned an early artifact into a career of receptor work. << Back to podcast list Strategic Partner(s) Dr. Graciela Piñeyro: Partial Agonism, Receptor Recycling, and the Limits of Bias For over a decade, biased agonism at opioid receptors offered a clean route to analgesics without the respiratory depression and tolerance that have defined opioid therapy. If the right ligand could engage G-protein signaling while sparing β-arrestin, pain relief might finally be separable from side effects. In this conversation, Dr. Graciela Piñeyro — who leads an opioid receptor pharmacology group at the CHU Sainte-Justine Research Center and the Université de Montréal — walks through what happened when her lab tested that hypothesis rigorously. Across 25 ligands profiled at the μ-opioid receptor, the team found no bias, only partial agonism. Recent β-arrestin knockout work from Australia, Germany, and the UK has converged on a similar sobering conclusion. The conversation also traces her earlier work showing that δ-opioid receptors recycle from the lysosome — the compartment meant to degrade them — and how recycling patterns, not internalization itself, predict analgesic tolerance. For Dr. Piñeyro, a physician-turned-pharmacologist whose early project in Michel Bouvier's lab felt like "torture" until the right quantitative model turned her artifacts into real pharmacological responses, the throughline has never been building a career. It has been a refusal to treat messy data as noise until the right math arrived to make sense of it. About the Guest Dr. Graciela Piñeyro is a principal investigator at the CHU Sainte-Justine Research Center and a professor in the Department of Pharmacology and Physiology at the Université de Montréal. Trained as a physician in Uruguay, she began doing research in the only way then available to her — through a medical pharmacology department studying how benzodiazepines and alcohol affected sleep architecture. She completed her PhD at McGill University with Claude de Montigny, working on serotonin and antidepressant mechanisms, and her postdoctoral training with Michel Bouvier at the Université de Montréal, where she shifted into opioid receptors. Her lab now studies δ- and μ-opioid receptor signaling, biased agonism, receptor trafficking and recycling, and more recently the cannabinoid entourage hypothesis — combining BRET-based biosensors, quantitative pharmacology, and clustering approaches to connect in vitro signaling signatures to clinical side-effect profiles. Scientific Themes of the Conversation The limits of biased agonism at the μ-opioid receptor — and why partial agonism keeps explaining what bias was supposed to δ-opioid receptor recycling from the lysosome — and why the post-internalization fate of a receptor predicts tolerance better than internalization itself Protean agonism and multiple active conformations — how the same ligand can behave as agonist or inverse agonist depending on receptor tone Quantitative pharmacology as rescue operation — using operational models and BRET-based biosensors to pull pharmacological signal out of what first looks like experimental noise The defense of simple systems — why HEK-cell data can still predict FDA pharmacovigilance outcomes, and where iPSC-derived somatic systems actually pay their cost The cannabinoid entourage hypothesis as a pharmacological question — turning folkloric claims about complex mixtures into testable quantitative work Key Insights from the Conversation Twenty-five μ-opioid ligands produced partial agonism, not bias. When Dr. Piñeyro's lab systematically compared G-protein and β-arrestin recruitment across 25 compounds — standard opioids and new ligands from Pfizer — they could not identify a ligand-bias signature. What they could do was classify the compounds by relative efficacy, and that classification alone predicted clinical side effects. β-arrestin is not the villain it was made to be. Newer knockout work from groups in Australia, Germany, and the UK has shown that respiratory depression from opioids persists in β-arrestin-null mice. The mechanistic story that guided a decade of biased-ligand drug discovery needs rebuilding from the underlying biology, not from the pathway labels. The δ-opioid receptor recycles from the lysosome, and the recycling pattern determines tolerance. Long treated as a non-recycling receptor destined for degradation, the δ-opioid receptor can in fact return from the lysosomal compartment. In Dr. Piñeyro's framework, the ligands that permit recycling are the ones that produce less tolerance, whether acute or chronic — an inversion of the older view that internalization itself was the key variable. A quantitative model can turn an artifact into pharmacology. Early in her postdoc, Dr. Piñeyro watched the same ligand behave as an agonist under one condition and an inverse agonist under another. The resolution came not from a new experiment but from a model — protean agonism, as Kenakin had just described it, combined with André deLéan's software for estimating active receptor conformations — which revealed that the apparent contradiction was a quantitative signature of multiple active conformations. HEK cells still earn their keep. Even as the field pushes toward iPSC-derived somatic systems, HEK-cell signaling profiles of μ-opioid ligands correctly predicted outcomes logged in the FDA pharmacovigilance database. Dr. Piñeyro argues that the predictive power of the simpler system, and the real cost of the more elaborate one, should be weighed honestly before the field walks away from what works. The cannabinoid entourage hypothesis deserves a rigorous test. Instead of treating cannabinoids as single molecules, her group is asking whether complex mixtures of cannabinoids and terpenes produce analgesic responses that pure compounds cannot — and whether the mechanism involves allosterism across GPCRs, TRPs, and enzymes of the endocannabinoid system. The open question about THC's long-term effects on adolescent cognition sits alongside the analgesic one, and both require the same quantitative discipline. Follow the questions, not the career. Asked what advice she gives young scientists, Dr. Piñeyro's answer is blunt: she does not think of herself as having built a career. She followed interests that pulled her. In a funding environment that rewards the opposite, the advice is harder to take than it sounds — and, in her telling, the only thing that sustained her through the years when the data refused to make sense. Episode Timeline 00:00 — Introduction 01:57 — Meet Dr. Graciela Piñeyro 02:45 — From Uruguay to McGill: the cold email that changed a career 04:40 — The closed door that opened another: landing in Bouvier's lab 05:30 — The side project that became the real work 08:22 — Protean agonism and the model that rescued the data 11:00 — δ-opioid recycling from the lysosome and the question of tolerance 14:43 — 25 μ-opioid ligands, no bias, and the β-arrestin reversal 21:11 — Receptor tuning and the quantitative discipline behind the analysis 24:25 — The case for HEK cells in an age of iPSC enthusiasm 30:40 — Cannabinoids, the entourage hypothesis, and THC in teenage brains 43:20 — Follow the question, not the career Timestamps were generated using AI for readability. Selected Quotes "We tried to look for bias and classify our drugs, new and standard drugs, according to a bias signature — but there was no bias signature. What we could do was classify our drugs according to the relative efficacies. And from those relative efficacies, we were able to predict secondary effects in the clinic." "The only idea to be able to measure and predict something will transform your artifact into a real response. So that is why I got so into the models — in order to salvage my project." "We found that the receptor is sent to the lysosomes, as it has been said — but it recycles from the lysosomes." "I do not think I have a career. What I do have is — I was interested in questions and I followed my questions. I was not building a career. I was simply following my interests." About this episode Dr. Graciela Pineyro’s love for GPCR pharmacology started in Uruguay where she first worked on the serotonin receptors. This interest in research and pharmacology took Graciela to Canada where she stayed ever since she arrived for her Ph.D. work. Graciela has done extensive work on the molecular pharmacology of opioid receptors, exploring their signaling, trafficking, and their ability to activate different signaling pathways and signaling bias. Today, Graciela and her team’s efforts are directed towards the characterization of the pharmacological properties of cannabinoids in conjunction with terpenes for pain relief. Dr. Graciela Pineyro on the web Dr. Graciela Pineyro on LinkedIn Dr. Graciela Pineyro - University of Montreal Dr. Graciela Pineyro - CHU Ste-Justine Research Centre Pineyro Lab Publications on Google Scholar Pineyro Lab on Pubmed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

When his lab closed in 2020, Dr. Paul Insel turned dry-lab science into a reframing of COVID-19 pathobiology as a GPCR signaling imbalance — and a figure in The Economist. << Back to podcast list Strategic Partner(s) Dr. Paul Insel: Rethinking COVID-19 Pathobiology Through GPCR Signaling In the spring and summer of 2020, pharmacologist Dr. Paul Insel did something unusual for a working lab scientist: he stopped pipetting, and started writing. With his UC San Diego postdoc Krishna Sriram, he reread the literature on ACE inhibitors and angiotensin receptor blockers in the context of severe acute respiratory illness and concluded — against a swell of clinical panic — that the case for their danger in COVID-19 didn't hold up. What came next was a series of papers reframing severe COVID-19 as a disease of signaling imbalance: an overdrive of AT1R activation by angiotensin II, paired with a loss of ACE2-generated angiotensin 1-7. The therapeutic logic that follows is less about attacking the virus and more about rebalancing a GPCR-driven system that the infection has thrown off-axis. A figure from that British Journal of Pharmacology paper was later redrawn by The Economist for a general-audience article on COVID pathobiology — an unexpected crossover for work that began as armchair science during a lockdown walk. This conversation matters to Dr. Insel personally because he is, in his own words, a vulnerable patient — immunosuppressed, older, asthmatic — and what he's describing is not abstract. It's what he would want a physician to understand if he were the one in the hospital bed. About the Guest Dr. Paul Insel is Distinguished Professor of Pharmacology and Medicine at UC San Diego, where he also co-directs the MD-PhD program. His research career has centered on GPCR signaling — with particularly deep work on beta-adrenergic receptors, cyclic AMP regulation, and receptor biology across tissue systems. Beyond the lab, he has been a long-standing contributor to the Goodman & Gilman textbook of pharmacology and is writing its next chapter on angiotensin signaling and angiotensin drugs. He is also involved nationally in MD-PhD program leadership. Scientific Themes of the Conversation The angiotensin imbalance hypothesis of COVID-19 pathobiology — AT1R overdrive versus ACE2/Ang 1-7 insufficiency Drug repurposing as a pandemic strategy — from ACE inhibitors and ARBs to PAR1 and PAR4 antagonists The "gas pedals and brakes" philosophy of cell signaling and pharmacology Dry-lab pharmacology and what becomes possible when wet-lab work stops GPCR density and tissue-specific therapeutic opportunity — type II pneumocytes, beta-2 receptors, and the asthma parallel The ethics of acting on conviction — off-label drug use during a pandemic Key Insights from the Conversation The ACE inhibitor scare was built on a bogus reading of the literature. Early in the pandemic, senior clinicians were stopping their own ACE inhibitors and ARBs based on hypothesis-driven fears of worse outcomes. Dr. Insel and Krishna Sriram went to the primary data and concluded the claim was not supported. The review was accepted at Clinical Pharmacology and Therapeutics within weeks. Severe COVID-19 may be a story of signaling imbalance, not just viral damage. The British Journal of Pharmacology paper reframes pathobiology as an imbalance between AT1R activation and ACE2-generated angiotensin 1-7. If the virus disrupts one arm of this receptor-peptide system, the therapeutic question stops being "what do we add?" and becomes "what do we rebalance?" Biology runs on opposing forces, and good pharmacology learns to see them. Kinases and phosphatases. Cyclases and phosphodiesterases. ACE1 and ACE2. Dr. Insel returns repeatedly to his "gas pedals and brakes" frame — a lens that has quietly shaped how he reads both disease mechanism and drug targets across a long career. The lung's beta-2 story has been sitting in plain sight for fifty years. Type II pneumocytes carry the highest beta-2 receptor density in the body. Long-acting beta-agonists paired with glucocorticoids have been the mainstay of asthma treatment for decades. The connection to acute respiratory distress syndrome — and to the mechanism through which dexamethasone actually works — is, in his reading, underdiscussed rather than speculative. "Don't just do something. Stand there." A clinical mentor's line that became the frame for the lockdown months. Four papers in roughly two months — what Dr. Insel calls armchair science. Not casual, not opinion-writing; dry-lab pharmacology done with the same seriousness as bench work, just with different tools. A figure can travel further than the paper it came from. The schematic from the BJP paper was redrawn by The Economist, with attribution, for a general-audience article on COVID pathobiology. Dr. Insel notes wryly that it's the only paper his family has ever really responded to. The ethics of acting on conviction is its own paper. Midway through writing the angiotensin work, Dr. Insel realized no one had written criteria for how to decide about off-label use of a drug during a pandemic — when mechanism is compelling, safety is reasonable, and trial evidence isn't there yet. He is writing that paper with an ethicist and a law-school colleague. It is exactly the kind of work a pharmacologist does when the lab is closed. Episode Timeline Timestamps were generated using AI for readability. 00:00 Opening and 2020 Summit context 01:45 Dry-lab science — how the work shifted when the wet lab closed 02:37 Rereading the ACE inhibitor scare — and the BJP paper that followed 07:40 Expanding the hypothesis — PAR1, PAR4, and upstream pathobiology 11:00 Gas pedals and brakes — biology's architecture of opposing forces 14:00 Type II pneumocytes, beta-2 density, and the asthma parallel 22:40 The ethics of off-label drug use during a pandemic 25:00 Genetic determinants of severity — ACE1 isoforms and population data 28:40 Vaccine development speed and public trust 33:40 Staying sane — pickleball, walking, and community Selected Quotes "Don't just do something. Stand there. That's sort of what we've been doing. And I think we've made some contributions that are pretty interesting. I really want to do something to help people. That's what this is all about, really." — Dr. Paul Insel "Almost most biological systems are all about gas pedals and brakes. We have kinases and phosphatases. We have cyclases that make cyclic AMP and phosphodiesterases that degrade it. Nature has built in these systems consistently." — Dr. Paul Insel "If you would have told me three months ago that I was going to end up having a figure in The Economist — forget about one of the science journals — in The Economist…" — Dr. Paul Insel "It's still about GPCRs." — Dr. Paul Insel About this episode Dr. Paul Insel is currently a Distinguished Professor of Pharmacology and the University of California San Diego. Paul thinks broadly about science and has been actively publishing papers about his ideas on how COVID symptoms could be treated while we wait for a vaccine, particularly about ACE2 and angiotensin. For the past 30 years, he has been the Director of MD/Ph.D. training program at UCSD and has served as Editor or Senior Editor of numerous scientific journals, including but not limited to the Journal of Clinical Investigation, Molecular Pharmacology, British Journal of Pharmacology, and American Journal of Physiology-Cell Physiology. Dr. Paul Insel on the web Insel Laboratory Institute of Engineering in Medicine UC San Diego UCSD Profiles Google PubMed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Terry Hebert on why challenge trials weren't ready, what it takes to hold a GPCR signaling lab together during a pandemic, and the BRET-based beta-1 adrenergic paper that landed in lockdown. << Back to podcast list Strategic Partner(s) Dr. Terry Hébert This resilience conversation with Dr. Terry Hebert was recorded in spring 2020, when Montreal was the national epicenter of the COVID-19 pandemic and every non-essential bench in the country was shut. The discussion moves across three scientific registers: the practical mechanics of holding a GPCR signaling lab together remotely; the continuity of receptor pharmacology work already in the pipeline before the shutdown, including a newly accepted BRET-based platform for beta-1 adrenergic receptor signaling built with the Bouvier lab; and a pharmacologist's reasoning about the then-unresolved question of whether human challenge trials were an ethical shortcut to a SARS-CoV-2 vaccine. Dr. Hebert's argument — that challenge trials depend on a reliable therapeutic the field did not yet have — sits at the intersection of drug discovery logic and public health ethics, and illustrates how GPCR scientists reason about pharmacology problems well outside their primary receptor. For Dr. Hebert, the conversation is also about what he had to let go of: the assumption that a lab, once built, runs on its own inertia. About the Guest Dr. Terry Hebert is a professor at McGill University in Montreal, where his lab studies G protein-coupled receptor signaling. His research spans BRET-based assay platforms for characterizing signaling downstream of specific GPCRs, the transcriptional regulation of signaling components as an underappreciated axis of pharmacological modulation, and long-running collaborations on beta-adrenergic receptor biology with the Bouvier lab and others. His work is grounded in careful assay development and a conviction that the signaling space around a receptor is richer than single-pathway readouts suggest. Scientific Themes of the Conversation Lab continuity during institutional shutdown — What it takes to maintain scientific output when the physical lab is closed and every operation has to happen remotely. BRET platforms for GPCR signaling — The role of resonance-energy-transfer-based assays in capturing signaling downstream of specific receptors, with the beta-1 adrenergic receptor as a worked example. Challenge trials and the therapeutic floor — Why the ethics of accelerating vaccine trials depend on having an adequate treatment for the disease under study. Vaccine development at scale — How to read a landscape of 90+ parallel vaccine candidates without confusing breadth of effort for probability of success. Mentorship under isolation — The practical and emotional work of keeping graduate students — especially international students far from their families — connected to a lab that has gone quiet. Pandemic preparedness as a scientific failure — The gap between what infectious disease researchers had been warning about and what institutions were actually ready to do. Key Insights from the Conversation Challenge trials don't work without a reliable drug. Dr. Hebert's core pharmacology argument is that proposing a challenge trial — where volunteers receive placebo or active virus — is ethically unworkable without a therapeutic that can rescue the ones who get sick. His position is that the drug problem has to be solved, or at least bounded, before the vaccine trial design can responsibly change. 90 vaccine candidates is a number about effort, not probability. The conversation pushes against the comfort of large numbers. A field running 90 parallel vaccine trials is a field hedging under uncertainty, not a field with 90 independent chances of success. Dr. Hebert is hopeful but careful about the distinction. BRET platforms carry work forward when the lab can't. The beta-1 adrenergic receptor paper — a BRET-based platform for capturing downstream signaling, built with the Bouvier lab — illustrates how assay-development projects remain productive when benchwork stops. The experimental data was in hand before the shutdown; the intellectual work of writing, reviewing, and revising kept going regardless. A lab is a social infrastructure, not just a physical one. Weekly Monday lab meetings, Friday journal clubs, daily Slack and Zoom contact, a faculty-vs-student trivia night — the lab's continuity came from translating routines, not suspending them. The most fragile link in the system was the isolation of international students away from their families. Reopening is a puzzle about labs, not benches. The hardest logistical problem isn't social distancing within a single lab — it's social distancing between labs sharing a floor, shared equipment, and a public transit system that funnels everyone through the same bottleneck. The warnings were there. Dr. Hebert's reflection on preparedness is quiet but pointed: the scientific community had been warning about this for years. The failure wasn't epistemic — it was institutional. And that failure is what will cost the most, borne hardest by the people least cushioned against it. The next one is coming. The most forward-looking moment in the conversation is also the most sober. This disease, for all its damage, is survivable for most people. The next one might not be. The open question is whether the system will have learned anything by then. Episode Timeline Timestamps were generated using AI for readability. 00:00 Welcome and Dr. GPCR Summit 2020 announcement 01:49 Check-in with Dr. Hebert — shutdown, reopening plans, and Montreal as epicenter 03:06 Paper acceptances, thesis writing, and 30 hours of Zoom teaching in one month 04:29 The beta-1 adrenergic BRET paper and a review on transcriptional regulation as a drug target 05:22 Lab meetings, journal clubs, and the Slack/Zoom scaffolding 06:12 Student wellbeing and the puzzle of reopening a shared floor 07:16 Why challenge trials aren't ready — and the remdesivir question underneath them 08:52 When pandemic infrastructure breaks down at national scale 10:16 Lessons for the next one, and the shape of the new normal Selected Quotes "So we made a decision a month and a half ago to kind of stop going to the lab. Montreal being the epicenter of the disease in this country — we don't regret that decision now." "I don't think [challenge trials] are a good idea because we don't really have good drugs to deal with the disease when people get sick. If we have a way to control the disease and keep people from getting really sick, I think we can go to challenge trials more rapidly." "Honestly it could be worse, right? This disease, most people survive. When the next one comes, let's hope we learn something from this one." "Those are the people we have to protect, not big corporations who, you know, are probably in a sense part of the cause. Globalization is not something that is without its consequences here." About this episode Dr. Terry Hébert is a Professor within the Department of Pharmacology & Therapeutics at McGill University. Much of his work is based on GPCR signaling in the context to cardiovascular diseases. In this special episode of the Dr.GPCR podcast , we re-connected with Dr. Terry Hebert to chat about how he and his team has been adapting to the new reality of working remotely. Terry tells us about the importance of adapting, communicating, and being mindful of those around us. Dr. Terry Hébert on the web Terry Hébert | Institute of Health Sciences Education Hébert Lab LinkedIn Hébert Lab The GPCR Consortium PubMed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

In this short resilience conversation, Dr. Graciela Pineyro shares what a forced lab shutdown taught her about prioritization, remote lab meetings, and running a research program across closed borders. << Back to podcast list Strategic Partner(s) Dr. Graciela Pineyro: Resilience, Lab Life, and the Zoom Effect Research doesn't pause neatly. In March 2020, Dr. Graciela Pineyro — a principal investigator at CHU Sainte-Justine in Montreal studying GPCR signaling — watched her lab close from one day to the next. This short resilience conversation, part of a Dr. GPCR Podcast series capturing the realities of scientific life, returns to Dr. Pineyro several months into the shutdown to hear what she learned. The discussion moves across three overlapping questions: how a forced pause reshapes scientific prioritization, how remote lab meetings alter who speaks up and why, and what it costs a scientist personally to keep a lab running across a closed international border. For Dr. Pineyro, whose husband remained in Uruguay for the duration of the shutdown, the scientific work and the human cost were never separate conversations. What emerges is a quiet argument that the structural shifts the pandemic forced — project planning in self-contained blocks, flatter meeting dynamics, planned reflection time — may deserve to survive the return to the bench. About the Guest Dr. Graciela Pineyro is a principal investigator at CHU Sainte-Justine in Montreal, where her research group works on GPCR signaling. She is a returning guest of the Dr. GPCR Podcast; her earlier episode covers her scientific profile in depth, including her research trajectory, laboratory focus, and contributions to the field. This resilience conversation captures her voice not as a researcher presenting results, but as a PI speaking candidly about how her program is navigating a moment no one planned for. Scientific Themes of the Conversation Forced pause as a prioritization tool — How closure reveals what a lab would otherwise never stop to question. The democratizing effect of remote meetings — Why some lab members speak more freely from home than they ever did in person. Experimental planning under uncertainty — Structuring projects into self-contained blocks so a lab can survive iterative shutdowns. The personal geography of modern science — What it costs a scientist when the research program and the family are in different countries. Civic responsibility in returning to the bench — Deconfining a research center slowly, with planning for possible return to closure. Key Insights from the Conversation The pause was never just a pause. Dr. Pineyro frames the shutdown not as lost time but as a rare moment of recul — the French word for a step back that allows for perspective. She talks about finally being able to ask which projects deserved to be finished first, second, third. The question was always there; the pause was what forced it to be answered. Zoom did not flatten the lab. It flattened the hierarchy of who gets heard. The most striking observation in the conversation: lab members who rarely spoke up during in-person meetings began contributing more on Zoom. Dr. Pineyro notes she isn't sure why — something about speaking from home, something about reduced interpersonal threat. But the finding is sharp enough to take seriously when in-person dynamics return. Planning in blocks is a form of resilience. The lab restructured projects into discrete, self-contained units — each one designed so that if the research center closed again, the team would still have something to analyze, something to write. This is operational wisdom that long outlives the pandemic. The personal cost doesn't stay outside the lab. Dr. Pineyro speaks openly about her husband being stuck in Uruguay since March, missing their planned reunion, hoping for Christmas. She does not separate this from the scientific conversation — and the listener shouldn't either. Running a lab during the pandemic was rarely just a scientific problem. Returning to the bench is a decision, not a default. The research center was deconfining at 20% capacity the week of the recording. Dr. Pineyro frames reopening as something her team is taking "civically with responsibility and a grain of salt" — acknowledging that back-and-forth closures may be the new baseline. That framing, made months before it became the standard narrative, is worth noticing. Some pandemic-era practices deserve to survive. The implicit argument threaded through the whole conversation: the structural shifts forced by the shutdown — planned reflection, remote meeting inclusion, block-based project design — may be worth keeping. Not because the pandemic was good for science, but because normal lab life had quietly suppressed some of the things the pause made visible. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction and 2020 Summit announcement 01:45 Welcoming a returning guest 02:02 How COVID reshaped the lab and the personal cost 03:30 Using forced pause for prioritization 04:10 Planning experiments in self-contained blocks 04:47 The Zoom effect — quieter voices speaking up 05:49 Closing reflections 06:01 Outro Selected Quotes "One day we were doing experiments, and the next we had to close. We have to go back now and start from scratch." "Zoom democratizes the world. People that usually do not speak so much in the lab meetings were speaking a little bit more through Zoom." "We are sort of thinking in advancing our projects in sort of blocks, closing some questions very tightly. So if we are sent back home, at least we have something to work on." "We are all prepared to take this civically with responsibility and also with a grain of salt, knowing that we might have to be going back and forth for a while before everything goes back to normal." About this episode: Dr. Graciela Pineyro is a professor of pharmacology at the department of pharmacology and physiology of the University of Montreal. She has done extensive work on the molecular pharmacology of opioid receptors and is currently focusing on the pharmacology of cannabinoids in the context of pain. We chatted about how the current pandemic has affected her personally and professionally. Dr. Graciela Pineyro on the web Dr. Graciela Pineyro on LinkedIn Dr. Graciela Pineyro - University of Montreal Dr. Graciela Pineyro - CHU Ste-Justine Research Centre Pineyro Lab Publications on Google Scholar Pineyro Lab on Pubmed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. 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A conversation with Dr. Silvio Gutkind on keeping a cancer research lab running at 10% occupancy, why rotation students act like a sorting hat, and why breakthroughs come from working hypotheses that fail. << Back to podcast list Strategic Partner(s) Dr. Silvio Gutkind: Building a Lab That Doesn't Shut Down Conversations that happen when a research community faces a shared constraint reveal as much about scientific practice as any experiment. Dr. Silvio Gutkind joins this resilience conversation from the UCSD Moores Cancer Center, where cancer patients cannot wait for normalcy to return. For Dr. Gutkind — carrying a personal loss in New York and leading a cancer center building that operated at 93% capacity during the early pandemic — the question was not abstract. He had to decide, week by week, what could pause and what couldn't, and whose careers would bear the cost of getting it wrong. He walks through the structure his team built: staggered schedules at 10–15% occupancy, written contracts with every lab member, a Zoom-based communication cadence, and an internal directive to read, think, plan, and write. The constraint did not slow the science; it redirected it. Bioinformatics projects flourished. Collaborations that would have waited for conferences started immediately. A harder question surfaces underneath: how much of what we call a lab is its physical walls, and how much is the community, the plan, and the willingness to let a failed hypothesis open a new direction? About the Guest Dr. Silvio Gutkind is Professor and Associate Director for Basic Science at the UCSD Moores Cancer Center. His research spans GPCR signaling in cancer biology, head and neck squamous cell carcinoma, and the molecular circuitry that drives tumor progression. Before moving to La Jolla, he spent decades at the NIH, where he led a branch at NIDCR. That dual lineage — extramural academic and intramural NIH — shapes how he thinks about research infrastructure, student training, and scientific community. Scientific Themes of the Conversation Institutional resilience and the architecture of a research lab under constraint The contract between scientific leadership and trainees during crisis Communication infrastructure as a substitute for physical proximity Chance and opportunity as drivers of a scientific career Rotation students as cross-pollinators between labs Why breakthroughs tend to come from working hypotheses that fail Key Insights from the Conversation Cancer centers don't get to pause. Dr. Gutkind describes operating his cancer research building at 93–94% capacity during the early pandemic because cancer patients couldn't wait for normalcy. The question was never whether to stay open — it was how to stay open safely, and how to absorb the stress that came with that responsibility. The NIH shutdown playbook made UCSD ready. Years at the NIH, where federal shutdowns were routine, gave Dr. Gutkind a pre-built mental model for what to freeze, what to protect, and what to let continue. When the pandemic hit, he reached for an infrastructure he already had. Every lab member needed a contract. Rather than making ad hoc decisions about who would come in and when, the team wrote down expectations — hours, distancing, critical versus deferrable work, and an explicit clause that no one should feel pressured to be on-site. The contract wasn't bureaucracy; it was protection, especially for students. The bioinformatics arm called it "heaven." Computational scientists suddenly had uninterrupted time at home with full data access and far fewer meetings. Dr. Gutkind reports that five years' worth of ideas accumulated in that stretch — more than the lab can realistically work through. "Physical distancing," not "social distancing." A small language correction with structural weight. Dr. Gutkind argues the scientific community grew closer during the pandemic, not further apart — the physical space contracted, but the community expanded through Zoom, shared drives, and unhurried collaboration conversations. Rotation students function like the sorting hat. Because trainees rotate through multiple labs, they carry science from one bench to another. Dr. Gutkind credits several of his most valuable collaborations to a rotation student recognizing a fit that no PI would have spotted from across campus. Breakthroughs come from working hypotheses that fail. Dr. Gutkind reflects that the most significant advances in his career didn't come from confirming a premise — they came from digging into why the premise broke. The discipline is not in being right, but in being willing to let go of the framework you built when the data refuses to fit it. Episode Timeline Timestamps were generated using AI for readability. 00:00 Welcome and introduction 01:46 Navigating research during the pandemic 03:30 Why cancer research couldn't stop 04:30 The NIH shutdown playbook 05:20 Writing the contract: occupancy, staggering, communication 06:50 The productivity paradox — "it's like heaven" 07:55 What will change after the pandemic 09:20 "Physical distancing, not social distancing" 11:31 Chance versus scientific knowledge in a career 12:20 Rotation students as the sorting hat 13:20 When the working hypothesis fails 14:30 Closing Selected Quotes "We have many more ideas than we can handle for at least the next five years." "I wouldn't call it social distancing — I would call physical distancing… as a community, we are even stronger." "These rotation students are like cross-pollination… almost like the sorting hat in Harry Potter." "Quite often, our breakthroughs are more often from when the working hypothesis did not work. The breakthrough came from getting deeper into why." About this episode Dr. J. Silvio Gutkind sheds light on his work and life since the beginning of COVID restrictions. A large component of his work is centered around dysregulated signaling in cancer and the development of novel mechanism-based cancer therapies. In this episode, Dr. J. Silvio Gutkind highlights how his past experience proves useful in current COVID times and potential benefits the changes in work environments can do for future collaborations. Dr. J. Silvio Gutkind on the web Gutkind Lab – UC San Diego Moores Cancer Center Gutkind Lab publications More Publications from the Gutkind Lab on Pubmed Dr. J Silvio Gutkind on LinkedIn Gutkind Lab on Twitter UCSD Moores Cancer Center Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. 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Jacob Lee and Jin Cho, co-founders of GeneMode, on the ten billion dollars American labs waste every year — and why rebuilding research software from scratch is the most direct path to faster cures. << Back to podcast list Strategic Partner(s) Jacob Lee and Jin Cho: Rebuilding the Software Layer Under Modern Research Most scientific research still runs on infrastructure built for a different century. Spreadsheets lock when two people open them. Freezer inventories live in a senior postdoc's head. An estimated ten billion dollars is spent every year in the United States rebuying reagents already sitting on a shelf nobody could find. In this conversation, Jacob Lee and Jin Cho — co-founders of GeneMode — describe what they saw when they looked at that infrastructure as outsiders and as scientists at once. Lee is a bioengineer whose first year of graduate school was defined by scheduling thirty-minute appointments on a senior postdoc's calendar just to access the lab's inventory software, and that experience is what turned frustration into a company. Cho came from engineering software for military drones at General Atomics, and was stunned when he saw what his friend's lab was paying for a tool that looked straight out of Windows XP. They talk about the slow architecture of drug discovery, the compounding cost of irreproducibility, and why rebuilding the tools scientists use every day is, for them, the most direct path to getting cures to patients faster. About the Guests Jacob Lee is the CEO and co-founder of GeneMode. He trained as a bioengineer and worked as a research scientist in stem cell and cancer labs before founding the company. His frustrations as a first-year graduate student navigating inaccessible lab software became the seed for GeneMode. He leads the company's product vision, focused on inventory, experiment management, and research reproducibility. Jin Cho is the CTO and co-founder of GeneMode. Trained in electrical and computer engineering, he began his career at General Atomics building software for military drones before reuniting with his high-school friend Lee to rebuild research tools from the ground up. At GeneMode he leads the engineering team and the platform's weekly release cycle. Scientific Themes of the Conversation The cost of irreproducibility — waste, delay, and the compounding friction of bad tools Access asymmetry in research — who gets to use the lab's software, and who waits Research software as infrastructure — why tools built for scientists behave differently than tools adapted to them The drug discovery timeline — preclinical, clinical, and regulatory phases, and where software actually matters Collaboration in shared labs — real-time editing, shared freezers, and the Excel-lock problem Lab automation and the hidden operating cost of being a scientist Key Insights from the Conversation Ten billion dollars vanishes every year into duplicate reagent orders. Lee describes an estimate that American labs spend roughly ten billion dollars annually on reagents they already own but can't locate. The cost isn't just money — it's the erosion of reproducibility that follows from not knowing what's in the freezer. Access to the lab's tools is often rationed by seniority. In Lee's first graduate lab, only the principal investigator and a senior postdoc had logins for the expensive inventory software. As a student, he scheduled thirty-minute appointments on a postdoc's calendar to learn how to use a tool the lab had already paid thousands of dollars for. Excel is the default research tool because no one built a better one for scientists. The co-founders argue that most lab software wasn't built for scientists — it was built for general business use and retrofitted. That explains the locked files, the manual re-entry, the outdated look, and the poor fit with how research actually moves. Lab infrastructure is the hidden variable in drug discovery timelines. COVID-era conversations about why vaccines take eighteen months tend to focus on the clinical and regulatory phases. Lee reframes the question toward the preclinical phase, where data management and reproducibility quietly compound every delay downstream. Private and shared workspaces both matter, even in collaborative labs. Cho and Lee describe designing for the reality of shared benchwork: most labs want everything visible to everyone, but individual scientists still need space for protocols-in-progress or personal collections they're not ready to publish internally. Fast release cycles are a signal of infrastructure maturity. Cho describes shipping updates weekly, prioritizing customer-reported bugs and feature requests with a design-to-test-to-ship loop that most scientific software vendors don't attempt. That cadence is itself a philosophical statement about who the tool serves. A ninth-grade English class is an unlikely origin for scientific infrastructure. The GeneMode story starts with two teenagers in the same high-school classroom, different majors, different career paths, and a late-night message asking whether lab software could be hacked together in a weekend. The answer turned out to be no — but the question turned into a company. Episode Timeline Timestamps were generated using AI for readability. 00:00 Summit week welcome and episode introduction 01:34 Meeting the co-founders — CEO Lee and CTO Cho 03:11 From stem cell research to bioengineering frustration 04:03 The ninth-grade English class where the story starts 04:59 Seeing Windows XP-era software inside a modern lab 07:01 What GeneMode actually does that Excel can't 10:15 Onboarding a ten-person lab onto one shared platform 12:18 Ten billion dollars in wasted reagents 16:13 What's coming next — tools across the experimental lifecycle 18:32 Algorithms that predict when reagents will run out 22:43 A weekly release cycle built around user feedback 24:13 Why vaccines still take eighteen months Selected Quotes "A lot of the problems that we're solving is around data sharing for scientists — by having inventory, experiment management, applications, and data all in one collaborative workspace." — Jacob Lee "It looks like software that was built a couple of decades ago. And what surprised me even more was his lab was paying thousands of dollars for this legacy-looking software. I was mind-blown." — Jin Cho "In a lab of ten people, only the principal investigator and a very senior postdoc had access to the software. And as a student, I had to actually schedule times on my postdoc's calendar in thirty-minute segments just to learn how to use that tool." — Jacob Lee "The end goal is really much bigger than helping scientists manage their research projects or inventory. Our mission is to make that research repeatable and reproducible so that we can get those cures faster." — Jacob Lee About this episode In this special episode of the Dr.GPCR podcast , I sat down with the co-founders of Genemod . Jacob Lee and Jin Choe met in ninth grade in English class and have been friends since. Although both went to the same college, Jacob and Jin choose different career paths. One day as they were catching up, Jacob shared his struggles of managing samples and an incredible amount of data and projects in the lab with Jin. Our of this need Genemod was born. Today, Genemod has built a freezer management tool and a project management tool where scientists can manage their reagents, samples, and projects on one intuitive platform. The team is planning on building even more tools that will make Genemod the go-to platform for all research scientists to make research more efficient. Genemode on the web Website Jacob Lee on LinkedIn Jacob Lee on Dr. GPCR Ecosystem Jin Choe on LinkedIn Jin Choe on Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. John Streicher on how HSP90 flips direction between brain and spinal cord, why isoform-selective inhibitors may rescue oral delivery of opioid adjuncts, and how a student's side project on intermittent fasting erased morphine reward in mice. << Back to podcast list Strategic Partner(s) Dr. John Streicher: Reorganizing Opioid Signaling Beyond the Receptor The dominant strategy for improving opioid therapy has been to engineer new ligands at the receptor itself — biased agonists, partial agonists, multi-target molecules. Dr. John Streicher's laboratory at the University of Arizona works a different angle. His team treats opioid signaling as a problem of circuit organization: the same kinases and second messengers produce radically different outcomes depending on how they are scaffolded inside a cell, and the chaperones that do that scaffolding are themselves druggable. In this conversation, Dr. Streicher describes how heat shock protein 90 plays directly opposite roles in the brain and the spinal cord, why isoform-selective HSP90 inhibitors may finally solve the "brain always wins" problem of oral delivery, and how a graduate student's skeptically-received side project on intermittent fasting produced some of the strongest opioid-sparing data his lab has generated. He came to this field because a signaling cascade felt like a puzzle he could not stop thinking about, and the puzzle has only gotten more interesting. Listeners will get a concrete look at what it means to modulate opioid pharmacology downstream of the receptor — and why the safety margins the field has been chasing for decades might actually live there. About the Guest Dr. John Streicher is an assistant professor in the Department of Pharmacology at the University of Arizona. His lab combines cell and molecular biology with animal pharmacology to identify new signaling regulators of the mu, delta, and kappa opioid receptors. Current lines of work include isoform-selective HSP90 inhibition as a strategy for widening the opioid therapeutic index, signal organization downstream of opioid receptors, and the unexpected effects of intermittent fasting on morphine pharmacology. Dr. Streicher trained in signal transduction during his PhD on heart failure and p38 MAP kinase, and moved into opioid pharmacology as a postdoctoral fellow with Dr. Laura Bohn at Scripps Research Institute. Scientific Themes of the Conversation Opioid signaling specificity as a problem of circuit organization, not molecular identity HSP90 as a region-specific signaling scaffold — opposite roles in brain and spinal cord Isoform-selective chaperone inhibition as an alternative to receptor-level drug design The current state and replication troubles of biased agonism at the mu opioid receptor Downstream pharmacology as an underexplored route to safer opioid therapy Intermittent fasting as a metabolic modulator of opioid antinociception and reward Key Insights from the Conversation Specificity lives in circuit architecture, not in the kinase itself. ERK MAP kinase is Dr. Streicher's recurring example: the same molecule promotes opioid antinociception in one context, drives chronic pain in another, and functions as a mitogen in cancer. You cannot explain specificity by assuming each node does one thing. What differs is how scaffold proteins localize the kinase into distinct submolecular circuits. He teaches his students to think of kinases as components — a diode in a radio and a diode in a nuclear bomb can be identical — and the organization around them decides the outcome. HSP90 runs opposite programs in brain and spinal cord. In the brain, HSP90 promotes ERK activation downstream of the mu opioid receptor and is required for antinociception. In the spinal cord, the same chaperone acts as a brake on ERK activation. Block it spinally and the dorsal horn lights up with phospho-ERK in response to opioid, routing through RSK1/2 to stronger pain relief. Block it in the brain and antinociception collapses. This is not a quirk — it is the central clue the lab has built a therapeutic strategy around. The "brain always wins" problem is solved by isoform selectivity, not by dose. With a non-selective HSP90 inhibitor given systemically, the brain effect dominates and pain relief is lost. But the brain only uses HSP90α in this context, while the spinal cord recruits α, β, and GRP94. Collaboration with Dr. Brian Blagg at Notre Dame on β-and-GRP94-selective compounds has produced proof-of-concept IV data that reproduces the spinal-cord benefits — more potent morphine, reduced tolerance — without the brain blockade. The route from "intrathecal only" to "oral pill" runs through isoform selectivity. Biased agonism is in a harder place than the field often acknowledges. TRV-130 was denied FDA approval for lack of clear safety advantage. A phospho-null mu knock-in mouse from Stephan Schulz's group showed reduced tolerance but no respiratory-depression benefit. Attempts to replicate the arrestin-knockout phenotypes on clean mouse backgrounds have failed. Dr. Mary Canals' group has argued that some of the apparent bias benefits may actually reflect low intrinsic efficacy. Dr. Streicher calls himself an "informed outsider" on bias now, but his read is that the field needs deeper mechanism before the strategy can be rescued. A student's side project erased morphine reward. Graduate student David Duran wanted to test intermittent fasting in mice. Dr. Streicher was skeptical but gave the project room. The result: a six-hour feeding window for seven days increased morphine's antinociceptive efficacy in multiple pain models, strongly reduced tolerance and constipation, and completely blocked morphine reward in conditioned place preference. Receptor signaling assays showed efficacy shifts in the spinal cord and tolerance attenuation in the periaqueductal gray. The paper is published in Pain , and the translational path is unusually short — you don't need a ten-year IND process to test a feeding schedule in patients. Do not pursue something "completely novel" as a junior scientist. HSP90 in opioids was far enough off the beaten path that Dr. Streicher spent years fielding reviewer skepticism — no one has studied this, is this even real? His retrospective advice is to pick something novel but "still in the tent" — close enough to what the field recognizes that you earn credibility before trying to chase the real heresies. The lesson is not to play it safe; it is that unfamiliarity costs you credibility before your data can speak. Broad targets are not automatically undruggable. HSP90 is 2–3% of the protein content of every eukaryotic cell. A trained pharmacologist's first instinct is that the side effect burden would be crushing. But second-generation pan-HSP90 inhibitors have shown acceptable tolerability in oncology trials, Dr. Brian Blagg's KU-32 actually promotes neuronal survival in diabetic peripheral neuropathy and is now in Phase 1, and isoform selectivity narrows the footprint further. Dr. Streicher argues the field's default assumption — pick a low-expression, tissue-restricted target — is more habit than rule. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 01:22 Meet Dr. John Streicher 01:49 From heart failure to opioids — a path through signaling 07:49 Why the mu receptor still anchors his lab 09:51 The specificity puzzle — why ERK does a million things 13:31 What happened to biased agonism — replications in trouble 19:08 What's missing, and why HSP90 flips in the spinal cord 28:44 The "brain always wins" problem and isoform selectivity 33:05 HSP90 as Pac-Man — co-chaperones and the AHA1 clue 38:52 Picking projects that are "novel but in the tent" 47:25 The student's side project that blocked morphine reward 59:52 Running a lab through the first months of COVID Selected Quotes "A diode in your radio at home and a diode in a nuclear bomb could be exactly the same component but do radically different things depending on how they're organized." "The brain always wins. And when the brain wins, the antinociception is blocked — which is not what you want." "I'm normally a pretty skeptical, hard-headed person. But the data is the data. And I'm going to follow it." "Pick something that is novel, but is sort of still in the tent." About this episode Our guest in this episode of the Dr.GPCR podcast is Dr. John Streicher from the department of pharmacology at the University of Arizona. John started grad school in 1999 and spent some time figuring out what he was interested in. It turns out that it was signal transduction, and he worked on the signaling cascades involved in heart failure. His encounter and interest in signaling in the context of GPCRs during his postdoctoral training in Dr. Laura Bohn’s lab at Scripps Research Institute in Florida. Today, John and his team focus on understanding how signal transduction cascades downstream of the opioid receptors work, including the unique organization of chaperone protein Hsp90 modulation of opioid signaling in the brain versus the spinal cord. Dr. John Streicher on the web University of Arizona Department of Pharmacology Google Scholar Pubmed LinkedIn Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Career coach Lauren Solano on the skills PhDs undersell, the careers they don't know exist, and the introspection exercise that maps functions to scientific training. << Back to podcast list Strategic Partner(s) Lauren Solano: Mapping Careers Beyond the Bench This episode steps outside the usual GPCR research conversation to examine the career architecture around it. Lauren Solano, CEO and co-founder of Propel Careers, has spent more than a decade coaching PhDs and postdocs and recruiting for biotech and life sciences companies — a vantage point that makes her uncommonly clear about the gap between how scientists describe themselves and how the market reads them. The discussion explores how to translate scientific training into career options that are often invisible to bench scientists, ranging from medical science liaison and clinical research roles to business development, scientific communications, venture capital, and consulting. Solano unpacks the specific transferable skills PhDs consistently undersell — collaboration, leadership, proactive ownership, communicating across technical audiences — and introduces concrete tools for self-assessment and exploration, including the "loved it, loathed it" exercise and a permission-granted approach to informational interviewing. For Solano, the stakes are personal: she didn't know the career she now has was even possible in 2008, which is precisely why she maps the option space for the scientists she coaches today. About the Guest Lauren Solano is CEO and co-founder of Propel Careers, a Boston-based firm that coaches scientists and recruits for biotech and life sciences companies. She trained as a scientist and spent her first decade in preclinical and early clinical drug discovery before pursuing an MBA in 2007 and co-founding Propel in 2009. Her practice centers on helping PhDs and postdocs translate technical training into career paths they often don't realize are open to them. Each year she delivers roughly a hundred talks at universities and research institutions on resumes, negotiation, informational interviewing, and the mechanics of biotech hiring. Scientific Themes of the Conversation The gap between scientific training and the career vocabulary scientists need Transferable skills in the PhD toolkit — and why they go unlisted Informational interviewing as a research method for career planning The limits and real signals of "company culture" in biotech COVID-era shifts in scientist hiring and career reflection Title-function mismatches in life sciences job descriptions Key Insights from the Conversation 1. The "loved it, loathed it" exercise as a career compass Over any given week, note which tasks you enjoyed and which you dreaded. Separate that list from what you're good at — the overlap reveals which career functions, not titles, are worth exploring next. 2. Function over title Job titles in biotech are often creative and inconsistent — a medical science liaison might be called a "clinical information specialist." Scientists navigating a career change are better served mapping careers by tasks and functions first, and treating titles as secondary metadata. 3. PhDs consistently undersell their transferable skills After thousands of conversations with scientists, Solano has found that collaboration, leadership, proactive ownership, and translating technical content across audiences are not universal traits. PhDs tend to have them in unusual concentration — and tend to leave them off their resumes because they assume everyone else has them too. 4. Informational interviews are already permitted Graduate students and postdocs often feel uneasy reaching out to people in other careers, as if the exploration hasn't been earned. Solano reframes this directly: because training ends, career exploration is required, and most people will give fifteen minutes if asked well. 5. "Company culture" is meaningless until you can point at behaviors Every company claims a strong culture. What matters is whether office layout, mentorship practices, and daily behaviors support the claim. The sharper question is what the company does , not what it says. 6. Safety at work is a concrete culture signal Would an employee feel comfortable telling a manager their child is sick, or would they invent another reason? Whether people feel safe at work is a harder measure of culture than any mission statement. 7. Post-pandemic career decisions are about alignment, not just advancement Solano observes that many scientists are using the moment to ask whether their current work matches who they are — not to chase the next rung, but to reset toward impact. Episode Timeline 00:00 Intro and Dr. GPCR Summit preview 01:30 Meet Lauren Solano and Propel Careers 03:11 The path from bench science to career coaching 07:56 Loved it, loathed it — the introspection exercise 10:29 Career options PhDs rarely consider 11:49 Transferable skills scientists undervalue 14:16 The informational interview — permission granted 23:57 The COVID shift in biotech hiring 26:14 Assessing real company culture 31:34 Master resumes and the title trap Timestamps were generated using AI for readability. Selected Quotes "If you had asked me in 2008 if I would be a recruiter slash career coach, I didn't even know that was possible because it hadn't even occurred to me that that is something that would have been a fit." "None of you should be ever worried or afraid or feel awkward reaching out to people for informational interviews because you are supposed to think about your future and learn about different things." "I can tell you in speaking with thousands of PhDs, not everyone is collaborative. Not everyone likes to do novel areas of research. Not everyone is amazing at communicating both to technical audiences and non-technical audiences. So don't undersell your experiences." "Life is frail, right? So if we're not making a difference, if we're not impacting something, why are we doing it?" About this episode In this special Dr. GPCR podcast episode, we sat down to chat with Lauren Celano to talk about career options for Ph.D.’s. Working in a lab allows scientists to gain amazing hard and soft skills, which opens the doors to several great careers that many have not even considered, yet. Lauren has a science background and is passionate about helping talented scientists find their dream position. She is also a speaker, connector, recruiter, and coach. Lauren Celano on the web LinkedIn Propel Careers Email: Lauren@propelcareers.com Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Advance your GPCR research with expert-led Masterclasses on pharmacology, efficacy, signaling, and drug discovery. Built for serious scientists. University / Masterclass On Demand Every Masterclass session. Anytime. At your pace. The full recording library of GPCR Masterclass sessions — revisit the science, catch what you missed, and explore topics at the depth they deserve. On-demand recordings are included inDr. GPCR University Try it for 14 days Recording library Explore the Masterclass library Full recordings of every Masterclass session. Filter by category, level, or instructor to find exactly what you need. Filter by Category Filter by Level Filter by Instructor Watch Now Kenneth A. Jacobson, Matteo Pavan Structure-Based Design of Modulators of Purinergic GPCRs Watch Now Terry Kenakin Designing with Time: GPCR Ligand Kinetics Watch Now Terry Kenakin Seeing is Believing: Assaying Drug Action Watch Now Terry Kenakin Assessing Bias: The Practical Approach Watch Now Terry Kenakin From Body to Benefit: Drug Disposition Watch Now Terry Kenakin NAMs & PAMs: Quantifying the Impact Watch Now Terry Kenakin Unconventional GPCR Ligands Watch Now Terry Kenakin The New Frontier of GPCR Therapeutics Watch Now Terry Kenakin GPCR Efficacy: The Biased Signal 1 2 3 1 ... 1 2 3 ... 3 The scientists Learn from world leaders in GPCR research Every session is led by a recognized expert with decades of experience in GPCR pharmacology and drug discovery. Dr. Kenneth Jacobson NIH Medicinal chemist leading purinergic GPCR drug discovery at the NIH, focused on adenosine and nucleotide receptors and their pharmacology. Recipient of major honors including the ACS Smissman Award and the ASPET Goodman and Gilman Award for Drug Receptor Pharmacology. Dr. Sam Hoare Pharmechanics GPCR signaling & biased agonism expert regularly consulted by top pharma companies for assay design strategies. Pioneer in quantitative pharmacology methods. Dr. Yamina Berchiche Dr. GPCR & Yamina's Corner Community builder for scientists with expertise in GPCR project strategy and translational applications. Dr. Matteo Pavan NIH Computational Chemist Driving Structure-Based Drug Discovery | Molecular Modeling | AI / Machine Learning Dr. Terry Kenakin Terry's Corner Author of 'A Pharmacology Primer', the definitive GPCR reference used by labs worldwide. Former GSK principal research investigator with 40+ years of experience. Topics covered Deep dives across the full scope of GPCR science Sessions span the entire landscape of GPCR pharmacology, from foundational principles to frontier research. Structure-Based Drug Design Innovation & Strategic Application Agonists, Antagonists & Core Mechanisms Advanced Quantitative Approaches Innovation & Strategic Application Innovation & Strategic Application Pharmacology Foundations Allosteric Modulation & Kinetics Allosteric Modulation & Kinetics How it works? Your library. Your pace. 1 Browse or search Filter by scientific category, instructor, or level. Find the session that matches what you're working on right now. 2 Watch at your pace Full recordings with no time limits. Pause, rewind, revisit. The science is here whenever you need it. 3 Go deeper Join the next live Masterclass to ask your questions directly. The recordings are the foundation — the live sessions are where you go further. Want to be in the room live? Live Masterclass sessions run regularly with interactive Q&A. See what's coming up next. See live sessions → What others are saying Dr. Hoare is very experienced in the field. What came as a pleasant surprise was how didactical and well-thought-out his course was—highly recommended. The really unexpected was that the Q&A sessions reached the highest level—beyond excellent. I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere GPCR researcher Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field GPCR researcher The content had enough depth to satisfy the hunger for theory while being full of practical knowledge GPCR researcher The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology GPCR researcher Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him GPCR researcher Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator. GPCR researcher About the GPCR Masterclass What is a GPCR Masterclass? The GPCR Masterclass is a live scientific discussion with a leading expert in GPCR pharmacology, receptor biology, or drug discovery. Sessions focus on research questions, experimental interpretation, and emerging challenges in GPCR science. Are the sessions live or recorded? Masterclass sessions are conducted live with an invited expert. After the event, recordings are added to the Masterclass course library,(https://www.ecosystem.drgpcr.com/gpcr-university-masterclass) where Premium Members can access them on demand. Who should join? The Masterclass is designed for GPCR researchers, pharmacologists, and drug discovery scientists working in academia, biotech, and pharmaceutical research. Can I watch sessions later if I miss the live event? Yes. All sessions are recorded and available in the Masterclass course library for Premium Members. Can I watch sessions later if I miss the live event? Yes. All sessions are recorded and available in the Masterclass course library for Premium Members. How do I fit this in my schedule? You can attend the live discussion or watch the recording later. The Masterclass library allows members to revisit sessions at any time. What makes the Masterclass different from reading papers or textbooks? The Masterclass focuses on scientific interpretation and discussion. Experts explain how they think about pharmacological data, experimental design, and discovery challenges—insight that is rarely captured in publications. What happens during the live discussion? 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Dr. Maria Waldhoer on why endpoint GPCR assays miss most of what ligands do — and what kinetic pharmacological fingerprints reveal instead. << Back to podcast list Strategic Partner(s) Dr. Maria Waldhoer: Pharmacological Fingerprints and the Limits of Bias Dr. Maria Waldhoer, CSO of InterAx Biotech AG, argues that endpoint assays — the field's default way of characterizing GPCR ligands — throw away most of the information a compound actually carries. Her team at InterAx models receptor signaling pathways as systems of time-dependent equations, then runs kinetic assays to refine the models and extract ten to fifteen pharmacological parameters from what would otherwise be three endpoint numbers. The approach sits in deliberate tension with the prevailing vocabulary of bias factors and functional selectivity, and with the common dismissal of HEK293-based work as too artificial to matter. Her answer to that dismissal is partly methodological and partly personal: the proudest moment of her scientific life was designing a compound in a HEK cell from a hypothesis, putting it in an animal, and watching the effect come back exactly as predicted. The conversation traces her path from neurobiology in Salzburg through academic labs in Vienna, Copenhagen, and Graz, to six and a half years at Novo Nordisk, and into biotech at InterAx — where the next challenge is using functional fingerprints to design ligands, not just describe them. About the Guest Dr. Maria Waldhoer is Chief Scientific Officer at InterAx Biotech AG in Switzerland. Her training began in zoology and neurobiology in Salzburg, followed by a PhD on GPCRs in Michael Freissmuth's lab in Vienna and postdoctoral work with Thue Schwartz in Copenhagen and Jennifer Whistler in San Francisco. After running her own academic group in Graz, she spent six and a half years at Novo Nordisk in early drug discovery, focused on incretin receptors. She has been at InterAx since 2017, where she leads the development of a computational systems biology and AI platform that produces time-resolved pharmacological fingerprints of GPCR ligands. Scientific Themes of the Conversation Kinetic versus endpoint characterization of GPCR ligands Systems biology modeling of receptor signaling pathways Pharmacological fingerprints as multi-parameter compound descriptors Ligand residence time as a driver of drug action AI combined with functional, not only structural, data The academic-to-Big-Pharma-to-biotech trajectory Key Insights from the Conversation Endpoint assays collapse the ligand's signature. Standard assay kits that read cAMP at thirty minutes or arrestin recruitment at ten collapse time-resolved signaling into a single number. Dr. Waldhoer argues that most of what distinguishes one compound from another lives in the shape of the kinetics, not the endpoint value. Model first, pipette second. InterAx treats GPCR pharmacology the way engineers treat aircraft design: build the mathematical model of the signaling pathways first, then use controlled kinetic assays as the "wind tunnel" that refines the model. Inverting the usual order changes what the experiment can be asked to do. Three inputs can yield fifteen outputs. With a well-constructed computational model and a small set of kinetic assays, one compound on one receptor can be described by ten to fifteen pharmacological parameters — internalization rates, recycling and degradation rates, G protein affinity for the ligand-receptor complex, and more — rather than a single EC50 or a single bias number. The HEK293 cell earned its keep. Her most formative scientific moment was designing a compound in HEK293 cells from a hypothesis at Novo Nordisk, putting it in an animal, and watching the effect come back exactly as predicted. The "artificial system" critique misses what those systems do for people who know how to ask the right questions of them. Bias factor is a start, not an answer. Functional selectivity has been in the vocabulary since her PhD years in Vienna. Picking a single time point for a single pathway and computing a bias factor captures far less than looking at how several pathways evolve over time — especially for compounds with unusual kinetics. The next challenge is multi-receptor, multi-disease complexity. With comorbidities and aging populations driving drug discovery, the one-receptor-one-drug frame is increasingly inadequate. The computational tools that now describe single receptors will need to extend to how multiple receptors in the same cell, in a diseased tissue, at a particular age, interact. Young founders should not build alone. The hardest-won lesson of her biotech years: great science does not rescue a company from inexperienced management. Scientists starting companies need experienced operators around them, and the honesty to know when to bring them in — a theme she returns to as her farewell message. Episode Timeline Timestamps were generated using AI for readability. 00:00 — Opening: end-of-2020 wrap-up, January break, announcements 01:28 — Meet Dr. Maria Waldhoer, CSO of InterAx Biotech 02:19 — From zoology to GPCRs: fate, not choice 06:48 — Academia to Big Pharma: speed, scale, and decisions from above 09:58 — InterAx's pivot from arrestin biosensors to kinetic systems biology 14:31 — Why endpoint numbers miss what a ligand is really doing 16:40 — AI plus "real intelligence": functional data in drug design 21:48 — Comorbidities, aging, and the multi-receptor frontier 24:07 — "What endogenous level would you like me to mimic?" 25:26 — The HEK293 experiment that predicted the animal 31:21 — Tools for the next decade: biosensors, tissues, high-throughput structure 38:43 — Career advice for scientists eyeing industry or biotech 42:35 — On starting a GPCR company: why not too early 57:30 — Aha moments, including the EU grant pitch in Brussels 01:01:53 — "You're only as good as the other people you're with" Selected Quotes "A long way through the bright and the dark side of science." "What endogenous level would you like me to mimic?" "We combine AI with RI — with real intelligence." "You're only as good as the other people you're with." About this episode Dr. Maria Waldhoer is originally from Austria. She earned her M.Sc. in Zoology and Neurobiology before completing a Ph.D. in Biology and Pharmacology at the University of Vienna. GPCRs led Maria to Thue W. Schwartz’s lab in Copenhagen where she completed her postdoctoral training. After working in the US and at the University in Graz in Austria, Maria worked several years at Novo Nordisk before joining InterAx Biotech in Switzerland as their Chief Scientific Officer. Even though Maria stumbled upon the GPCR field, her 20 years in both academia and in the industry working on GPCRs make her a strong and dedicated scientific leader. Dr. Maria Waldhoer on the web LinkedIn InterAx Biotech Pubmed Dr. GPCR Ecosystem Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

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<< Back to podcast list Strategic Partner(s) Dr. Ilana Kotliar About Dr. Ilana Kotliar "Ilana Kotliar is a postdoctoral associate in the lab of Tom Sakmar at The Rockefeller University, where she just recently defended her PhD thesis. Ilana uses chemical biology-based methods to study the regulation and protein-protein interactions of GPCRs and a small family of accessory proteins called RAMPs. Ilana’s research is multi-disciplinary and involves a close collaboration with proteomics experts at The Science for Life Laboratory in Sweden. She is a recipient of the prestigious Women in Entrepreneurship Award, an NIH T32 Training Grant, and two Nicholson Fellowships. Outside of the lab, Ilana is a leader within her community, spearheading several outreach initiatives including a global mentoring initiative that matches graduate student mentors to PhD applicants. Ilana graduated Summa cum laude from Cornell University, where she studied Chemistry and Chemical Biology and was recognized as a Merrill Presidential Scholar." Dr. Ilana Kotliar on the web Google Scholar LinkedIn Twitter Dr. GPCR Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Recent Podcast Articles Asking Better Questions in Science: A Practical Guide for Emerging Researchers When the Islet Lit Up: Advancing GPCR Imaging in Native Tissue How Collaboration Sparked a GPCR Imaging Breakthrough in Chemical Biology Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>