<< Back to podcast list Strategic Partner(s) Dr. Peter Robert Banks About Dr. Peter Robert Banks Peter Banks is currently the Scientific Director at BioTek Instruments , now a part of Agilent . His responsibilities include the management of the company’s applications team and providing scientific guidance to the senior management team on new technology and emerging trends impacting life sciences. Before joining BioTek in 2008, Banks was employed by PerkinElmer for a decade. These roles included management of PerkinElmer’s BioPharma R&D program and Chair of the company’s Scientific Advisory Board. Prior to experiences at PerkinElmer and BioTek, Banks was an Assistant Professor in Analytical Chemistry at Concordia University, Montreal, Canada from 1994 to 1998. Dr. Peter Robert Banks on the web LinkedIn Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Julia Gardner About Julia Gardner Julia is a senior undergraduate student at Duke University, where she studies chemistry and Chinese. Julia has been working as a researcher in Duke's Rajagopal Lab since her first year as an undergraduate. In the Rajagopal Lab, Julia studies the mechanisms of 'biased signaling' at GPCRs, with a specific focus on the chemokine receptor CXCR3. She recently led a project that demonstrated the GPCR kinases (GRKs) can translocate to endosomes, and that the subcellular localization of the GRKs affects a GPCR's biased signaling profile. Last summer, Julia worked at as the first-ever summer intern at Septerna, the GPCR-based biotechnology company founded by Duke Nobel laureate Dr. Robert Lefkowitz. In the fall, Julia will begin her MD/PhD training. Julia Gardner on the web Rajagopal Lab Google Scholar ResearchGate LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) The Role of Quantitative Sciences in GPCRs with Dr. Nagarajan Vaidehi About Dr. Nagarajan Vaidehi "Nagarajan Vaidehi, Ph.D., is professor and chair of the Department of Computational and Quantitative Medicine (DCQM) at the Beckman Research Institute of the City of Hope in Los Angeles, CA. She is also the Associate Director of the City of Hope Comprehensive Cancer Center. Dr. Vaidehi received her Ph.D. in quantum chemistry from the Indian Institute of Technology in India, where she was honored with the Distinguished Alumni Award in 2016. Following her postdoctoral studies on protein dynamics simulation methods at University of Southern California, and at Caltech, she became the director of biomolecular simulations at the Materials and Process Simulation Center, Beckman Institute at Caltech. Dr. Vaidehi joined the Beckman Research Institute of the City of Hope in 2006 as a Professor and became chair of DCQM in 2018. She has advanced the use of computational methods to meet the challenges of designing therapeutics with lower off target effects. She is an internationally recognized biophysicist for her contributions in developing constrained molecular dynamics simulation methods with emphasis on application to G-protein coupled receptors and drug design." Dr. Nagarajan Vaidehi on the web City of Hope Google Scholar LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Irfan Dhanidina, Dr. Kathleen Caron and Dr. Lauren Slosky About Irfan Dhanidina "My interest in oncology research led me to pursue a BSc in Biology & Economics from Carleton University, and an MSc in Biotechnology at McGill. However, after insightful experiences in academic, hospital, and industry labs, I decided to pursue a role in business development. In my role at Orion Biotechnology, I work at the intersection of science and business, which includes target selection, preclinical strategy and business development. With respect to GPCRs, I'm particularly interested in peptide/small protein receptors and the mechanisms that facilitate their role in various indications. To that end, I'm grateful to be working alongside the very talented team at Orion who translate important GPCR research into novel therapies for patients. " Irfan Dhanidina on the web LinkedIn The Org DIBIZ Dr. GPCR About Dr. Kathleen Caron " "Kathleen M. Caron, Ph.D. is the Frederik L. Eldridge Distinguished Professor and Chair of the Department of Cell Biology & Physiology at The University of North Carolina at Chapel Hill—a large, interdisciplinary basic science department consistently ranked in the Top 5 in the Nation in NIH funding. Dr. Caron received a BS in Biology and BA in Philosophy at Emory University and a PhD at Duke University while training with Dr. Keith Parker to elucidate the role of steroidogenesis in regulating sexual determination and adrenal and gonadal development using genetic mouse models. She pursued postdoctoral training with Nobel Laureate Dr. Oliver Smithies at UNC-CH, where she was the first to discover the essential role of adrenomedullin peptide for embryonic survival. With a special emphasis on G protein coupled receptors and receptor activity modifying proteins in vascular biology, the Caron laboratory has gained valuable insights into the genetic basis and pathophysiology of lymphatic vascular disease, preeclampsia and sex-dependent cardiovascular disease. Dr. Caron has received numerous awards including a Burroughs Wellcome Fund Career Award in the Biomedical Sciences, an Established Investigator Award and an Innovator Award from the American Heart Association, a Jefferson Pilot Award in Biomedical Sciences and a UNC-CH Mentoring Award. She currently serves as Associate Editor of Physiological Reviews; the #1 ranked journal in Physiology (IF 46.5). Dr. Caron is also past Associate Editor at JCI and served as the inaugural Associate Editor at ACS-Pharmacology and Translational Science. Dr. Caron currently holds multiple scientific advisory roles in academia, industry and the National Institutes of Health." " Dr. Kathleen Caron on the web UNC-Chapel Hill Department of Cell Biology and Physiology UNC Lineberger Comprehensive Cancer Center Twitter Google Scholar ORCID ResearchGate Dr. GPCR About Dr. Lauren Slosky "Lauren Slosky is an Assistant Professor in the Department of Pharmacology and a member of the Medical Discovery Team on Addiction, a multidisciplinary initiative within the University of Minnesota’s Medical School to advance research and treatment in the field of drug addiction. Dr. Slosky’s research is focused on understanding how neuropeptide G protein-coupled receptors (GPCRs) regulate motivated behavior and how these receptors can be targeted for therapeutic benefit. Dr. Slosky was awarded a B.S. with honors in Molecular and Cellular Biology and Psychology from The University of Arizona in 2011. She received a Ph.D. in Medical Pharmacology from The University of Arizona in 2015 and completed a postdoctoral fellowship in the laboratory of Dr. Marc G. Caron at Duke University. Dr. Slosky opened her laboratory at the University of Minnesota Medical School in 2021. While a postdoctoral fellow, Dr. Slosky characterized a new class of β-arrestin biased allosteric modulators (BAMs) for the neurotensin receptor 1. These ligands stimulate receptor β-arrestin recruitment without activating canonical G protein signaling. Critically, these ligands reduce addiction-associated behaviors in animal models without the side effects characteristic of balanced receptor activation. Because BAMs engage less well-conserved allosteric sites and exert pathway-specific effects on receptor signaling, they are exciting tools for linking distinct signaling pathways with their physiological effects and may serve as the basis for more selective therapeutics. This work was made possible by the optimization of longitudinal intravenous self-administration paradigms for genetically modified mice. Integrating GPCR biology, behavioral pharmacology, and systems neuroscience approaches, the Slosky Lab is now working to understand how the principles of receptor allosterism and functional selectivity can be leveraged in the development of safe and effective treatments for stimulant and opioid use disorders. Dr. Slosky’s work has been recognized through several travel and research awards, including the William James Psychology Award, the Hank Yamamura Endowed Fellowship in Pharmacology, an NIH F32 Postdoctoral Fellowship, and an NIH K99/R00 Pathway to Independence Award. In addition to research, Dr. Slosky is passionate about training the next generation of scientists and increasing diversity, equity, and inclusion in science. An advocate for trainees at all levels, she served as Service Chairperson and Interim President of the Duke University Postdoctoral Association. She is currently a faculty trainer for the University of Minnesota's MS and Ph.D. programs in Pharmacology, Graduate Program in Neuroscience, and Life Sciences Summer Undergraduate Research Program and is working to build relationships with key stakeholders through institutional and community service." Dr. Lauren Slosky on the web University of Minnesota Department Page Twitter LinkedIn Google Scholar PubMed Research Gate Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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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Equip your research team with expert-led GPCR pharmacology training. Get 25% off Annual Premium Memberships for teams of five or more. Activate in days. Home Courses Articles About Log In / Sign Up Equip Your Team with Terry Kenakin’s Pharmacology Frameworks Used by discovery scientists across biotech, pharma, and academia. Shared pharmacology discipline for discovery teams. When scientists interpret pharmacology through the same frameworks, experiments become clearer and program decisions become stronger. Train 5 or more team members and receive 25% off annual access. $2,249.25 per person / year Activate Team Membership Why Teams Use Terry’s Corner Discovery programs move faster when scientists interpret pharmacology through the same mechanistic frameworks. Terry’s Corner helps teams align how they analyze receptor pharmacology, signaling data, and translational outcomes. That alignment reduces misinterpretation and improves experimental strategy across programs. What Your Team Gets? • Pharmacology frameworks used in modern drug discovery • Monthly live AMA discussions with Terry Kenakin • Ongoing Terry’s Corner lessons and analysis • Ability to suggest topics relevant to your programs • Access for biotech, pharma, and academic discovery teams • Full Dr. GPCR University Premium access for every team member How Team Membership Works? 1 — Prepare Your Team Gather at least 5 scientists who will participate. Each participant must have a Dr. GPCR Ecosystem account . 2 — Submit Your Team Details Provide names, emails, and organization information so we can activate access correctly. 3 — Complete the Payment Secure your team membership and receive confirmation. 4 — Membership Activation Our team activates all seats and confirms access. Activation typically takes 3–10 business days . Need to add members later? Our team can help expand your membership anytime. Apply for Team Membership First name* Last name* Email* Company name* Company Website* Names & Emails of Each Team Member (minimum 5)* Team Size* Annual Premium Team access. Minimum five seats. Priced per person per year. $2,249.25 Order Now 💡 Have questions? Contact us at Hello@DGPCR.org Terry’s Pharmacology Corner — Created by Dr. Terry Kenakin , powered by Dr. GPCR . Stay connected on LinkedIn and YouTube . Explore : Foundational Lessons — Build Your Pharmacology Core Emerging Drug Hunter — Expand Your Edge Expert-Level Mastery — Advanced Pharmacology Live AMA Sessions with Terry

<< Back to podcast list Strategic Partner(s) Dr. Raul Gainetdinov About Dr. Raul Gainetdinov Raul R. Gainetdinov is the Institute of Translational Biomedicine Director at Saint Petersburg State University (SPBU), Russia. Before SPBU, Raul R. Gainetdinov was a Senior Researcher in the Department of Neuroscience and Brain Technologies at the Italian Institute of Technology in Genova, Italy (2008-2016) and an Associate Research Professor in the Department of Cell Biology at Duke University in North Carolina, USA (1996-2008). From 2013-2018, he was also a Professor at the Skolkovo Institute of Science and Technology (Skoltech), Moscow. Before joining the Department of Cell Biology in 1996 as a postdoc and becoming faculty at Duke in 2000, he researched at the Institute of Pharmacology Russian Academy of Medical Sciences in Moscow (1988-1996). He received a Ph.D. in pharmacology in 1992 from the Russian Academy of Medical Sciences and an M.D. in 1988 from the Second Moscow Medical Institute, Moscow, Russia. Since 2013, he has been elected Chair of the subcommittee for the Dopamine receptors of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR). As of August 2022, he has over 270 publications in scientific journals (including Science, Nature, Cell, and PNAS) and co-authored 13 patents. His papers were cited over 28,000 times (H-index – 81, ISI Web of Science). In 2018-2020, Raul R. Gainetdinov was included in the Web of Science (WOS) Highly Cited Researchers (HCR) list, representing the top 0.1% of scientists worldwide. Dr. Raul Gainetdinov on the web Saint-Petersburg State University Wikipedia Google Scholar Researchgate Google Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Aylin Hanyaloglu About Dr. Aylin Hanyaloglu Dr. Aylin Hanyaloglu has been a Principal Investigator at Imperial College London since 2007. She received her BSc in Human Biology from King’s College London in 1997, and while her Ph.D. commenced at the MRC Human Reproductive Sciences Centre, Edinburgh, a move to Perth, Australia resulted in her Ph.D. in Molecular Endocrinology being awarded in 2002 with Distinction from the University of Western Australia. Dr. Hanyaloglu undertook her postdoctoral training at the University of California, San Francisco with Professor Mark von Zastrow where she identified novel core cellular machinery critical for G protein-coupled receptor trafficking and signaling. Her research focuses on understanding the fundamental cell biological mechanisms regulating GPCR activity, including spatial control of GPCR signaling and receptor crosstalk, and applying these mechanisms for distinct GPCRs in diverse physiological and pathophysiological systems, with particular focus on women's health, pregnancy, and nutrient sensing in the gut. Her work is currently funded by Biotechnology and Biological Sciences Research Council (BBSRC), Diabetes UK, Wellcome Trust, and the Medical Research Council. Dr. Aylin Hanyaloglu on the web LinkedIn Researchgate Twitter Imperial College London Elsevier Loop Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) 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 Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

Sokhom Pin shares how he built a biotech career around GPCRs, designed a custom PhD path, and led teams through empowerment and purpose. << Back to podcast list Strategic Partner(s) GPCR Pharmacology, Career Twists & Serendipity with Sokhom Pin From the Bench to the Boardroom Sokhom Pin’s story begins not with prestige or privilege but with grit and commitment. From his early work as a technician at Johns Hopkins Hospital to leading biology at Servo Therapeutics, Sokhom’s journey is rooted in practicality and purpose. He shares: "All my industry experience has been GPCR-focused." Starting at DuPont, then BMS, Novartis, and eventually founding in vitro pharmacology departments, Sokhom always stayed anchored to G protein-coupled receptors (GPCRs). Family First, Always The decision to shift from academia to industry wasn’t driven by disillusionment—it was about responsibility. “I had two kids and realized I just couldn’t support a family on a technician’s salary.” This pragmatic decision led him to high-throughput screening at DuPont, proving that scientific ambition doesn’t have to mean sacrificing personal commitments. Falling in Love with GPCRs GPCR pharmacology captured his scientific curiosity. Sokhom recalls how binding assays at BMS introduced him to the depth and complexity of receptor pharmacology: “It’s not just about IC50s. There’s allosterism, receptor desensitization… it opened a whole new world.” This moment became pivotal—transforming technical proficiency into passion. Designing a Non-Traditional PhD While working full-time, Sokhom architected a one-of-a-kind PhD program between BMS and UConn. “I had to find a way. I wanted a PhD, but I couldn’t quit my job.” Through strategic coordination, he executed a PhD entirely in the industry setting—efficient, targeted, and rooted in real-world projects like CGRP receptor antagonists. From Scientist to Leader At Alkermes, Sokhom took his first leadership role and finally experienced the power of empowerment . “That’s the moment that changed my entire career. I was trusted to build a team from scratch.” He focused on culture—ensuring passion and purpose drove performance. The Power of the Right Culture Whether it was Alkermes or Cerevel, Sokhom emphasized that team culture trumps individual genius . “It doesn’t matter how brilliant someone is—if they’re toxic, I don’t want them on the team.” He built what others called the “happiest team at Alkermes,” showing that joy and scientific rigor aren’t mutually exclusive. Network or Miss Out One powerful shift came when Sokhom leaned into networking—despite being an introvert. “I changed from being an extreme introvert to someone who thrives on connection.” His story underscores how something as simple as forwarding a resume or reaching out for coffee can change careers. The Lifecycle of GPCR Popularity Sokhom has witnessed the waves of scientific fashion: “There was a time GPCRs were hot, then ignored. Now they’re back.” His unwavering dedication through these cycles became an asset—many others shifted focus, leaving a smaller, highly skilled group of GPCR specialists. Lessons from Molecules and Mentors He draws inspiration from scientific complexity and colleagues like Arthur Christopoulos and Terry Kenakin. “What fascinates me is how the same molecule behaves differently depending on one amino acid.” He blends classical receptor pharmacology with biosensor technology, always adapting to new tools and insights. Don’t Let Weakness Define You The episode ends with a deeply human reflection: “Don’t let your weakness define your life. Overcome it. I used to sweat thinking about presentations. Now I love them.” Whether it’s networking, leadership, or technical mastery, Sokhom’s message is clear: keep evolving, and don’t settle. Key Takeaway Sokhom Pin's journey is a masterclass in scientific persistence , non-traditional success , and values-driven leadership . For any scientist navigating career uncertainty—his story is both roadmap and inspiration. About Sokhom Pin Sokhom Pin is a receptor pharmacologist with over 20 years of drug discovery research in the pharmaceutical industry, where he works mainly on GPCRs as therapeutic targets. He is passionate about mechanistic profiling of therapeutic molecules as well as drug discovery in general. Outside of science Sokhom enjoys outdoor activities such as hiking, boating, fishing, and biking. Sokhom Pin on the web LinkedIn Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Patrick Sexton About Dr. Patrick Sexton Patrick Sexton is a Professor of Pharmacology, National Health and Medical Research Council of Australia Senior Principal Research Fellow, and Director of the Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins ( www.ccemmp.org ). He is a leader in the study of GPCRs, biased agonism, and also on allosteric interactions between GPCRs and other proteins and small molecule ligands. More recently, his team has been at the forefront of the application of cryo-EM to elucidate of the structure and dynamics of GPCRs. Prof. Sexton has published over 320 peer-reviewed journal articles and has been cited >26,000 times (Google Scholar). He is a 2021 Clarivate Analytics Highly Cited Researcher in two disciplines: Pharmacology & Toxicology and Biology & Biochemistry, a corresponding member of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, and a member of the Faculty of 1000 (Molecular Pharmacology division) and an elected Fellow of the British Pharmacological Society (BPS). Prof. Sexton’s awards include the Australasian Society for Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) Lecturer award, Endocrine Society of Australia Senior Plenary award, Rand Medal (ASCEPT), Paxinos-Watson Award (Australian Neuroscience Society), Vane Medal (BPS), Gordon Hammes Lectureship Award (American Chemical Society) and the GSK Research Excellence award. Prof. Sexton is also a co-founder of the San Francisco-based biotechnology company Septerna Inc . Dr. Patrick Sexton on the web CCeMMP Monash University Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Silvia Sposini About Dr. Silvia Sposini " I'm originally from Rome, Italy, where I studied Biological Sciences as a BSc student. I moved to London as a short experience (3 months) during my MSc but I ended up staying for a full year and and a PhD! During my time in London I investigated regulatory mechanisms of GPCR action, namely dimerization and membrane trafficking, in Dr Aylin Hanyaloglu 's lab at Imperial College London. In 2018 I got married and moved to France, to join the Interdisciplinary Institute for Neurosciences in Bordeaux. Still working on GPCR trafficking but this time in neurons. In 2021 I became mum of a gorgeous baby girl, Elena. I am currently funded by a postdoctoral fellowship from Wellcome Trust, working on a collaborative project (Dr Hanyaloglu's lab at ICL + Dr Perrais' lab at IINS) focused on understanding the interplay between GPCR signalling and trafficking in neurons using microscopy and proteomics based techniques. " Dr. Silvia Sposini on the web Bordeaux Neurocampus LinkedIn ResearchGate X (Twitter) Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Josh Pottel About Dr. Josh Pottel "I lead Molecular Forecaster Inc. (MFI): a reliable, self-sustaining computational chemistry service provider, developing its own software for application in various drug discovery campaigns. I have extensive training in computer-aided drug design. I completed my PhD at McGill University in the lab of Prof. Nicolas Moitessier, and went on to a postdoc with Prof. Brian Shoichet at UCSF. While in San Francisco, I completed Startup101 - a course a offered by the entrepreneurship center. I am now combining my training as a chemist and as an entrepreneur to grow a sustainable service and software provider in drug discovery. More broadly, I hope to be a critical contributor to a growing Canadian biotech sector in both scientific research and fostering entrepreneurship." Dr. Josh Pottel on the web Molecular Forecaster LinkedIn BlueSky Google Scholar Twitter Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Davide Calebiro About Dr. Davide Calebiro "Davide Calebiro is Chair of Molecular Endocrinology and Wellcome Trust Senior Research Fellow at the Institute of Metabolism and Systems Research (IMSR) of the University of Birmingham and Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE) of the Universities of Birmingham and Nottingham. He studied Medicine in Milan and Stockholm, and obtained a PhD in Molecular Medicine and a Clinical Specialisation in Endocrinology and Metabolic Disease from the University of Milan. Between 2009 and 2017, he was a Group Leader at the Institute of Pharmacology and Toxicology and Rudolf Virchow Center of the University of Würzburg, Germany. He leads a multidisciplinary research team comprising biologists, chemists, physicists, engineers and computer scientists focusing on the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in endocrine, metabolic and cardiovascular diseases. To study GPCR signalling, they develop and use innovative optical methods based on FRET and single-molecule microscopy, which allow them to directly observe signalling events in living cells and tissues with unprecedented spatiotemporal resolution. His major scientific contributions include the discovery that GPCRs are not only active at the plasma membrane but also at intracellular sites and that these receptors interact among themselves and with other membrane proteins to form dynamic nanodomains at the plasma membrane. Davide’s work has been published in prestigious scientific journals such as Nature, Cell, New England Journal of Medicine, Journal of Clinical Investigation, PLoS Biology, PNAS, Nature Communications and Science Advances, attracting several prizes and awards. He has served on multiple panels and committees, including the ENDO Annual Meeting Steering Committee and the MRC Molecular & Cellular Medicine Board." Dr. Davide Calebiro on the web University of Birmingham Twitter Google Scholar LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. G. Aditya Kumar About Dr. G. Aditya Kumar Dr. Aditya Kumar is a postdoctoral fellow at the University of Michigan Medical School. Aditya is interested in understanding the role of the membrane microenvironment in the subcellular organization, trafficking, and signaling of GPCRs. He received his Ph.D. from the Centre for Cellular and Molecular Biology at Hyderabad, India, where he studied the interaction of membrane cholesterol with the serotonin-1A receptor and its effects on receptor signaling and endocytosis. In addition, he explored the role of the host membrane in the entry of intracellular pathogens into macrophages. He currently uses high-resolution fluorescence microscopy and biochemistry to study GPCR trafficking mechanisms. In his (future) independent research career, Aditya aims to work at the interface of GPCR molecular pharmacology, subcellular trafficking, and membrane biology to better understand how the dynamic receptor microenvironment contributes to GPCR organization and function. Dr. G. Aditya Kumar on the web University of Michigan Puthenveedu Lab Google Scholar NIH ORCID LinkedIn Twitter Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

Livingston on allosteric opioid modulators, receptor internalization, and navigating the transition from academic GPCR research to biotech. << Back to podcast list Strategic Partner(s) Kathryn Livingston: Allosteric Opioid Modulators and Receptor Signaling Beyond the Membrane Opioid receptors belong to a class of GPCRs where the pharmacology extends well beyond what equilibrium binding data can show. The first allosteric modulators of opioid receptors were discovered through an academic-industry collaboration and immediately raised a foundational question: without competing for the orthosteric site, how do these compounds actually work? Livingston's PhD research at the University of Michigan addressed this systematically - mapping selectivity, mechanism, and the long-term consequences of modulator exposure on receptor desensitization and tolerance acquisition. Her postdoc in von Zastrow's lab at UCSF introduced a different framework entirely. Rather than measuring endpoint states, she learned to watch receptors move, internalize, and continue signaling from inside the cell - a finding that challenged the membrane-centric assumption underlying much of classical receptor pharmacology. The conversation traces the scientific and personal logic behind each transition: from chemistry to pharmacology, from membrane to endosome, from bench to product development. For Livingston, GPCRs were never purely academic - her entry into the field began with a forensic toxicologist father who tested crime scene samples for controlled substances, and a question about why molecules change who we are. About the Guest Livingston completed her PhD in pharmacology at the University of Michigan, where she investigated the first allosteric modulators of opioid receptors under Traynor, characterizing their selectivity, binding mechanisms, and effects on acute and chronic receptor signaling. She trained as a postdoctoral fellow in von Zastrow's lab at UCSF, where she worked on beta-2 adrenergic receptor internalization using live-cell imaging approaches that track receptor dynamics in real time. She now works at Gator Bio, where she transitioned from Field Application Scientist - serving as a technical liaison between GPCR researchers and analytical instrumentation - to Product Manager, translating customer research needs into commercial tools. Scientific Themes of the Conversation Allosteric modulation of opioid receptors - mechanism, selectivity, and therapeutic rationale Receptor internalization and post-endocytic signaling as a paradigm shift in GPCR pharmacology Assay design as an epistemic constraint on pharmacological interpretation Equilibrium vs. dynamic frameworks for studying receptor biology The Field Application Scientist as a career model for GPCR-trained scientists The structural complementarity of academic and industry research in drug discovery Key Insights from the Conversation 1. Allosteric opioid modulators bypass the orthosteric site entirely Rather than competing with morphine or endogenous opioids at the binding pocket, allosteric modulators act at a distinct site on the receptor. Livingston's PhD project was among the first to characterize how these compounds operate - mapping whether activity is receptor-dependent, whether they shift affinity or efficacy, and whether effects persist through desensitization and tolerance. The therapeutic logic is that decoupling from the orthosteric site might preserve pain relief while altering the signaling profiles responsible for side effects. 2. Internalized receptors don't stop working The membrane-centric view of receptor pharmacology assumes signaling ends when a receptor is endocytosed. Von Zastrow's lab challenged this directly, demonstrating that GPCRs continue to generate signals after they leave the cell surface. For Livingston, encountering this finding after a PhD grounded in equilibrium binding required a genuine conceptual reset - the receptor she had been mapping was not anchored to the membrane in the way her training had assumed. 3. An assay measures a specific thing - not the biology you assume it measures One of Livingston's most consistently held principles: understanding exactly what your assay is measuring is not optional. A readout that captures a downstream marker, a surrogate signal, or a population average can yield clean data while systematically pointing in the wrong direction. Misinterpreting assay specificity is, in her view, one of the most consequential and underacknowledged sources of error in pharmacological research. 4. Live-cell imaging makes the dynamic pharmacology of GPCRs visible Where equilibrium assays capture endpoint states, live-cell microscopy reveals what happens between them. During her postdoc, Livingston transitioned from pulling numbers off instruments to watching receptors traffic, cluster, and internalize in real time. She describes the shift as both technically disorienting and visually striking - a different relationship to data than any endpoint assay can produce. 5. Academia and industry are structurally complementary - not competing versions of the same thing Academia can sustain a 15-year investigation of a single receptor question. Industry can screen tens of millions of compounds in the time it takes to write a grant. Livingston argues these structural constraints make the two sectors dependent on each other - and notes that her PhD emerged directly from an academic-industry collaboration that would not have produced the allosteric modulators without both sides present. 6. The Field Application Scientist role is one of the least-known best fits for GPCR-trained scientists The FAS role combines technical depth, customer-facing science, and teaching - a combination Livingston describes as a natural extension of what she valued most in training. The role is rarely discussed in academic career advising, yet it draws directly on GPCR pharmacology skills: deep assay knowledge, the ability to troubleshoot complex data, and fluency across multiple experimental systems. Episode Timeline Timestamps are AI-generated based on transcript analysis and may not reflect exact chapter breaks in the final audio or video. Use as a navigational guide. 00:00 Introduction and ecosystem announcements 02:15 From inorganic chemistry to GPCR pharmacology 03:17 The origin story - forensic toxicology, mental disorders, and GPCRs 06:58 PhD research: first allosteric modulators of opioid receptors 11:58 Know your assay - and why getting it wrong costs more than data 12:36 Choosing von Zastrow's lab and the internalization paradigm shift 14:17 How to choose a postdoc with no trial period 19:07 Beta-2 adrenergic receptors and live-cell imaging at UCSF 22:02 The moment academia stopped making sense 30:54 From Field Application Scientist to Product Manager 38:58 What both roles look like day-to-day 39:28 Three steps for PhDs and postdocs considering industry Selected Quotes "Instead of directly targeting the receptor like morphine or buprenorphine, we target allosterically. We enhance your endogenous tone, we cause pain relief, maybe we mitigate some of these side effects." "To go to Mark's lab where everything is dynamic, everything is moving - this is a live cell where pieces are internalizing, moving - and then to flip it on its head again and say the receptor at the surface might not be the center of the world." "You have to know what your assay is actually measuring. Because you can get this data and you interpret it one way, but if you don't know the nuances, the very intricacies about your assay - you don't actually know what the specificity of the thing you're measuring is - then you can interpret it in a really wrong way." "In industry, you can't spend 15 years trying to solve one problem. There's no way. But in academia, you also can't screen 30 million cell lines in an afternoon. They're completely complementary." About Dr. Kathryn E Livingston Dr. Kathryn E Livingston is currently a Product Manager at Gator Bio , a biotechnology company providing solutions to researchers studying protein-protein interactions. Kathryn obtained her BS in Chemistry from Carnegie Mellon University and went on to receive a Ph.D. in Pharmacology at the University of Michigan. Working under the supervision of Dr. John Traynor , Kathryn worked to develop and understand first-in-class allosteric modulators of opioid receptors. Research into their mechanism of action in purified systems formed the base of her thesis work. Following this, Kathryn did a post-doctoral fellowship at UCSF in the laboratory of Dr. Mark von Zastrow . There she researched the beta-2 adrenergic receptor and developed assays to investigate real-time activity in intact cellular systems. Kathryn’s passion is developing solutions to problems in whatever form is most efficient: novel instrumentation, novel methods, or novel communication. Dr. Kathryn E Livingston on the web LinkedIn ResearchGate Pubmed Google Scholar Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) The Scientist's Compass: From Academia to Entrepreneurship with Dr. Dmitry Veprintsev In this episode, Yamina sits down with Prof. Dmitry Veprintsev , a molecular pharmacologist at the University of Nottingham, to discuss his scientific journey, GPCR research, and the intersection of academia and entrepreneurship. Key Takeaways: From Protein Folding to GPCRs – How Dmitry transitioned from biophysics and protein folding to cannabinoid receptor research, guided by key mentors like Michel Bouvier. Why GPCRs? – The challenge and excitement of working with notoriously difficult-to-study membrane proteins. The Power of Asking the Right Question – Dmitry emphasizes that mastering a technique isn’t enough—true scientific breakthroughs come from formulating the right biological questions. Building Z7 Biotech – The unexpected journey into biotech entrepreneurship, providing GPCR profiling services to pharma and biotech companies. Interdisciplinary Research & Future Directions – Exploring combinatorial drug actions, receptor interactions, and novel profiling approaches. Networking & Career Growth – Overcoming introversion, the importance of talking to people, and how networking (or just genuine curiosity) opens doors in science. 💡 Big Takeaway? Whether in academia or industry, success comes from curiosity, persistence, and knowing your values. Tune in to hear how Dmitry navigated his career, the challenges of studying GPCRs, and why talking to others will always lead to answers! Summary made with AI About Dmitry Veprintsev Dmitry is Professor of Molecular and Cellular Pharmacology at the Centre of Membrane Proteins and Receptors (COMPARE), University of Nottingham, where he provides leadership in structural and biophysical pharmacology of G protein coupled receptors. He is author of over 100 papers, including several in Nature, Science and Cell. Dmitry studied biophysics at the Moscow State University, followed by a PhD (1998) in protein folding at the Russian Academy of Sciences and at the Ohio State University, USA. He joined the MRC Centre for Protein Engineering and later at the MRC Laboratory of Molecular Biology in Cambridge, UK as a postdoctoral fellow and later as a staff scientist, focusing on the biophysical studies of the tumour suppressor p53. In 2010 he became a group leader at the Paul Scherrer Institute and ETH Zürich in Switzerland, changing his attention to structural pharmacology of G protein-coupled receptors (GPCRs). In 2017 Dmitry became a full professor at the Centre of Membrane Proteins and Receptors, COMPARE, a joined venture between the University of Birmingham and the University of Nottingham. In 2021 he co-founded Z7 Biotech, developing and providing innovative GPCR drug screening and precision pharmacology services. Dmitry Veprintsev on the web LinkedIn Veprintsev Lab Z7 Biotech University of Nottingham Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

Randy Hall on the receptor tail the field ignored, the adhesion GPCR experiment that did the opposite of what he expected, and writing Lefkowitz's memoir. << Back to podcast list Strategic Partner(s) Randy Hall: Adhesion GPCRs and the Tail Nobody Wanted SCIENTIFIC ABSTRACT Most of what the field now takes for granted about the C terminus of a GPCR was, in the mid 1990s, considered uninteresting. Randy Hall arrived in Bob Lefkowitz's lab from a background in ionotropic glutamate receptors, noticed that the beta adrenergic receptors carried short motifs resembling the ones that recruit scaffold proteins to NMDA receptors, and asked what bound there. He was told the answer was nothing. At the time, the lab chasing the first GPCR crystal structure was cutting the tail off entirely. What he found reframed how the field explains why closely related receptor subtypes produce different effects on cell physiology. This conversation follows that thread into adhesion GPCRs, a subfamily of 33 human receptors with enormous extracellular N termini that cleave themselves and then stay together. Hall describes the experiment designed to kill receptor signaling that instead amplified it, the tethered agonist model his lab proposed in 2011, and why a family once dismissed as undruggable now looks like a serious therapeutic frontier. He also explains how he came to write the memoir of his mentor, a project he pitched three times over fifteen years before the answer was yes. ABOUT RANDY Randy Hall is Professor of Pharmacology and Chemical Biology at Emory University School of Medicine, where he has run his lab since 1999. He trained with Gary Lynch at UC Irvine on ionotropic glutamate receptors, then with Thomas Soderling at the Vollum Institute on receptor trafficking and phosphorylation, before joining Bob Lefkowitz's lab at Duke to work on adrenergic receptor regulation. His lab uses proteomic and interaction screening approaches to map the proteins that bind GPCR intracellular tails, and has published on receptors from the adrenergic, purinergic, glutamatergic, GABAergic and adhesion subfamilies. Recent work centers on GPR37 and GPR37L1 and on the adhesion receptors BAI1, BAI2 and GPR56, with a particular focus on disease associated mutations that disturb receptor signaling or trafficking. He is a Fellow of the AAAS and coauthor, with Bob Lefkowitz, of the 2021 memoir A Funny Thing Happened on the Way to Stockholm. SCIENTIFIC THEMES OF THE CONVERSATION - Why the GPCR C terminus turned out to determine subtype specific function - Adhesion GPCRs: self cleaving receptors, huge N termini, and the tethered agonist model - Constitutive activity as a disease mechanism, from the alpha 1 receptor to BAI2 - Orphan receptors and where the next generation of GPCR drugs will come from - In silico screening, and what human plus machine collaboration means for drug discovery - Problem selection: how young scientists choose what to spend years on - Writing a scientific memoir, and why honesty is the load bearing part KEY INSIGHTS FROM THE CONVERSATION Changing subfields is when discovery happens Hall deliberately chose a second postdoc in a different receptor family rather than extending his graduate work. He argues that staying close to a hot topic feels safe but narrows a scientist's development, and that the moment you carry one field's questions into another is often the most productive window of a career. His own case is the evidence: NMDA receptor scaffolding logic applied to beta adrenergic receptors. The tail everyone was discarding When Hall asked what the C termini of the beta adrenergic receptors did, the lab's answer was that they could be removed with G protein coupling intact. The structural effort underway at the time simply deleted them. That consensus is precisely why he went looking, and the distinct binding partners he found for beta 1 and beta 2 offered an explanation for how two subtypes coupling to the same G protein can have opposite effects on cell physiology. Skepticism first, then a crowded field The early data drew hard questions at Gordon conferences from senior figures who were not convinced. Within a few years, dozens of labs were running similar studies across every GPCR subfamily. Hall describes the real measure of acceptance as the moment other groups start doing the experiments themselves. The experiment that did the opposite Predicting that an endogenous ligand acted on the large N terminus of GPR56, his lab truncated it, expecting a dead receptor. Signaling increased massively instead, and the same held for BAI1. That inversion became the basis for the model his lab proposed in 2011, in which removing or reconfiguring the N terminus unveils a cryptic tethered agonist, and it has since been reproduced across the family by other groups. From undruggable to promising Drug development veterans long treated large adhesive proteins as poor targets because their interaction interfaces are too big to disrupt with small molecules. Hall's counterpoint is that adhesion GPCRs are not only adhesive proteins, they are also GPCRs, with a seven transmembrane pocket. Screening work has since produced agonists and antagonists, and the first cryo EM structure of an adhesion GPCR, GPR97, showed glucocorticoid binding, raising the possibility that steroid activation of G protein pathways has been hiding in this family. When receptors are tuned and mutations detune them The BAI2 mutation Hall's lab linked to a neurodegenerative condition sits on the C terminus and makes the receptor constitutively overactive, pointing back to the protein interactions he has studied since the 1990s. He traces the concept to basic work by Susanna Cotecchia on the alpha 1 receptor in the early 1990s, research with no clinical intent that became the template for explaining a long list of human diseases. Choose important problems, not easy ones Hall's advice to junior scientists is that trivial questions are not measurably easier to solve than important ones, so the years spent are better invested in something that matters. He recommends heading for subfields in turmoil, where there is disagreement and unsolved mystery, with the single constraint that the technology to answer the question must already exist. EPISODE TIMELINE Timestamps were generated using AI for readability. - 00:00 Opening announcements - 01:34 Introducing Randy Hall - 02:02 The Feynman book, and pitching a memoir to Bob Lefkowitz three times - 06:45 Deciding which stories survive, and finding a publisher who believed in science memoirs - 17:03 Nature walks, synaptic plasticity, and falling for the first event in cell signaling - 19:39 Switching subfields, and spotting a motif nobody was looking at - 23:51 Pushback at Gordon conferences, and what acceptance actually looks like - 26:34 Moving the lab toward orphan and adhesion GPCRs - 34:00 The truncation that was supposed to kill signaling - 37:34 Pulling the pin from the grenade: the tethered agonist model - 39:38 Are adhesion GPCRs druggable, and what GPR97 changed - 46:46 In silico screening, chess, and humans working alongside machines - 52:09 Disease mutations across the adhesion family - 1:00:41 Choosing important problems over easy ones - 1:07:10 Openings in the Hall lab SELECTED QUOTES "That was how lowly regarded the C terminus was. They were just throwing it in the trash." "Go for subfields where the seas are rough and the sky is dark and there are a lot of mysteries." "If you are surprised by the result of your own experiment, then probably other scientists will also be surprised." "There is no connection between the importance of a problem and how easy it is to solve." GUEST LINKS - Hall Lab: http://www.pharm.emory.edu/hall/index.html - LinkedIn: https://www.linkedin.com/in/randy-hall-79923839 - Google Scholar: https://scholar.google.com/citations?user=tfsXwHUAAAAJ&hl=en&oi=ao - ResearchGate: https://www.researchgate.net/profile/Randy-Hall - A Funny Thing Happened on the Way to Stockholm: https://www.simonandschuster.com/books/A-Funny-Thing-Happened-on-the-Way-to-Stockholm/Robert-J-Lefkowitz/9781643136387 - Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/search?q=Randy+Hall Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) 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 Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) A Brief History of allosteric modulation with Dr. Arthur Christopoulos About Dr. Arthur Christopoulos " Arthur Christopoulos is the Professor of Analytical Pharmacology and the Dean of the Faculty of Pharmacy & Pharmaceutical Sciences, Monash University, Australia. His research focuses on novel paradigms of drug action at GPCRs, particularly allosteric modulation and biased agonism, and incorporates computational and mathematical modelling, structural and chemical biology, molecular and cellular pharmacology, medicinal chemistry, and preclinical models of behaviour and disease. His work has been applied to studies encompassing neurological and psychiatric disorders, cardiovascular disease, obesity, diabetes, chronic pain and addiction. He has received substantial, long-term support from international and national competitive, charitable and commercial sources, as well as being academic co-founder of three GPCR-focussed biotechnology companies. Professor Christopoulos has over 360 publications, including in leading international journals such as Nature,Science and Cell, and has delivered over 180 invited presentations. He has served on the Editorial Board of 8 international journals and was a Councillor of the International Union of Basic and Clinical Pharmacology (IUPHAR). He has also been the recipient of multiple awards, including the John J. Abel Award and the Goodman and Gilman Award from the American Society for Pharmacology and Experimental Therapeutics; the Rand Medal from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists; the British Pharmacological Society’s Gaddum Memorial Award; the IUPHAR Sir James Black Analytical Pharmacology Lecturer; the GSK Award for Research Excellence and a Doctor of Laws (Honoris Causa) from the University of Athens. Since 2014, Clarivate Analytics have annually named him a Highly Cited Researcher in ‘Pharmacology & Toxicology’, and in 2021 also named him a Highly Cited Researcher in the additional category of ‘Biology & Biochemistry’. In 2017, he was elected a Fellow of the Australian Academy of Health and Medical Sciences, in 2018 as a Fellow of the British Pharmacological Society, and in 2021 he was elected a Fellow of the Australian Academy of Science for his seminal contributions to drug discovery. In 2023, he was elected a Fellow of the Pharmaceutical Society of Australia. " Dr. Arthur Christopoulos on the web Monash University Wikipedia Google Scholar LinkedIn Dr. GPCR AI Summary Quick recap Yamina and Arthur discussed Arthur's career journey in pharmacology, including his mentors and significant discoveries related to allosteric receptors. They explored the evolution of the field, allosteric modulation concepts, and potential therapeutic approaches involving autoantibodies and allosteric modulators. Additionally, they covered the importance of target product profiles, reproducibility in experiments, and collaborative efforts such as a potential book on GPCR history. Next steps - Arthur will continue to collaborate with other researchers and drug companies to advance the understanding and application of allosteric modulation. - Arthur will work on designing ligands for specific receptors, aiming to create biased agonists for therapeutic use. Summary Arthur's Career Journey and Allosteric Receptors Yamina and Arthur discussed Arthur's career journey and his contributions to the field of pharmacology, with a focus on allosteric receptors and their modulation. Arthur highlighted his mentors' influence, such as Fred Mitchelson and Nigel Burch, and significant discoveries like the concept of synthetic allosteric modulators by Bruns and Fergus. He also discussed the evolution of the field, from biochemical radioligand binding assays to cell-based functional assays, and the influence of Terry Kenakin and chemical programs on his later work. The conversation ended with Arthur's ongoing research and his development of a new operational model. Yamina emphasized the importance of understanding the historical context of the field and the significance of Arthur's contributions. Allosteric Modulation and Hybrid Molecules Arthur and Yamina discussed the development of an operational model for allosteric modulation, emphasizing the balance between mechanism and empiricism. Arthur shared his career journey, including his collaboration with Patrick Sexton and Jim Burch, and the discovery of hybrid molecules with functional selectivity. They also discussed the re-emergence of interest in certain programs, the importance of connections across receptor families, and the potential of hybrid molecules. Arthur's strategy of consulting drug companies and targeting their posters at conferences was also shared with Yamina. Pharmaceutical Industry Experiences and GPCR History Arthur shared his experiences in the pharmaceutical industry, highlighting the differences between big pharma and biotech. They discussed strategies for analyzing large compound screening data, emphasizing robust assays and addressing issues like shifting curves. Arthur recounted a 2004 visit to a pharma company using replicates in assays. Yamina proposed compiling a book on GPCR history through collaborative interviews, considering a symposium to align terminology. For their upcoming project, Yamina favored a conversational approach, while Arthur suggested a kickoff meeting, with Yamina planning chapters and interviews. Bias Mitigation in Symposium Ideas Arthur and Yamina discussed the concept of bias in the context of the history of the Symposium idea. They reviewed significant early papers related to the topic, including work by Brian Roth, Terry Kenakin, Bill Clarke, and Kelly Burke. They also discussed their own research on chemokine receptors and the importance of understanding the natural environment in drug discovery. Lastly, they touched on a project with Nicola Smith that challenged their previous theories. Allosteric Modulation and Drug Discovery Yamina and Arthur delved into the complexities of protein-protein interactions, specifically allosteric modulation. They discussed various modulatory elements, such as RAMPs, G proteins, and GRKs, with Arthur recounting his initial collaboration with Patrick Sexton on RAMPs and amylin receptors. They also delved into the different signaling of Class B receptors and the potential for modulation at various levels. The discussion underscored the potential of allosteric modulators as drugs, despite challenges in the past due to a lack of understanding about the principles involved. They highlighted the importance of fine-tuning the approach to suit different diseases and interdisciplinary collaboration. The discussion also emphasized the need for a disease-specific approach, considering the clinical context and dialing in the desired effect, as well as the significance of rational drug design principles. Allosteric Modulation and Autoantibodies Discussion Arthur and Yamina discussed the potential of autoantibodies and allosteric modulation in the context of disease and therapeutic approaches. Arthur explained the concept of endogenous allosteric ligands and the possibility of using a neutral allosteric ligand as a preferred therapeutic approach, emphasizing the importance of looking for low level cooperativity factors. They also discussed the potential of certain drugs, like flumazenil, as 'nails' or compounds that could be developed into medicines. The conversation highlighted the importance of establishing the correct disease context, setting up appropriate assays, and understanding the models for their work. They both agreed on the necessity of understanding the target product for an allosteric modulator and working backwards from there. TPP, Allosteric Modulators, and Reproducibility Yamina and Arthur discussed the concept of a target product profile (TPP) in drug development, with Arthur explaining its application in other contexts as well. Yamina appreciated Arthur's expertise and indicated she would be creating an outline for an episode on allosteric modulators. They highlighted the importance of reproducibility in scientific experiments, sharing personal experiences and anecdotes. They also discussed their upcoming trips to the GPCR Colloquium in California and current research in their fields. Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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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<< Back to podcast list Strategic Partner(s) Dr. Nicola J. Smith About Dr. Nicola J. Smith Dr. Nicola J Smith is an expert in molecular pharmacology with a track record in exploring GPCR structure-function relationships in the context of cardiovascular disease and metabolic disorders. She is a National Heart Foundation of Australia Future Leader Fellow and runs a laboratory of 7 Ph.D. and Honours students at UNSW Sydney, where she has recently been promoted to Associate Professor. Most recently, Dr. Smith’s team has made advances in the understanding of how an orphan GPCR exerts its effects both in vitro (cell culture and ex vivo models) and in vivo (measures of physiological and pathological cardiometabolic function in unconscious and conscious mice). Together with Irina Kufareva , UCSD, her team developed a novel approach to identifying ligands for orphan GPCRs by developing a powerful new computational tool for identifying ‘surrogate’ ligands (borrowed from other receptors) for orphan GPCRs, named GPCR-CoINPocket. Her career goal is to leverage this expertise to establish a research program that takes orphan GPCRs from ‘locked’, inaccessible receptors to well-characterized and understood ‘unlocked’ therapeutic targets with high-affinity ligands. Dr. Nicola J. Smith on the web UNSW Sydney LinkedIn Retraction Watch Twitter Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Hannes Schihada About Dr. Hannes Schihada Following studies in Pharmacy in Regensburg, Germany, I joined the receptor pharmacology group of Martin Lohse at the Institute of Pharmacology & Toxicology in Würzburg, Germany, in 2015. My project involved the development of FRET/BRET -based GPCR conformational biosensors, which can be employed in high throughput ligand screening. After my Ph.D. defense in 2019, I moved with a DFG (German research council) PostDoc fellowship to Stockholm, Sweden, in order to focus my research on class Frizzled GPCR s in the lab of Gunnar Schulte at the Karolinska Institute. I spent 2 1/2 years in his lab and developed novel conformational sensors for these intriguing receptors, allowing us to better understand their mode of action. By the end of 2021, I moved back to Germany and joined the pharmaceutical chemistry group of Peter Kolb in Marburg. I was recently awarded a Marie Sklodowska Curie PostDoc Fellowship in order to investigate and find better ligands for the orphan class A GPCRs , GPR3 , GPR6 , and GPR12 . Dr. Hannes Schihada on the web Karolinska Institutet Twitter Adher´n Rise LinkedIn Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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. 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) 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 Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Gregory Tall About Dr. Gregory Tall " Dr. Gregory Tall earned his Ph.D. in Biomedical Sciences from U.T. Southwestern Medical Center with Bruce Horazdovsky, Ph.D. They worked on the interactome of yeast and mammalian Rab5 homologs including identification of Rab5 GEFs. In 2000, Dr. Tall moved upstairs to conduct his postdoctoral work on heterotrimeric G proteins and the novel interactor, Ric-8 with Alfred Gilman, M.D. Ph.D. In 2007, Dr. Tall joined the faculty in the Department of Pharmacology and Physiology at the University of Rochester Medical Center, there establishing his lab and major research directions. Dr. Tall moved to the University of Michigan in 2016 as an Associate Professor of Pharmacology and is a current active member of the department. The current goals of the Tall lab are to understand the basic mechanism by which Ric-8 proteins fold all heterotrimeric G protein alpha subunits, to exploit a Ric-8-based technology to purify recombinant G proteins and to use the G proteins in assays to explore the mechanisms of action of the 33-member adhesion GPCR family or Family B2 GPCRs. We found that adhesion GPCRs are activated by a tethered peptide agonist mechanism that differed from the common example known at the time, protease activated receptors (PARs). PARs have an N-terminal leader sequence that is clipped by exogenous proteases to reveal a new N-terminus that serves as the tethered agonist. Adhesion GPCRs pre-cleave themselves and the two resultant fragments of the receptor remain together to conceal the tethered peptide agonist. Mechanical dissociation of the two fragments aided by protein binding ligands and cell movement serves to decrypt the tethered agonist for binding to its orthosteric site. Our current goals are to explore this mechanism in detail and to understand how it may happen for the 33 adhesion GPCRs in complex physiological contexts…one being our discovery that GPR56 is the platelet receptor that senses collagen and shear force to initiate the platelet activation program. Dr. Tall has been continuously funded by the NIH since receiving an early RO1 award at Rochester. He has continued funding at Michigan through the MIRA R35 program. Dr. Tall has presented his work at 59 invited seminars including national and international meetings and academic departmental seminars. " Dr. Gregory Tall on the web The Tall Lab University of Michigan Google Scholar Twitter Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

mGlu2 can suppress drug seeking across four addictive substances - but its clinical results have never been published. Johnson explains why the circuit matters more than the receptor. << Back to podcast list Strategic Partner(s) Kari Johnson: mGlu2, Addiction, and the Brain Circuits Alcohol Rewires The brain circuits governing reward, motivation, and decision making are not fixed - they are continuously reshaped by experience. In alcohol use disorder and other substance addictions, one of the most consequential changes is the shift from goal-directed to habitual behavior: a state in which drug seeking persists not because of pleasure, but because the underlying circuit no longer responds to consequences. mGlu2, a presynaptic metabotropic glutamate receptor coupled to Gi/o proteins, sits at a critical junction in this process. By suppressing glutamate release across circuits in the basal ganglia, mGlu2 is positioned to modulate drug seeking, habit formation, and reward processing - and has been pursued as a potential therapeutic target in addiction, depression, schizophrenia, and Parkinson's disease. Kari Johnson's research follows this receptor from the bench to the behaving animal, using optogenetics and circuit-selective mouse models to ask which specific corticostriatal pathways are driving behavioral change after alcohol exposure - and whether pharmacological rescue is possible after those circuits have already been disrupted. The question has been central to Johnson's career since long before the tools to answer it properly existed. ABOUT THE GUEST Kari Johnson is an assistant professor of neuropharmacology at the Uniformed Services University of Health Sciences in Bethesda. Her lab investigates how GPCRs modulate synaptic transmission in brain circuits involved in reinforcement learning, with a particular focus on how chronic alcohol exposure disrupts those mechanisms across levels ranging from gene expression to neural circuit function to behavior. She trained in high-throughput drug discovery at Vanderbilt - contributing to early functional assay development for metabotropic glutamate and muscarinic receptors - before completing postdoctoral training at the National Institute on Alcohol Abuse and Alcoholism with Dave Lovinger. Her current work combines whole-cell patch clamp electrophysiology, optogenetics, and operant behavioral pharmacology to study mGlu2 function in specific corticostriatal circuits and its role in the transition from controlled to compulsive drug use. SCIENTIFIC THEMES OF THE CONVERSATION mGlu2 as a convergence target across addiction, psychiatric disease, and movement disorders Circuit-specific GPCR modulation and the "modulomics" framework Goal-directed versus habitual behavior as a mechanistic framework for understanding addiction Pharmacological rescue of alcohol-disrupted receptor function using positive allosteric modulators The translational gap: why a decade of preclinical mGlu2 evidence has not yet reached clinical success The limits of brain slice electrophysiology - and why optogenetics redefines the questions the field can ask KEY INSIGHTS FROM THE CONVERSATION mGlu2 Sits at the Center of Multiple CNS Disorders Because mGlu2 regulates glutamate release in brain regions linked to reward, executive function, motivation, and stress responses, it has become a target of interest across an unusually broad disease landscape - alcohol use disorder, schizophrenia, depression, Parkinson's disease, and multiple other substance addictions. That breadth is a signal of the receptor's centrality in CNS function. It is also a complication: a receptor that modulates so many circuits will inevitably produce wanted and unwanted effects that are difficult to predict from any single experimental system. Alcohol Disrupts mGlu2 - But a PAM Can Restore It Johnson's lab demonstrated that adolescent alcohol exposure disrupts mGlu2 function in the striatum in a way that might seem to close off therapeutic targeting - if the receptor is impaired, can it still be activated pharmacologically? Their answer was yes: a positive allosteric modulator restored mGlu2 signaling even after alcohol-induced disruption. This finding shifts the question from whether mGlu2 is a viable target in addiction to how to reach it once its function has already been compromised. The Years Before the Tools Existed For most of the history of GPCR electrophysiology, researchers used electrical stimulation in brain slices and could observe that a receptor modulated synaptic transmission - but not which specific set of synaptic inputs was responsible. For Johnson, this was a formative constraint she navigated across her entire training: drawn to circuit-level questions that her early tools could not fully answer, she made the shift to optogenetics and genetically defined neuronal populations specifically because the biology demanded it. The tools arrived late relative to the questions. That gap, in Johnson's framing, is both a limitation of the past and an argument for the field's current momentum. Modulomics: Naming the Question Changes What You Can Ask Johnson's postdoc mentor Dave Lovinger coined the term "modulomics" to describe the systematic study of circuit-specific neuromodulation by GPCRs - using light-activated ion channels expressed in anatomically or genetically defined neurons to isolate receptor effects at individual synaptic inputs rather than across an entire stimulated pathway. Giving the approach a name formalizes it as a research program, not just a technique. Johnson's lab has extended this using conditional knockout mice that allow selective deletion of mGlu2 from specific cell types, enabling circuit-level pharmacology with direct behavioral readouts. The Habit Framework Changes What Addiction Means Pharmacologically The shift from goal-directed to habitual behavior is not just a behavioral description of addiction - it implies a specific circuit mechanism. Goal-directed behavior is sensitive to changes in outcome value; habitual behavior is not. When alcohol exposure biases the brain toward habit formation, the circuit underlying that inflexibility becomes the pharmacological target. Johnson's lab uses this framework to ask whether activating mGlu2 in specific corticostriatal circuits can reverse the habit bias that chronic alcohol produces - not just dampen the pleasure of drinking, but restore the flexibility of the decision that precedes it. Clinical Trial Results for mGlu2 Ligands Have Not Been Made Public Johnson noted that multiple clinical trials testing mGlu2 ligands in substance use disorders - including for smoking cessation and cocaine use disorder - have been conducted and completed. The results have not been released to the research community. Without access to those data, researchers cannot determine why promising preclinical findings did not translate, cannot adjust future trial designs, and cannot evaluate whether the receptor was genuinely ineffective or whether confounds such as prior antipsychotic exposure were responsible - a hypothesis already supported by subsequent preclinical work following the disappointing schizophrenia trials. The gap is consequential, and Johnson named it directly. Translating GPCR Research May Require Releasing Attachment to Specific Receptors One of Johnson's more quietly contrarian observations is that attachment to a "favorite receptor" may be limiting translational success. If mGlu2 activation produces the desired circuit effect in rodents but not in humans, the value of that work is not lost - it defines the functional target. A different receptor capable of achieving the same circuit-level effect in a human brain might carry the therapy further. The question, in Johnson's framing, is not which receptor you prefer, but which receptor is correctly positioned in the human circuit you need to modify. EPISODE TIMELINE Note: Timestamps are AI-generated from the transcript and may require manual verification after video editing. 00:00 Introduction 01:27 Johnson's career path - from Vanderbilt drug discovery to NIH postdoc to independent lab 07:31 Alcohol disrupts mGlu2 in adolescent mice - and a positive allosteric modulator rescues it 09:45 Why mGlu2 is Johnson's receptor of focus: synaptic plasticity and long-term depression 11:26 mGlu2 and drug seeking: preclinical evidence across alcohol, cocaine, methamphetamine, and heroin 13:28 How mGlu2 modulates dopamine release and the neurobiology of habit formation 16:28 Optogenetics and modulomics - studying circuit-specific GPCR function in the basal ganglia 20:45 Operant behavioral models: how habit formation is measured in mice 25:25 Clinical trials for mGlu2 ligands - what advanced, what disappointed, and what remains unpublished 28:41 Are GPCRs still good drug targets? A circuit-level argument 33:12 Advice for junior scientists: let the biology lead the method 35:28 Diversity in STEM and who carries the labor of change SELECTED QUOTES "Even if we see that these experiences cause an impairment in receptor function, there might be pharmacological strategies that we can use to rescue that." "We're really just beginning to scratch the surface of understanding how these receptors work in specific neural circuits - and that has the potential to impact our understanding of how they influence a really wide range of behaviors, especially since mGlu2 is expressed in so many different brain areas." "Maybe the effect that I want to have by activating mGlu2 has the effects I want in a rodent brain, but doesn't have it in a human brain. But maybe there's another receptor there that will have the effect that we want in the human brain." "Let the science lead you. If you take that approach, you'll have plenty of moments where you realize that a new tool could take your research to another level. But there's no reason to force it just because you feel like you should be incorporating a popular technique." About this episode Dr. Kari Johnson is currently an assistant professor at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. She is a neuropharmacologist with an interest in the long-term effects of alcohol abuse on neural circuits. Kari completed her Ph.D. in Pharmacology at Vanderbilt University before continuing her training as a postdoctoral fellow at the Vanderbilt Center for Neuroscience Drug Discovery, the National Institute of General Medical Sciences, and the National Institute on Alcohol Abuse and Alcoholism. All through her career, the recurring theme in Kari’s work has been GPCRs and more specifically Metabotropic Glutamate Receptors. Join me and learn more about how Kari studies GPCRs in basal ganglia circuits following chronic alcohol exposure in mice. Dr. Kari Johnson on the web LinkedIn Google Scholar Research Gate USU Twitter Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

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) 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 Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

Five scientists audit what AI can and can't do for GPCR drug discovery — from orphan receptors and biased signaling to the true-negatives problem nobody writes into grant proposals. Recorded at the 3rd EARNEST meeting. << 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 Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Oliver Hartley About Dr. Oliver Hartley Oliver Hartley is VP for Drug Discovery at Orion Biotechnology . He is the inventor of OB-002 as well as the key technology underlying Orion’s discovery platform. Trained as a biochemist, he completed a PhD in protein engineering (Cambridge, UK) with Sir Gregory Winter (Nobel Prize for Chemistry, 2018). Since then Oliver has worked at the University of Geneva, where his research on peptide engineering and GPCR pharmacology has led to a series of high-profile publications and new intellectual property, and at the Mintaka Foundation for Medical Research with a role as co-founder and Chief Scientific Officer. Dr. Oliver Hartley on the web LinkedIn Orion Biotechnology Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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) Dr. Lukas Grätz About Dr. Lukas Grätz "After a BSc in biology and a MSc in bioinformatics, I have been working in David Gloriam's group as a bioinformatician. My initial focus was on creating an automated chimeric homology modeling pipeline for GPCRs and since have branched out to multiple areas of GPCR research such as sequence alignments, generic numbering systems, structure data, G protein and arrestin coupling and more. As a developer, and more recently the lead developer of GPCRdb my day-to-day work centers around the maintenance and resource/tool development of GPCRdb and its sister databases. I am also affiliated with György Keserű's group at the RCNS in Hungary. I lived in Denmark, Poland, now I live in Hungary. I am married, I have two daughters. In my free time I like to play the guitar, sing and play board games. " Dr. Lukas Grätz on the web Karolinska Institutet ResearchGate PubMed Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>

Find answers to all your questions about the Dr. GPCR Ecosystem: courses, podcasts, memberships, events, and more. Frequently asked questions Webinar University Vault Premium Pricing GPCR Masterclass YC-Biotech YC-VC YC-CRO Terrys Corner Media Partner General University Dr.GPCR Podcast What are GPCR webinars? GPCR webinars are live online scientific sessions focused on G protein-coupled receptor (GPCR) biology, pharmacology, signaling, and drug discovery. Each session explores mechanistic models, translational challenges, and real-world therapeutic implications. These webinars are designed for scientists who want deep, data-driven discussion rather than surface-level overviews. Who should attend these GPCR pharmacology webinars? These webinars are ideal for: GPCR pharmacologists Medicinal chemists working on receptor targets Structural biologists Translational scientists Biotech and pharmaceutical researchers Postdoctoral fellows and graduate researchers entering drug discovery If you work directly with receptor systems, ligand design, efficacy modeling, or signaling pathways, these sessions are built for you. Are these GPCR webinars suitable for industry scientists? Yes. The content is highly relevant for biotech and pharmaceutical scientists. Topics frequently address: Receptor efficacy and bias Allosteric modulation PK/PD relationships Irreversible binding and safety considerations Translational pharmacology challenges The discussions are grounded in practical drug discovery, not just academic theory. How are these different from academic seminars or conferences? Most academic seminars focus on a single dataset or publication. These GPCR webinars focus on conceptual frameworks, models, and translational insight that apply across programs. Unlike large conferences, the live format allows direct interaction, questions, and scientific debate in real time. The goal is not presentation — it is scientific advancement. Are the webinars live or pre-recorded? The sessions are delivered live to allow direct Q&A with the speaker. Live participation gives you the opportunity to ask technical questions and engage in discussion with other scientists in the GPCR community. Selected recordings may be available afterward through the Dr. GPCR platform. Do I need prior knowledge of GPCR pharmacology? These webinars are designed for scientists with foundational knowledge in receptor pharmacology, signaling, or drug discovery. While some sessions may introduce key concepts, the overall level is advanced and assumes familiarity with pharmacological models and terminology. What topics are typically covered in GPCR webinars? Topics may include: Receptor efficacy and operational models Allosteric modulators (PAMs and NAMs) Biased agonism Dose–response modeling Calcium and signaling assays Drug–receptor kinetics Translational pharmacology strategies GPCR structure–function relationships Each session focuses on mechanistic clarity and practical application. Are these GPCR webinars free? Yes. All live GPCR webinars are free to attend. To receive early notifications, event reminders, and priority updates, you can join the Dr. GPCR Ecosystem as a free member. If you would like to go deeper beyond the live sessions, you can explore the full GPCR educational library inside Dr. GPCR University. Will attending help with continuing education or professional development? Yes. These webinars are designed to support ongoing scientific development in GPCR pharmacology and drug discovery. They provide exposure to current thinking, advanced modeling approaches, and expert interpretation of complex receptor behavior. For researchers working in biotech, pharma, or academia, this type of continuing education can strengthen both technical expertise and strategic thinking. How often are new GPCR webinars added? New live GPCR webinars are added regularly as part of the Dr. GPCR Ecosystem’s ongoing educational initiative. Upcoming sessions are announced in advance and updated on this page. Where can I find advanced GPCR training online? Dr. GPCR provides live GPCR webinars, masterclasses, and in-depth educational resources focused specifically on receptor pharmacology and drug discovery. These programs are designed for scientists seeking advanced, mechanism-focused training in GPCR biology.

<< Back to podcast list Strategic Partner(s) Dr. Ralf Jockers About Dr. Ralf Jockers Ralf Jockers studied in Cologne and received a Ph.D. in biotechnology and biochemistry from the University of Braunschweig, Germany. For postdoctoral training, he joined the laboratory of Dr. Strosberg AD in France, where he worked on the regulation of ß-adrenergic receptors. He is the Research director at INSERM with a specific interest in G protein-coupled receptors by developing original BRET and TR-FRET assays. His laboratory is currently located at the Institute Cochin – Inserm (Paris, France). His laboratory was among the first to demonstrate the oligomerization of GPCRs. He showed the formation of melatonin receptor heteromers in vitro and in vivo and their importance in retinal physiology. He established the concept of ligand-independent functions of orphan receptors in heterodimers with other GPCRs. He discovered multiple rare and loss-of-function variants of the MT2 melatonin receptors that are associated with type 2 diabetes (TD2) development. Many MT2 variants are biased and their defects are signaling pathway-specific opening new perspectives for T2D treatment and precision medicine. His lab was among the first to discover mitochondrial functions of GPCRs. He was the director of the French network of GPCRs (GDR-3545), currently directs the International Research Network (IRN) i-GPCRnet of the CNRS, is chair of IUPHAR « Melatonin receptor » sub-committee, Editor-in-Chief of « Frontiers in Cellular Endocrinology » and AE of « J Pineal Research”. He is a highly cited researcher – 2019 and 2020 identified by Clarivate Web of Science ™. Dr. Ralf Jockers on the web Jockers Lab WGDR-3545 Pubmed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ 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 >>