Dr. Paul Insel: Unbiased Discovery and the GPCRs We've Been Missing

The GPCR field has produced thousands of studies on a small number of well-characterized receptors. But what if the ones that matter most in human disease are the ones we haven't prioritized?

Dr. Paul Insel's lab at UC San Diego has pursued this question using unbiased expression profiling — GPCR arrays, RNA-seq, and single-cell analysis — to catalog which receptors are actually highly expressed across human tissues and disease states. In pancreatic cancer, proton-sensing GPCRs such as GPR68 are dramatically upregulated in cancer-associated fibroblasts, creating feedback loops between the tumor microenvironment and stroma that may drive disease progression. Across 45 cancer types, numerous GPCRs show elevated expression without corresponding mutations — a pattern the mutation-centric oncology paradigm has largely missed.

For Dr. Insel, this shift began with a single dataset — a postdoc's unbiased expression profile showing the most abundant receptor in a normal human cell type had almost no literature behind it. Listeners will gain perspective on how asking broader questions about receptor biology can reshape drug discovery priorities.

About the Guest

Dr. Paul Insel is Distinguished Professor of Pharmacology and Medicine at the University of California, San Diego. His research spans four decades of GPCR signaling, from cyclic AMP and adrenergic receptor biology to purinergic receptors and, most recently, proton-sensing GPCRs in the tumor microenvironment. His lab combines bioinformatic analysis of GPCR expression across human cancers with wet-lab validation in animal models, particularly in pancreatic cancer. Dr. Insel also directs UCSD's MD-PhD Medical Scientist Training Program, a role he has held for over 30 years.

Scientific Themes of the Conversation

1. Unbiased receptor discovery — Why hypothesis-free expression profiling reveals GPCRs that decades of targeted research missed
   

2. GPCRs in the tumor microenvironment — Proton-sensing receptors, cancer-associated fibroblasts, and the role of low pH in tumor signaling
   

3. Drug repurposing through receptor mapping — Identifying already-approved drugs that target overexpressed GPCRs in cancer
   

4. Reductionism vs. native cell biology — The limits of studying purified components and the case for understanding receptors in intact cellular environments
   

5. Biased signaling in practice — Why the promise of biased agonism is more complicated than the field hoped
   

6. Breadth as a scientific strategy — How reading across disciplines and resisting premature narrowing drives discovery

Key Insights from the Conversation

1. The biggest discoveries came from asking what was being overlooked Dr. Insel's late-career pivot began with a deceptively simple question: are we studying the right GPCRs? When his lab ran unbiased expression profiles on normal human cells, the most highly expressed receptor — PAR1 — had almost no functional literature behind it. Nature had placed it at the top; science had barely looked.

2. Proton-sensing GPCRs create a feedback loop in pancreatic cancer GPR68 is dramatically upregulated in cancer-associated fibroblasts — not the cancer cells themselves. The tumor signals fibroblasts to raise GPR68 expression, and the low pH of the tumor microenvironment then activates that receptor, which signals back to promote cancer survival. It is a positive feedback loop that exploits the acidic environment tumors naturally create.

3. GPCRs are overexpressed across dozens of cancers — without mutations A large bioinformatic study from Dr. Insel's lab examined GPCR expression across 45 human cancer types and found widespread over expression without corresponding increases in copy number or mutation frequency. This challenges the mutation-centric framework that dominates oncology and suggests GPCRs may contribute to pathophysiology through expression changes alone.

4. The field's reductionism may be hiding how receptors actually work Dr. Insel has long argued that purifying receptors, depleting GTP, and stabilizing conformations through mutations teaches us about components — not about how cells actually use them. He compares the biochemist's approach to smashing a television with a wrecking ball and trying to reassemble the pieces to understand how it works.

5. Biased signaling is real but harder to exploit than expected GPR68 couples to both Gq and Gs, and the functional effects in cancer-associated fibroblasts appear to run primarily through Gs. In principle, biased antagonists could selectively block the disease-relevant pathway. But Dr. Insel is cautious — signaling bias operates on a conformational continuum, and clinical translation has not yet matched the elegance of the concept.

6. A career redirected by a dinner and an empty schedule In 1975, Dr. Insel was the only unmarried scientist at a dinner with Al Gilman. The group needed someone to visit Gilman's lab to learn radioligand binding — and he was the one with nothing else to do. That accidental assignment launched a career in GPCR signaling that has now spanned over four decades.

7. The "unknown unknowns" should change how we fund and train scientists Dr. Insel believes the training system pushes young researchers to narrow too early, at the cost of the cross-disciplinary thinking that leads to real discoveries. His own career has been shaped by reading broadly and importing ideas from other fields — a strategy he sees as increasingly essential as GPCR biology intersects with cancer, immunology, and systems biology.

Episode Timeline

• 00:00 Introduction and context

• 01:08 Dr. Insel's path from medicine to molecular pharmacology

• 05:15 The origin story — dinner with Al Gilman and the start of a GPCR career

• 09:06 Evolving receptor loves: from adrenergic to purinergic to proton-sensing GPCRs

• 13:19 Proton-sensing GPCRs: what they are and why they matter

• 16:18 GPR68 and the feedback loop in pancreatic cancer

• 19:46 Challenges of targeting GPCRs in oncology — funding, skepticism, and the mutation paradigm

• 25:05 AI, in silico screening, and the limits of computational drug discovery without structures

• 31:33 Biased signaling: promise, complexity, and caution

• 35:00 The case against reductionism — why native cell biology matters

• 38:05 Advice for young scientists: think broadly, resist narrowing too fast

• 42:14 Aha moments — the data that changed the direction of a lab

• 47:30 The future of the GPCR superfamily and the work still to be done

Selected Quotes

About this episode

In 1975, Dr. Paul Insel was at the FASEB experimental biology meeting in Atlantic City. During dinner with colleagues and Alfred Gillman, co-recipient of the 1994 Nobel Prize in Physiology or Medicine for their discovery of G-proteins and their role in signal transduction in cells, Paul was designated to go to Gillman’s lab. That summer, he used radioligand binding methods to dissect receptor function from the adenylyl cyclase activated by ligands, including adrenaline. From that point on, Paul was hooked and has since studied receptor function in human physiology, receptor molecular pharmacology in cells, and animal models, and as he puts it has now he’s "gone full circle" back to studying GPCRs important in human pathophysiology. Today, Paul and his team focus on previously unrecognized receptors with the hopes to use these as novel drug targets.

Dr. Paul Insel on the web

• Insel Laboratory

• Institute of Engineering in Medicine

• UC San Diego

• UCSD Profiles

• Google

• PubMed

• Dr. GPCR Ecosystem