Dr. Paul Insel: Rethinking COVID-19 Pathobiology Through GPCR Signaling

In the spring and summer of 2020, pharmacologist Dr. Paul Insel did something unusual for a working lab scientist: he stopped pipetting, and started writing. With his UC San Diego postdoc Krishna Sriram, he reread the literature on ACE inhibitors and angiotensin receptor blockers in the context of severe acute respiratory illness and concluded — against a swell of clinical panic — that the case for their danger in COVID-19 didn't hold up.

What came next was a series of papers reframing severe COVID-19 as a disease of signaling imbalance: an overdrive of AT1R activation by angiotensin II, paired with a loss of ACE2-generated angiotensin 1-7. The therapeutic logic that follows is less about attacking the virus and more about rebalancing a GPCR-driven system that the infection has thrown off-axis. A figure from that British Journal of Pharmacology paper was later redrawn by The Economist for a general-audience article on COVID pathobiology — an unexpected crossover for work that began as armchair science during a lockdown walk.

This conversation matters to Dr. Insel personally because he is, in his own words, a vulnerable patient — immunosuppressed, older, asthmatic — and what he's describing is not abstract. It's what he would want a physician to understand if he were the one in the hospital bed.

About the Guest

Dr. Paul Insel is Distinguished Professor of Pharmacology and Medicine at UC San Diego, where he also co-directs the MD-PhD program. His research career has centered on GPCR signaling — with particularly deep work on beta-adrenergic receptors, cyclic AMP regulation, and receptor biology across tissue systems. Beyond the lab, he has been a long-standing contributor to the Goodman & Gilman textbook of pharmacology and is writing its next chapter on angiotensin signaling and angiotensin drugs. He is also involved nationally in MD-PhD program leadership.

Scientific Themes of the Conversation

• The angiotensin imbalance hypothesis of COVID-19 pathobiology — AT1R overdrive versus ACE2/Ang 1-7 insufficiency

• Drug repurposing as a pandemic strategy — from ACE inhibitors and ARBs to PAR1 and PAR4 antagonists

• The "gas pedals and brakes" philosophy of cell signaling and pharmacology

• Dry-lab pharmacology and what becomes possible when wet-lab work stops

• GPCR density and tissue-specific therapeutic opportunity — type II pneumocytes, beta-2 receptors, and the asthma parallel

• The ethics of acting on conviction — off-label drug use during a pandemic

Key Insights from the Conversation

The ACE inhibitor scare was built on a bogus reading of the literature. Early in the pandemic, senior clinicians were stopping their own ACE inhibitors and ARBs based on hypothesis-driven fears of worse outcomes. Dr. Insel and Krishna Sriram went to the primary data and concluded the claim was not supported. The review was accepted at Clinical Pharmacology and Therapeutics within weeks.

Severe COVID-19 may be a story of signaling imbalance, not just viral damage. The British Journal of Pharmacology paper reframes pathobiology as an imbalance between AT1R activation and ACE2-generated angiotensin 1-7. If the virus disrupts one arm of this receptor-peptide system, the therapeutic question stops being "what do we add?" and becomes "what do we rebalance?"

Biology runs on opposing forces, and good pharmacology learns to see them. Kinases and phosphatases. Cyclases and phosphodiesterases. ACE1 and ACE2. Dr. Insel returns repeatedly to his "gas pedals and brakes" frame — a lens that has quietly shaped how he reads both disease mechanism and drug targets across a long career.

The lung's beta-2 story has been sitting in plain sight for fifty years. Type II pneumocytes carry the highest beta-2 receptor density in the body. Long-acting beta-agonists paired with glucocorticoids have been the mainstay of asthma treatment for decades. The connection to acute respiratory distress syndrome — and to the mechanism through which dexamethasone actually works — is, in his reading, underdiscussed rather than speculative.

"Don't just do something. Stand there." A clinical mentor's line that became the frame for the lockdown months. Four papers in roughly two months — what Dr. Insel calls armchair science. Not casual, not opinion-writing; dry-lab pharmacology done with the same seriousness as bench work, just with different tools.

A figure can travel further than the paper it came from. The schematic from the BJP paper was redrawn by The Economist, with attribution, for a general-audience article on COVID pathobiology. Dr. Insel notes wryly that it's the only paper his family has ever really responded to.

The ethics of acting on conviction is its own paper. Midway through writing the angiotensin work, Dr. Insel realized no one had written criteria for how to decide about off-label use of a drug during a pandemic — when mechanism is compelling, safety is reasonable, and trial evidence isn't there yet. He is writing that paper with an ethicist and a law-school colleague. It is exactly the kind of work a pharmacologist does when the lab is closed.

Episode Timeline

Timestamps were generated using AI for readability.

• 00:00 Opening and 2020 Summit context

• 01:45 Dry-lab science — how the work shifted when the wet lab closed

• 02:37 Rereading the ACE inhibitor scare — and the BJP paper that followed

• 07:40 Expanding the hypothesis — PAR1, PAR4, and upstream pathobiology

• 11:00 Gas pedals and brakes — biology's architecture of opposing forces

• 14:00 Type II pneumocytes, beta-2 density, and the asthma parallel

• 22:40 The ethics of off-label drug use during a pandemic

• 25:00 Genetic determinants of severity — ACE1 isoforms and population data

• 28:40 Vaccine development speed and public trust

• 33:40 Staying sane — pickleball, walking, and community

Selected Quotes

About this episode

Dr. Paul Insel is currently a Distinguished Professor of Pharmacology and the University of California San Diego. Paul thinks broadly about science and has been actively publishing papers about his ideas on how COVID symptoms could be treated while we wait for a vaccine, particularly about ACE2 and angiotensin. For the past 30 years, he has been the Director of MD/Ph.D. training program at UCSD and has served as Editor or Senior Editor of numerous scientific journals, including but not limited to the Journal of Clinical Investigation, Molecular Pharmacology, British Journal of Pharmacology, and American Journal of Physiology-Cell Physiology.

Dr. Paul Insel on the web

• Insel Laboratory

• Institute of Engineering in Medicine

• UC San Diego

• UCSD Profiles

• Google

• PubMed

• Dr. GPCR Ecosystem