Dr. Foord: Serendipity, RAMPs, And Industrial GPCR Pharmacology

Scientific Abstract

This conversation traces how GPCR pharmacology, receptor signaling, and drug discovery evolved inside one of the world’s largest pharmaceutical organizations. Dr. Foord reflects on his path from academic neuroendocrinology to introducing molecular biology and molecular pharmacology into Glaxo’s GPCR programs, and on the combination of rigor, bioinformatics, and serendipity that led to several influential discoveries. He describes the purification and cloning of the CGRP receptor, the identification of receptor activity-modifying proteins (RAMPs), and the realization that CGRP signaling required receptor complexes rather than a single seven-transmembrane protein, reshaping thinking about peptide receptor activation and ligand binding.

Dr. Foord also discusses work on angiotensin, GABA B, free fatty acid, nicotinic acid, and prostaglandin EP4 receptors, showing how orphan receptors were deorphanized using expression systems, electrophysiology in Xenopus oocytes, and early bioinformatics. The discussion highlights the gap between identifying a target and delivering a drug, the challenges of target validation, and the realities of industrial decision-making around receptor selectivity, safety, and market focus. Along the way, Dr. Foord reflects on the limits and promise of human genetics, the underexploited potential of GPCR antibodies, and the importance of team composition, negative data, and scientific community in navigating complex receptor biology.

About the Guest

Dr. Foord is a physiologist and pharmacologist who spent more than two decades at Glaxo, Glaxo Wellcome, and GlaxoSmithKline working on GPCR pharmacology and drug discovery. Trained in neuroendocrinology, he helped bring molecular biology into traditionally pharmacology-driven GPCR programs and worked across migraine, cardiovascular, pain, and inflammation projects. His work contributed to the identification of RAMPs in the CGRP receptor system, deorphanization of several GPCRs including GABA B and carboxylic acid receptors, and discovery of a prostaglandin EP4 modulator that advanced as a drug candidate.

Later in his career, Dr. Foord led bioinformatics for neuroscience and played a central role in GSK’s early large-scale genetics initiative, integrating GPCR targets, ion channels, transporters, and ligands into association studies. His experience spans receptor cloning, expression systems such as Xenopus oocytes, electrophysiology, molecular pharmacology, and the use of informatics to mine sequence, structural, and genetic data for new receptor targets.

Key Insights from the Conversation

RAMPs Reframed Peptide GPCR Pharmacology. Dr. Foord explains how attempts to clone the CGRP receptor from SK-N-MC cells, combined with highly sensitive cAMP readouts in Xenopus oocytes, unexpectedly pulled out RAMP1 rather than a conventional seven-transmembrane receptor. The realization that RAMPs co-assemble with CRLR to form CGRP and related receptors forced a reconceptualization of peptide receptor activation and made clear that receptor complexes, not single proteins, could underlie pharmacological specificity.

Serendipity Depends on Experimental Design and System Choice. The discovery of RAMPs was only possible because the assay tied receptor signaling to a highly amplified electrophysiological readout, revealing dramatic effects that might have been lost in noisier systems. Similarly, placental tissue became the source for CGRP receptor purification simply because binding studies showed it combined high receptor density with practical availability, illustrating how pragmatic choices in model systems can open unexpected paths in GPCR pharmacology.

Deorphanizing Receptors Blends Bioinformatics and Bench Work. Dr. Foord describes a period where his group repeatedly identified ligands for orphan receptors: the second GABA B subunit via yeast two-hybrid, a carboxylic acid receptor when the solvent turned out to be the real agonist, and a nicotinic acid receptor by intersecting tissue expression data with orphan GPCRs. These stories show how careful pharmacology, informed sequence analysis, and attention to apparent artifacts can reveal new receptor signaling pathways relevant for metabolism and cardiovascular disease.

Target Validation Is Harder Than Cloning a Receptor. From the non-existent second AT1 angiotensin receptor to the MAS oncogene as a poor angiotensin responder, Dr. Foord emphasizes how easy it is to be misled by overexpressed systems and noisy orphan receptor data. Southern blotting, cross-hybridization, and later genetic analyses ultimately showed that some hypothesized subtypes were artifacts, underscoring that robust target validation is a distinct and often more challenging problem than receptor cloning or initial ligand binding assays.

Drug Discovery Is Constrained by Selectivity, Safety, and Strategy. The CGRP story illustrates how structural biology and pharmacology intersect with corporate decisions: once it became clear that the CRLR binding pocket is shared across CGRP, amylin, and adrenomedullin receptors, small-molecule selectivity looked problematic. Later hepatotoxicity concerns and the success of antibody therapeutics further shifted strategy. Similar strategic considerations shaped the fate of the EP4 partial agonist that ultimately found a niche in veterinary medicine rather than human rheumatoid arthritis.

Genetics and Informatics Offer Power but Not Simple Answers. As Head of Bioinformatics for Neuroscience, Dr. Foord participated in GSK’s early large-scale association genetics effort, feeding GPCRs, ion channels, and transporters into case–control studies. Apart from APOE4 in Alzheimer’s disease, most signals failed to reach robustness with available cohort sizes, tempering expectations that genetics alone would deliver pipelines of GPCR targets. He argues that integrating structural biology, computational pharmacology, and genetics may still be key to understanding receptor activation in patients, but requires realistic views of effect sizes and trial design.

Scientific Careers Depend on Teams, Mentors, and Community. Reflecting on his path from physiology to molecular pharmacology to bioinformatics, Dr. Foord highlights how good mentors, diverse teams, and open sharing of reagents and ideas enabled progress. He stresses the value of lab “optimists and cynics,” the importance of talking about negative results, and the role of informal networks in preventing wasted effort. For younger scientists, his advice centers on doing work you genuinely enjoy, finding supervisors who connect you to the broader GPCR community, and being willing to pivot as new methods and questions emerge.

Episode Timeline

00:00 — Early academic work in neuroendocrinology, self-experimentation with TRH and somatostatin, and first encounters with hormones and GPCRs.

02:00 — Move to Roger Craig’s lab, purification of the CGRP receptor from human placenta, and practical considerations in choosing receptor-rich tissues.

05:00 — Transition from academia to Glaxo, early HIV TAT work in Xenopus oocytes, and the emergence of molecular pharmacology within a pharmacology-led organization.

10:30 — Expression cloning of the CGRP system, discovery of RAMP1, and how oocyte electrophysiology revealed a massive potentiation of endogenous CRLR signaling.

18:00 — Industrial migraine programs, small-molecule CGRP antagonists, challenges with selectivity and liver toxicity, and the later success of CGRP antibodies.

20:00 — Angiotensin receptor work, using Southern blots to hunt for a non-existent AT1 subtype, and the MAS oncogene as a cautionary tale in receptor signaling artifacts.

30:00 — Discovery of the prostaglandin EP4 receptor while searching for angiotensin-related sequences, development of an EP4 partial agonist, and its path into veterinary medicine.

34:00 — GABA B receptor complex, identification of the second subunit via yeast two-hybrid, and closing the chapter on proposed additional GABA B subtypes.

39:00 — Large-scale genetics and bioinformatics at GSK, expectations for GPCR target discovery from association studies, and reflections on why many signals remained elusive.

52:00 — Career advice on doing work you enjoy, the importance of mentors and connectedness, and how team composition and negative data shape GPCR research and drug discovery.