A Drug Hunter Finds Greater Freedom at a Nonprofit Institute

Episode Summary

Executive Summary: The episode explores atrial fibrillation (AFib), a common but poorly treated heart rhythm disorder, and how Sanford Burnham Prebys is using stem cells, flies, and mice to identify genes driving the disease and find atria-specific drug targets. Chris Larson argues AFib is heterogeneous, likely driven by multiple genetic and non-genetic factors, and that nonprofit drug discovery can pursue high-risk, high-need targets that industry often avoids.

Main Topics: What atrial fibrillation is and why it matters (Priority: 5/5): Larson explains AFib as an electrical conductance disorder of the atria that causes rapid, irregular heartbeats, reduced cardiac output, symptoms like weakness and palpitations, and serious risks including stroke and heart failure. Disease burden and epidemiology (Priority: 5/5): The discussion emphasizes AFib’s large and growing prevalence in the U.S. and globally, and its major contribution to stroke incidence and mortality. Underlying causes and heterogeneity (Priority: 5/5): Larson argues AFib is not a single disease with one cause; it likely reflects a mix of genetic risk, aging, environmental stressors, surgery, and distinct clinical subtypes that may require different therapeutic strategies. Current treatment limitations (Priority: 5/5): Available therapies include anticoagulation, rate control, antiarrhythmic drugs, and ablation procedures, but Larson says none adequately solves the problem because efficacy is limited and side effects can be significant. Nonprofit drug discovery at Sanford Burnham Prebys (Priority: 4/5): Larson describes why working at a nonprofit institute enables pursuit of unmet medical needs and early-stage target discovery that may be too risky for typical commercial pipelines. Gene discovery platform using cells, flies, and mice (Priority: 5/5): The team’s approach is to knock out human genes in atrial cardiomyocytes, validate hits in Drosophila heart models, and then test promising candidates in mice to find atrial-specific disease drivers. Toward precision medicine and partnering (Priority: 4/5): The long-term goal is not just target discovery but linking targets to AFib sub-phenotypes and advancing lead molecules far enough to attract industry partners or licensing opportunities.

Key Arguments: AFib is an electrical problem of the heart, specifically a failure of coordinated signaling in the atria, not merely a generic aging issue. The disease is heterogeneous; patients with long-duration arrhythmia and brief episodic arrhythmia likely have different underlying biology. Current therapies mainly reduce stroke risk or manage symptoms/rate, but they do not adequately eliminate AFib or its complications. Atria-specific targets are preferable because many existing drugs affect ventricular tissue too, creating safety concerns. A nonprofit research environment can take on early, risky target-discovery work when commercial ROI is uncertain. A multi-model pipeline spanning stem cells, flies, and mice increases confidence that discovered genes are relevant to human disease. The team expects only a small fraction of the genome-wide candidates to become druggable targets, but those could form the basis for future therapies.

Data Points: U.S. prevalence of AFib: up to 6.1 million Americans - Introductory framing of the disease burden Global prevalence of AFib: about 33 million people - Larson cites worldwide burden of atrial fibrillation U.S. new AFib cases annually: about 1 million - Larson notes rising incidence in the United States AFib-associated strokes in the U.S.: 75,000 to 100,000 strokes per year - Estimate of strokes attributed to atrial fibrillation Normal atrial/ventricular rate: 60 to 100 beats per minute - Typical heart rate range described for both chambers AFib atrial rate: 400 to 600 beats per minute - Very rapid, unsynchronized atrial contractions in AFib AFib ventricular rate: potentially 140 to 160 beats per minute - Venticular response can also increase in AFib AFib risk over age 80: about 20% - Larson highlights age as a major risk factor Genome size being screened: ~30,000 genes - The project aims to test essentially every human gene affecting heart rhythm Expected final candidate count: about 5 to 10 genes - Larson estimates the number of genes likely to emerge as high-priority drug targets Current project completion: about 20% - Progress so far on the genome-wide discovery effort Time to complete cell-based screen: about 1 year - Estimated timeline for the stem-cell cardiomyocyte phase Time to validate in flies: another 1 to 2 years - Estimated timeline for Drosophila validation Full pipeline timeline: about 5 years - Estimated duration from cells to flies to mice Average IND cost: about $100 million - Used to explain why nonprofit groups will likely need partners to advance candidates Age of AFib in humans: risk rises throughout life; diagnosis common after 60 to 65 in polygenic cases - Used to distinguish lower-risk, later-onset cases from monogenic disease

Pivotal Quotes: "basically we don't handle it well" — Chris Larson: Larson’s blunt assessment of current AFib treatment options "the genome is really more about potentiality of a phenotype as opposed to a direct determinism of a phenotype" — Chris Larson: His view on why genetics contribute to AFib risk but do not fully determine disease outcome "we can really follow an unmet medical need wherever that's going to take us" — Chris Larson: Why the nonprofit setting enables his drug discovery work

Implications: AFib may be better treated through subtype-specific, atria-focused precision medicine. If this platform succeeds, it could yield new targets and lead molecules for partnership, while reshaping how complex arrhythmias are classified and drugged.