Radiolab: "The Medical Matchmaking Machine"

Host: Latif Nasser (WNYC Studios)
Guest: Dr. David Fagenbaum (University of Pennsylvania, Every Cure)
Date: August 22, 2025

Episode Overview

In this episode, Latif Nasser sits down with Dr. David Fagenbaum, a physician-scientist whose personal and professional journey through near-fatal illness led him to become a groundbreaking advocate for medical innovation. What began as his desperate, data-driven search for a treatment for his own rare disease has evolved into a global effort—powered by artificial intelligence—to revolutionize drug repurposing for all diseases. The episode traces David’s deeply personal origin story, the science behind his recovery, the glaring inefficiencies and economic challenges in our healthcare system, and finally, his ambitious plan to publicly release an AI-driven matchmaking tool—"the Matrix"—that could match existing drugs to untold diseases.

Detailed Breakdown & Key Points

1. Dr. David Fagenbaum’s Origin Story: Crisis and Motivation

[02:12–07:15]

• Football Dreams and Trauma: David, once singularly focused on playing college football, had his life upended by his mother’s brain cancer diagnosis and eventual death.
  • Quote [06:58] David: “I told her, I was like, ‘Mom, I’m going to dedicate my life to trying to help people like you. …I’m going to be a doctor, and I’m going to dedicate my life to just find treatments for this horrible thing that was taking my mom from me.’”
• Resolve Transformation: This loss transformed David’s ambitions from athletics to medicine, fueling a deep resolve to take on intractable diseases.

2. Facing His Own Medical “Beast”: Diagnosis with Castleman Disease

[07:20–12:49]

• During med school, David falls mysteriously and severely ill; doctors struggle to diagnose his rapidly progressing multi-organ failure.
• After 11 weeks, he’s diagnosed with idiopathic multicentric Castleman disease—something so rare he’d only vaguely heard of.
  • Quote [10:02] David: “When I heard it…I think I’ve heard that once in med school. That’s how rare it was.”
• The disease has a worse prognosis than lymphoma; doctors tell his family to prepare for his death.
  • Memorable Moment: [12:32] Last rites, family farewells in the ICU.

3. Pivot to Action: Self-Research and the Hunt for a Cure

[13:00–19:20]

• On May 12, 2012, after multiple relapses and no remaining treatment options, David activates:
  • He assembles a team, gathers his medical records and biological samples, and analyzes his own blood for abnormal signals.
  • Discovers that his immune system’s mTOR pathway is hyperactive. He remembers an old drug, sirolimus (rapamycin), that could target this pathway.
    • Quote [17:36] David: “Rapamycin is the drug that saved my life.”
  • He convinces his doctor to try it, even with only a 10–20% chance of success—and it works. David has now been in remission for 11+ years.
    • Quote [19:20] David: “Amazingly, it weakens my immune system in the right way so that I don’t attack my own organs.”

4. Scaling Up: From Personal Miracle to Systemic Change

[23:30–31:21]

• David and his lab expand their focus to help others, including using drug-repurposing strategies for his uncle’s rare cancer and his brother-in-law’s ALS.
  • His persistence leads to a trial of pembrolizumab for angiosarcoma, resulting in a new standard of care—without a formal clinical trial, simply by repurposing a known drug.
    • Quote [27:00] David: “About a third of people with this horrible cancer…will respond really well to pembrolizumab…It’s now standard of care for his form of cancer.”
  • Memorable Moment: [25:49] David’s “Dumb and Dumber” optimism: “So you’re saying there’s a chance.”

5. The Systemic Problem: Why Drug Repurposing Is So Hard

[27:53–31:21]

• Legal and economic structures incentivize companies to seek approval for one disease and discourage wide repurposing, especially once drugs go generic.
  • 20–30% of prescriptions are “off-label,” but the system doesn’t financially reward discovering new uses for old drugs.
    • Quote [29:00] David: “…once a drug becomes generic…no one in our system makes any money off finding a new disease for that drug.”
  • Explanation: Complexity and cost drives how drug companies decide on which diseases to target first, limiting wider application.

6. Enter AI: Building “The Medical Matchmaking Machine” (MATRIX)

[31:21–39:19]

• Motivated by COVID-19 and the broader potential for drug repurposing, David and his team build an AI/ML-based tool—a massive biomedical “knowledge graph”—to systematically map every known drug-disease-gene-pathway connection.
  • Score every possible combination (75 million in all) to surface hidden matches, accelerating new discoveries that would be impossible for humans alone.
    • Quote [34:24] David: “…now what we do is we train machine learning algorithms on all of those known treatments…And then we say, okay, algorithm, now go and score…the connection between every other drug versus every disease.”
  • The AI, called MATRIX (ML Aided Therapeutic Repurposing and Extended Uses Matrix), is set to soon go public:
    • Quote [38:15] David: “…we feel this tremendous responsibility that once we share it, that, you know, it’s out. …we will share it.”

7. The Ethics & Risks of Public AI-Driven “Cures”

[39:19–55:12]

• Latif expresses both optimism and deep concern: is it helpful or reckless to unleash such a powerful tool to the public?
  • Doctor friends split: rare disease experts are excited; other clinicians worry about the impact on the doctor-patient relationship (cf. “ivermectin for cancer”).
    • Quote [49:17] Latif: “…the doctor-patient relationship is already in a bad place…if patients come in with these drug recommendations…she has to be the doorstop, she has to be the one who crushes the hopes and dreams and has to hold the line.”
  • David assures: MATRIX will be caveated—meant as a research idea generator, not as a prescription engine.
    • Quote [44:34] David: “…if we’re going to put our eyes on them, the world should be able to put their eyes on them…”
    • Quote [48:29] David: “…this is not a solution engine. This is an idea generator…if you’re a patient, that might mean working with a research lab to do the work to figure this out…”
  • AI is prone to “hallucinations”—e.g., a rival tool suggested “car fume exhaust” for Castleman’s. Human oversight is essential.
    • [47:00] David: “…literally one of the top five predicted drugs for Castleman disease…was car fume exhaust as a treatment.”

8. Hope, Reality, and the Limits of Fighting

[55:12–59:57]

• Philosophical tension: Should we always be “throwing Hail Marys” for more life, or is there value and dignity in not fighting everything? Latif contrasts David’s stance with Dr. Blair Bigham’s (“Death Interrupted”) more accepting philosophy.
  • David acknowledges: the decision must be personal. Echoes a recent patient who, despite benefiting from a repurposed drug, ultimately chose quality of life over continued treatment.
    • Quote [59:57] David: “…maybe that’s the big takeaway is that it seems like everyone wants to tell us what everyone else’s decision should be…But I think that maybe that’s the real fundamental thing this comes down to. It's got to be that patient’s decision.”

Notable Quotes & Memorable Moments

• On Football and Grit:

  • [03:25] Latif: “But you actually get your dream. You get to…”
  • [03:27] David: “…I get my dream. I get this opportunity to go to Georgetown to play football…”

• On Fortune and Responsibility:

  • [19:27] David: “I just feel this tremendous sense of responsibility that…if you’re going to get lucky enough to have one of these medicines help you, you sure as hell better spend the rest of your time trying to find as many more of these medicines to help other people.”

• On Systemic Stagnation:

  • [29:00] David: “…no one in our system makes any money off finding a new disease for that drug.”

• On the Limits of AI:

  • [47:00] David: “I will tell you, there is a drug repurposing platform…where literally one of the top five predicted drugs for Castleman disease or predicted treatment…is car fume exhaust as a treatment.”

• On Personal Agency:

  • [59:57] David: “It's got to be that patient’s decision.”

Selected Timestamps for Important Segments

• [06:58] – David’s vow to his dying mother to fight disease
• [10:02] – The shock of being diagnosed with a disease even doctors barely know
• [17:36] – Discovery of rapamycin and its lifesaving role
• [19:27] – Sense of mission to help others
• [27:00] – Breakthrough with uncle’s angiosarcoma (“now standard of care”)
• [34:24] – How the AI “Matrix” finds drug-disease matches
• [38:15] – Matrix to be released to the public for research
• [47:00] – The problem with AI “hallucinations” in medical predictions
• [49:17] – Dangers of undermining doctor-patient trust
• [59:57] – The ultimate question: agency and dignity at the end of life

Episode Takeaways

• Hope and Individual Agency: David’s story is a testament to scientific curiosity, personal grit, and the power of existing medicines hiding in plain sight.
• AI as an Accelerator and Democratizer: The "Matrix" AI could massively accelerate global biomedical discovery, but only if coupled with responsible, human-centered oversight.
• Medical Ethics in the Algorithm Age: Democratizing access to AI-generated drug suggestions is both hopeful and fraught—patient safety, scientific rigor, and the doctor-patient bond must remain central.
• Medicine’s New Frontier: Beyond “precision medicine,” this is “precision repurposing”—mapping not just people to drugs, but drugs to untold medical mysteries.

Further Listening

• “Death Interrupted” (Radiolab): On end-of-life choices and the limits of fighting.
• “The Dirty Drug and the Ice Cream Tub” (Radiolab): The saga behind rapamycin, the drug that saved David’s life.

For more on Dr. Fagenbaum’s work: everycure.org
His book: Chasing My Cure