Huberman LabDr. David Fajgenbaum on Huberman Lab: How Old Drugs Cure
Fajgenbaum survived Castleman disease on a repurposed drug from his local pharmacy; now AI is scanning all FDA-approved generics for overlooked cancer cures.
CHAPTERS
- 0:00 – 7:00
A System Blind Spot: Old Drugs, Untapped Cures
Fajgenbaum opens with the moment his doctor told him there were no options left, prompting his realization that the medical system had only tried a tiny fraction of existing drugs for his disease. Huberman frames the episode’s central thesis: many effective treatments or even cures already exist but remain unknown or unused because of how drugs are studied, patented, and categorized.
- •Doctor declares Fajgenbaum 'out of options' after multiple chemotherapies and an experimental drug fail.
- •David recognizes they’ve only tried seven of ~4,000 FDA‑approved drugs, not everything that could plausibly help.
- •Commits to dedicating whatever life he has left to finding an existing drug that can treat Castleman disease.
- •Huberman outlines the episode focus: drug repurposing, structural blind spots in medicine, and patient agency.
- 7:00 – 27:00
Existing Drugs, Hidden Uses: Aspirin, Viagra, Lidocaine & More
The discussion moves into concrete examples of drugs whose lesser-known benefits could be saving more lives. They explore how the economics of generics and patents, not just scientific evidence, determine whether secondary uses like aspirin in colon cancer or lidocaine in breast surgery become standard of care.
- •Aspirin: widely known as a pain reliever and for heart attack prevention, but also reduces colon cancer recurrence in specific mTOR‑mutant patients, yet underutilized.
- •Viagra/Cialis: repurposed from heart and prostate-related applications to erectile dysfunction and even a rare pediatric lung disease.
- •Lidocaine: Indian RCT in 1,600 women found peri-tumoral lidocaine prior to breast cancer surgery cut 5‑year mortality by ~29%, but global uptake is minimal.
- •Generic status and tiny profit margins mean no company is incentivized to push such findings into guidelines and clinical practice.
- •Every Cure feels responsible to validate mechanisms and evidence before promoting such interventions broadly.
- 27:00 – 44:00
Patents, Profits, and Why Repurposing Stalls
Huberman and Fajgenbaum dissect how the patent system drives pharma behavior and leaves most repurposing opportunities on the table. They distinguish between formulation tweaks to extend a patent in the same disease versus genuine new indications and highlight the 14,000 diseases with no approved treatment at all.
- •As patents near expiration, companies tweak dose/formulation to extend IP in the same disease, not to seek new diseases.
- •Once a drug is generic, R&D to test it in new indications essentially stops; there’s no clear financial owner.
- •There are ~4,000 approved drugs for ~4,000 diseases but ~18,000 human diseases overall; most have no approved therapy.
- •80% of FDA‑approved drugs are generic, creating a huge un-incentivized zone for potential repurposing.
- •Fajgenbaum sees a CVS shelf and thinks of untapped life-saving uses sitting idle for lack of system-level incentives.
- 44:00 – 59:00
How to Self‑Advocate: Disease Groups, Experts, and Questions
They outline practical strategies for ordinary people to find cutting-edge options without medical training. Case studies like the TNF inhibitor for DADA2 illustrate how a single clinician’s observation remained siloed for years until a motivated parent and collaborators turned it into guidelines that now save children globally.
- •Step 1: Find the disease-specific organization (e.g., Castleman Disease Collaborative Network, ALS Association, Michael J. Fox) which often tracks off‑label use globally.
- •Step 2: Identify the true world expert and, if possible, arrange a consultation; their knowledge often exceeds local standard practice.
- •Step 3: Ask, after hearing the standard plan, “Is there anything being tried elsewhere or off‑label that’s promising?”
- •DADA2 example: TNF inhibitor dramatically stopped childhood strokes in one clinic, but the insight remained obscure for a decade.
- •Physician-parent Chip Chambers helped build evidence and treatment guidelines, transforming outcomes for children with DADA2.
- 59:00 – 1:20:00
Repurposed Drug Wins: Thalidomide, Pembrolizumab, Colchicine
Fajgenbaum walks through notable successes where drugs found second or third lives in seemingly unrelated diseases. These stories underscore how often the key evidence already exists in the literature but hasn’t been translated into practice, and how little brilliance is sometimes required beyond connecting the dots.
- •Thalidomide: notorious for causing birth defects when used for morning sickness, later repurposed for leprosy and multiple myeloma due to anti‑angiogenic properties.
- •Pembrolizumab: originally for melanoma and lung cancer; his lab used a 2013 paper showing PD‑L1 expression in angiosarcoma to justify first use, leading to ~18% response rate and multi‑year remissions.
- •Case of Michael with metastatic angiosarcoma: first known PD‑1 inhibitor use; now in nine-year remission and walked his daughter down the aisle.
- •Colchicine: ancient gout drug repurposed via dose‑adjusted formulation to reduce heart attack risk in post‑MI patients, especially with diabetes.
- •These examples show how economic tweaks (new dosage/IP) sometimes are necessary to fund large prevention trials.
- 1:20:00 – 1:43:00
From Supplements to Statins: Rethinking ‘Natural’ vs. ‘Pharma’
Huberman and Fajgenbaum blur the line between natural substances and drugs, pointing out that many prescriptions originate from plants, microbes, or soil. They discuss examples like rapamycin from Easter Island soil, kratom, coca, and Mucuna pruriens, arguing that the key issue is not natural vs. synthetic but evidence, dosing, and control.
- •Rapamycin (sirolimus) was discovered in soil from Rapa Nui/Easter Island during a bioprospecting expedition; originally investigated as an antifungal.
- •Many supplements (e.g., L‑DOPA‑rich Mucuna pruriens, kratom alkaloids, coca plant derivatives) share mechanistic overlap with prescription drugs.
- •Over-the-counter products lack strict dosing and purity controls, leading to both therapeutic potential and significant risk.
- •Huberman calls for more structured, safe bioprospecting plus rigorous preclinical and clinical testing, not uncontrolled consumer experimentation.
- •Time and cost constraints make it unrealistic to run full trials on every candidate molecule; AI triage becomes essential.
- 1:43:00 – 1:58:00
David’s Origin Story: Losing His Mother, Football, and Medicine
Fajgenbaum shares how his mother’s fatal glioblastoma shifted him from a football-obsessed teen to a mission-driven future physician. Her resilience and humor in the face of brain surgery, captured in her ‘Chiquita banana lady’ joke post‑op, became a template for how to reclaim agency and dignity amid severe illness.
- •At 18, while achieving his dream as a Division I quarterback at Georgetown, David learns his mother has terminal brain cancer.
- •Witnessing her 15‑month battle and eventual death profoundly reorients his life toward medicine and drug discovery.
- •He promises her he will devote his life to helping patients like her; her final words to him are “unconditional love.”
- •The ‘Chiquita banana lady’ moment after awake brain surgery models taking emotional agency even while physically devastated.
- •This experience seeds his long-term mission to find treatments and his emotional approach to facing his own future illness.
- 1:58:00 – 2:21:00
Castleman Disease: From Healthy Med Student to Multi‑Organ Failure
He recounts his abrupt collapse from healthy, high-performing medical student and athlete into a critically ill ICU patient with multi‑organ failure. Misdiagnosed as lymphoma or autoimmune disease, he endures months of transfusions, dialysis, and 100 pounds of fluid overload before finally getting a Castleman disease diagnosis and a temporary reprieve from combination chemotherapy.
- •Initial symptoms: enlarged neck lymph nodes, extreme fatigue, abdominal pain, ankle edema developing over weeks.
- •ER labs show liver, kidney, and bone marrow failure; he’s hospitalized, rapidly worsens, becomes temporarily blind in one eye from retinal hemorrhage.
- •Requires daily transfusions and dialysis, gains ~100 pounds of fluid; receives last rites when death seems imminent.
- •Pathology ultimately reveals Castleman disease, an atypical lymphoproliferative disorder with autoimmune-like cytokine storm destroying organs.
- •Aggressive multi‑agent chemotherapy saves his life but only temporarily; he relapses repeatedly.
- 2:21:00 – 2:35:00
The ‘Santa Claus Theory’ of Medicine and Its Collapse
Huberman and Fajgenbaum examine the naive belief that somewhere there is a coordinated workshop of experts solving every medical problem as fast as possible. David’s experience—learning that a Castleman drug existed in Japan yet was unknown to his US team—shatters this illusion and highlights the randomness and fragmentation of real‑world biomedical progress.
- •David’s ‘Santa Claus theory of civilization’: imagined rooms of scientists/doctors working like elves to get cures out instantly.
- •Reality: no unified workshop; efforts are fragmented, slow, and heavily influenced by incentives and chance.
- •Castleman drug tocilizumab existed and was approved in Japan, repurposed later for rheumatoid arthritis, yet was not tried for him at first.
- •Information asymmetry means therapy choice can depend on geography, luck, and who your doctor knows.
- •This realization pushes him from individual doctor to systems-level problem solver.
- 2:35:00 – 2:54:00
Almost Dying Five Times and Discovering Rapamycin
After multiple near-fatal relapses and being told there is nothing left to try, Fajgenbaum decides to become his own scientist. He collects his own samples, learns lab methods, and eventually identifies hyperactivation of the mTOR pathway in his tissues, leading him to propose high‑dose sirolimus—an organ transplant drug—as a therapy. It becomes his long-term lifeline.
- •Despite an experimental Castleman drug and multiple chemotherapies, he keeps relapsing; one expert visit ends with “there is nothing more.”
- •He starts storing his own blood every two weeks, runs flow cytometry and serum proteomics, and secures lab bench space from a colleague.
- •After a fifth near-fatal relapse, he awakens in ‘overtime’ and immediately starts organizing sample transfers to analyze.
- •Integrated data (proteomics, flow, immunohistochemistry on lymph nodes) reveals hyperactive mTOR signaling.
- •He proposes sirolimus (rapamycin), an mTOR inhibitor used for organ transplant rejection; on a full transplant dose he enters a remission that has now lasted nearly 12 years.
- 2:54:00 – 3:17:00
From Personal Cure to Global Mission: Lab, Every Cure, and AI
With his own disease controlled by sirolimus, Fajgenbaum formalizes his approach: he completes business school to learn systems and incentives, founds a research lab at Penn, and co-founds Every Cure. They use AI and knowledge graphs to systematically generate and rank all plausible drug–disease matches and then validate the top candidates experimentally and clinically.
- •Back at Penn, he sets up a translational lab focused on Castleman, then broadens to other diseases.
- •Uses sirolimus successfully in other Castleman patients (e.g., Joey in Philadelphia) confirming it isn’t just an N-of-1 fluke.
- •Discovers and deploys ruxolitinib (myelofibrosis drug) for certain Castleman patients who fail sirolimus, and pembrolizumab for angiosarcoma.
- •Co-founds Every Cure with partners experienced in AI for pharma; shifts from individual diseases to an all-drugs vs. all-diseases strategy.
- •Nine active repurposing programs and 14 drug successes to date set the stage for a growing validated portfolio.
- 3:17:00 – 3:36:00
Balancing Innovation With Safety: Off‑Label Use and Risk
They confront the ethical and practical risk of trying drugs off‑label in desperate situations. While N-of-1 repurposing has saved lives, a single catastrophic outcome could chill entire fields—as happened historically with gene therapy or contaminated supplements—so Every Cure emphasizes rigorous evidence synthesis, clear communication, and physician-driven decisions.
- •Huberman raises the concern: one death from a speculative repurposing could halt progress and trigger regulatory backlash.
- •Historical parallels: early gene therapy death stalled the field; contaminated tryptophan batch removed tryptophan from the market.
- •Every Cure distinguishes between speculative off‑label ideas and those backed by convergent lab, clinical, and observational evidence.
- •They aim to avoid one-off Hail Marys unless there’s a strong rationale and no alternatives, always via the treating physician.
- •Goal is to move from last‑ditch rescue to preemptive, guideline-level use of validated repurposed drugs.
- 3:36:00 – 4:01:00
Hope, Tenacity, and the Neuroscience of ‘Overtime’
The conversation turns inward as Fajgenbaum describes the psychological tools that sustained him—living in ‘overtime’, breaking suffering into one-more-breath or one-more-day increments, and drawing strength from family. Huberman maps this onto specific brain circuitry, especially the anterior mid‑cingulate cortex, which appears central to perseverance and the will to live.
- •David describes his experience of ‘overtime’: life after expected death, where every moment feels both scarce and precious.
- •He survived six months of extreme ICU pain by focusing on surviving the next minute, hour, or day, never the whole horizon.
- •Family (especially his sister Gina’s “Just breathe, Dave”) served as external anchors, giving him reasons to take one more painful breath.
- •He articulates a ‘hope–action–impact’ loop: concrete hope → specific action → observable impact → renewed hope → more action.
- •Huberman references neurosurgeon Joe Parvizi’s work showing stimulation of the anterior mid‑cingulate cortex generates a felt drive to confront challenge, and its preservation in ‘super‑agers’ suggests a neural locus for this loop and the will to live.
- 4:01:00
How to Engage With Every Cure and the Path Forward
In closing, they discuss how clinicians, patients, and the public can support and participate in Every Cure’s work. With substantial government and philanthropic backing already in place, the project aims to translate AI-identified matches into lab validation, trials, guidelines, and ultimately a world where no one dies simply because a cheap, existing drug wasn’t tried.
- •Every Cure is a nonprofit funded roughly half by ARPA‑H and half by private donors; it holds no IP on repurposed uses in most cases.
- •Ways to help: submit repurposing ideas (everycure.org/ideas), sign up as an expert collaborator (everycure.org/experts), donate, and share content like Fajgenbaum’s TED Talk.
- •Most successful repurposings will likely use existing doses/formulations of generics, meaning no one profits directly but patients benefit.
- •Rarely, a new formulation might be needed (e.g., better brain penetration), in which case a spin-out company could be justified.
- •Both agree that AI plus open, problem-centered collaboration can fundamentally change how quickly existing science becomes real-world cures.
