Armchair Expert with Dax Shepard

David Fajgenbaum (on repurposing medicine)

November 26, 2025

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  • David Fajgenbaum's commitment to medicine was solidified by a promise made to his dying mother, leading him to shift focus from sports medicine to finding treatments for patients like her. 
  • Fajgenbaum survived multiple near-fatal relapses of Castleman disease by strategically pursuing off-label drug repurposing after conventional treatments failed, ultimately finding remission with the mTOR inhibitor Sirolimus. 
  • The experience of near-death provided Fajgenbaum with a profound 'right sizing' of priorities, leading him to realize that solving rare diseases requires overcoming organizational and business barriers, not just scientific ones. 
  • David Fajgenbaum's remission from Castleman disease using an off-label drug inspired his mission to find new uses for existing medicines through the non-profit Every Cure. 
  • The primary obstacles to repurposing existing drugs are the lack of financial incentive for pharmaceutical companies (especially for generic drugs) and the sheer impossibility for humans to synthesize the vast amount of existing medical data. 
  • Artificial intelligence and biomedical knowledge graphs are essential tools for Every Cure to systematically analyze the 4,000 existing drugs against 18,000 diseases to identify high-potential treatment matches, as demonstrated by successful repurposed treatments for conditions like Poem syndrome and cerebral folate deficiency. 
  • The speaker reflects on a personal struggle to perform acts of service secretly, realizing his instinct is to seek external validation and applause for benevolent actions. 
  • True personal evolution involves reaching a stage where one performs good deeds purely for self-satisfaction, without needing observation or external reward. 
  • The desire for public recognition of generosity is rooted in social survival, as reputation within a group is crucial, yet overtly stating generosity often negates its positive effect. 

Segments

Georgetown Football Connection
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(00:00:21)
  • Key Takeaway: David Fajgenbaum was recruited to play football at Georgetown, connecting him with ‘Perfect 10 Charlie’.
  • Summary: David Fajgenbaum was a football tight end at Georgetown, where he was quarterbacked by his friend, known on the show as ‘Perfect 10 Charlie’. Georgetown’s team mascot is the Hoya, derived from the Greek phrase ‘Hoya Saxa’ meaning ‘What rocks’. Fajgenbaum maintained his pre-med focus even while playing football and being physically imposing.
Mother’s Cancer Diagnosis
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(00:08:32)
  • Key Takeaway: Glioblastoma surgery on his mother prompted Fajgenbaum to immediately pivot his career focus from sports medicine to finding cancer treatments.
  • Summary: Fajgenbaum’s mother was diagnosed with operable glioblastoma shortly after he started college, leading to a heartbreaking surgery where she made a joke about looking like the ‘Chiquita banana lady’. He promised his mother he would dedicate his life to finding treatments for patients like her, shifting his academic focus entirely to medicine.
Post-Graduation and Grief Management
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(00:12:46)
  • Key Takeaway: Fajgenbaum pursued a Master’s at Oxford focused on health promotion before establishing AMF to support grieving college students.
  • Summary: After Georgetown, Fajgenbaum studied at Oxford, focusing on disease prevention, though he connected better with students from Oxford Brooks than Oxford University. He channeled his grief over his mother’s death into instrumental grieving by creating the AMF organization for college students struggling with loss.
Onset of Critical Illness
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(00:16:35)
  • Key Takeaway: Despite being a healthy medical student, Fajgenbaum experienced rapid organ failure due to an undiagnosed condition, leading to hospitalization and temporary blindness.
  • Summary: While on an OBGYN rotation in his third year of medical school, Fajgenbaum began experiencing severe fatigue, enlarged lymph nodes, and fluid retention, symptoms he initially ignored. His liver, kidneys, and bone marrow began shutting down, requiring hospitalization, dialysis, and daily transfusions while doctors searched for a diagnosis.
Castleman Disease Diagnosis and Treatment
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(00:27:38)
  • Key Takeaway: Fajgenbaum was diagnosed with Castleman disease, a rare immune disorder, and survived multiple relapses after failing initial treatments.
  • Summary: The diagnosis was Castleman disease, an idiopathic condition where the immune system attacks vital organs because it fails to turn off surveillance mode. After failing initial chemotherapy, he was told doctors were out of options, prompting his decision to pursue off-label drug repurposing.
Off-Label Drug Repurposing Success
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(00:33:10)
  • Key Takeaway: Fajgenbaum identified the mTOR pathway as hyperactive in his disease and successfully treated himself with Sirolimus, an existing drug for transplant rejection.
  • Summary: Realizing his previous chemotherapy success implied other drugs might work, Fajgenbaum researched related diseases and collected his own samples to identify the faulty pathway, which pointed to overactive mTOR signaling. He convinced his doctors to prescribe Sirolimus, an mTOR inhibitor used for organ transplants, which put him into full remission for over 11 years.
Drug Remission Longevity
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(00:43:27)
  • Key Takeaway: David Fajgenbaum measured his remission duration precisely, reflecting the uncertainty of long-term off-label drug efficacy.
  • Summary: The duration of remission achieved through off-label drug use is a critical, uncertain factor for patients. Fajgenbaum meticulously tracked his remission in months, similar to tracking sobriety milestones, due to the unpredictable nature of the treatment’s effectiveness.
Transition to Research Career
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(00:44:12)
  • Key Takeaway: Following remission, Fajgenbaum dedicated his professorship at Penn to exploring off-label uses for existing medicines.
  • Summary: After recovering, David Fajgenbaum became a professor at Penn’s medical school to systematically investigate the 18,000 diseases that might be treatable with the 4,000 existing medicines. This pursuit immediately raised the question of whether Artificial Intelligence would be necessary for such a massive undertaking.
Realization of Missed Cures
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(00:44:40)
  • Key Takeaway: Fajgenbaum realized the drug that saved him was available in common pharmacies, highlighting a massive gap in medical knowledge accessibility.
  • Summary: The realization struck Fajgenbaum that the life-saving drug was likely available in a common CVS during the three years he was dying. This underscores how existing, known medications can remain undiscovered treatments for rare diseases because no one connects the dots.
Sponsor Break: BetterHelp
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(00:45:05)
  • Key Takeaway: Therapy is encouraged as a proactive step, especially during darker seasons, with BetterHelp offering licensed therapists matched via a questionnaire.
  • Summary: Seasonal affective disorder and the general busyness of life make reaching out for support important. BetterHelp provides access to fully licensed therapists in the U.S. who are matched based on user needs through a short questionnaire, allowing users to switch matches easily.
Sponsor Break: A Diamond is Forever
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(00:46:17)
  • Key Takeaway: Desert-toned diamonds are presented as a unique way to celebrate personal evolution and unexpected life journeys.
  • Summary: Diamonds in unique, unexpected colors like warm whites, pale champagnes, and deep ambers reflect an individual’s evolving journey. Gifting a desert diamond is positioned as a way to celebrate continuous personal growth and transformation.
Sponsor Break: Hill’s Pet Nutrition
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(00:47:11)
  • Key Takeaway: Pet ownership involves unavoidable guilt due to the pressure of being a pet’s entire world, which Hill’s Science supports through nutrition.
  • Summary: Humans with pets often experience unavoidable ‘pet parent guilt’ because they are their pets’ whole world, leading to worry when things go wrong or when traveling. Hill’s Pet Nutrition aims to support pet parents by providing science-backed food solutions.
Sponsor Break: ZipRecruiter
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(00:47:54)
  • Key Takeaway: ZipRecruiter’s matching technology efficiently connects employers with qualified candidates, often within the first day.
  • Summary: Hiring for seasonal or specialized roles can be challenging, but ZipRecruiter’s platform uses matching technology to quickly connect employers with top talent. Four out of five employers posting on the site find a quality candidate within 24 hours.
Medicine Myopia and Incentives
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(00:49:14)
  • Key Takeaway: The specialization within medicine and the lack of profit incentive prevent doctors and pharma companies from synthesizing information to find off-label drug uses.
  • Summary: Medical fields are often myopic due to specialization, making it difficult for individual doctors to synthesize information across disciplines. Furthermore, pharmaceutical companies are not incentivized to pursue clinical trials for existing generic drugs that offer minimal profit margins, even if they could treat millions.
Founding Every Cure
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(00:50:55)
  • Key Takeaway: Every Cure was founded as a non-profit to systematically find new uses for existing, safe medicines to save lives where the commercial system fails to act.
  • Summary: Driven by the desire to save lives with existing treatments, Fajgenbaum co-founded Every Cure to overcome the systemic lack of incentive for drug repurposing. The organization focuses on rare inflammatory diseases, cancers, and autoimmune conditions that share biological overlaps.
Repurposing Success Stories
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(00:51:24)
  • Key Takeaway: Repurposed drugs have successfully treated rare conditions like Castleman disease and Angiosarcoma, sometimes based on previously disregarded lab research.
  • Summary: The team found additional repurposed drugs for Castleman disease and successfully treated an uncle with Angiosarcoma using a drug whose potential had been published but never tested in patients three years prior. For Angiosarcoma, the treatment worked for about 18% of patients, allowing one patient to live nine years longer.
AI’s Role in Drug Discovery
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(00:53:43)
  • Key Takeaway: AI allows Every Cure to scale its search by scoring all 4,000 drugs against all 18,000 diseases, a task impossible for human labs.
  • Summary: Artificial intelligence became crucial about three years ago, enabling the organization to move beyond studying a few diseases to globally scoring every drug against every disease. This ‘all versus all’ approach identifies the highest probability matches across the entire medical landscape.
Cerebral Folate Deficiency Treatment
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(00:55:00)
  • Key Takeaway: Folinic acid, a derivative of folate used in chemotherapy, can bypass the blocked folate receptor in nonverbal autistic children with cerebral folate deficiency.
  • Summary: Some nonverbal children have cerebral folate deficiency due to antibodies blocking the folate receptor needed for brain development. Folinic acid, a derivative of folate, can bypass this blockage via an adjacent channel (RFC) and has shown improvements in verbal communication in clinical trials.
Impact of Folinic Acid on Children
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(00:57:07)
  • Key Takeaway: A nonverbal child named Ryan spoke his first statement, ‘Daddy, I love you,’ within two weeks of starting folinic acid treatment.
  • Summary: Ryan, nonverbal for five years, could only repeat what was said to him (echolalia) before treatment. After starting folinic acid, he communicated executive statements, including telling his father he loved him. Another patient, Mason, said his first word, ‘more,’ within three days.
Knowledge Graph Construction
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(00:58:32)
  • Key Takeaway: The AI model is trained using a biomedical knowledge graph that maps every drug, disease, gene, and known relationship from published literature.
  • Summary: A knowledge graph constructs nodes for medical concepts (drugs, diseases) connected by lines representing relationships found in published data. This graph serves as the training material for machine learning algorithms to recognize patterns in known treatments, allowing the AI to then predict new drug-disease matches.
Systemic Failures in Drug Repurposing
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(01:00:08)
  • Key Takeaway: The system fails to repurpose existing generic drugs because there is no profit incentive for clinical trials, and no single entity (like the NIH or FDA) has taken responsibility for this gap.
  • Summary: Eighty percent of existing drugs are generic, meaning profit margins are too low (pennies per pill) for companies to invest millions in clinical trials for new uses. This financial barrier, combined with a lack of governmental entity ownership over the problem, creates a massive gap where suffering patients are not being helped by known, safe drugs.
Joseph Coates Poem Syndrome Case
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(01:02:00)
  • Key Takeaway: Three drugs typically used for multiple myeloma were recommended for a Poem syndrome patient in hospice, leading to his recovery and potential cure via stem cell transplant.
  • Summary: Joseph Coates, diagnosed with Poem syndrome, was days away from being taken off life support when David Fajgenbaum suggested three myeloma drugs to his doctor. The doctor agreed to try them, and Joseph responded positively, eventually undergoing a stem cell transplant that potentially cured him.
Balancing Systemic vs. Individual Aid
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(01:04:28)
  • Key Takeaway: Fajgenbaum struggles to balance the systematic, AI-driven pipeline of Every Cure with the urgent, individual ‘Hail Mary’ requests from desperate patients.
  • Summary: Every Cure maintains a systematic approach, advancing nine drug-disease matches through lab work and trials, which requires focus. However, the team is constantly contacted by patients like Joseph, creating a major internal struggle on how to allocate resources between systematic progress and immediate, high-stakes interventions.
Lidocaine for Breast Cancer
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(01:05:22)
  • Key Takeaway: Injecting lidocaine around a breast cancer tumor before surgery reduced patient mortality by 29% in a large Indian trial, possibly by preventing cancer cell migration during the operation.
  • Summary: A trial of 1,600 patients showed that injecting lidocaine (a common numbing agent) before tumor removal significantly lowered five-year mortality. The hypothesis is that lidocaine paralyzes cancer cells, stopping them from migrating and metastasizing during the trauma of surgery.
Botox and Bachman-Bup Examples
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(01:07:23)
  • Key Takeaway: Repurposed treatments include Botox injections improving mood for three to four months and DFMO treating the rare pediatric condition Bachman-Bup.
  • Summary: Clinical studies suggest Botox injections between the eyebrows can improve mood for several months, illustrating the mind-body connection. Bachman-Bup, a rare condition where children are tube-fed due to high OCE1 enzyme levels, is being treated with DFMO, a drug used for African sleeping sickness which also elevates OCE1.
Supporting Every Cure
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(01:08:49)
  • Key Takeaway: The public can support Every Cure through donations and by spreading awareness, as awareness campaigns can directly benefit patients by disseminating existing knowledge.
  • Summary: Supporters are encouraged to donate at everycure.org and help raise awareness, as spreading the word about existing drug possibilities is crucial when the science is already done. David Fajgenbaum’s TED Talk is highlighted as a resource for learning more about the organization’s work.
Aaron’s Dangerous Roof Work
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(01:10:29)
  • Key Takeaway: Aaron undertook dangerous roof work using a harness and rope anchored to a chimney on a metal roof, resulting in a fall to the first story.
  • Summary: Aaron planned to use a harness and rope system to work on the second-story roof, but the metal roof prevented standard anchoring, forcing him to use the chimney. He fell to the first story but was uninjured, though the harness left significant marks on his body.
Aaron’s Christmas Light Display
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(01:14:44)
  • Key Takeaway: Aaron significantly over-delivered on decorating the house for Christmas, creating an elaborate, stylized display that resembled Clark Griswold’s house.
  • Summary: The contractor noted that Aaron’s Christmas light installation was highly stylized and thoughtful, far exceeding expectations. The display was so extensive that the hosts joked about charging neighbors $20 for admission.
Secret Turkey Tradition and Spoilers
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(01:15:31)
  • Key Takeaway: The hosts participate in a ‘Secret Turkey’ gift exchange before Thanksgiving, with Dax expressing a strong preference for avoiding spoilers about his gift.
  • Summary: The friendship group engages in a ‘Secret Turkey’ tradition where gifts must be handmade or customized. Dax values the anticipation of unwrapping presents and dislikes spoilers, contrasting with his daughter Lincoln, who enjoys knowing outcomes in advance.
Unibrow History and Hair Growth
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(01:20:44)
  • Key Takeaway: Dax’s childhood unibrow disappeared despite increased body hair growth later in life, possibly due to the permanent damage caused by repeated plucking or Nair use.
  • Summary: Dax used to shave and then use Nair on his unibrow in high school, causing irritation, but the hair has since disappeared entirely. This is contrasted with his current experience of proliferating body hair, leading to speculation that aggressive removal methods can cause hair follicles to stop producing growth in specific areas.
King’s Gray Hair Allegory
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(01:30:03)
  • Key Takeaway: A story exists about a king who must abdicate or face death upon growing a single gray hair, teaching that one must recognize mortality and prioritize wisdom over worldly power.
  • Summary: The allegory warns that the appearance of a gray hair signals the end of youth and the imminence of death. The moral lesson is that life is too short for mere power, requiring dedication to wisdom and righteousness upon recognizing signs of aging.
Dax’s Weekend of Service
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(01:31:08)
  • Key Takeaway: Dax spent his weekend fulfilling service obligations (driving, attending events) and struggled with the internal desire to seek recognition for his sacrifices.
  • Summary: Dax’s weekend involved driving to and sitting through a volleyball game and a birthday party, which he perceived as significant personal sacrifices. His instinctual reaction was to call attention to the effort he was making for others.
Mortality and Life’s Purpose
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(01:30:39)
  • Key Takeaway: A philosophical lesson suggests that even a long life is too short for worldly pleasures, necessitating dedication to wisdom and righteousness upon recognizing mortality.
  • Summary: A story about a king receiving a ‘messenger of death’ implies that youth, middle age, and old age are finite, demanding a focus beyond temporary power. The core moral emphasizes dedicating life to wisdom and righteousness after acknowledging aging and mortality. This realization strongly resonated with the speaker.
Struggle with Secret Generosity
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(01:31:08)
  • Key Takeaway: The speaker struggles against the ingrained need for external validation, finding that performing generous acts secretly feels pointless without an audience to observe and approve.
  • Summary: The speaker recounts a weekend dedicated to service, resisting the urge to complain about the sacrifice, guided by advice to never ask, ‘What about me?’ He then performed an abnormally generous act for a stranger but felt compelled to tell his mother, highlighting the difficulty of acting without seeking applause or validation.
Social Need for Benevolence Display
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(01:35:02)
  • Key Takeaway: Humans naturally seek to display benevolence because reputation is vital for trust and standing within a social group, though overt bragging diminishes the act’s value.
  • Summary: The need to show benevolence stems from being social animals where reputation dictates trust; people naturally want others to see their good deeds. However, stating generosity directly often has the opposite effect, making the act distasteful, though others may eventually find out through indirect means. Doing things secretly is identified as a powerful, albeit difficult, goal for personal growth.
Glioblastoma Facts and Folic Acid
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(01:38:39)
  • Key Takeaway: Glioblastoma is statistically more common in men (about 60% more likely) than women, and folic acid supplementation is recommended for women with epilepsy planning pregnancy to prevent birth defects.
  • Summary: Research confirmed that glioblastoma affects men significantly more often than women, though the exact reasons are not fully understood. The discussion pivoted to folic acid, which is recommended for individuals with epilepsy, especially women of childbearing age, to prevent neural tube defects in children. This supplementation is necessary because certain anti-epileptic drugs can cause folic acid deficiency.
Podcast Promotion and Outro
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(01:42:16)
  • Key Takeaway: Listeners can access ‘Armchair Expert with Dax Shepard’ early and ad-free by joining Wondry Plus on various platforms.
  • Summary: The podcast is available on the Wondry app, Amazon Music, or other podcast providers. Joining Wondry Plus grants early and ad-free access via the Wondry app or Apple Podcasts. Listeners are encouraged to complete a survey at wondry.com/slash survey.