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Dr. 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.

Dr. David FajgenbaumguestAndrew Hubermanhost
Nov 3, 20251h 58mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 4:06

    David Fajgenbaum

    1. DF

      ... my doctor explained to me that we were out of options. He said, "David, we've tried everything. You know, we tried these chemotherapies, we tried this one experimental drug. Um, there's nothing more that we can do." There was, uh, a few-minute period where my dad and my sisters and, and my girlfriend around me, and we were just, um, just bawling our eyes out. You know, we're, "This is the world's expert." And I kept probing him, like, "Is there any cell type or signaling pathway or is there something we can target?" Like, and then he said, "David, there's nothing." "Is there anything in an early stage of development?" "David, there is nothing." I, I heard what he was saying, but then I thought to myself, "You just gave me seven chemotherapies that were made for lymphoma and my- multiple myeloma, and they've saved my life now three times. They're not... It's not long-term. Like, I know I keep relapsing, but, like, if these seven chemotherapies are working, how do we know there's not an eighth chemotherapy or a ninth drug for something else? Like, you can't tell me... We haven't tried all 4,000 drugs. We've just tried the drugs that maybe we've thought to try." And so I just locked in right then, and I turned to my family and just sort of wiped away my tears and said, "I'm gonna dedicate the rest of my life, however long that's gonna be, it might be a couple of days, maybe it'll be a couple of months, but however long I've got to try to find out, is there a drug out there that could help me and other patients with my disease that's made for another condition?" I just believe that the 4,000 drugs we have today should help all the patients who can benefit from them.

    2. AH

      Mm-hmm.

    3. DF

      Period. Like, no one should suffer if there's a drug at your CVS that could help you.

    4. AH

      Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. David Fajgenbaum. Dr. David Fajgenbaum is a professor of translational medicine and human genetics at the University of Pennsylvania. His work focuses on finding novel cures to both rare and common human diseases by using drugs and other treatments that already exist and that are approved for use in humans for other purposes. As it turns out, most approved drugs impact at least 40 different pathways and mechanisms across the human brain and body, but these drugs are generally approved for use in just one or two of those pathways. David shares with us the many commonly unknown yet powerful benefits of drugs that are already approved for things like heart health, combating cancer, neurodegeneration and more. From his own near-death experience with Castleman's disease, David discovered that the medical profession already has in hand excellent treatments and perhaps even cures for many of the childhood and adult diseases that the medical profession deems uncurable or untreatable. In addition to running his laboratory, where they search for novel treatments and cures using already approved drugs, David has started a not-for-profit called Every Cure, which helps people find treatments and cures to diseases that the medical field has essentially deemed untreatable. And that work has already saved countless lives. Our discussion today is about how to navigate your health journey and how to approach the treatment of any illness that you or a relative may face. It's also about the fact that while the fields of medicine and science are truly incredible and well-intentioned, they do have a giant blind spot built into them, which is that many effective treatments, and in some cases, cures, exist to diseases that we are told are hopeless to treat, and that even the best-trained and well-meaning MDs are often unaware of those treatments, not because they are lazy or that they have some other agenda, but simply because of how medications are studied, patented, and categorized. As you'll soon learn, Dr. Fajgenbaum is on a mission to educate doctors, scientists, and most importantly, you, the general public, about these facts. He has lived them directly. He's an MD who got very sick with what he was told was a terminal disease, and when the existing system left him at a cliff, he went about curing that disease using old medications in new ways, and he is now helping others who need to do the same. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. David Fajgenbaum.

  2. 4:06 – 6:44

    Self-Agency in Healthcare; New Uses for Old Medicines

    1. AH

      Dr. David Fajgenbaum, welcome.

    2. DF

      Thanks so much for having me.

    3. AH

      These days, people are very concerned about their health, even if they're healthy, and I think the reason for that is ever since, uh, 2020, I think people have started to realize that they need to do more self-advocacy in terms of their health, whether or not it's behaviors to take care of their health, uh, learning how to explore medical a- and health information online more effectively. No one knows who to trust. Um, and yet people are realizing that they are a critical element in their health, and should they encounter challenges to their health, they realize they can no longer be passive participants and just go to their doctor-

    4. DF

      Yeah.

    5. AH

      ... um, that doctors are human too. Um, so you have a very unique health story, and, and we'll get into that, but maybe we just start off by educating people a little bit about some of the, um, common misperceptions in order to, uh, give them more sense of agency, uh, about what they can do. One of the things that you've been, uh, very vocal about is that you believe through experience and observation that many of the treatments or even potential cures for the things that challenge people may already exist-

    6. DF

      Right.

    7. AH

      ... in the form of medicines that are prescribed or available maybe even over-the-counter-

    8. DF

      Mm-hmm.

    9. AH

      ... but that people, including doctors, are not aware of that. Could you just elaborate on that? What we're basically saying is, the answers may already be here.

    10. DF

      Sure. Well, first of all, I love that you're talking about agency in, in health and in medicine because I think oftentimes we talk about agency, you know, I can get a good night's sleep or I can exercise an- and eat well in the sense of wellness, but oftentimes when people get really sick with a horrible disease, whether it's cancer or Castleman's, feel like, "Well, we're just gonna do whatever our doctor, our local doctor tells us to do." Um, but you're right. I think that, um, there's so much more that we can do and there's so much agency that we can take. And part of it, to your point, is that there are drugs that we have. There's 4,000 FDA-approved drugs that are approved for about 4,000 diseases, but we know from laboratory work and also from clinical trials that many of those drugs can be used in more diseases, but unfortunately the system really isn't set up to find new uses for old medicines, and so-... that's the work that I do, but I also think it gives all of us, uh, uh, really a sense of responsibility that if we're diagnosed with a bad disease, that we find out what's the disease organization advocacy group. Maybe they're aware of a drug being used in one part of the world, but others aren't. Who's the leading expert? Can you go drive to see the leading expert? And can you make sure that once the expert tells you what to take, you ask questions, like, "Is there, is there potentially something else?"

  3. 6:44 – 8:53

    Other Uses of Aspirin & Viagra; Drug Development & Approved Use

    1. DF

    2. AH

      Mm-hmm. I think of aspirin, for instance.

    3. DF

      Yeah.

    4. AH

      Um, most people think of aspirin as a pain reliever.

    5. DF

      Yep.

    6. AH

      But aspirin is now used as a way to offset heart attacks.

    7. DF

      Mm-hmm.

    8. AH

      For its blood thinning effects, among other effects. Um, just off the top of your head, um, not, not trying to, uh, test you here, you're, you're the, uh, the MD, uh, I'm the PhD as we were talking about before, and I'm not gonna test you on medicine-

    9. DF

      No.

    10. AH

      ... I'm not, I'm not equipped to. Um, but are there other uses for aspirin that we perhaps haven't heard of or, or similar-

    11. DF

      Yeah.

    12. AH

      ... drugs that might surprise people?

    13. DF

      Yeah, aspirin also has been shown to reduce risk of recurrence of colon cancer. Um, particularly individuals with colon cancer that have a mutation actually in the mTOR pathway. Um, but because it's aspirin and because it's sort of widely available and it's not, um, doesn't have, uh, maybe the same sort of system behind its use, it's really not actually utilized by all the patients that have colon cancer to reduce the risk of recurrence of colon cancer. And, like, that's sort of mind-blowing in itself, and there are other great examples. Um, uh, many, uh, folks have probably heard about how Viagra was repurposed from heart disease to its well-known use, most people are aware of erectile dysfunction, but most people don't realize that it's also been repurposed for a rare pediatric lung disease. Kids were dying because they weren't getting enough blood flow to their lungs, and if they take Viagra, they can actually get blood flow to their lungs and, and live full lives on Viagra. And that fortunately was discovered early on in the patent life of Viagra, so there was really a, a way to push it forward, but a lot of times these happen after drugs are generic.

    14. AH

      Isn't it, um, that the cousin of Viagra, Cialis, was-

    15. DF

      Mm-hmm.

    16. AH

      ... initially tadalafil used to encourage prostate health, circulation to the prostate, and then only later was it discovered to have these other effects related to sexual function?

    17. DF

      That's right, yeah. And, you know, we talked about the side effect of a drug, um, can be bad or can be good. Uh, we were chatting earlier, you know, the average small molecule, so a drug that's approved for a condition, can bind between 20 and 30 different proteins in the body. So we call a drug, you know, we say it does one thing, but actually-

    18. AH

      Mm-hmm.

    19. DF

      ... it's doing a lot of other things in the body, and unless that drug company began working on it early on for that condition, um, oftentimes those insights and those other roles for the medicine just fall through the cracks.

    20. AH

      So the

  4. 8:53 – 11:36

    Lidocaine & Breast Cancer; Pharmaceutical Companies & Incentives

    1. AH

      idea that a drug is useful for other things aside from what it's best known for-

    2. DF

      Yep.

    3. AH

      ... is seldom discussed, whereas side effects are being discussed more and more nowadays.

    4. DF

      Yep.

    5. AH

      Tell us about lidocaine.

    6. DF

      Sure.

    7. AH

      Uh, this is fascinating.

    8. DF

      Sure. So, um, yeah, I couldn't believe it when we came across this. So, so I run a nonprofit called Every Cure, we scan the world's knowledge of every drug and every disease to find new uses for the medicines we have, and when we came across lidocaine, we were just sort of blown away. So lidocaine, of course, the numbing medicine you get if you go to the dentist and, um, you know, uh, it's used all over the body for, um, for, uh, numbing all kinds of things. Um, there's interesting data, actually a large trial that was done in India, um, of 1,600 patients where women who had localized breast cancer, if they had lidocaine injected around the tumor before surgery, eight to 10 minutes before surgery, there was a 29% reduction in mortality at five years versus those who did not have lidocaine injected.

    9. AH

      Wow.

    10. DF

      Now, lidocaine is already gonna be used during the surgery, it's used at the site of the incision, it's widely used, you know, in so many cases, and what's so interesting, it was published in a great journal, the Journal of Clinical Oncology, yet there's still been barely any uptake all around the world. And so this is just sort of another example for us for why you've got to have an entity that's looking for these great opportunities and then actually doing the work to make sure that they get into patients, because there's close to no downside of something like lidocaine and, and if the upside's as high as a 30% reduction in mortality, I don't know how it's not being used all over the place.

    11. AH

      Is lidocaine an expensive drug?

    12. DF

      It's a very inexpensive drug. Um, it's, you know, pennies an injection. And that doesn't mean anyone's hiding lidocaine. I'm of the belief that drug companies do such important work to develop brand new drugs and they're so good at it, they do a great job getting those drugs to be used for the uses that they're intended for. And it's no one's fault, but once that drug becomes generic, like lidocaine has been generic for decades, that means that there's a number of other companies that make the exact same drug, and the profit for each of those doses becomes close to, you know, pennies an injection. And so again, it's not that anyone's hiding it, but it's just that no entity is incentivized to actually go call on doctors and say, "Hey, did you do the lidocaine before your surgery?" Or to, like, to really push to get them into guidelines. And I will say this was a really major study, this study that was published or that was done in India, it was published in a great journal. There's interesting laboratory data, but we at Every Cure actually feel responsible to better understand the potential mechanism for how it might work and also to review the evidence wholly before we actually go out and start, you know, encouraging everyone to do it. So there's, there's still steps that have to be taken, but, but our belief is that when you come across something, you know, that looks promising like this, we need to have some group that's actually pushing and pushing to make sure that it actually gets to patients once you feel comfortable with the data.

  5. 11:36 – 14:16

    Sponsors: Eight Sleep & Rorra

    1. AH

      I'd like to take a quick break and acknowledge our sponsor, Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure a great night's sleep is to make sure that the temperature of your sleeping environment is correct, and that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees, and in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep automatically regulates the temperature of your bed throughout the night according to your unique needs. Eight Sleep has just launched their latest model, the Pod 5, and the Pod 5 has several new important features. One of these new features is called Auto Pilot. Auto Pilot is an AI engine that learns your sleep patterns to adjust the temperature of your sleeping environment across different sleep stages. It also elevates your head if you're snoring, and it makes other shifts to optimize your sleep. The base on the Pod 5 also has an integrated speaker that syncs to the Eight Sleep app and can play audio to support relaxation and recovery. I've been sleeping on an Eight Sleep mattress cover for over four years now, and it has completely transformed and improved the quality of my sleep. If you'd like to try Eight Sleep, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350. Today's episode is also brought to us by RORA. RORA makes what I believe are the best water filters on the market. It's an unfortunate reality, but tap water often contains contaminants that negatively impact our health. In fact, a 2020 study by the Environmental Working Group estimated that more than 200 million Americans are exposed to PFAS chemicals, also known as forever chemicals, through drinking of tap water. These forever chemicals are linked to serious health issues such as hormone disruption, gut microbiome disruption, fertility issues, and many other health problems. The Environmental Working Group has also shown that over 122 million Americans drink tap water with high levels of chemicals known to cause cancer. It's for all these reasons that I'm thrilled to have RORA as a sponsor of this podcast. I've been using the RORA countertop system for almost a year now. RORA's filtration technology removes harmful substances, including endocrine disruptors and disinfection byproducts, while preserving beneficial minerals like magnesium and calcium. It requires no installation or plumbing. It's built from medical-grade stainless steel, and its sleek design fits beautifully on your countertop. In fact, I consider it a welcome addition to my kitchen. It looks great, and the water is delicious. If you'd like to try RORA, you can go to rora.com/huberman and get an exclusive discount. Again, that's RORA, R-O-R-R-A, .com/huberman.

  6. 14:16 – 18:40

    Pharmaceutical Companies, Patents & New Uses; Lithium

    1. AH

      There are a couple avenues that we could explore given what you've said so far, but the one I'd like to drill into a bit is this thing related to drug companies and patents.

    2. DF

      Mm-hmm.

    3. AH

      I don't want to set up the idea that, um, everything is, um, conspiratorial, and yet years ago when my laboratory was working on eye diseases, glaucoma in particular, I spent a lot of time around people working at companies that develop dr- drug treatments for eye diseases. They've developed great drugs for the treatment of, um, over vascularization of the eye-

    4. DF

      Yeah.

    5. AH

      ... for instance, that can cause blindness or it's related to some blinding diseases, and I learned that many of these drugs, um, go to market. They are, quote-unquote, "blockbuster drugs." People symptoms improve. These drug companies make a lot of money, and then the patent is headed toward expiration, and at that point, the cost of the drug drops-

    6. DF

      Yeah.

    7. AH

      ... markedly. So the drug companies are heavily incentivized, I learned, to find new uses for that drug, to renew the patent under this new application-

    8. DF

      Mm-hmm. Yep.

    9. AH

      ... to basically keep the generics away. And on the one hand, it makes sense because the, the research and development for a drug is exceedingly expensive-

    10. DF

      Yeah.

    11. AH

      ... and so if they can repurpose a drug and maintain the patent for two diseases, essentially-

    12. DF

      Yeah.

    13. AH

      ... one drug, two diseases, this is, uh, kind of the, the bread and butter of how drug companies get and remain very wealthy. It has two what I consider, um, kind of darker, uh, sides to it. One is that the generic cheaper drugs, um, don't arrive on market for a much longer period of time.

    14. DF

      Mm-hmm.

    15. AH

      The other side of the coin, however, is that, you know, uh, people suffering from a different disease now can take this drug.

    16. DF

      Yeah.

    17. AH

      But that second darker piece is that drug companies are not very incentivized to go look for new molecules to treat new, uh, conditions. They are heavily incentivized to use old molecules to treat new conditions and maintain control.

    18. DF

      Yeah.

    19. AH

      There's a lot in, in this-

    20. DF

      Yeah.

    21. AH

      ... uh, statement, but my understanding is this is how it works, and so how do you reconcile that? I mean, how is it that we should be exploring existing drugs for new conditions, but do it in a way that's really driven toward curing an disease as opposed to just kind of finding a new purpose so we can keep the generics out for a while?

    22. DF

      Yeah. It's, it's such a great question. So you're, you're absolutely right that, um, as drugs begin to, uh, reach their patent cliff, um, oftentimes the drug will be... the dose might be changed slightly, the formulation might be changed slightly to create new intellectual property so that way this sort of new version can be used in that same initial disease. Um, which to your point, there's, there's, you know, I wouldn't say pros and cons. There's, there's, there's, you know, side effects of that sort of a system, but what is pretty clear is that companies will typically not, as it's getting close to patent exclusivity, find a new disease to go after with that drug. It's usually the same disease, it's just a new formulation, um, so that way they can keep working that disease. And what that means is that though that drug might be able to u- be used for a different disease, that's rarely explored, and so especially to your point, once it's generic, I mean, all, all, all research and development discontinues, and even-Yeah, I mentioned ear- earlier that there's 4,000 FDA-approved drugs. They, they work for 4,000 diseases. That's incredible, um, but there's still 14,000 diseases that don't have a single treatment right now. And of the 4,000 drugs we have, 80% of them are already generic, which means that there is no incentive to find a new use for those medicines. So like, every time I walk past a CVS, all I think about is how many drugs are in there that are used for one condition, but could actually help so many more kids or- or adults with other conditions.

    23. AH

      I mean, we're hearing a lot these days about lithium-

    24. DF

      Mm-hmm.

    25. AH

      ... as a potential, um, protectant-

    26. DF

      Yep.

    27. AH

      ... uh, for Alzheimer's or other forms of dementia. I don't know that the data are so solid that I'm ready to-

    28. DF

      Yeah.

    29. AH

      ... run out and take lithium, so I'm not suggesting that to anybody. But I know a few psychiatrists that, uh, tell me for years they've been taking low-dose lithium for a couple months out of the year-

    30. DF

      Mm-hmm.

  7. 18:40 – 21:53

    Tools: Finding Reliable Health Sources, Asking Questions & Disease Organizations; DADA2 Treatment

    1. AH

      Where and how should the typical person, without any training in medicine or science, or even a little background in science, go to find information about existing drugs, generic or otherwise, that could help them treat their ailments, be it a skin condition-

    2. DF

      Yeah.

    3. AH

      ... or something as serious as cancer?

    4. DF

      What I'd recommend is the, the first is, is to make sure that you're connecting with whatever the disease group is for your condition. They oftentimes are so well-connected with physicians all over the world, they hear about what things are being tried. So connect with whatever your condition is, whatever that disease organization is.

    5. AH

      Disease, could you explain disease organization?

    6. DF

      Sure, so like the Castleman Disease Collaborative Network is the group that's come together to support Castleman's patients, and, and to physicians and researchers. There's a- an ALS association, for example. There's, uh, Michael J. Fox, uh, for Parkinson's disease. So find that group that, um, has coalesced around your condition, 'cause they'll oftentimes have, to your point, understanding about, "Hey, I heard this one patient's using this one thing." So I'd go t- I'd go there first. The second is I would figure out where is the world's expert. Who is that person that really is, is the guru? They'll oftentimes have insights on these things. And then the third i- is to, is to really keep asking questions. So like even when they say, "This is the first thing that's recommended," well, is there something else that's, like, used somewhere else? And, and I'll share one example of this. Um, it's, it's, it's a bit heartbreaking, but also, um, really powerful and informative, and that's that there's a, a rare condition called DADA2. Um, basically kids are born with a, a mutation in a gene that results in them having dozens and dozens of strokes from the time they're born until they usually pass away in their teenage years because of the accumulated effect of literally dozens of strokes. It's horrible. Well, about 20 years ago, a doctor apparently was treating a patient with DADA2 and also treating a patient with a, a form of vasculitis, and, and, and treated that patient with vasculitis with what's called a TNF inhibitor. It inhibits this one cytokine called TNF. And he apparently had left TNF inhibitor in his vial, and he was like, "You know what? We've got this kid over here having all these strokes. Why don't I just try what I've got in this vial in this kid?" Well, the kid stopped having strokes, and that was amazing. And so this doctor, the next few patients he had with DADA2, he treated them for their strokes. But about 10 years went by. Meanwhile, hundreds and thousands of kids around the world are dying from DADA2, where the word wasn't being spread until this amazing doctor named Chip Chambers, um, sadly had two children born with DADA2, and he started looking around to figure out and learned about, oh my gosh, TNF inhibitors. Um, I was, um, honored to be able to help Chip and his team to basically bring data together on the effectiveness of TNF inhibitors, also even come up with treatment guidelines for how do you treat DADA2. And it turns out that if you start kids on a TNF inhibitor, they stop having strokes. All over the world, literally it's a life-changer. And so, the reason I share this as an example is that the world knew, someone in the world knew, that you could save kids' lives with a TNF inhibitor, but the world didn't know, and we hadn't gotten the word out about it. And, and to me, like, that's such ... It's so heartbreaking. It's almost like a travesty, you know? It's one thing if you have a horrible disease, um, and, and everyone dies from it, and there's nothing out there, but I think it's so much more heartbreaking when you think that, oh my gosh, there was something there. We just, we as a system hadn't done the work to make sure people get the medicine.

  8. 21:53 – 24:36

    Medical Community & Connections; Integrated Medical Databases

    1. DF

    2. AH

      Yeah, I think it's a, a harsh reality that one's knowledge network really has a big impact on outcomes to disease.

    3. DF

      Yeah.

    4. AH

      I mean, I sit surrounded by MDs and PhDs and people working on disease and treating disease, and I'll tell you, uh, there's no question in my mind that because I've experienced it when a friend's spouse or-

    5. DF

      Yeah.

    6. AH

      ... kid is dealing with something, I, I'm just one example of somebody who knows who to call-

    7. DF

      Yeah.

    8. AH

      ... because I don't know the answer, but I know-

    9. DF

      Yes.

    10. AH

      ... who might know the answer.

    11. DF

      Exactly.

    12. AH

      And within two or three calls, that person is in touch with somebody who is, uh, is in communication with the five or six people who are best at this around the world. But most people don't have access to that.

    13. DF

      Exactly. Yeah.

    14. AH

      I mean, it's one of the reasons I started this podcast, frankly-

    15. DF

      Yeah.

    16. AH

      ... uh, to get people like you on here, people like Eddie Chang, who's a lifetime friend and chair of neurosurgery at UCSF. Like, I always say, "May you never need his help."

    17. DF

      Yes.

    18. AH

      Right? You know, but these are the people that I call when friends have questions about things unrelated to neurosurgery-

    19. DF

      Yeah.

    20. AH

      ... for instance. So, it seems to me there- there's a pretty straightforward solution, that in addition to these, these groups, um, that are centered around certain diseases, there should be databases. There should be ways that people can not just go online and, and ask a question-

    21. DF

      Yep.

    22. AH

      ... but go to a database-

    23. DF

      Yep.

    24. AH

      ... and say, uh, "You know, I was just diagnosed with," or, "I'm having symptoms that are the following, and what are the existing prescription and non-prescription meds known to treat this? What are the side effects? But also, what are the potential pathways that overlap-

    25. DF

      Yeah.

    26. AH

      ... with other approved drugs that are prescription or over-the-counter?" And then it should feed into a pipeline of how to get ahold of the people that could help treat that. It should be-

    27. DF

      Yeah.

    28. AH

      ... that straightforward.

    29. DF

      Yeah.

    30. AH

      I mean, this is 2025.

  9. 24:36 – 28:45

    Drug Repurposing, Thalidomide, Pembrolizumab

    1. AH

      help but ask, uh, of some other examples of drugs that have been shown to treat things other than what most people associate that drug with.

    2. DF

      Sure. Uh, a few come to mind. So the, the first one's thalidomide. You probably have heard about the horrible birth defects that thalidomide caused, uh, 50-plus years ago. Uh-

    3. AH

      Originally designed as a misc- anti-miscarriage drug.

    4. DF

      Well, it was originally designed as anti-nausea for, um, for pregnant women.

    5. AH

      Okay.

    6. DF

      Um, so the thought was that it could help them with their nausea-

    7. AH

      I see.

    8. DF

      ... but it ended up causing horrible birth defects.

    9. AH

      I see.

    10. DF

      Um, children were born without limbs, and so it was taken off the market. But then about 20 years later, researchers figured out that it could be effective for leprosy, so it's FDA-approved for leprosy, and then what's crazy is that shortly thereafter, it got FDA approval for multiple myeloma, a rare, or somewhat rare, um, hematologic blood cancer. And the reason that it can work for leprosy and multiple myeloma and also the reason that it causes birth defects is it has, um, a major anti-angiogenic effect, so it, it reduces blood vessel growth. So in the same way that you need blood vessel growth to grow limbs, um, you also need blood vessels, uh, or you need, uh, uh, over, uh, uh, production or, or increased blood flow for multiple myeloma cells to survive, um, and, and also in leprosy. And so the same compound that causes birth defects, helps treat leprosy also treats multiple myeloma. It's, it saved thousands and thousands of lives of multiple myeloma patients. Again, the reason that that in particular has been utilized, um, in, in multiple ways was that it had a full patent life when the work was first begun for leprosy and then myeloma was discovered shortly thereafter. But, you know, if a drug like thalidomide was, you know, it was discovered for leprosy and then 20 years later, someone figured out it could be useful for multiple myeloma, patent is gone. Um, and so there wouldn't have been an incentive to then figure out that, oh, thalidomide could also be useful for multiple myeloma. Um, the, the, the list sort of sadly, um, goes on and on. I mean, one of my, my favorite examples is a drug called pembrolizumab that is now used for dozens of cancers, but initially it was, uh, first developed for melanoma and for lung cancer, and actually, um, the, the work that we did in my lab, um, I guess this is 2016, um, and it was actually simple work. I, I, I... Uh, a patient came to us in 2016 with metastatic angiosarcoma, which is a horrible form of cancer, and, um, his doctors told him that he was out of options, and we did something really simple. We went on PubMed and looked for, like, "angiosarcoma treatment." I mean, it was that, that simple. And we came across a paper from 2013 where, um, uh, a researcher had looked at five tumors from five different patients with angiosarcoma, and four out of the five tumors had increased expression of PD-L1, which is a marker that you might respond to a PD-1 inhibitor. And so even though the paper was published in 2013 and, and this gentleman came to us in 2016 and, of course, hundreds of people had died in the previous three years, no one had ever actually tested whether a PD-1 inhibitor could be used over angiosarcoma, even though, again, it was just, it was a laboratory study published three years earlier, but no one had ever translated that insight into using it in patients. So we treated Michael as the first patient ever that we're aware of with a PD-1 inhibitor, and he responded so incredibly well. Uh, a couple things happened. One is that his doctor started prescribing it to all patients with angiosarcoma. It turns out it works in about 18% of patients. So, it was a uniformly fatal cancer within one year. Now about 20% of people will live beyond a year, and it can be really transformative. So it changed clinical practice for, um, for angiosarcoma. The other thing it did specifically for, um, for Michael is that it has put him into now a nine-year remission. Just last month, he walked his daughter down the aisle on her wedding day in Nashville, Tennessee, nine years after he was told that this is it. And so these drugs are out there, um, and sometimes there's even breadcrumbs. Like, it didn't require any brilliance from my lab. We, we literally just had to find a study that was published three years earlier, and that, again, is really what drives us with, with this, with this work now to say, "Can we find all these breadcrumbs? Can we put them together? And can we make sure people actually benefit from all the great science that's being done all over the world? Let's actually translate them into patients."

    11. AH

      Yeah, it seems to me

  10. 28:45 – 33:51

    Medical Research Databases, Mapping Disease Connections

    1. AH

      that PubMed and other sources of, of science knowledge, um, are great for stacking papers-

    2. DF

      Mm-hmm.

    3. AH

      ... and, and they're pretty decent in terms of how they're organized, you know, by keyword search. I mean, they're not perfect, but you can find stuff-

    4. DF

      Yeah.

    5. AH

      ... and you get suggestions about related articles, and, and somebody with a little bit of time and energy will, will get some degree of information there. But it seems to me that no one has really organized the, the enormous database of information about science as it relates to disease. It, it occurred to me a, a moment ago, there should be a database where one can enter whatever knowledge they have about how old their grandparents were when they died-

    6. DF

      Mm-hmm.

    7. AH

      ... and of what, how old their parents are or were, maybe they're alive, maybe they're deceased. Any knowledge-

    8. DF

      Yeah.

    9. AH

      ... any, any kind of family history. This is the first thing-

    10. DF

      Yeah.

    11. AH

      ... a doctor would ask you.

    12. DF

      Yeah, yeah, exactly, yeah.

    13. AH

      If I come in and you're the MD-

    14. DF

      Yeah.

    15. AH

      ... and if I say, "Hey, listen, you know, I've got this swollen lymph node on the left-hand side," I don't, I don't think you're gonna say, "Hey, like, go get it scanned." You'll say, "Any history of blank and blank-"

    16. DF

      Yes, exactly.

    17. AH

      "... in your family?" First thing-

    18. DF

      Yep.

    19. AH

      ... right?

    20. DF

      Yep.

    21. AH

      One should be able to do this from home and then-... enter any symptom profiles they might be having, and with the appropriate cautionary notes, g- get some ideas back about what might be going on.

    22. DF

      Yep.

    23. AH

      Now, that might sound like, oh, this is people playing their own doctor, but I'll tell you right now, if I put in, uh, left armpit lymph node pain-

    24. DF

      Yeah.

    25. AH

      ... uh, or swelling into any online search engine, it's gonna tell me some of the worst possible outcomes.

    26. DF

      Yes. Yes. Totally.

    27. AH

      So it's not like we need to shield people from potential outcomes. But it seems to me that this should be pushed through an AI read of PubMed, which already exists, right?

    28. DF

      Mm-hmm.

    29. AH

      Th- th- most of the large language models are trained on the entire internet, including PubMed.

    30. DF

      Yup.

  11. 33:51 – 37:57

    Every Cure Database & Programs, Bachmann-Bupp Syndrome; Colchicine & Heart Disease

    1. DF

      what we're trying to do with, with EveryCure and with our work is trying to start this conversation and keep the conversation going, so that way, you can go to your doctor with, you know, with X drug, um... You know, um, I mentioned that we have nine active programs, so on the one end of the spectrum, really common is, is our program with lidocaine and breast cancer, where we're doing laboratory work. We're also evaluating clinical data, and I hope at some point in the future that the data's strong enough. And if it is, then we'll, we'll, we'll work to, to encourage every woman who's about to go in for breast cancer surgery to talk to their surgeon beforehand and say, "Hey, I wanna make sure you do this," and so really empowering them in that way. But all the way through even to the rarest of conditions, there's a condition called Bachmann-Bup syndrome where kids are born with a mutation that cause them to have elevated levels of an enzyme called OCE1. And basically, they're, uh, on feeding tubes, they are, uh, wheelchair b- or bed-bound, um, unless you give them a drug that was made for African sleeping sickness, which is a perfect covalent binder to OCE1. So that enzyme that's too high in these kids, African sleeping sickness medicine actually binds to OCE1. And if you start it early enough in life, these kids get their feeding tube taken out. They might be able to sit up. They can even play with their siblings. And so the reason I mention this is that there aren't that many people with Bachmann-Bup. In fact, it's only been described in, in 20 kids, which means there's probably hundreds of kids, um, because the medical, uh, literature's typically behind reality. But let's say there's hundreds of kids, at some point, we're gonna need to get the word out, so that way, you know, we can find every kid possible, you know, with Bachmann-Bup so they can get this, this medication, DFMO. And so, um, that, these are microcosms of what you're talking about, which is that, like, no one should suffer from Bachmann-Bup without being on DFMO. No one should have breast cancer without having had lidocaine. No one should be a healthy 50-year-old man who might be able to have their risk of heart attack reduced. It might be that colchicine, um, is, is helpful for, um, for reducing your risk of heart disease. But to your point, how can we get this more proactively so we're not just sort of like hoping and waiting that, that all these random things line up?

    2. AH

      We used to use colchicine in the lab.

    3. DF

      So colchicine's an interesting one. So, um, colchicine, uh, is typically utilized for gout. Um, it's this, it's been f- around forever. Actually, I learned that it's, like, 3,000 years ago was when it started being used, um, because, uh, gout often occurs in individuals who consume too much alcohol. And so, like, apparently-... in, like, Egypt 3,000 years ago, some of the, um, wealthy people were drinking too much alcohol and somehow they figured out that this molecule, uh, colchicine, of course, I think it was a, a root at the time, could be helpful for reducing gout. Um, and, uh, we should fact check that, that statement 'cause I need, I don't know the exact details, but it's been around a long time.

    4. AH

      If there were a database, you could just go to the-

    5. DF

      That's right. (laughs)

    6. AH

      ... database. You can tell-

    7. DF

      We immediately-

    8. AH

      You can tell where my mind is going.

    9. DF

      Yeah, exactly.

    10. AH

      Yeah.

    11. DF

      So, so colchicine's been around forever. It's been used for gout for many, for decades. Um, people who have gouty arthritis, they get these painful joints. If you give them colchicine, it helps them out. Well, a researcher a couple of decades ago, um, had a hypothesis that because of its antiinflammatory properties, um, and, and a few other properties of colchicine, that it might be able to reduce the risk of heart attacks in people who have already had a heart attack or, or maybe in general, but in particular, in people who have already had a heart attack. And, um, because it's been around forever, they couldn't, um, they really couldn't raise the funding needed to do all the trials to prove it 'cause cl- um, heart disease prevention trials are big, expensive trials. You gotta follow people for years to prove that they didn't get a heart attack versus people who did, who got a placebo. So they ended up changing the dose o- of that medicine, of colchicine. So it's a slightly different dose from the one they use for gouty arthritis, but it has a very substantial reduction in heart disease risk if you had a prior heart attack and, in particular, if you had a prior heart attack and you have diabetes. A really, really meaningful reduction. So it got FDA approval for, for that particular subpopulation. But I mention it because if they hadn't changed the dose, it would've been a paper that some academic would've published that I think colchicine could help, and no one would have ever done the big trial. And again, that's sort of the tragedy here is that people are literally not having heart attacks right now 'cause they're on colchicine. But if not for someone figuring out a way to make the system work, you know, they would've had their heart attack.

    12. AH

      We've

  12. 37:57 – 40:41

    Sponsors: AGZ by AG1 & David

    1. AH

      known for a long time that there are things we can do to improve our sleep, and that includes things that we can take, things like magnesium threonate, theanine, chamomile extract, and glycine, along with lesser-known things like saffron and valerian root. These are all clinically supported ingredients that can help you fall asleep, stay asleep, and wake up feeling more refreshed. I'm excited to share that our longtime sponsor, AG1, just created a new product called AGZ, a nightly drink designed to help you get better sleep and have you wake up feeling super refreshed. Over the past few years, I've worked with the team at AG1 to help create this new AGZ formula. It has the best sleep-supporting compounds in exactly the right ratios in one easy-to-drink mix. This removes all the complexity of trying to forage the vast landscape of supplements focused on sleep and figuring out the right dosages and which ones to take for you. AGZ is, to my knowledge, the most comprehensive sleep supplement on the market. I take it 30 to 60 minutes before sleep. It's delicious, by the way, and it dramatically increases both the quality and the depth of my sleep. I know that both from my subjective experience of my sleep and because I track my sleep. I'm excited for everyone to try this new AGZ formulation and to enjoy the benefits of better sleep. AGZ is available in chocolate, chocolate mint, and mixed berry flavors. And as I mentioned before, they're all extremely delicious. My favorite of the three has to be, I think, chocolate mint, but I really like them all. If you would like to try AGZ, go to drinkagz.com/huberman to get a special offer. Again, that's drinkagz.com/huberman. Today's episode is also brought to us by David. David makes a protein bar unlike any other. It has 28 grams of protein, only 150 calories, and zero grams of sugar. That's right, 28 grams of protein, and 75% of its calories come from protein. That's 50% higher than the next closest protein bar. These bars from David also taste amazing. Right now, my favorite flavor is the new cinnamon roll flavor, but I also like the chocolate chip cookie dough flavor, and I also like the salted peanut butter flavor. Basically, I like all the flavors. They're all delicious. Also, big news, David bars are now back in stock. They were sold out for several months because they are that popular, but they are now back in stock. By eating a David bar, I'm able to get 28 grams of protein in the calories of a snack, which makes it very easy for me to meet my protein goals of one gram of protein per pound of body weight per day and to do so without eating excess calories. I generally eat a David bar most afternoons, and I always keep them with me when I'm away from home or traveling because they're incredibly convenient to get enough protein. As I mentioned, they're incredibly delicious, and given that 28 grams of protein, they're pretty filling for just 150 calories. So they're great between meals as well. If you'd like to try David, you can go to davidprotein.com/huberman. Again, that's davidprotein.com/huberman.

  13. 40:41 – 49:10

    David’s Medical & Career Journey, Glioblastoma, Castleman Disease

    1. AH

      Well, I feel like we could spend hours going through the catalog of drugs for which, uh, these examples exist. Um, and we may return to a few more. But, um, putting in a strong vote for this database. I know you're working hard on this. I'd like to talk about your journey into this because you are not a typical doctor. Um, I think that's apparent to people already. Uh, you care very much about human health and treating human disease. Uh, but you have a very unusual and interesting trajectory into medicine, and I do believe it's helped lead you to this, uh, very unique orientation within the field of medicine and science. So tell us that story, and, uh, teach us about Castleman's Disease.

    2. DF

      Sure. Um, well, my story, um, I think really starts back when I was 18 years old and, um, I was a, a freshman at Georgetown. Um, we, we were talking earlier about I, I played football at Georgetown, and that, for me growing up, that was my dream, to be a Division I college quarterback. That's all I could think about. I, I was not quite as jacked as you, but somewhere, somewhere in that realm.

    3. AH

      I saw a photo. You were larger than I was.

    4. DF

      Um-

    5. AH

      Yeah, we'll put up a, a link to a photo. I-

    6. DF

      (laughs)

    7. AH

      David was 230.

    8. DF

      Yeah.

    9. AH

      You're taller than I am.

    10. DF

      Yeah.

    11. AH

      I'm 6'1", so you're probably about 6'3"-

    12. DF

      Like 6'2". Yeah, something like that.

    13. AH

      ... 6'2" ... I think you might be 6'3". Either that or I'm shrinking.

    14. DF

      (laughs)

    15. AH

      Um, and, uh, super large, fit, low body fat.

    16. DF

      Yeah.

    17. AH

      I mean, you, you, you look, um, y- y- clearly you were a quarterback-

    18. DF

      Yeah.

    19. AH

      ... but you were large even for a quarterback.

    20. DF

      I was, yeah.

    21. AH

      Yeah. Okay.

    22. DF

      So, you know, that was my dream. It was, you know, I wanted to play college football, and I got there, and I was, had been on campus at Georgetown for a couple weeks, and, um-I got a call that changed my life. My dad called and, and told me that my mom had brain cancer. And, uh, Andrew, I went from, like, all I could think about was football and, like, you know, I'm finally at this, you know, goal that I'd always set to, oh my gosh, this has just, just changed everything. My, my mom, uh, my mom and I were so close and, um, I was heartbroken for her. Uh, glioblastoma brain tumors are, uh, uniformly fatal. They're horrible. Um, uh, you know, I was only 18, so I don't think I, I knew just how bad it was, but I knew it was really bad. And, um, watching her battle with cancer over the next 15 months, um, just changed everything in me. Um, it, it, it completely locked me in and I, I told her just before she passed away that I would dedicate my life to trying to find treatments for patients like her. And, um, she, she couldn't say many words, um, at the, at the end, but she said unconditional love, those were the two words that she said when I told her I would do that. And I was like, "All right, I gotta do this." You know? (laughs) She, she, um, you know, she wants me to do it. And for me, I, I sort of haven't been able to stop thinking about helping people like her from the moment that I started seeing this, um, horrible cancer, um, uh, you know, take her life in front of me. And, um, and of course the promise that I made to her. I also learned so much from her in watching her, her battle a- against brain cancer. I mean, I'll, I'll just tell one, one quick story. Um, so I got that call from my dad, I immediately came home to North Carolina, and, uh, within a few days she was, um, having brain surgery to get the tumor, um, resected. And they did a surgery where, um, they put you to sleep to open up your skull and then they actually wake you up while your skull's open. And, um, the reason for that, which you're very familiar with, is that as they're cutting out particularly on the left side of the brain, cutting out parts of the brain tumor, you wanna be able to see where, how far you wanna go. Um, you ask people to speak and sort of when they start slowing their speech, you stop cutting. And so they went through this whole surgery, it was like a four-and-a-half-hour surgery, cut out most of the tumor but not everything. And, um, they, you know, uh, uh, woke her back up after, after the surgery and, um, she was in the waiting area and we went back to see her. And I remember, um, my dad ... I've got two amazing older sisters, my dad and I, we, um, went back to see her and we were, you know, so nervous, like, is it gonna be our mom who's gonna come out? They took out a lot of her brain, um, as part of this surgery. And, um, so nervous and we walked back, Andrew, and pulled the curtain back and I'll never forget, I saw my mom sitting there just about as far away as you are, and she had a wrap around her head, um, bandages and she had this bulb coming out, um, that was collecting fluid. And she looked at her, at her, uh, she looked at us and she pointed it up to her head and she said, "Chiquita banana lady." (laughs) And we just burst into laughter. She was saying she looked like the Chiquita banana lady. And like, that for me was this incredible moment of just, like, taking agency back from this, like, horrible cancer. Like, you just went through surgery, but, like, you're gonna find something to laugh about and something to get your family to laugh at and to show that, like, you're still there. Um, and so that was sort of the, the, the first of many lessons that I learned from my mom, obviously in her health, but also in her illness. And so that set me on this journey which is, okay, I'm going to dedicate my life to trying to find treatments for patients like my mom, I'm gonna try to live, um, in, in, in the way that she did. And, um, I was sort of well on my way, I, um, finished medical ... or sorry, finished undergrad at Georgetown. I did a, a graduate degree at Oxford and then I was a couple years into med school at Penn, um, when, uh, you mentioned Castleman disease, when I went from being totally healthy, I shared earlier I'd won a bench pressing contest right around that time I was so healthy, to, uh, being in the ICU with all my organs shutting down.

    23. AH

      The story about your mom is a remarkable one. Uh, my first thought when, uh, you mentioned the Chiquita banana lady reference is that, uh, even though she was the patient, it seemed like she was, uh, successfully taking care of all of you.

    24. DF

      She was tr- she was trying to take care of us.

    25. AH

      Yeah. I know very little about her, only what you've shared, but she sounds like a very impressive woman.

    26. DF

      She was amazing. I so appreciate you saying that.

    27. AH

      Yeah. Um, that comes through. So Castleman, I've never heard of it. Who's Castleman in, uh, these physicians like to name-

    28. DF

      (laughs) .

    29. AH

      ... diseases after themselves. Um, but my guess is that they're not the ones with the diseases, they're the ones that discover the diseases, correct?

    30. DF

      That's right. Yep. So Benjamin Castleman was a doctor in, um, Boston, uh, at Harvard. He'd been getting these cases of patients that were thought to have lymphoma and they, they appeared like they had lymphoma, getting very, very sick very quickly. Um, but when he looked under the microscope at them, they didn't look like a typical lymphoma patient. And so, um, maybe as I, as I share, you know, sort of what my progression looked like, I mean, I was third year med student, I had just, um, finished, uh, an OB-GYN rotation, I had just delivered babies into the world, which is sort of a peak, uh, moment in medical school. And then within a couple weeks, I noticed that I had, uh, enlarged lymph nodes in my neck. Um, I felt more tired than I'd ever felt. Um, and you're tired in med school and grad school, you know well, but I was more tired than ever. I had horrible abdominal pain, and I noticed fluid pooling around my ankles and I thought, "This is so weird. What's going on?" Um, but the fatigue got worse and worse and worse. Um, and over the course of, it really was just a couple weeks, um, I got so bad that I went, I took a med school exam, then I went down the hall to the emergency department and I basically stumbled down to the ER and, and just told them my symptoms and they ran blood work. And, um, I remember my, my doctor coming back and, um, and looking at me and saying, "David, your liver, your kidneys and your bone marrow are all shutting down. We have to hospitalize you right away." And I'm like, "What do you mean?" Like, I was just, like, I delivered a baby a couple weeks ago. Like, how, wh- what, all my organs are shutting down? And so they hospitalized me and I, and I deteriorated really rapidly. I had a retinal hemorrhage that made me temporarily blind in my left eye. I gained a total of about 100 pounds of fluid because my liver and my kidneys stopped working. You saw that picture where I had just fluid everywhere, um, 'cause of the, the multiorgan failure. And, um, I needed daily transfusions of red blood cells and platelets just to keep me alive. I was on dialysis at the time as well. So basically everything was shutting down and we had no diagnosis. So we didn't know what it was. My doc- some doctors thought it was lymphoma, others thought maybe it was an autoimmune disease, others had no idea what it was. Um, but over the course of about 11 weeks, I got worse and worse and worse. And at one point, I was so sick that, um, I said goodbye to my, my dad and my sisters and my girlfriend at the time, Caitlin. And, um, a priest came in my room and read me my last rites. ... when I was 25 years old. Fortunately, right around the time, um, of having my last rites read to me, which was really the end, I mean, I didn't, didn't have more than a couple days left, that's when the diagnosis came in of Castleman disease. Um, so basically, a pathologist looked at my lymph node and they, they thought I had lymphoma. They figured it was a really aggressive lymphoma, which is a form of cancer. Um, but they looked at it, and just like Benjamin Castleman did, looked at it and said, "This doesn't look like lymphoma. This actually looks different. It looks like this thing called Castleman disease," um, which is basically, um, what we call an atypical lymphoproliferative disorder. So it's kinda like lymphoma, um, but it's got features that are more like an autoimmune disease. And so basically, your immune system becomes highly activated and starts attacking all your vital organs. So the reason that all my organs were shutting down is 'cause my immune system was producing cytokines and other factors that were, were basically, um, shutting it down.

  14. 49:10 – 52:52

    Autoimmune Disease, Driven Personality, Stress & Immune System

    1. DF

    2. AH

      Do you think that the, um, long hours of medical school plus being athletic, ver- very driven contributed to the autoimmune flare-up? I mean, we don't often discuss this, but anyone that's dealt with an autoimmune issue, even if it's, like, psoriasis or something, um, which can be very severe, but in most cases-

    3. DF

      Yep.

    4. AH

      ... it's kinda minor to, you know-

    5. DF

      Yep.

    6. AH

      ... there are over-the-counter things you can use, I think. But, um, it's associated with people who are pushing very, very hard and-

    7. DF

      Yeah.

    8. AH

      ... and, uh, tend to pull long hours. And, and as a consequence, the immune system understandably ramps up its activity and then goes past a tipping point where it starts attacking one's native tissue.

    9. DF

      Yeah. It's, it's funny. No one, no one ever asked that, but it's the right question to ask, and I think people are always sort of afraid to, you know, get into, like, the whys of these things happening to you. I'm glad you asked because actually, there was a paper that was published a couple years ago, um, I think it was in Cell, where mice that were sleep-deprived, like significantly, like multi-day sleep-deprived, what actually killed them was a cytokine storm due to their immune system pro- re- producing all these cytokines. Like they actually... So like, 'cause we know that sleep deprivation is deadly, right? You don't sleep enough, you know this very well. But again, in these mouse studies, this, the actual thing that killed them was their immune system producing cytokines, including interleukin-6, which is an important cytokine in Castleman's. Um, and by just trying a couple medicines that basically block the production of some cytokines, you could keep the mice alive longer, really pointing to this idea that it's sleep causing some disruption in immune balance, causing excess production of cytokines, causing death. And, and so, um, I, I don't know if you, had you, had you seen that? I can share the paper with you. It's, it's, it's pretty fascinating.

    10. AH

      I'm not familiar with that one.

    11. DF

      Yeah.

    12. AH

      I just-

    13. DF

      But it connects to your point, right?

    14. AH

      Yeah, I mean, coro- I mean, again, this is all anecdotal coming from-

    15. DF

      Yeah.

    16. AH

      ... my side, uh, anyway, is that, you know, but growing up in, in Silicon Valley-

    17. DF

      Mm-hmm.

    18. AH

      ... I've known a lot of people who've cancers and who-

    19. DF

      Yeah.

    20. AH

      ... seem to be dealing with autoimmune things, and I know a lot of very ambitious, hard-driving people. It's baked into the culture I grew up-

    21. DF

      Yep, yep.

    22. AH

      ... in, you know? And, um, and sometimes I've just wondered about these naturalistic observations, again, these are not controlled studies, where some of the most, um, hardworking, uh, long-hour, athletic, academic, hybrid founder people are the ones that oftentimes are dealing with severe health issues.

    23. DF

      Yeah.

    24. AH

      And, you know, like, "How could that be?" Well, maybe there's a relationship. And the more I learn about the kind of general backdrop of supporting health, sleep being fundamental-

    25. DF

      Yeah.

    26. AH

      ... and all the rest, and, you know, natural light exposure, but not too much UV, and, you know-

    27. DF

      Yeah.

    28. AH

      ... this kinda thing, you gotta kinda wonder. You, you... I'm not saying people shouldn't work hard. I, I, otherwise I'm headed for a quick-

    29. DF

      (laughs) Yeah, exactly.

    30. AH

      ... for a quick death-

  15. 52:52 – 55:54

    Castleman Disease, Treatment, Chemotherapy

    1. AH

      so you get this diagnosis.

    2. DF

      Yeah.

    3. AH

      Thank goodness they figured out it wasn't lymphoma and it was Castleman's, 'cause that at least gave you a kind of a thin end of the wedge to start exploring various treatments. At the time, was there any treatment for Castleman's disease, known treatment?

    4. DF

      At the time, there were no approved treatments, um, but sort of as we were talking about earlier about, like, sort of information asymmetry, um, there was a drug that was, um, uh, originally developed in Japan, uh, for Castleman's. Um, but my doctors didn't know to try it. They gave a form of chemotherapy to me, um, which fortunately chemo sort of saved my life just in time. But there was this drug in Japan that, like, has pretty strong data that it works for Castleman's, but that just, like, information hadn't, and the drug is available in the US for another condition. That information exchange just hadn't happened. And actually, I'll, I'll share a quick story about that drug. It's called tocilizumab, and, um, it was made by a doctor named Kazu Yoshizaki, or discovered by a doctor named Kazu Yoshizaki. And, um, uh, I had heard from a colleague that Kazu had given it to himself before it was given to any other humans to prove that it was safe. And, um-

    5. AH

      Old school medicine.

    6. DF

      Right? This is the '90s, and, and monoclonal antibodies were a new technology, and so apparently he was afraid to give it to patients 'cause he didn't know what it was gonna do, so he was like, "I'll give it to myself." So I heard that, and I said, "Kazu, I heard you gave your- yourself tocilizumab." He said, "No, no, I didn't give it to myself. The nurse, the nurse gave it to me." (laughs)

    7. AH

      Ah. (laughs)

    8. DF

      I was like, "All right, all right, Kazu." Yeah.

    9. AH

      I love the specificity.

    10. DF

      Exactly. Um, and so he gave it to himself, and he didn't die when he got it, um, but you know, it was safe enough for him. So he studied it in Castleman's patients, it got approval for Castleman's in Japan, um, and then it got repurposed for rheumatoid arthritis here in the US and a number of other autoimmune diseases. So it's approved in the US for autoimmune diseases. Um, but like I said-... it was made for Castleman's in Japan, approved and available, but my doctors didn't even think to try it. Um, chemo saved my life, um, but then I relapsed a few weeks later. We tried that drug from, from Kaza, from Japan, it didn't work for me. It on- it works in about a third of patients. And so, um, I ended up needing a combination of seven different chemotherapies, Adriamycin, Cytoxan, Etoposide, Velcade, Xylitol, Rituxan, like the worst chemos out there, um, was what I ended up needing to get my disease into- into remission. And- and just to give you a sense for how sick I was, this is now the third time that I almost died in a six-month period. I was so sick that once they started giving me that combo of seven chemos, I started feeling better with every dose. And these are, like, the worst chemos in the world, but because they were killing my immune system, which was producing cytokines, which was killing me, I actually felt better on chemotherapy. And- and eventually, um, I got well enough to where I could be discharged from the hospital, and- and there's that picture I showed you from the book, which is me a couple weeks after I got out of the hospital, um, and I was just so thankful to be alive.

    11. AH

      Yeah, we'll post a link to that photo as well, and to your book, uh, of course. Um, yeah, that photo, uh, if you show that photo to the typical person, they're- they're not gonna say that's a healthy looking person. But you said you were so grateful to be alive-

    12. DF

      So grateful.

    13. AH

      ... because relative to where you were before-

    14. DF

      Exactly.

    15. AH

      ... I mean, 100 pounds of fluid-

    16. DF

      It's crazy.

    17. AH

      ... accumulating in your legs and body prior to that.

  16. 55:54 – 1:03:32

    Physician Continuing Education, Santa Claus Theory of Civilization; Science Collaboration

    1. AH

      You were in a very unique position because you have this, um, inquisitive mind, it's very clear you were motivated not just from your illness, but motivated generally based on-

    2. DF

      Yep.

    3. AH

      ... the- the- the story about your mom. Um, and people would listen to you, is my guess.

    4. DF

      Mm-hmm.

    5. AH

      They would at least listen to your questions. That's-

    6. DF

      Yeah.

    7. AH

      I'm- I'm reading into this-

    8. DF

      Yeah.

    9. AH

      ... a bit. But I think many patients don't know what questions to ask.

    10. DF

      Yep.

    11. AH

      They don't know whether the person they're asking has access to the best answers or even the answers. Um, I- I like to think most doctors are benevolent.

    12. DF

      Yep.

    13. AH

      So let's just assume that.

    14. DF

      Mm-hmm.

    15. AH

      But they're also busy and, um, they get as confused as anybody. Uh, I'm not trying to knock on medicine here-

    16. DF

      Mm-hmm.

    17. AH

      ... but this is just the reality. So simple question, when a physician finishes their, uh, their training all- all the way through residency and they- and they start practicing, let's say an oncologist or-

    18. DF

      Yeah.

    19. AH

      ... a general practitioner in the United States, but perhaps elsewhere, is the typical physician accessing the literature often? I know they're required to do some continuing medical education, but it could be the case that their education around a disease is just locked in at-

    20. DF

      Yep.

    21. AH

      ... the time they phys- finish their residency, plus any major updates that come-

    22. DF

      Yep.

    23. AH

      ... through. How does this work? Because I wanna know when my physician finished training, and I wanna know how often they read papers, and I wanna know who else is on their, uh, committee of- of- of people that they share ideas with.

    24. DF

      Yeah.

    25. AH

      I want the most connected physician in the world to be treating me.

    26. DF

      Yeah, and- and- and I do too, and I think that the problem is, is that given all of the constraints and requirements of a typical physician, they just don't really have that much time to do all of the things that- that we want them to be doing. So, um, you're right, physicians are reading the literature, but typically it's because they have a patient with something that maybe led them to it or maybe, um, someone sent that paper to them, it's- it's very random and sort of piecemeal, you know, no doctor can- can look at millions of papers, for example, and- and they can't even look at the hundreds that they, maybe would be relevant for the diseases that they treat. And so they get sort of some watered-down summaries, they go to a conference and they hear sort of what's being told, but it's very piecemeal. And I think the big takeaway from- from this whole conversation is that so much of this is piecemeal and it's not systematic and it is random and it's did your doctor happen to come across this one paper? Um, as opposed to the world that we should be in, which is where, um, where it shouldn't matter what doctor you go to see 'cause the data's the data. I mean, this whole idea of, like, you know, we talked about getting second opinions from doctors, it's like for some reason we call it a second opinion, yet we believe that what's being told is, like, exactly what should be done. And it's like, well, it's an opinion, right? And- and oftentimes second opinions, you know, um, aren't consistent with the first opinion because they're opinions. I mean, they're educated, they're driven in science and driven in, um, or oftentimes grounded in evidence, um, but it's still y- y- you just don't know if- if your doctor's gonna have the information that's needed for you. Which is sort of scary, right? Like, we- we sort of, we- we- we wanna go to our doctor and believe that, like, we c- like, you know, full trust, like, you- you know, you've got all the answers, and actually I sort of have this concept that I- I- I talk about in my book, which, um, maybe even resonate with, you know, what we're talking about now, I called it the Santa Claus theory of civilization, which is before I got sick with Castleman's and when I was a medical student, I had this sort of idea that there were, like, rooms of scientists and doctors collaborating, working together to come up with solutions, kinda like Santa's, you know, workshop and all the elves are working together, and as soon as they, as soon as humanly possible that a drug could be discovered, it's at your doorstep. Like, as soon as they can figure out... But then I've- I've sort of realized that actually, like, there isn't a- a, you know, there aren't workshops, there aren't groups of- of scientists and doctors, you know, sitting together to figure out solutions, um, and if they are, it's just not necessarily at the pace that you had hoped that it would be at. And so I think that that's just, you know, one of the- the many things that's been a bit depressing.

    27. AH

      Yeah, I mean, I'll- I'm going to resist the temptation to editorialize too much on that point, uh, because I wanna get more information from you, but I can't, uh, resist saying that one of the things I've really wished for for a long time is that the- the model of how biomedical research is done in the United States would shift from what we call the independent investigative model-

    28. DF

      Yep.

    29. AH

      ... where we each have a lab, you know, Huberman Lab is not just a podcast, it, you know, was and to some extent still is a- a laboratory space.

    30. DF

      Yep.

  17. 1:03:32 – 1:12:46

    Medical School, Relapse & “Overtime”, Finding a New Treatment, Rapamycin

    1. AH

      if you would, uh, you're sitting here now v- very, very much alive. Wh- how did this story progress?

    2. DF

      Sure. So, um, you know, I mentioned I got that chemotherapy, got out of the hospital, um, went back to med school at Penn, um, as a third-year med student, um-

    3. AH

      How much time did you gap?

    4. DF

      Spent six months in the hospital and then about six months in medical leave just sort of building myself back up. Um, uh, amazingly, I had this, um, girlfriend, Caitlin, by my side through it all. Um, Caitlin never left my side. Um, was just amazing. And, um, got back to med school. So it was now a total of a year, 'cause six months in the hospital, six months, um, recovering. And I was so excited to be back and to really get back on that path that I had before, which is that I'm gonna go into oncology, I'm gonna help patients like my mom. And, um, I was on an experimental drug. Uh, it's actually a drug that's very similar to the drug that, um, that my friend Kazu made. And, um, unfortunately, uh, about a year after I got out of the hospital, I was back in the hospital again with a relapse. And, um, that relapsed was really tough, um, for a few reasons. One, I, I almost died again for the fourth time, um, and I was in the ICU for a month, um, with all of my organs shutting down. But maybe what was even harder than that was that I was on that experimental drug that we had hoped would keep me in remission and it was helping other patients. And, um, my doctor explained to me that we were out of options. He said, "David, we've tried everything. You know, we tried these chemotherapies, we tried this one experimental drug. Um, there's nothing more that we can do." And, um, there was a, a few-minute period where my dad and my sisters and, and my girlfriend around me and we were just, um, just bawling our eyes out. You know, we're... This is the world's expert, you know, to use the Santa Claus theory. Like, this is Santa Claus telling you, like, "There's nothing more." And I kept p- probing him, like, "Is there any cell type or signaling pathway or is there something we can target?" Like, anything. He said, "David, there's nothing." "Is there anything in early stage of development?" "David, there is nothing." And, um, so we just, you know, we just bawled. Um, and then I had a, a really sort of moment of... a moment of clarity where it was basically I, I heard what he was saying, but then I thought to myself, "You just gave me seven chemotherapies that were made for lymphoma and multi- myeloma, and they've saved my life now three times. They're not... It's not long-term. Like, I know I keep relapsing, but, like, if these seven chemotherapies are working, how do we know there's not an eighth chemotherapy or a ninth drug for something else? Like, you can't tell... We haven't tried all 4,000 drugs. We've just tried the drugs that maybe we thought to try." Right. And so I just locked in right then and I turned to my family and just sort of wiped away my tears and said, "I'm gonna dedicate the rest of my life, however long that's gonna be, it might be a couple of days, maybe it'll be a couple of months, but however long I've got to try to find out, is there a drug out there that could help me and other patients with my disease that's made for another condition?" And, um, I became just totally locked in on this. And, and part of it too, for why it had to be a repurposed drug, is that I didn't have a billion dollars and 15 years to make a new drug from scratch. I mean, I wouldn't even have known where to start, right?... but I had examples where my life was saved by drugs that weren't made for me, and so I just said, "W- w- we should do everything we can to find something else." And so I started storing blood samples on myself every couple weeks. Um, shortly thereafter, started doing some work in the lab. I was literally an MD who had a master's in public health who knew nothing about the lab, (laughs) um, but started working-

    5. AH

      We call that, uh, dangerous.

    6. DF

      Yeah, exactly.

    7. AH

      (laughs)

    8. DF

      Very dangerous, and, and with a clock ticking, right? So you've got a lack of skills, which the clock's ticking down. Um, very dangerous, and so, um, started doing, uh, laboratory experiments. Um, did a lot of flow cytometry to characterize immuni- i- immune cells that were activated. Did something called serum proteomics, where I measured a thousand proteins in my blood.

    9. AH

      Who's letting you do all ... I mean, whose lab space are you using?

    10. DF

      So a, a colleague.

    11. AH

      Were you breaking in at night?

    12. DF

      No, I wasn't breaking in at night. A colleague was very generous to-

    13. AH

      People have done it.

    14. DF

      (laughs) A ver- very kind colleague gave me some space in her lab, and so, um, I was doing this work in the lab, and also trying to look at other drugs that were being used for, um, other related conditions, um, to see, you know, what- what could work for me. And, um, we were making progress. I started a foundation called the Castleman Disease Collaborative Network. We really were, were, were pushing things forward, and I was optimistic that we would find something, and then I relapsed, fifth time. Back in the ICU, organs shutting down, doctor explaining to my family that this is it. In fact, it was so bad at one point that, um, I'd ... I ha- for some reason over these years, I think it was maybe a bit of denial, I'd never put together a will. But, um, this time, the fifth time, my doctor told family, "You need ... This, you need to put down." And so, um, I, like, had a printer, piece of printer paper that the nurse gave me, and I sort of wrote down who I wanted my things to go to, and I didn't have much, but, but, um, cried, hugged my girlfriend. We were ... My f- she was my fiancee at that time, Katelyn. Like, just so disappointed that, like, I hadn't figured something out, 'cause what I didn't mention is that from that lab work, I thought two drugs might be able to work, and we tried both of them. We tried cyclosporine and we tried IVIG and it didn't work, and I got worse, and I ended up, you know, back in the hospital. And so the two drugs we'd tried, I thought I'd ... That was it. Like, I got my shot and I, and I missed, um, and, uh, I felt so disappointed, um, and I remember saying goodbye to everyone, and, um, and, and starting to sort of have life fade away, and I thought that was it. And they gave me all the chemo. They gave me the highest dose of, uh, etoposide, this horrible chemo that you could imagine, and, um, two days later, I started to wake up. And, uh, Andrew, there's this sense, I, I, I call it overtime, and it's basically like, it's like extra time in a game, where, like, it ... every second counts. And I can't tell you the joy that comes from, like, getting ex- ... Like, when you start to wake up, after you've said goodbye to the people you love and you're looking at them and, like, my sister Gina's here and Katelyn's here and my dad's there, I'm like, "Oh my gosh." Like, when you start getting life back that you thought you lost, and this is now the fifth time, I- I can't put into words what it was like. But I remember, like, as soon as I started waking up, I saw them and I was like, "Gina, I need you to get the lymph node that's in North Carolina to Philadelphia. Katelyn, I need you to get my serum samples that are downstairs in Little Rock, Arkansas, to Philly." Like, "I got another shot at this." Like ... And I remember, like, starting to wake up and being like, "Oh my gosh. I'm gonna get another shot." And so, um, about three weeks later, I was out of the hospital. I was back in Philadelphia and, um, that started about a month-long period where I thawed all those samples. I did more flow cytometry, I did more serum proteomics, I did immunohistochemistry on my lymph node, and when you put all the data together, um, what I discovered was that a communication line in, in your immune system, or in all of our immune systems, called mTOR, um, was turned into overdrive. And I had a lymph node that I had resected during my last relapse where I actually looked at it and I stained it for mTOR activation and it came back blazingly positive. And, um, so I took the data to my doctor, and, um, you know, said, "What do you think about trying an mTOR inhibitor on me?" Sirolimus had never been used before. Rapamycin's the other name for this drug. Had never been used before for Castleman's, but it's approved for organ transplant rejection, and, um, I sort of had nothing else to try, and so my doctor prescribed it to me and, um, you know, Rapa-

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