Using Existing Drugs in New Ways to Treat & Cure Diseases of Brain & Body | Dr. David Fajgenbaum

Andrew Huberman: My doctor explained to me that we were out of options. He said, David, we've tried everything. We tried these chemotherapies. We tried this one experimental drug. There's nothing more that we can do.

Andrew Huberman: There was a few-minute period where my dad and my sisters and my girlfriend around me, and we were just bawling our eyes out. This is the world's expert. And I kept probing him, like, is there any cell type or signaling pathway? Is there something we can target? Like, anything. He said, David, there's nothing. Is there anything in the early stage of health? David, there is nothing.

Andrew Huberman: 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 multi-myeloma, and they've saved my life now three times. 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've thought to try.

Andrew Huberman: 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 going to dedicate the rest of my life, however long that's going to be. It might be a couple of days, maybe it'll be a couple of months, but however long I've got to trying 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. Period. Like no one should suffer if there's a drug at your CVS that could help you.

Andrew Huberman: 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 Fagenbaum. Dr. David Fagenbaum 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.

Andrew Huberman: 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.

Andrew Huberman: 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.

Andrew Huberman: 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.

Andrew Huberman: As you'll soon learn, Dr. Fagenbaum 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.

Andrew Huberman: 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 Fagenbaum. Dr. David Fagenbaum, welcome.

David Fagenbaum: Thanks so much for having me.

Andrew Huberman: These days, people are very concerned about their health, even if they're healthy. And I think the reason for that is ever since 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, learning how to explore medical and health information online more effectively. No one knows who to trust. 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, that doctors are human too.

Andrew Huberman: So you have a very unique health story and we get into that. But maybe we just start off by educating people a little bit about some of the common misperceptions in order to give them more sense of agency about what they can do. One of the things that you've been 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 in the form of medicines that are prescribed or available, maybe even over the counter, 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.

David Fagenbaum: Sure. Well, first off, I love that you're talking about agency in health and in medicine, because I think oftentimes we talk about agency in the sense of wellness—I can get a good night's sleep or I can exercise and eat well. But oftentimes when people get really sick with a horrible disease, whether it's cancer or Castleman's, they feel like, well, we're just going to do whatever our local doctor tells us to do. But you're right, I think that there's so much more that we can do and there's so much agency that we can take.

David Fagenbaum: Part of it, to your point, is that there are drugs that we have. There are 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. Unfortunately, the system really isn't set up to find new uses for old drugs. And so that's the work that I do, but I also think it gives all of us really a sense of responsibility that if we're diagnosed with a bad disease, we find out what the disease organization or advocacy group is. Maybe they're aware of a drug being used in one part of the world that 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 potentially something else?

Andrew Huberman: I think of aspirin for instance, most people think of aspirin as a pain reliever. But aspirin is now used as a way to offset heart attacks for its blood thinning effects, among other effects. Just off the top of your head, I'm not trying to test you here. You're the MD. I'm the PhD, as we were talking about before. I'm not going to test you on medicine. I'm not equipped to. But are there other uses for aspirin that we perhaps haven't heard of, or similar drugs that might surprise people?

David Fagenbaum: Yeah. Aspirin also has been shown to reduce risk of recurrence of colon cancer, particularly individuals with colon cancer that have a mutation actually in the mTOR pathway. But because aspirin is sort of widely available and it doesn't have 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 that's sort of mind-blowing in itself.

David Fagenbaum: There are other great examples. Many 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 live full lives on Viagra. And that fortunately was discovered early on in the patent life of Viagra, so there was really a way to push it forward.

Andrew Huberman: A lot of times these happen after drugs are generic. Isn't it that the cousin of Viagra, Cialis, was initially 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?

David Fagenbaum: That's right.

Andrew Huberman: Yeah. And we talked about the side effect of a drug. It can be bad or it can be good. We were chatting earlier, the average small molecule drug that's approved for a condition can bind between 20 and 30 different proteins in the body. So we call a drug, we say it does one thing, but actually 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, oftentimes those insights and those other roles for the medicine just fall through the cracks.

Andrew Huberman: So the idea that a drug is useful for other things aside from what it's best known for is seldom discussed, whereas side effects are being discussed more and more nowadays. Tell us about lidocaine.

David Fagenbaum: Sure. This is fascinating. I couldn't believe it when we came across this. 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 it's used all over the body for numbing all kinds of things.

David Fagenbaum: There's interesting data, actually a large trial that was done in India of 1,600 patients, where women who had localized breast cancer, if they had lidocaine injected around the tumor before surgery, eight to ten minutes before surgery, there was a 29% reduction in mortality at five years versus those who did not have lidocaine injected. Now, lidocaine is already going to be used during the surgery. It's used at the site of the incision. It's widely used 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.

David Fagenbaum: And so this is just another example for us of 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 if the upside is as high as a 30% reduction in mortality, I don't know how it's not being used all over the place.

Andrew Huberman: Is lidocaine an expensive drug?

David Fagenbaum: It's a very inexpensive drug. It's 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 are a number of other companies that make the exact same drug, and the profit for each of those doses becomes close to pennies per injection.

David Fagenbaum: 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 really push to get them into guidelines. And I will say this was a really major study. 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 encouraging everyone to do it. So there are still steps that have to be taken. But our belief is that when you come across something that looks promising like this, we need to have some group that's actually pushing to make sure that it actually gets to patients once you feel comfortable with the data.

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Andrew Huberman: There are a couple of 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. I don't want to set up the idea that everything is 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 drug treatments for eye diseases. They've developed great drugs for the treatment of the eye, for instance, that can cause blindness or are related to some blinding diseases. And I learned that many of these drugs go to market. They are, quote unquote, blockbuster drugs. People's 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 markedly.

Andrew Huberman: So the drug companies are heavily incentivized, I learned, to find new uses for that drug, to renew the patent under this new application, to basically keep the generics away. And on the one hand, it makes sense because the research and development for a drug is exceedingly expensive. And so if they can repurpose a drug and maintain the patent for two diseases essentially—one drug, two diseases—this is kind of the bread and butter of how drug companies get and remain very wealthy. It has two, what I consider, kind of darker sides to it. One is that the generic cheaper drugs don't arrive on market for a much longer period of time. The other side of the coin, however, is that people suffering from a different disease now can take this drug. But that second darker piece is that drug companies are not very incentivized to go look for new molecules to treat new conditions. They are heavily incentivized to use old molecules to treat new conditions and maintain control.

Andrew Huberman: There's a lot in this statement, but my understanding is this is how it works. And so how do you reconcile that? 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 a disease as opposed to just kind of finding a new purpose so we can keep the generics out for a while?

David Fagenbaum: Yeah, it's such a good question. So you're absolutely right that as drugs begin to reach their patent cliff, oftentimes the drug will be changed slightly—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. To your point, there are side effects of that sort of system. But what is pretty clear is that companies will typically not, as it gets close to patent exclusivity, find a new disease to go after with that drug. It's usually the same disease, just a new formulation, so that way they can keep working that disease.

David Fagenbaum: And what that means is that though that drug might be able to be used for a different disease, that's rarely explored. And especially to your point, once it's generic, all research and development discontinues. And I mentioned earlier that there are 4,000 FDA approved drugs. They work for 4,000 diseases. That's incredible. But there are 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 every time I walk past the 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 adults with other conditions.

Andrew Huberman: We're hearing a lot these days about lithium as a potential protectant for Alzheimer's or other forms of dementia. I don't know that the data are so solid that I'm ready to run out and take lithium. So I'm not suggesting that to anybody, but I know a few psychiatrists that tell me for years, they've been taking low dose lithium for a couple months out of the year based on their understanding of the data. So you've got doctors doing things. People don't often talk about this, but doctors often will do things based on their read of the literature that they're not talking to their patients about because they're not in a position to do it ethically. There's too much liability there.

Andrew Huberman: 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 or something as serious as cancer?

David Fagenbaum: What I'd recommend is first 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, whatever that disease organization is.

Andrew Huberman: Could you explain disease organization?

David Fagenbaum: Sure. So like the Castleman Disease Collaborative Network is the group that's come together to support Castleman's patients and physicians and researchers. There's an ALS association, for example. There's Michael J. Fox for Parkinson's disease. So find that group that has coalesced around your condition because they'll oftentimes have understanding about, hey, I heard this one patient is using this one thing. So I'd go there first.

David Fagenbaum: The second is I would figure out where is the world's expert. Who is that person that really is the guru? They'll oftentimes have insights on these things. And then the third is to really keep asking questions. So even when they say this is the first that's recommended, ask, well, is there something else that's used somewhere else?

David Fagenbaum: And I'll share one example of this. It's a bit heartbreaking, but also really powerful and informative. There's a rare condition called DADA2. Basically, kids are born with 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.

David Fagenbaum: Well, about 20 years ago, a doctor apparently was treating a patient with DADA2 and also treating a patient with a form of vasculitis. He 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.

David Fagenbaum: 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, sadly, had two children born with DADA2. And he started looking around to figure out and learned about, oh my gosh, TNF inhibitors. I was honored to be able to help Chip and his team to basically bring data together on the effectiveness of TNF inhibitors, and also even come up with treatment guidelines for how do you treat DADA2. 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.

David Fagenbaum: 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 to me, that's so heartbreaking. It's almost like a travesty. It's one thing if you have a horrible disease 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, as a system, hadn't done the work to make sure people get the medicine.

Andrew Huberman: Yeah, I think it's a harsh reality that one's knowledge network really has a big impact on outcomes to disease. I mean, I sit surrounded by MDs and PhDs and people working on disease and treating disease. And I tell you, there's no question in my mind that because I experienced it when a friend, spouse, or kid is dealing with something, I'm just one example of somebody who knows who to call because I don't know the answer, but I know who might know the answer. And within two or three calls, that person is in touch with somebody who 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.

Andrew Huberman: It's one of the reasons I started this podcast, frankly, to get people like you on here, people like Eddie Chang, who's a lifetime friend and chair of neurosurgery at UCSF. I would say, may you never need his help. But these are the people that I call when friends have questions about things unrelated to neurosurgery, for instance. So it seems to me there's a pretty straightforward solution that in addition to these groups that are centered around certain diseases, there should be databases. There should be ways that people can not just go online and ask a question, but go to a database and say, 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 with other approved drugs that are prescription or over-the-counter?

Andrew Huberman: And then it should feed into a pipeline of how to get a hold of the people that could help treat that. It should be that straightforward. I mean, this is 2025. There's no reason why people should have to know somebody in the medical or scientific field at a major institution in order to be able to navigate this.

David Fagenbaum: I totally agree. And I think that the more I've gotten into this, the more surprised I've been that there hasn't been something like that. This nonprofit I mentioned, Every Cure, we use what are called biomedical knowledge graphs, basically mapping out what the world knows about human biology. We use an AI platform and machine learning models to quantify how likely every drug is to treat every disease, and then we start at the top to see what match looks promising. We've got nine active programs, and from those we're moving them forward to reach patients. The idea is that, hopefully, all nine of them end up being effective in helping patients. That's the start of this, hopefully, master list of additional uses for medicines we already have. But to your point, it's not just that they are speculative, but that the work has been done to really prove they actually work.

Andrew Huberman: I can't help but ask for some other examples of drugs that have been shown to treat things other than what most people associate that drug with.

David Fagenbaum: Sure. A few come to mind. The first one is thalidomide. You've probably heard about the horrible birth defects that thalidomide caused 50-plus years ago. Originally designed as an anti-nausea drug for pregnant women. The thought was it could help with nausea, but it ended up causing horrible birth defects. Children were born without limbs, and so it was taken off the market. Then about 20 years later, researchers figured out 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 hematologic blood cancer. The reason it can work for leprosy and multiple myeloma, and also the reason it causes birth defects, is it has a major anti-angiogenic effect—it reduces blood vessel growth. In the same way you need blood vessel growth to grow limbs, you also need overproduction or increased blood flow for multiple myeloma cells to survive, and also in leprosy. So the same compound that causes birth defects helps treat leprosy and also treats multiple myeloma. It's saved thousands and thousands of lives of multiple myeloma patients. The reason it was utilized in multiple ways was that it had a full patent life when the work first began for leprosy, and then myeloma was discovered shortly thereafter. But if a drug like thalidomide was discovered for leprosy and then 20 years later someone figured out it could be useful for multiple myeloma, the patent is gone. There wouldn't have been an incentive to then figure out that thalidomide could also be useful for multiple myeloma.

Andrew Huberman: The list sadly goes on and on.

David Fagenbaum: One of my favorite examples is a drug called pembrolizumab, now used for dozens of cancers, but initially developed for melanoma and lung cancer. The work we did in my lab, I guess this was 2016, was actually simple work. A patient came to us in 2016 with metastatic angiosarcoma, a horrible form of cancer. His doctors told him he was out of options. We did something really simple: we went on PubMed and looked for angiosarcoma treatment. We came across a paper from 2013 where 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-1, a marker that you might respond to a PD-1 inhibitor. Even though the paper was published in 2013 and this gentleman came to us in 2016, and hundreds of people had died in the previous three years, no one had ever actually tested whether a PD-1 inhibitor could be useful for angiosarcoma. It was just a laboratory study published three years earlier, but no one had ever translated that insight into using it in a patient. We treated Michael as the first patient ever, that we're aware of, with a PD-1 inhibitor. He responded incredibly well. A couple of things happened. One, his doctor started prescribing it to all patients with angiosarcoma. It turns out it works in about 18% of patients. 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. It changed clinical practice for angiosarcoma. The other thing it did specifically 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. These drugs are out there, and sometimes there are even breadcrumbs. It didn't require any brilliance from my lab. We literally just had to find a study that was published three years earlier. That really drives us with this work now: can we find all these breadcrumbs, put them together, and make sure people actually benefit from all the great science being done all over the world? Let's actually translate it into patients.

Andrew Huberman: It seems to me that PubMed and other sources of science knowledge are great for stacking papers. They're pretty decent in terms of how they're organized by keyword search—not perfect, but you can find stuff. You get suggestions about related articles. Somebody with a little bit of time and energy will get some degree of information there. But it seems to me that no one has really organized the enormous database of information about science as it relates to disease. It occurred to me 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 and of what, how old their parents are or were, any knowledge, any kind of family history. This is the first thing a doctor would ask you. If I come in and you're the MD, and I say, "Hey, I've got a swollen lymph node on the left-hand side," you're not going to say, "Go get it scanned." You'll say, "Any history of blank and blank in your family?" First thing, right? One should be able to do this from home, enter any symptom profiles they might be having, and with appropriate cautionary notes, get some ideas back about what might be going on. That might sound like people playing their own doctor, but I'll tell you right now, if I put "left armpit lymph node pain or swelling" into any online search engine, it's going to tell me some of the worst possible outcomes. It's not like we need to shield people from potential outcomes. It seems to me this should be pushed through an AI read of PubMed, which already exists. Most of the large language models are trained on the entire internet, including PubMed. It should point somebody in some actionable directions, including which of the various groups for a given disease is the best one. If somebody's kid, God forbid, has a blood cancer, which group do you go to? Is there a best one? Are these rated by anybody? I'm not trying to throw our arms around all of medicine here and all of the problems in the world, but it seems to me that all of this is tractable. Someone just needs to get organized about the databases.

David Fagenbaum: I completely agree. I think there's such randomness to healthcare and to our biomedical research system. That's probably the most heartbreaking part of this all: because it's so random, Michael gets a drug and walks his daughter down the aisle nine years later, and a bunch of other people don't get a drug and they aren't alive. I love the idea of that centralized database. There's a company called Open Evidence which is trying to basically create a GPT but for healthcare. I don't think it's to where you described it, where you can really put in your personal family information and get answers, but I'm hopeful that others will. The role I see our work and my work fitting into that is basically finding as many of these connections and proving them out in the lab and in clinical trials as possible. That way, when you type in your disease and your situation, that drug we worked on rises at the top because it wasn't just a connection in PubMed, but a connection we vetted in the lab and did the trial to prove it works.

Andrew Huberman: It's kind of wild that on a completely different end of the spectrum, recently everyone is talking about creatine. I've been taking creatine since my teens because I heard back then it would help make me stronger. Now people are talking about creatine for women, for men, for older people, under conditions of sleep deprivation, for cognitive support. The effects, while documented, are fairly mild for cognitive support, but they're there. This isn't being touted as a treatment for dementia, although it might help offset some minor dementia. The point is people are talking about it. It's in the news. It's covered all the time. But we really should be talking about drugs like aspirin that can be very useful for colon cancer and for heart attack, not just for pain, and all the other examples out there. I think there's this fear that if you talk about a drug, people will just start taking it as a prophylactic. There's a lot of caution around that for understandable reasons. But I want to know—I just turned 50—I want to know all the things I could be taking to potentially offset heart attack, because I'm already exercising and trying to get my sleep and doing all that stuff. Then I can make a decision. Where's the database of information about, as a 50-year-old male who does the following things to support his health, no history of heart disease in my family that I'm aware of? What drugs are on the counter or molecules that exist behind a script from a doctor that could potentially extend my life? I want to know that information. We're talking about creatine. For once, I'm not being disparaging of supplements, but it doesn't make any sense. The conversation is skewed in the wrong direction.

David Fagenbaum: I think what we're trying to do with Every Cure and with our work is trying to start this conversation and keep it going, so you can go to your doctor with X drug. I mentioned we have nine active programs. On one end of the spectrum, really common, is our program with lidocaine and breast cancer, where we're doing laboratory work and evaluating clinical data. I hope at some point in the future the data is strong enough, and if it is, we'll work to encourage every woman who's about to go in for breast cancer surgery to talk to their surgeon beforehand and say, "I want to make sure you do this." It's about empowering them. All the way through to even the rarest of conditions. There's a condition called Bachmann-Bupp syndrome where kids are born with a mutation that causes them to have elevated levels of an enzyme called OCE1. They're on feeding tubes, wheelchair or bed bound, unless you give them a drug made for African sleeping sickness, which is a perfect covalent binder of OCE1. That enzyme that's too high in these kids—the African sleeping sickness medicine actually binds to OCE1. 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. There aren't that many people with Bachmann-Bupp. It's only been described in 20 kids, which means there are probably hundreds of kids because the medical literature is typically behind reality. But let's say there are hundreds of kids. At some point, we're going to get the word out so we can find every kid possible with Bachmann-Bupp so they can get this medication, DFMO. These are microcosms of what you're talking about. No one should suffer from Bachmann-Bupp 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 is helpful for reducing your risk of heart disease. But to your point, how can we get this more proactively so we're not just hoping and waiting that all these random things line up?

Andrew Huberman: We used to use colchicine in the lab. Colchicine is an interesting one. It's typically utilized for gout. It's been around forever. I learned it's like 3,000 years ago when it started being used, because gout often occurs in individuals who consume too much alcohol. Apparently in Egypt 3,000 years ago, some wealthy people were drinking too much alcohol, and somehow they figured out that this molecule colchicine—I think it was a root at the time—could be helpful for reducing gout. We should fact-check that statement because I don't know the exact details, but it's been around a long time. If there were a database, you could just go to the database. You can tell where my mind's going.

David Fagenbaum: Exactly. Colchicine's been around forever. It's been used for gout for decades. People with gouty arthritis get painful joints, and colchicine helps them out. A researcher a couple of decades ago had a hypothesis that because of its anti-inflammatory properties and a few other properties, it might be able to reduce the risk of heart attacks in people who have already had a heart attack, or maybe in general, but particularly in people who have already had a heart attack. Because it's been around forever, they couldn't raise the funding needed to do all the trials to prove it. Heart disease prevention trials are big, expensive trials. You have to follow people for years to prove they didn't get a heart attack versus people who got a placebo. They ended up changing the dose of that medicine, colchicine, so it's a slightly different dose from the one used for gouty arthritis. But it has a very substantial reduction in heart disease risk if you had a prior heart attack. In particular, if you had a prior heart attack and you have diabetes, a really meaningful reduction. It got FDA approval for that particular subpopulation. I mention it because if they hadn't changed the dose, it would have been a paper some academic would have published saying, "I think colchicine could help," and no one would have ever done the big trial. That's the tragedy here: people are literally not having heart attacks right now because they're on colchicine. If not for someone figuring out a way to make the system work, they would have had their heart attack.

[Sponsor break for AGZ by AG1 and David protein bars]

Andrew Huberman: Well, I feel like we could spend hours going through the catalog of drugs for which these examples exist. We may return to a few more. But I'm 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. That's apparent to people already. You care very much about human health and treating human disease, but you have a very unusual and interesting trajectory into medicine. I do believe it's helped lead you to this very unique orientation within the field of medicine and science. So tell us that story and teach us about Castleman's disease.

David Fagenbaum: Sure. My story really starts back when I was 18 years old. I was a freshman at Georgetown. We were talking earlier about me playing football at Georgetown. For me growing up, that was my dream: to be a Division I college quarterback. That's all I could think about. I was not quite as jacked as you, but somewhere in that realm.

Andrew Huberman: I saw a photo. You were larger than I was. We'll put up a link to a photo. David was 230, you're taller than I am. I'm 6', so you're probably 6'3". I think you might be 6'3". Either that or I'm shrinking. And super large, fit, low body fat. You look like a quarterback, but you're large even for a quarterback.

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

Andrew Huberman: The story about your mom is a remarkable one. My first thought when you mentioned the Chiquita Banana Lady reference is that even though she was the patient, it seemed like she was successfully taking care of all of you.

David Fagenbaum: She was trying to take care of us.

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

David Fagenbaum: She was amazing. I so appreciate you saying that.

Andrew Huberman: So, Castleman's. I've never heard of it. Who's Castleman? Physicians like to name diseases after themselves, but my guess is they're not the ones with the diseases—they're the ones that discover the diseases, correct?

David Fagenbaum: That's right, yep. Benjamin Castleman was a doctor in Boston at Harvard. He'd been getting these cases of patients thought to have lymphoma. They appeared like they had lymphoma, getting very sick very quickly, but when he looked under the microscope, they didn't look like a typical lymphoma patient. Maybe as I share what my progression looked like—I was a third-year med student. I had just finished an OB-GYN rotation. I just delivered babies into the world, which is a peak moment in medical school. Within a couple weeks, I noticed I had enlarged lymph nodes in my neck. I felt more tired than I ever felt. You're tired in med school and grad school, you know well, but I was more tired than ever. I had horrible abdominal pain. I noticed fluid pooling around my ankles. I thought, "This is so weird. What's going on?" The fatigue got worse and worse. Over the course of really just a couple weeks, I got so bad that I took a med school exam and then went down the hall to the emergency department. I basically stumbled down to the ER and told them my symptoms. They ran blood work. I remember my doctor coming back, 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." I'm like, "What do you mean? I just delivered a baby a couple of weeks ago. How are all my organs shutting down?" They hospitalized me, 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 kidneys stopped working. You saw that picture where I had fluid everywhere because of the multi-organ failure. I needed daily transfusions of red blood cells and platelets just to keep me alive. I was on dialysis as well. Basically, everything was shutting down, and we had no diagnosis. Some doctors thought it was lymphoma. Others thought it might be an autoimmune disease. Others had no idea what it was. Over the course of about 11 weeks, I got worse and worse. At one point, I was so sick that I said goodbye to my dad, my sisters, and my girlfriend at the time, Caitlin. A priest came into my room and read me my last rites when I was 25 years old. Fortunately, right around the time of having my last rites read to me, which was really the end—I didn't have more than a couple of days left—that's when the diagnosis came in of Castleman disease. A pathologist looked at my lymph node. They thought I had lymphoma, a really aggressive form of cancer. But they looked at it, just like Benjamin Castleman did, and said, "This doesn't look like lymphoma. This looks different. It looks like this thing called Castleman disease," which is what we call an atypical lymphoproliferative disorder. It's kind of like lymphoma, but it has features more like an autoimmune disease. Your immune system becomes highly activated and starts attacking all your vital organs. The reason all my organs were shutting down is because my immune system was producing cytokines and other factors that were basically shutting them down.

Andrew Huberman: Do you think that the long hours of medical school, plus being athletic, very driven, contributed to the autoimmune flare-up?

Andrew Huberman: We don't often discuss this, but anyone that's dealt with an autoimmune issue, even if it's like psoriasis or something, which can be very severe, but in most cases, it's kind of minor. There are over-the-counter things you can use. But it's associated with people who are pushing very, very hard and tend to pull long hours. 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.

David Fagenbaum: Yeah, it's funny. No one ever asked that, but it's the right question to ask. I think people are always sort of afraid to get into the whys of these things happening to you. I'm glad you asked because there was a paper published a couple years ago, I think it was in *Cell*, where mice that were sleep deprived—significantly, multi-day sleep deprived—what actually killed them was a cytokine storm due to their immune system producing all these cytokines. We know sleep deprivation is deadly, but in these mouse studies, the actual thing that killed them was their immune system producing cytokines, including interleukin-6, which is an important cytokine in Castleman's. By just trying a couple of medicines that block the production of some cytokines, you could keep the mice alive longer. It really pointed to this idea that sleep causes a disruption in immune balance, causing excess production of cytokines, causing death.

Andrew Huberman: I'm not familiar with that one, but it connects to your point. Growing up in Silicon Valley, I've known a lot of people with cancers and who seem to be dealing with autoimmune things. I know a lot of very ambitious, hard-driving people. It's baked into the culture I grew up in. Sometimes I've wondered about these naturalistic observations. Some of the most hardworking, long-hour, athletic, academic, hybrid founder people are the ones oftentimes dealing with severe health issues. You're like, how could that be? Maybe there's a relationship. The more I learn about the general backdrop of supporting health—sleep being fundamental, natural light exposure but not too much UV—you got to wonder. I'm not saying people shouldn't work hard, otherwise I'd be headed for a quick death because I always worked very long hours, mostly from a place of enthusiasm, sometimes fear. But the immune system is a highly conditional system. I'm not saying mellow laid back people don't get cancers, but has that ever been looked at—whether temperament and propensity for autoimmune induced diseases correlate?

David Fagenbaum: I haven't seen it. There may be. What I have seen, and to your point, there's really strong data that among people who have autoimmune diseases, stress results in flares. So if you have it, stress, lack of sleep, all this stuff can result in flares. I haven't seen data on whether it's at the etiological level of actually causing it. But this mouse study was eye-opening for me. I was working crazy hours. As you heard, I was on a mission. I'm still on a mission, which is to find drugs for patients like my mom. That meant I worked crazy, crazy hours. I teach medical students and they work crazy hours. It's impressive and striking and at times a little concerning.

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

David Fagenbaum: At the time, there were no approved treatments. But as we were talking about earlier with information asymmetry, there was a drug originally developed in Japan for Castleman's. My doctors didn't know to try it. They gave me a form of chemotherapy, which fortunately saved my life just in time. But there was this drug in Japan with pretty strong data that works for Castleman's. The information hadn't exchanged, and the drug wasn't available in the U.S. for that condition. I'll share a quick story about that drug—it's called tocilizumab, discovered by a doctor named Kazu Yoshizaki. I heard from a colleague that Kazu had given it to himself before it was given to any other humans to prove it was safe.

Andrew Huberman: Old school medicine.

David Fagenbaum: Right, this was the 90s and monoclonal antibodies were a new technology. Apparently he was afraid to give it to patients because he didn't know what it was going to do, so he said, "I'll give it to myself." I heard that and said, "Kazu, I heard you gave yourself tocilizumab." He said, "No, no, I didn't give it to myself. The nurse gave it to me."

Andrew Huberman: I love the specificity.

David Fagenbaum: Exactly. So he gave it to himself, he didn't die, so it was safe enough for him. He studied it in Castleman's patients. It got approval for Castleman's in Japan, and then it got repurposed for rheumatoid arthritis here in the U.S. and a number of other autoimmune diseases. It's approved in the U.S. for autoimmune diseases, but it was made for Castleman's in Japan. My doctors didn't even think to try it. Chemo saved my life, but then I relapsed a few weeks later. We tried that drug from Kazu from Japan. It didn't work for me. It works in about a third of patients. I ended up needing a combination of seven different chemotherapies—adriamycin, cytoxan, etoposide, velcade, thalidomide, rituxan—the worst chemos out there. That's what I needed to get my disease into remission. To give you a sense of how sick I was, this was the third time 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. These are the worst chemos in the world, but because they were killing my immune system which was producing cytokines that were killing me, I actually felt better on chemotherapy. Eventually I got well enough to be discharged from the hospital. There's that picture I showed you from the book, a couple weeks after I got out of the hospital. I was just so thankful to be alive.

Andrew Huberman: We'll post a link to that photo and to your book. That photo—if you show it to a typical person, they're not going to say that's a healthy looking person, but you said you were so grateful to be alive because relative to where you were before—100 pounds of fluid accumulating in your legs and body prior to that. You were in a very unique position because you have this inquisitive mind. It's clear you were motivated, not just from your illness, but generally based on the story about your mom. People would listen to you, is my guess. They would at least listen to your questions. I'm reading into this, but I think many patients don't know what questions to ask. They don't know whether the person they're asking has access to the best answers or even the answers. I like to think most doctors are benevolent, so let's assume that. But they're also busy and they get as confused as anybody. I'm not trying to knock medicine here, but this is the reality. Simple question: when a physician finishes their training through residency and starts practicing—let's say an oncologist or a general practitioner in the United States—is the typical physician accessing the literature often? I know they're required to do continuing medical education, but it could be that their education around a disease is locked in at the time they finish their residency, plus any major updates that come through. How does this work? I want to know when my physician finished training, and I want to know how often they read papers, and I want to know who else is on their committee of people that they share ideas with. I want the most connected physician in the world to be treating me.

David Fagenbaum: Yeah, and I do too. The problem is that given all the constraints and requirements of a typical physician, they just don't have that much time to do all the things we want them to be doing. You're right, physicians are reading the literature, but typically it's because they have a patient with something that led them to it, or maybe someone sent that paper to them. It's very random and piecemeal. No doctor can look at millions of papers. They can't even look at the hundreds that might be relevant for the diseases they treat. They get some watered down summaries, they go to a conference and hear what's being told, but it's very piecemeal. The big takeaway from this whole conversation is that so much of this is piecemeal and it's not systematic and it is random. It's, "Did your doctor happen to come across this one paper?" as opposed to the world we should be in, where it shouldn't matter what doctor you go to see because the data is the data. We talk about getting second opinions from doctors. For some reason we call it a "second opinion," yet we believe that what's being told is exactly what should be done. But it's an opinion. Oftentimes second opinions aren't consistent with the first opinion because they're opinions. They're educated, driven in science, grounded in evidence, but you just don't know if your doctor is going to have the information that's needed for you. That's scary. We want to go to our doctor and believe that they've got all the answers. I have this concept I talk about in my book that might resonate with what we're talking about now. I called it the Santa Claus Theory of Civilization. Before I got sick with Castleman's, when I was a medical student, I had this idea that there were rooms of scientists and doctors collaborating, working together to come up with solutions—kind of like Santa's workshop with the elves working together. As soon as humanly possible that a drug could be discovered, it's at your doorstep. But then I realized that actually there aren't workshops, there aren't groups of scientists and doctors sitting together to figure out solutions. And if they are, it's just not at the pace you would hope it would be.

Andrew Huberman: I'm going to resist the temptation to editorialize too much on that point because I want to get more information from you. But I can't resist saying that one of the things I've really wished for is that the model of how biomedical research is done in the United States would shift from what we call the independent investigator model, where we each have a lab. Huberman Lab is not just a podcast. It was, and to some extent still is, a laboratory space, although I've certainly pared down the size of my lab in recent years. In this country, you get a PhD, you decide to do a postdoc and start a laboratory. You have a laboratory that's named after you. You get funding to do things that are really associated with your name. It's like a small startup that can grow into a medium-sized or large startup, but you stay independent. The whole notion of the independent investigator is a very romantic model of science, but I think we've reached the point where the sharing of information and collaboration around a particular goal is far more powerful. I don't have a magic wand and the level of influence I will have over the NIH is questionable. But what I'm really pushing for is laboratories named after a puzzle or a disease or a challenge, with people coming together to try and solve those issues. Because it's not just a matter of naming and branding. It has everything to do with how willing people are to share ideas as opposed to feeling like they have to fight for their piece of the pie.

David Fagenbaum: That's exactly right.

Andrew Huberman: So this is perhaps a conversation for another time, but you've done a marvelous job of not just trying to educate people about Castleman's and your story, but of trying to solve a problem that was life or death for you, and then taking that knowledge and instead of just saying, "Hey, I'm going to help other people with Castleman's," which you have, to really say, "Let's do this for all of disease, all of medicine." It's so admirable. I have to ask, are there other physicians doing what you are doing? Or are you the lone wolf out there?

David Fagenbaum: I think I'm probably the lone wolf in the scope of what we're doing. It's all FDA-approved drugs, all 4,000, and all 18,000 human diseases. I'm not aware of anyone else who's taking this sort of all-versus-all systematic approach to find the lowest hanging fruit. But there are amazing colleagues of mine who work within hematology. A doctor named Luke Chen calls me up when he's got patients on death's doorstep to figure out what we can do, what we can try. We brainstorm, try this or try that. Oftentimes they work and the patient is alive because we tried a combination of five different chemotherapies that weren't made for that cancer. There are incredible doctors all over the country who are pushing the boundaries of what's possible. But I'm not aware of any other effort at the system level that says, "I don't care about the name of the disease or the name of the drug. I believe that the 4,000 drugs we have today should help all the patients who can benefit from them. Period." No one should suffer if there's a drug at your CVS that could help you. That's not the world we're in. The problem is we've got to create that world, and that's what we're doing.

Andrew Huberman: Most scientists are incentivized to find new things. And most physicians are not scientists. I'm not saying scientists are better, but the two need each other.

David Fagenbaum: That's right.

Andrew Huberman: I will now pull back on my desire to editorialize about how the system could be better. My hope is that some of this will be implemented going forward. But if you would, you're sitting here now very much alive. How did this story progress?

David Fagenbaum: Sure. I mentioned I got that chemotherapy, got out of the hospital, went back to med school at Penn as a third year med student.

Andrew Huberman: How much time did you spend?

David Fagenbaum: Six months in the hospital and then about six months on medical leave, just building myself back up. Amazingly, I had this girlfriend Caitlin by my side through it all. She never left my side. It was just amazing. I got back to med school. So it was a total of a year—six months in the hospital, six months recovering. I was so excited to get back on that path I had before: going into oncology to help patients like my mom. I was on an experimental drug, very similar to the drug my friend Kazu made. Unfortunately, about a year after I got out of the hospital, I was back in the hospital again with a relapse. That relapse was really tough for a few reasons. One, I almost died again for the fourth time. I was in the ICU for a month with all of my organs shutting down. But maybe what was even harder was that I was on that experimental drug we had hoped would keep me in remission, and it was helping other patients. My doctor explained that we were out of options. He said, "David, we've tried everything. We tried these chemotherapies. We tried this one experimental drug. There's nothing more that we can do." There was a few-minute period where my dad, my sisters, and my girlfriend were around me and we were just bawling our eyes out. This is the world's expert, to use the Santa Claus theory. This is Santa Claus telling you there's nothing more. I kept probing him: "Is there any cell type or signaling pathway? Is there something we can target? Anything?" He said, "David, there's nothing." "Is there anything in early stage development?" "David, there is nothing." So we just bawled. Then I had a moment of clarity. I heard what he was saying, but then I thought to myself, "You just gave me seven chemotherapies that were made for lymphoma and multiple myeloma. They've saved my life now three times. It's not long term—I know I keep relapsing—but if these seven chemotherapies are working, how do we know there's not an eighth chemotherapy or a ninth drug for something else? You can't tell me. We haven't tried all 4,000 drugs. We've just tried the drugs we thought to try." I locked in right then. I turned to my family, wiped away my tears, and said, "I'm going to dedicate the rest of my life, however long that's going to be—maybe a couple of days, maybe a couple of months—to trying to find out if there's a drug out there that could help me and other patients with my disease that's made for another condition." I became totally locked in on this. Part of 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 wouldn't even know where to start. But I had examples where my life was saved by drugs that weren't made for me. I said, "We should do everything we can to find something else." I started storing blood samples on myself every couple of weeks. Shortly thereafter, I started doing some work in the lab. I was an MD with a master's in public health who knew nothing about the lab, but I started working.

Andrew Huberman: We call that dangerous.

David Fagenbaum: Yeah, exactly. Very dangerous. With a clock ticking. So I started doing laboratory experiments, did a lot of flow cytometry to characterize immune cells that were activated, did something called serum proteomics where I measured a thousand proteins in my blood.

Andrew Huberman: Whose lab space are you using? I mean, you weren't breaking in.

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

Andrew Huberman: Rapa.

David Fagenbaum: Rapa, at the dose of a transplant dose. I take rapamycin at the same dose a kidney transplant patient would take. It's a lot higher than the typical longevity dosing that people do.

Andrew Huberman: My dose of Rapa for longevity is zero. I'm not a fan. We can talk about that a little later. A lot of people who were taking Rapa for longevity purposes—I don't want to get it wrong. I don't know what Peter Attia is doing right now, he's a friend, we could call him. But my understanding is that a number of people who were very bullish on Rapa for longevity are no longer bullish on it.

David Fagenbaum: Yeah, I've definitely seen that shift. I'm not sure if it's based on human data because I don't think anyone's ever done the study in humans. The reason people were bullish on it is that every organism you give rapamycin to, the earlier you give it to them, the longer they live. These are organisms in cage settings not getting exposed to viruses and pathogens. Whatever longevity benefit you might get from the metabolic aspect of rapamycin, I think it's counteracted by the fact that we don't live in cages and we actually get exposed to pathogens. There's probably a negative effect in terms of survival because rapamycin is a very potent immunosuppressant. The doses I take—I take such a high dose that if I were to get your kidney transplanted into me, my immune system wouldn't notice your kidney in my body. That's the level of dose I take. Sirolimus is approved for organ transplant rejection. As you mentioned, it's used sometimes in the setting of longevity. It had never been used before for Castleman's. In the three and a half years before I started taking it, I almost died five times from my disease. I said goodbye to my family on five different occasions. My doctors were sure I wasn't going to survive. Since starting rapamycin, it's now been 11 and three quarter years that I've been in remission on this drug. It feels like such a dream.

Andrew Huberman: Awesome. Just no other word for it. Your description of overtime is a very apt one. I find it equally apt that when you're emerging from near death, you're calling plays like a quarterback. You're telling your sister what she's going to do with your lymph nodes. She's going to run the lymph nodes downfield. You're calling plays. You're the quarterback playing quarterback again. I can't help but ask—the past that you had as an athlete, do you think it served you?

Andrew Huberman: I mean, the level of drive and determination to say like, "Oh, these eight drugs helped me for a while. They're no longer helping. There's got to be a ninth. Try the ninth. Doesn't work. Okay, let's try something else. Almost dead. Come out of near death. All right, you run the lymph node this way." I mean, it's almost impossible to not wonder whether or not you learned some of that resilience playing sport.

David Fagenbaum: A lot from playing sports. I mean, I think that your listeners may not know Georgetown even has a football team, but we do.

Andrew Huberman: Is that good?

David Fagenbaum: Depends on who you ask.

Andrew Huberman: I'm sure it's very good. Good enough to be in some league.

David Fagenbaum: Yeah, it's division. We play Ivy League schools. It's like Patriot League, Ivy League schools. But the reason I mentioned that is that we lost a lot of football games. So, certainly, there's a bunch of things I learned from football. I mean, first off, I decided when I was eight years old that I wanted to be a Division I college quarterback. I decided as an eight-year-old, and Andrew, I literally had poster boards all over my walls with how far I could throw a football, how accurate I was, how fast my 40-yard dash time was, how fast my mile dash for the next 10 years. That's literally all I could think about. I was just locked in. And that sort of 10 years of working towards a mission is the same sort of approach you need to take to solve a massive problem in healthcare. To discover a drug, it's that same sort of constant drive. So I think one part was that it was the first of what's now been a few of these like sprints that I've gone on.

Another is the sort of loss and resilience. We lost a lot of football games. You get back up and you just sort of keep fighting. But also physical pain and challenges. I've broken both my collarbones, broken both my hands at different times. I remember there were times when for punishment for the team, we did something called rolling, where you just start rolling on your side on a football field until everyone gets sick and then you stop rolling. That's the kind of physical demands that get put on your body that enable you to then gain a hundred pounds of fluid in the hospital and be in the worst pain you could ever imagine. It was way worse pain than breaking my collarbones, but I'd felt bad pain before. So I can feel some bad pain now. I think a lot of that came from football.

I also think that when I was in the ICU for that first six-month period, I learned a lot about myself and how to overcome challenging situations. There were three things that really helped me. The first was that the whole time I was in the ICU, I had this clear vision for the future, which was a family with Caitlin, who I was dating at the time, and a career discovering drugs for patients in memory of my mom. That clear vision for the future helped me deal with the horrible, excruciating pain because of the fluid that you gain around your organs. It felt like I was getting basically simultaneously stabbed for months at a time. So one is vision for the future.

Two was that I got so much strength from my family around me—my dad, my sisters, Caitlin. They were holding my hands and I could feel their strength in my hands. They were literally helping me to keep going. I remember a moment when I very first got sick, the first time I almost died from my disease. Doctors came in and said I wasn't going to make it. We had no diagnosis at this time. I said goodbye to my family, just heartbroken. I remember with every breath I took, there was horrible pain. When you have that much pain with every breath, you start slowing your breathing. I was starting to let go. I thought I was maybe going to miss out on a couple days of life, but I'm in a lot of pain, so I'm just going to slow down and let go.

I remember hearing my sister, Gina, who was on my left side. She was holding my hand. Everyone else was crying and sort of had an idea for what was going to happen. But Gina was holding my hand and she said, "Just breathe, Dave. Just breathe." When I heard that, I was like, "All right, I'm going to do one more breath, and it's going to be really painful, but I got this." I did one more, and I did another one. Fortunately, the medicines I'd received helped me to make it a little bit longer. The key takeaway for me was that you can do anything for one minute or one hour or one day, but if you told me at the beginning, "David, you're going to be in the worst pain of your life for six months, it's going to be horrible, your organs will be failing," no way I would have the strength to survive that. But I could survive for one minute and one hour and one day. I think I learned some of that from playing football. Putting your body through a lot of challenges helped me a lot.

Andrew Huberman: Older sister or younger sister?

David Fagenbaum: Two older sisters. Yeah. Lisa and Gina are seven and five years older than me.

Andrew Huberman: Awesome, man. As the younger brother of an older sister.

David Fagenbaum: They're the best.

Andrew Huberman: They're the best.

David Fagenbaum: They're the best.

Andrew Huberman: Big, big, big shout out for the sisters. Older and younger.

David Fagenbaum: Yes, the best.

Andrew Huberman: I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFAS, or forever chemicals. Function not only provides testing of over 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas.

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Yeah, an amazing team. So another parallel to football and another signal that for people combating disease or just general health issues, that social support piece is so key. There's so much data on this. We've done podcasts about this, and we could probably do 100 more. The message is always the same: to the best that you can, surround yourself with at least one person you can rely on. The best way to do that is to be that person to people. Should you stay healthy, you have that person. Should you not be healthy, you have that person. So yeah, over and over. It's really an incredible story because you emerge from it with 11 years of overtime. Do you still think about it as overtime?

David Fagenbaum: Fifth overtime, yeah. Although I will admit, to your question, I don't have the same sort of—because in overtime, there's both fear and clarity. The fear drives some clarity. I will say as 11 years and three-quarters of a year go by, there isn't maybe the same heightened sense of "I'm in overtime." But every once in a while, I have a port where I get my infusion every few months on my chest. I've got scars on my neck from where lymph nodes got taken out. Every once in a while, I just sort of put my hand here and here, and it reminds me, "Okay, I'm in overtime. I got to be really thankful because we don't know how much time we have."

Andrew Huberman: The brain's wild in this way. We had a guest on this podcast, Michael Easter. He wrote the book *The Comfort Crisis*. It's an incredible book about how to navigate life generally and doing really hard things voluntarily. He goes on really hard expeditions and then comes back from them with a renewed sense of gratitude for the smallest things. I asked him, "How long does that gratitude last?" I think he said about two months, and then it resets. Of course, those weren't life-or-death circumstances of the sort that you're describing, so he just goes on more of these things. It's a wonderful book and an important book for people healthy and certainly sick. I think this notion that you're on borrowed time or overtime is hard to hold on to because you also have to just live your life. But clearly, you're making the most of that in service to others.

As I mentioned earlier, your background as an athlete helped you navigate this health challenge. Then the health challenge dovetails with your work as a physician. You're really a physician-scientist because you hold both titles formally and as a practitioner. So nowadays, do you get contacted by people all the time whose kid or themselves are dealing with a challenging disease with the question, "Is there a drug that's approved that can help me, or a combination of drugs?"

David Fagenbaum: We do get contacted a lot. To share what these last 11 and a half years have looked like: after medical school, I actually enrolled in business school in part because I realized that the greatest barriers to progress did not appear to be scientific or medical. They had to do with things like getting people to collaborate with one another, efficient use of resources, coming up with a strategy to solve a disease. It was actually in business school that I discovered sirolimus to save my life. After business school, I joined the faculty at Penn and set up a lab. We got started first focused on Castleman's, and first it was about understanding how mTOR plays a role in Castleman's disease, sort of treating other patients with the drug that I'm on, sirolimus.

I'll never forget: we treated a patient in Brazil and then treated a patient in New Zealand, but I just heard about them, I wasn't physically with them. Then the fourth patient we treated was a patient named Joey, who was a child, a 13-year-old boy at Children's Hospital of Philadelphia. It completely turned his disease around. He was literally dying in the children's hospital. We used sirolimus, and I would come in every day to see him. I'll never forget seeing the blood work, seeing him the couple days after we started sirolimus. It was so incredible to see this boy who was on death's doorstep start to turn around because of the drug that saved me. Now we're saving other people. We'd used it in Brazil, used it in New Zealand, but I hadn't seen them. I hadn't felt what his family was feeling. I actually just saw Joey a couple days ago and his parents as well. He's a college student at Temple University now. That for me was this huge moment. It's like, "Oh my gosh, the drug I'm on is helping other people. It's not just this one-off thing."

Then we found a drug that's used for a bone marrow condition called myelofibrosis that we thought could also treat Castleman's patients. There was a young girl named Kyla in a hospital in Chicago. She wasn't responding to anything, and she didn't respond to my drug either, sirolimus. We recommended her doctor try ruxolitinib, first time ever for Castleman's disease. She responded incredibly well. She's in college now at Marquette University. She's going to be a nurse. That was amazing. I was like, "Okay, not only did we find this drug for me and give it to other people, but now we find another drug for Castleman's. Maybe there's even more we can do."

Our lab kept working and working. That's when Michael, the patient with angiosarcoma, came to us back in 2016. We found out that this drug for melanoma could actually treat his angiosarcoma cancer. "Oh my gosh, we can find for another disease." Over the course of the last 11 years, this has totaled 14 drugs for diseases they weren't intended for. With every one of them, we get so excited. Then we also think to ourselves, "How many more drugs are there out there that are made for one disease that could actually treat more diseases?"

That meant that three years ago, as artificial intelligence was really continuing to move forward at an incredible pace, my co-founders, Grant Mitchell and Tracy Zukora—Grant was utilizing artificial intelligence to support drug companies with finding new uses for their medicines, to find subpopulations that might benefit from their medicines. But we thought, "What if instead of using AI one drug company at a time to find one new use for a medicine, what if we could utilize artificial intelligence to scan across all drugs and all diseases to find the best opportunities?" So we started Every Cure three years ago.

Since starting Every Cure, you're absolutely right, we get contacted by lots of patients and families, and we try to help them any way we can. I'll share a couple really exciting examples. At the same time that we're having all these incomings about people that are on death's door, what we keep focusing on is: can we find these matches like lidocaine for breast cancer or DFMO for Bachmann-Bupp syndrome? Can we find these matches and do the work so that people don't get to death's doorstep? Do the clinical studies, get the word out so doctors are prescribing them, so they're not coming to us for a Hail Mary, but we're actually getting the work done ahead of time so the drug is just being used. Can we match every drug to every disease that they can treat and do the work to get it to people? Because that's really the way that we solve problems at scale, as opposed to that one-off Hail Mary approach.

But I'll share a couple one-off approaches that I'm really proud of. One of them is a patient named Al in Vancouver who wasn't responding to any medicines. He also has Castleman's, the subtype that I have, the really deadly one. The number one ranked drug in our machine learning algorithm for Castleman disease, when we ran it for the first time two years ago, was a TNF inhibitor, actually.

Andrew Huberman: For Castleman?

David Fagenbaum: For Castleman.

Andrew Huberman: TNF? Tumor necrosis factor?

David Fagenbaum: Yeah, TNF inhibitor. So we gave him adalimumab, and he responded incredibly well. He's been doing great now for two years. Published in the *New England Journal of Medicine* earlier this year.

Andrew Huberman: Can I ask you—forgive me for interrupting. So an inhibitor of tumor necrosis factor alpha. TNF alpha is involved in inflammatory response. Earlier you said that this inhibitor can help treat this condition of multiple strokes in childhood. Strokes are basically bleeding out in brain areas, essentially, right? I'm sure there's a mechanistic pathway that can be connected to that involving any number of things. I think I've seen papers where TNF alpha is involved in the kind of endothelial neural interface, and then you have inflammation, and then you have some shearing, and then you're bleeding. So I can create a "just so" story in my mind that works, right? Does it matter? Or is the goal to screen drugs in patients as these Hail Mary passes and figure out things that work and then worry about mechanism later?

This is typically not the way science and medicine is done, especially in this country. People don't like the notion of eating a plant or eating a seed and then seeing benefits and not knowing what the molecules are. We like reductionist science in this country. This is changing somewhat, but that's been the pattern. To you, for a patient that's suffering, is all that matters that they get better? I could understand why that might be the case.

David Fagenbaum: Yes, 100%. Ever since I saw my mom die from brain cancer, all I've wanted to do is think about how can we help people with these horrible conditions. Then when I went through my own experience, I realized that helping people with these horrible conditions may not be spending my whole career to develop one drug. It might actually be spending my whole career finding out all the uses for all these other drugs. To use a football analogy, it's like we've got all these drugs that are on the one-yard line that could be useful for a new condition, but there's no incentive to do that. So can we just push them in? So yes, it's all about can we help patients.

I think it goes bidirectionally. When a drug helps a patient like that TNF inhibitor helped Al, we believe it's because T cells in Castleman's patients, CD4 positive T cells, are producing too much TNF when they become activated, and we've shown that in the lab. So you can actually start working backwards. When a TNF inhibitor helps a patient, let's look at their blood and figure out why, and then maybe we can learn something for the next patient. I think it should be bidirectional—clinical observations and in the lab—and let it go in both directions.

I also want to share about another patient named Joseph, who has a rare cancer called POEMS syndrome. His girlfriend Tara reached out to us in one of these sort of Hail Mary attempts because his doctors were getting ready to take him off life support because he was dying from his POEMS syndrome. We recommended three drugs that are typically used for multiple myeloma. We mentioned myeloma earlier. Myeloma and POEMS are really, really similar. Again, it wasn't rocket science to recommend three drugs that are used for a really similar form of cancer for his condition. But he was dying. His doctors were afraid to try chemotherapy. They were worried that the drugs themselves would kill him. But they were going to take him off life support, so they tried it. He responded incredibly well. He's been doing great. It's been over a year and a half of remission.

I mention all of these examples because each one of them teaches us something else about this. They're similar conditions, yet we weren't thinking creatively. There were no treatments for POEMS syndrome, but there were treatments for myeloma. There are shared mechanisms between the two. Some doctors are doing this, but we have to create a system where we uncover these and then get it out to the masses so they use them.

Andrew Huberman: The fear is that you try one of these novel drug applications—existing drug used in a novel way, to be very specific with the language—and a patient gets sick or dies. It wasn't but maybe a decade and a half ago that a kid was given gene therapy and died. That delayed the whole field of gene therapy by a very long time. All it takes is one patient death. In the supplement realm, I don't know if you remember this, but tryptophan—the amino acid to induce sleep because it's in the serotonin synthesis pathway—the binders used in a particular batch of tryptophan that was sold out of Japan ended up being contaminated, and somebody got very ill and died. You couldn't buy tryptophan for a long time. Tryptophan is not as critical as life-saving drugs, but all it takes is one bad situation and the whole thing gets vaulted for a very long time.

So how do you mitigate that risk? Is it by only focusing on patients that are really at the end of their rope in terms of possibilities? It seems to me that the medical community has been pretty open to what you're doing, but I have a little bit of a traditionalist fear voice in the back of my head. What if you start giving aspirin to kids with this other condition and kids start getting really, really sick and you can't pull those symptoms back? Because it's one thing to halt a drug and symptoms stop. It's another to halt a drug and those side effects persist. God forbid a kid dies. So what you're doing is extremely exciting, but it's also risky.

David Fagenbaum: You're asking all the right questions. There are a couple of ways that we think about this. One is that we really do try to avoid the Hail Marys. As you mentioned, lots of people are reaching out to us. Unless we have solid evidence about a drug for that disease, we don't want to just speculate. Because to your point, speculation can actually lead to harm. There's a fine line between speculation that could save a life and harm. We are only doing what we're doing to help people. It's a nonprofit organization. We literally exist just to help people. There's nothing else to it. So we definitely don't want to cause harm.

One part is that we focus on looking across everything versus everything—every drug versus every disease—to find the best opportunities, and then we move them forward in a really rigorous way. We do laboratory studies, we do clinical trials, we evaluate the results of those trials, we look in observational data so we can be really rigorous about the things that we advocate for at the end of the day. That's one way to do it. The other thing to consider is that there's always a physician prescribing the medicine to the patient. The best thing we can do is to educate those physicians and those patients on what it is that maybe we found in a clinical trial or in the lab works, but it's still got to be a decision between the patient and their physician.

Andrew Huberman: What about outside the domain of disease in the domain of health? Very brief anecdote. Some colleagues of mine don't like it when I tell this story, but I'm going to tell it anyway.

David Fagenbaum: Love it.

Andrew Huberman: Many years ago, I went to visit Columbia University School of Medicine. Columbia Med is a fantastic place. There's a Nobel Prize-winning neuroscientist there. I met with him to discuss his work. He happens to be an MD, but he's a researcher. I noticed he chewed six pieces of Nicorette inside the 45 minutes we met. So I asked him, "What are you doing?" The guy was in his late 60s then, now he's in his late 70s. Very, very sharp. The Nobel Prize wasn't an accident. He looked at me like this and said, "Nicotine is protective against Alzheimer's and Parkinson's." He said smoking will kill you, but nicotine isn't carcinogenic. Nicotine, despite raising blood pressure, protects dopaminergic neurons and cholinergic neurons. "That's why I do it." He said he used to smoke and he was much sharper. Now he uses Nicorette.

I thought, "Should I use Nicorette?" So I said, "Should I be doing this?" He said, "You're young. You probably want to wait until you're in your sixties or seventies. But it's protective against Parkinson's and Alzheimer's." He also said, "Don't get your head hit. Don't play football." So I took that and decided, "All right, someday I'll chew Nicorette." Now nicotine is all the rage. I actually don't suggest that most people take nicotine because of the blood pressure effects. It's a constrictor. There could be other things. It's very, very popular, but very, very habit-forming and addictive. So I want to be very clear about that.

But I realized there are really smart people inside of my profession who have medical degrees who are doing things to promote their health, like take lithium—not continuously, but for one or two months per year. I know a colleague doing that. A colleague taking nicotine is now in his late 70s and still very, very sharp. You can't be the control experiment for yourself. But what I want to know is: do you think that there are things of value that people can and should explore to maintain or promote their health, to avoid disease, in the same kind of framework that you're approaching the treatment of disease?

David Fagenbaum: Absolutely. I think we need to be as rigorous in this realm as in the world of treating disease. I think the challenge is that there's such limited data. Like you said, your one friend is doing really well, but it's hard to know: was it because of the Nicorette, or was he going to be fine either way?

Andrew Huberman: I just think we got to figure out ways. And I think you've done such a great job of spotlighting these opportunities. So that way people will think about it more and actually will do further investigation.

I was thinking in terms of this prevention side of things, of course, about GLP-1s. There's interesting evidence emerging, and you'll know better than I will, around improvement in Parkinson's symptoms in patients that are on GLP-1s and have Parkinson's disease. Improvements or reduction in risk of Alzheimer's and also breast cancer in people who are on GLP-1s. There's likely a very complex interplay between weight loss and maybe the GLP-1s are reducing risk of these things because of metabolic effects. Maybe there's direct effects. Maybe it's anti-inflammatory.

So these are preventative concepts with pharmaceutical products that I think we need to be thinking about. And to your point, there really isn't an actual line between natural and pharmaceutical. I mean, think about the drug I'm on, serolimus. It's called rapamycin because it was found on the island of Rapa Nui in the soil of – I don't know if you know that story.

David Fagenbaum: It was found in – so rapamycin or serolimus, the other name for it, was found in the soil of the island of Rapa Nui. There was a researcher at Wyeth Pharmaceuticals who was going all around the Pacific Ocean to a bunch of different islands and picking up soil samples. He thought that maybe he could find some drugs in the soil. He eventually found this molecule now called rapamycin where they synthesized a bunch of it. It's completely naturally occurring from – and the other name for Rapa Nui is Easter Island. It's from Easter Island.

So they synthesized it and initially thought that it might be a good drug as an antifungal, but it's a lousy antifungal. They tried to figure out what else it could do and they found out that it's a really potent immunosuppressant. In fact, the research into the immunosuppressant role ended up really accelerating understanding of how the mTOR pathway works in the first place. It's an amazing story that was done on Radiolab about how at one point it was shelved, Wyeth and Pfizer decided not to study it, and then it sort of got taken off the shelf and it got approved for organ transplant rejection.

I just think about something like that. If that scientist hadn't picked up the soil sample in Rapa Nui, I'm not sitting here with you talking to you. Incredible. And of course, there's thousands of people all over the world who aren't sitting here talking to anyone because that drug wouldn't have been discovered and it was in the soil. It's not some pharmaceutical synthetic thing. This is a totally naturally occurring compound.

So I think the line that we put between creatine and serolimus and GLP-1s, there's a lot of overlap here. And yes, some of these molecules are very much synthesized. You think about the chemos that I've gotten, they're horrible compounds that you probably don't want to put in your body. But it's a lot grayer than I think we like to think it is.

Andrew Huberman: I think the term is bioprospecting. When people from pharmaceutical companies go out and look for things in nature and then develop drugs from them. We had a guy on here, very impressive guy, Chris McCurdy, who's down in Florida. He studies kratom and kratom leaf products. Kratom is being sold as a kind of natural opioid replacement. I just should, anytime it comes up, I have to be very careful because you all cut clips and you take them out of context. I'm going to just, I've learned how to guard against that, forgive me.

But Kratom products and the Kratom leaf have been used by some former prescription opioid addicts to get off those prescription drugs. However, it's very clear that a lot of these products, which are sold over the counter in convenience stores, corner stores, 7-Eleven, et cetera, CVS, can also be highly addictive alone. And they're sold to kids. It's a serious, serious issue.

But the kratom leaf, kratom, I think is the way it's the traditional pronunciation, contains a bunch of different plant alkaloids. The synthesized purified kratom is the one that has this pain relief aspect that also can be very addictive. We discussed the coca plant and cocaine, but also other elements within the coca plant that he runs a laboratory that are being isolated and being tested for different pain relief and psychoactive properties that can be very beneficial to people.

So bioprospecting is something that drug companies don't really discuss a lot. But the way they're doing this is going into nature, looking at the kratom leaf, the coca plant. Mucuna purines is this velvety bean that is 99% L-DOPA.

David Fagenbaum: Oh, really? Wow.

Andrew Huberman: Yeah. You can buy this over the counter. So the line between supplementation and prescription drug is very, very fine. It's just that there's no control over the over-the-counter stuff. And so this is where it runs into problems and gets a bad reputation. And understandably so, we don't want people harming themselves with this.

I'm beginning to think that what's really needed. And people in the current administration do listen to the podcast. I don't know if they, what they do with the information, but I think we need more thoughtful, safe bioprospecting to develop drugs that can be tested in preclinical models. Preclinical means animals, folks, and then eventually clinical trials. But I don't know that we have the time for clinical trials on all these bioprospective molecules or even the molecules that you're talking about, which are already FDA approved. It sounds like a lot of it just has to be run in real time in people. Like the experiment in some sense has to be done in humans. I just don't see – otherwise it's going to be another 50 years before we have a cure for Alzheimer's or we solve some of the most serious psychiatric illnesses.

David Fagenbaum: I agree. The answer comes from actually testing these things in humans. There are so many things that cure mice and that don't ever translate to humans and vice versa. So I think that I'm really bullish on the idea of leveraging the world's biomedical knowledge and using artificial intelligence to help to prioritize among all of these different things.

At the end of the day, we talk about the 4,000 drugs, the 18,000 diseases. The reason we do the scoring on everything versus everything is so that we can just know where to start. We rank everything versus everything. Maybe the fifth highest scoring thing is the thing to go after. Maybe the 10,000th highest scoring thing. The point being is that AI can at least help us to focus in on where do you start. Because to your point, there's so many opportunities of the existing drugs that we have, of the molecules that are already available in nature. But you need somewhere to start. And I think AI is really well positioned to direct us humans to where to start.

Andrew Huberman: Amen to that. Because in theory with AI, you could develop, I guess they call it in silico. You could say, let's run 10,000 cell cultures in parallel. The graduate student costs nothing. They don't need to sleep. It's AI after all. And with all the properties of this immune cell type, different concentrations of drug, and while it's not a real-world experiment, you can get an indication of what the outcome might be and what might be worth taking a better look at. Is that what you're imagining?

David Fagenbaum: That's right. And also, that's a true simulation where the work hasn't been done. And what also is the case is that, as you know, there are labs all over the world running experiments all the time on various cell lines and animal models and in humans. All of that's happening. So what I really am bullish on using AI for is not to simulate something that hasn't been done yet, but it's actually to find connections between what has been done.

So we know the example earlier that one lab found increased PD expression in this one form of cancer and this drug inhibits PD. So therefore, let's make a connection that no one had made yet. So there are two truths that hadn't been connected. A and B are connected. B and C are connected. Let's connect A to C. I think that AI is particularly well-suited to find these patterns of things that we know. So it's not a simulation. It's actually just connecting really like breadcrumbs into one story.

Andrew Huberman: You're a parent. I am. How do you navigate health care for a kid knowing what you know about medicine and knowing what you know about what medicine doesn't know?

David Fagenbaum: I'm a very rigorous parent of two kids when it comes to health care. I've got a 7-year-old and a 3-year-old, which it feels like a dream to be here talking to you 15 years after I went through all that I've gone through. It definitely feels like a dream that I'm able to tell you I've got a seven-year-old and a three-year-old. I'm just so lucky.

But like you said, I'm really rigorous. One of my doctors suggests, try this for my daughter. I ask a lot of questions. I try to really stay on top of things. And it sort of gets me thinking about something I was hoping to ask you about. Over the course of my challenges and the ups and downs that I've had in my health and the work that I've done to find treatments, I've found that I think there's this circuit that I'd love to get your thoughts on.

I find that it starts with hope. So I'm hoping for some future. Maybe it's that my child's health condition will be improved or my health condition will be improved. You start with some sort of hope that you hope something will happen. And then that drives some amount of action. Like in my case, I've run experiments on my own blood samples. And then that results in some impact that, maybe I learned something, maybe that drug is going to work for me. And that impact gives me more hope. And then it creates this circuit. So it's hope, action, impact, which gives you more hope, action, impact.

I haven't figured out exactly if there's some neuroscience behind this, but I found that for me, and just thinking about your question around whether that's helping your child with a medical issue that they're facing, or again, my own, that circuit has just been a game changer for me. I don't know if there's some neuroscience behind that that you can help me to understand this hope, action, impact.

Andrew Huberman: There absolutely is. And the person who deserves credit for revealing this circuit is my colleague Joe Parvizi at Stanford, who's a neurosurgeon. He was in the brain of awake patients, stimulating different brain areas in anticipation of a neurosurgery, like you described earlier, and had electrodes in a structure called the mid-singulate cortex. It's part of a larger network, of course, as is every brain structure. He noticed when he stimulated a sub-region called the anterior mid-cingulate cortex that patients would report in real time that they felt like there was some challenge kind of bearing down on them, like going into a storm. Each one described it differently, but that the stimulation also made them feel as if they wanted to lean into that challenge.

Now, here's where it gets really interesting. If he marches the electrode back a millimeter or less, completely different set of effects. Laterally, completely different set of effects. So the anterior mid cingulate cortex seems to be the seat of some sort of sense of tenacity to lean into challenge.

It gets really interesting when you start looking at the data of kind of volumetric imaging of this structure in people that, for instance, successfully overcome obesity through exercise and diet, or people who decide to undertake some other challenge, like a cognitive challenge or learning how to dance, something that's challenging. And then you look at the literature on longevity and you look at this group of so-called super agers, which is a misnomer because they actually age very slowly. What you find is that psychologically, they report a very strong will to live. And their anterior mid-cingulate cortex is one of just several areas that seems to maintain volume as they age relative to these age-matched cohorts.

None of these are perfect experiments on their own, but when you start to put these together as a collection of things, you realize that all the things that are the reverse of depression. What's major depression? A lack of positive anticipation of the future. Lack of understanding or belief, rather. Lack of belief that changing one's behavior could change circumstances, like get a job or new relationship or overcome something. And you see the exact inverse of that in people with a kind of naturally large or perhaps self-built anterior mid-cingulate cortex. These people report a lot of positive anticipation about some hopeful future event.

Wow. And it's not always a big monumental thing. Sometimes these are closer milestones. Sometimes it's a bigger thing. And they live longer and they have this incredible will to live. So it seems that taking this to its kind of extreme conclusion, the will to live sits somewhere in the network of this structure. It's not just this structure and it's intimately related to dopamine networks. So reward reinforcement and learning networks and all the rest. But it's hard to pinpoint one structure, but if I had to put a pin in one structure, it would be Joe Parvizzi's discovery of the anterior mid-cingulate cortex. And it has all the elements of, you described hope, plan, and action. Exactly. Repeat. Yes.

And so for people who are not ill or who are ill having that sequence. A good friend who was in tier one special operations in the SEAL teams, he described this as when there's a challenge, you have to shorten the horizon, get a forward center of mass, but think duration, path, and outcome. What path, how long, outcome, iterate. And it's the same way you work down a football field is the way you kind of lay through these challenges.

So again, I'm creating a tapestry from a bunch of disparate things here, but none of it is outside the realm of peer-reviewed science. It all sits there. So we haven't scanned your brain. I don't think we need to, to know that your anterior mid-cingulate cortex is clearly very robust. And I would wager the hypothesis that it was probably built and reinforced through your postering up of athletic goals on the wall of your childhood bedroom.

David Fagenbaum: I think you're right. I think you're right. The more you work, the better your times get, the better those numbers get. And then, as you said, it becomes a true circuit. The thing you're hoping for when you get closer to that thing you're hoping for, it drives you to take more action. And then you can keep going in that circuit.

Andrew Huberman: Well, clearly you are living in that circuit and it lives in you. Could you tell us about ways that people can get involved with EveryCure? I have to imagine more information is better than less. So what can people do?

David Fagenbaum: Sure. Anyone can go to everycure.org/ideas and tell us about a drug that you were prescribed off-label by your doctor. Maybe you're a researcher and you think that a drug could be used in a new way. So you can go to everycure.org/ideas, tell us about that medicine, and we'll look into it. We'll compare it next to our AI predictions and we'll determine whether maybe it can be moved forward.

If you're an expert, say in neuroscience or you name the area, you can go to everycure.org/experts and you can sign up so that if we find a drug that might be useful for a condition that you're an expert in, you might be able to give us advice and guidance on maybe what the right development path is.

And anyone who's watching can help us to raise awareness about the work that we're doing. So you can follow us on social media at everycure.org and beyond. I did a TED Talk recently. You can help us spread the word and check that out.

And finally, of course, people can support our work financially. We're a nonprofit organization. Clinical trials are expensive. You can go online to everycure.org/donate and donate to our work. We're just so excited for this opportunity we have to help people with the drugs that we have. But we realize that we can't do it alone. We actually really need the whole community to get behind us.

Andrew Huberman: Where is funding currently derived from? Is it just public support?

David Fagenbaum: Right now, about half of our funding actually comes from the U.S. government, from an agency called ARPA-H. They're one of our earliest supporters. And the other half comes from individuals who've decided that this is important. It may be that they have a loved one that has a condition that they would love for us to work on, or maybe it's that they just want to see us be able to help patients with the drugs that we already have. We are just so excited of that opportunity to match the drugs we have to the patients who need them.

Andrew Huberman: Fantastic. And I should ask, if a drug application is discovered, is there a feedback mechanism for you guys to derive income from it or this is a completely nonprofit?

David Fagenbaum: It's completely nonprofit. So I think by the end of the next few years, I will guess that nearly all of the opportunities that we advance forward are the same dose, the same formula. No one makes any money off of them whatsoever. I think there'll be rare cases where, let's say the drug looks like it'll be effective, but it needs to get into the brain where a tweak will have to be made, where a different dose or formulation will be needed. I think there'll probably be rare cases where probably a company will be needed to be spun out to do it. But for the vast majority, we're a nonprofit. We just want to take the drugs we already have to use them for the diseases that could benefit from them.

Andrew Huberman: Terrific. We'll put a link to it in the show notes.

David Fagenbaum: That'd be awesome.

Andrew Huberman: David, thank you so much for coming here today to share your story with us and just a ton of actionable knowledge for people that are healthy. Continue to explore options safely. Think about what's possible. Understand there are things that are known. There are a lot of unknowns. And again, explore safely. For people that are ill, find a disease group that really has an eye on what's new, what's existing, who the best people are. Search for a few of those is kind of what I took away from that.

And thank you for doing the work you do. It's amazing. We need more people like you. You're truly one of a kind. So we're immensely grateful that you've taken the hardship and transmuted it into so much good and love to have you back sometime to talk about all the other things we didn't have time to talk about, but this has been incredibly enriching for me and I'm certain it has for everyone else.

David Fagenbaum: Well, thanks so much for having me. Thanks for all that you do to advance the public health and also to get the word out about the work we're doing through EveryCure.

Andrew Huberman: Thank you for joining me for today's discussion with Dr. David Fagenbaum. To learn more about his laboratory's work and his nonprofit, EveryCure, please see the show note captions.

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