David Fajgenbaum (on repurposing medicine)

19:24The main thing has to be in threat. Yeah, yeah, yeah. Okay, so sorry. We go down the hallway. We go down the hall. They do some blood work. I'm a med student, so I'm used to being on the other side. It usually takes a while to come back and see the patient, unless there's something really serious, and then they come back really quickly. Yeah. The doctor comes back like 10 minutes later, or maybe it was 15 minutes, but it was quick. He said, David, your liver, your kidneys, and your bone marrow are shutting down. We have to hospitalize you right away. And I'm like, wait, what? I was just like, I delivered a baby a couple weeks ago.

19:53What do you mean my organs are shutting down? So they hospitalized me, and then over the next couple weeks, I go from my organ shutting down to being unconscious, gaining 100 pounds of fluid all over my body. Did you see the picture? 100 pounds of fluid all over my body because my liver and my kidneys weren't working. So everything's just backing up. You're not urinating at all, so the fluid's just going everywhere. I had a retinal hemorrhage, which made me temporarily blind in my left eye, so I couldn't see anything out of my left eye. Couldn't have thrown any passes. Depth perception's gone.

20:22That's exactly what I can think about, actually. I was like, darn it. This is going to really hurt my life. You want to know if you're throwing 10 feet or 25 feet away. And so I was getting so sick because of all the organs shutting down. I was on dialysis because kidneys weren't working. I was getting daily transfusions of red blood cells and platelets. They were just trying to keep me alive. And no one knew what the diagnosis was. In that state, is your white blood cell count just like off the charts? So white blood cell count was pretty normal at that time. I don't have a good explanation for why.

20:49White blood cells were normal, but the platelets and the red blood cells were just class. And you need platelets in order to prevent basically from you bleeding out at all times. Because you have these little microbleeds that happen all over your body, including your brain. And your platelets just sort of sop it up. Always. It's like fix-up all over your body all day, every day. And so when you get as low as mine, where you're in this critical state where you can have a little bleed in your brain and then you die from it. Let's take a second for your poor fucking father. Oh, my God. He loves his wife.

21:13And now he's visiting his... Yeah. He spent every night in the hospital room by my side. So, like, you know how they just, like, pull out couch things? This is horrifying. He spent every night with me. My sisters were amazing. Stay tuned for more Armchair Expert, if you dare.

21:52have one conversation with Alexa and it handles everything. Dinner reservations, entertainment, the works. It learns your style and puts thousands of services at your fingertips. What I love about this concept is how natural it feels. You're not barking commands, you're just talking. And it works across your compatible devices, Echo, Fire TV, and more. It's your all new, smart, proactive AI assistant. And honestly, the idea of having AI that actually anticipates what you need, that sounds pretty amazing to me. Check it out at amazon.com slash new Alexa.

22:31Also, you told your mom you were going to be okay. And then that was another promise. No, I thought about a lot. The promise I made sure I was like, I promised her I was going to help people. I was like, and I've just been like working, working, working to help people. Shocking up the system. I was thinking about that. Now you say it, like, darn. You know what I was thinking? I'm not going to help. I did all this training, and now I'm not going to help anyone. I told her I would. So with Francisco, he came in to see me. He, like, leaned in to give me a hug. And he's a med student also, so he has a stethoscope around his neck.

22:55And I remember it was, like, slow motion because he comes and gives me a hug. And I see the stethoscope coming because any sort of trauma to my body could create one of these bleeds. And I see the stethoscope coming, and it just, like, hits me, like, right between the eyes. And we're just, like, looking at one another. and for a split second, we're like, oh my gosh, did he just kill me? They're like, my best friend just like, just like hit me in the head with his tethoscope. And then we like, we're sort of still for a second and then I didn't black out because of an internal hemorrhage. And then we were okay and then we laughed about it.

23:21But it's crazy. That was what things were like back then when I was in the hospital. Yeah. Oh. Okay, so they end up giving you a crazy cocktail of chemotherapy. That's right. It was a last ditch effort. At this point, how long were you in the hospital? So I was in the hospital for seven weeks before they gave me, this first, First, they actually gave me high-dose steroids because we didn't have a diagnosis. So first, they gave me high-dose steroids. Things start to improve. And then four weeks later, it's roaring again. And this time is when I had my last rights read to me. This was now 11 weeks into my illness, right when we finally had the diagnosis.

23:53So diagnosed with Castleman disease, this rare disease where your immune system attacks your vital organs. Right around the time of diagnosis, they give me first one chemotherapy. And thankfully, that's enough to sort of hold things at bay. But then four weeks later, I'm back in the ICU again. and that's when they give me seven chemotherapies. So yeah, your own immune system's killing you. And so they need to carpet bomb your immune system so that's non-functional and that works. It does. The time they gave it to me now, it's the third time that I'm on death's doorstep. And they tell me before, you know, we're out of options so we're going to carpet bomb you with every chemotherapy we can think of at the highest dose possible.

24:27You know, I remember closing my eyes and being like, well, this is it. It's not going to happen. Hug my family goodbye. Was there any peace at any point during this? You know, I have to admit, during that six-month period, there was never a moment. Oh, actually, no, there was one moment apiece. But for the most part, it was this fight. Like, I can't believe this. Like, such sadness. With the diagnosis of Castleman, that doesn't get you shit, right? Because there's no real treatment for Castleman. Do they even know? I got quite curious whether we think this is a genetic condition or environmental.

24:56Do we have any sense of how Castleman comes about? Yeah, so my step-step is called idiopathic. Multicenter Castleman's idiopathic means we don't know the cause. You don't ever want to have a disease that's called idiopathic. But we do know that even within a deopathic, that about 5 % of patients will have a family member with Castleman's as well. And so those people, we feel pretty confident there's some sort of genetic heritability. But in the rest of us, we don't know what triggers this. I run a lab and our lab does spend time trying to figure this out. And we have found some what are called somatic mutations.

25:23So they're basically not mutations you're born with, but mutations you acquire over the course of your life. It's in the same way that cancer occurs because you acquire mutations in your life in those cells. were observing somatic mutations in Castleman's patients. And where is that centered? Generally in the lymph node. And part of the reason that that makes sense is that the lymph node is sort of the home base for your immune system. So like if you're fighting an infection, you'll notice your lymph nodes get enlarged. And that's because your immune cells are fighting something and they go back to the lymph node and they talk to one or they communicate and they go back and they fight.

25:50They come back and they go out and fight. And so the lymph node is like the home base for your immune system. And so we think these are occurring in the lymph node. Therefore, all these immune cells are going out and wreaking havoc. So they're leaving mutated. And so they're not good at reading its own DNA. The big thing is that in both of your immune systems, you want your immune system to be in surveillance mode, which means it's turned off looking for bad things. And when it sees a bad thing, you want it to kill that bad thing. Then you want to turn itself back off and go back into surveillance mode.

26:18What we find in Castleman's is that our immune system turns on and then it doesn't turn off. And when your immune system's on and it's releasing all these bad things, it starts attacking healthy, good things like your heart, your lungs, your kidneys. That's autoimmune disorders in general, right? And autoimmune disorders typically are focused on one particular organ or one tissue type. So it might be the joints or it might be the heart. I have psoriatic arthritis. Yes. And so that's your skin and it's also your joints. And so Castleman's is like that, but it seems to be more nonspecific. It's not directed at the skin or the joints like in psoriatic arthritis, but it's more general.

26:51All over. Okay. So this intense carpet bombing works, but it works for how long? for about a year. So now I'm out of the hospital for a year. I'm back in med school. And by the way, my girlfriend, Caitlin, and I were dating. And somehow she wants to stay with me during all this. You look rough. You did a 180. I did. I did. Yeah, yeah. Well, yeah, you had 100 pounds of fluid. And that kind of distended stomach you get when you have... I forget what condition that's called. But yeah, there's a lot happening. A lot's happening. Yes. When do we put the MBA in the mix? So the MBA comes two years after I get sick with Castleman's because I spend the next two years, certainly bad on my disease, but also when I have this relapse after I get the carpet bomb chemo, I decide I'm going to dedicate my life to trying to find a cure for Castleman's.

27:34But it took getting the carpet bombing and then I was actually put on an experimental drug that I would hope would keep me in remission. And it was after it didn't work that then I was like, I got to dedicate my life to this. And then it was in the course of trying to figure out a cure for Castleman's that I realized that the barriers in the way of a cure for Castleman's were not science and technology. They were like, can you get people to work together? And can you collect enough blood samples for research? And can you come up with the right strategy? And can you raise money? And like, these are organizational business problems.

28:02And I was like, oh, the science is clear. The administrator stuff is going to prevent me from solving this disease. And actually, I mentioned that experimental drug is called Siltuximab. And it's hard for me to put into words what it meant when I got started on this drug, because Caslam is a rare disease. So there's 18 ,000 human diseases, and more than half of them are very rare. And so like, you probably never heard of literally 10 ,000 plus diseases ever. Caslam is one of those, super rare. and it's very rare for them to have a clinical trial of a drug that might work. Like 95 % don't have any treatments.

28:29Mine actually had a trial and I was like, oh my gosh, I know there's no solutions, but maybe this drug's gonna work. I was so hopeful and I got put on it after the carpet bombing chemo and I really believed and hoped that it would keep me in remission. And then a little bit over a year later is when I had that relapse and it all came back. I'm back in the ICU with all my organs shutting down and that was so difficult emotionally to go from like, I think we got it, like this is the thing. And I think it's going to keep me in remission. And I actually met other patients who were in remission. I like saw them.

28:57They told me how they were in ICU for months. One person had part of his bowel resected. He had all these strokes and he was walking around on this drug. And I was like, oh my gosh, I can be like him. And then when it came back, it just wrecked me. True vulnerability hits when you relapse like that. And you had three relapses in five years? The total of four relapses of five episodes of this disease. And each one was so difficult for the emotional parts. I mean, obviously there was the physical part. I'm in the ICU. Because for each of them, I'd gotten really hopeful. And I was like, we did it.

29:25And then it just all came back. Okay, so when do you get the kind of breakthrough thought that maybe I should approach this in an off-label way? And let's just talk about off-labeling in medicine and how that works. It was during that big relapse. And now this is flare number four. So the third relapse. And my doctors explained to me, okay, you've now failed to respond to the only drug in development. Like sultoximab is it. There's nothing else. It didn't work for you. He said, all of your organs are shutting down. I'm going to try the same seven chemotherapies again. There's just a few problems.

29:53One is that who knows if they're going to work again. You know, you've gotten them multiple times. They tend to lose their effectiveness as time goes on. Two, you're approaching the lifetime maximum of a drug called atriomycin. There's only so much of these chemos that you can actually get before they cause cancer and organ dysfunction on their own. So you're approaching your lifetime max. I don't know how many more times we can do this. And the third thing he said was, we've tried everything. There's nothing more we can do. And my sisters and my dad and my girlfriend, Caitlin, were sitting in the hospital room.

30:18And I remember we were just heartbroken because he's telling us... End of the road. Yeah. This is it. Like, this is it. And we're crying and it's horrible. And around maybe a minute or two of just like us all crying and bawling, I just remember thinking to myself, I'm like, wait a minute, you just gave me seven chemotherapies and none of them were made for Castleman's. They were all made for lymphoma and myeloma and they worked. I know I keep relapsing, but how do we know there's not like an eighth drug out there? Did we try all the other drugs? There's 4 ,000 drugs. 4 ,000 FDA approved prescriptions one could be given.

30:47Exactly. And so I've gotten 10 of them now between the different drugs. There's nothing. Still like a lot left. And not to say every drug is possible, but how can you tell me that we've tried everything? We're at the end of the road. If I hadn't benefited from those seven, I wouldn't have thought that. They'd be like, oh, nothing else is going to work. I'm like, okay, they're probably right, nothing else will work. But they gave me drugs that were working. So that became really clear. So I told my family, I was like, I'm going to dedicate my life to trying to find a drug for this disease. And they sort of were like, all right, Dave.

31:11Weren't particularly optimistic at that moment. As someone who loves someone going through that stuff, you're always really having a hard time debating whether or not you're going to snuff out their hope or help them get to the part where we have closure. That's what you're trying to navigate. Like, no, my love, it's time for us to take stock of all the good stuff and have as much gratitude as we can have on the way out. It's hard. It's really hard because I also think back with my mom, probably two of the most important months of my life were the two months after the cancer was coming back where we just were like present with one another.

31:40We were like looking at old home videos together. Not fighting. Exactly. And then I like, look at how I've handled this. I'm like, wait a minute, I didn't do that at all. We watch no home videos. I was like in the lab trying to figure out is there a drug that could save me? And I'm like fighting, fighting, fighting, right? It really was. I was like, let's go. So yeah, it's hard to put those two things together. So once you have this idea, where do you start? There's 4 ,000 drugs. You start doing classes of drugs. How do you start weeding out? Great question. So the first thing I did was to try to start to understand what does the world know about this disease?

32:09And so there were 2 ,000 papers. I read those 2 ,000 papers to try to understand what do we know about Castleman disease? Second, I connected with all those doctors for all the papers that were written to try to start connecting them through an organization called the Castleman Disease Collaborative Network. So I created this nonprofit just basically let's centralize all the doctors, the patients, the loved ones. Let's get an understanding for what do we know? Because I even heard there was a doctor in Japan that was trying this one drug. I'm like, well, I want to try that drug. How are you doing all this?

32:32Weren't you so tired? I mean, your organs are in flux. How are you doing this? I should mention that I did none of this for the month that I was in the ICU. So like I made the promise to my family and then I'm out for the next four weeks fighting for my life. But it's then once I started to make it through that, that then it's like, all right, let's get to work. And so started reading papers, started reaching out to doctors. So coming up with sort of this network. And then the second thing was, let me look at all the related diseases. These are kind of like Castleman's that are weird immune disorders, like psoriatic arthritis.

32:59What's out there? What are all these drugs that exist for other conditions? Because we would agree these labels are arbitrary. They are very arbitrary. There's a doctor dealing with six patients over here that calls it this thing. It could be the same thing, right? Exactly. And the drug companies, when they pick a disease to pursue, they've got a lot to pick from. Like they picked the IL-17 drug for psoriatic arthritis, but they could have picked a lung disease with the same drug. And they pick for a lot of reasons that have nothing to do with biology and nothing to do with whether it's going to work.

33:23It's like they have to figure out the most profitable opportunity. Yeah, kind of market. Just because it's not approved for it doesn't mean it's not going to work. So my mindset was, okay, let's figure out what we know about Castleman's. Let's start looking at related diseases that are like Castleman's. And then the last bucket, which was probably the scariest, or at least the most challenging was I'm going to start collecting blood samples on myself and start trying to do research on my own samples. And the reason that was scary is because I didn't really know all that much about laboratory research.

33:47I found this amazing colleague at Penn who gave me some space in her lab, but I could do the first two. Like I could build a network and I built that organization AMF. I could understand what other diseases there were, but like starting to do experiments, that was certainly the most challenging. And so, yeah, over the next year, built out the network and started identifying, you know, potential related drugs, was storing my blood samples every couple of weeks in the lab. So as opposed to you taking one of the medicines and monitoring your symptoms, you were actually able to apply the medicine to your blood in some kind of a Petri dish and observe it?

34:16So what I was doing was actually trying to understand in my blood samples, which of my immune cells were turned on? What were the proteins that were elevated in my blood versus healthy people? And see if that could give me a fingerprint for what was wrong in my disease. My idea was that if I could figure out what was wrong, I could then see, is there a drug that can reverse the thing that's wrong? Like if something's too high here, find a drug that can maybe make it go down. Yes. That was that third bucket in my mind that I wanted to do. How hard was this to figuring out which of these T cells or immune cells were the ones that were problematic?

34:48That feels hard enough right there. It is hard. I didn't even get to the third bucket before I then had my fifth relapse. I was just storing these samples. So by that stage, I started business school because I'd finished med school and I had this relapse. And I had this long spreadsheet. And I remember now I had a couple of drugs at the top that I thought maybe we should try. because they were used in related diseases. I hadn't yet done the experiments in my own blood to figure out what could be maybe useful for me. And I remember I talked to my doctors about trying this one drug called psychosporin.

35:14We tried it, we were so hopeful, and then it didn't work at all. My disease was just roaring through it. Organs were shutting down. All the markers were bad. I was getting like worse and worse every day. And then I asked my doctors to try it. The number two drug on my list is a drug called IVIG. It requires an infusion. I remember I'm going to get that infusion. And my doctor who I asked to do this, she asked me, she was like, do you want some fries for that order, David? because I'm like asking for this idea. That was going to be one of my questions. Like, were you able to prescribe yourself this stuff because you had your medical degree or were you reliant?

35:43And how hard is it to get other doctors to sign on to this approach? I was reliant on the other doctors and it's appropriately hard to get these medicines, right? Like it should be hard. You know, it shouldn't just be the drugs get thrown all over the place. But while it was appropriately hard and I needed to show them evidence and reasoning, I was dying. They'd already told me they tried everything. They told me they didn't have anything else for me. So I'm telling them things that maybe we could try. You're like, I'm here to be a lab rat now. Exactly. And I was willing to take on all the risks.

36:09I was like, I know that the drug could kill me, but I'm not going to live much longer. And so the IVIG, they gave me the infusion. Everything stopped. All the things that were getting worse halt. In like what time frame? Within a couple of days. So like it's halting and I'm with Caitlin and we're engaged and we're like - Are you scared to trust it as well though? Yeah. I sort of wish I was. You're just so hopeful. You're so nice. I was like, IVIG? I remember literally saying the words, we did it, Caitlin. We did it. And so a couple more days go by and then all of a sudden, things start getting worse again.

36:43I'm like, this can't be. We're going for blood work. It's getting horrible. Within a couple of weeks, now I'm back in ICU with everything shutting down. And I just tried the two things that were like the top of our list. I gave it my best. I wasn't ready to like fully accept it, but at least we tried it. And I had the feeling like we tried and we failed. And then my doctors gave me the same seven chemotherapies. This time they gave me the highest dose they'd ever given a human of this one drug called a Tobicide. And I remember saying goodbye to my family again and saying goodbye to Caitlin. I was just heartbroken about it.

37:12And Caitlin and I were supposed to get married five months later and I felt like I'd failed her. She wasted all this time. Yeah, I mean, she'd been with me for all this time and she was just amazing. I remember sort of starting to close my eyes and let go. I remember falling asleep and realizing that this was it. And a couple of days passed and that crazy intense chemo worked just enough. Like I squeaked by. I remember starting to wake up and just being shocked. It was a lot of feelings. Like one was shocked. Another was, oh my gosh, this is so exciting. Like I'm, ah, it worked. The amount of times you've said it worked.

37:47But this time I didn't say it worked. I was like, this is what happened just a couple weeks before. But then it was immediately the sense of urgency was like, okay, I've got a window. I don't know how long it's going to be. I turned, my sister Gina was on my left side and Caitlin was on my right side. And I remember turning to Gina and I was like, hey, G. And they were like, oh my God, Dave. I was like, hey, G, can you go downstairs and see if you can get that lymph node? They just cut out and send it to Philadelphia. And I was like, and Caitlin, will you call UNC and send those blood samples to Philly?

38:13Can you get the records to go down too? And they're both like, what? And I was like, because I'm getting out of here. I was like, and we got to find a drug for this thing. And so it was about three weeks of me recovering. Just like, I got to get to Philly. I got to get to Philly. I got to get to Philly. So I got to Philly and I thought the blood samples and started doing experiments. This is when I was now in that third bucket, which is what are those immune cells doing? What proteins are too high? I spent about three weeks doing experiments. And by the end of it, I was pretty convinced that this one part of my immune system called mTOR.

38:39So your immune cells, they're all over your body, literally billions of cells. They have to communicate with one another and be able to let cells in different parts know what's going on. One of the key communication lines in your immune system is called mTOR. The research I had done on my own samples suggested it was turned into overdrive. There's like too much mTOR on. You can imagine like if your fire alarm is mTOR and it's saying like there's a fire here and it's stuck in overdrive, your immune system is going to go berserk. In my opinion, the data suggested it's a false alarm. Like the alarm is going off.

39:04It's going berserk, but there's nothing to fight. So when I saw this result, I got so excited because there are drugs that are called mTOR inhibitors. They've been around for decades. They actually were made for organ transplant rejection. Because if you get a kidney, your immune system will attack that organ and it'll turn mTOR on. But if you turn mTOR off, the alarm goes off and you don't attack that kidney. So I was like, oh my gosh, we can try an mTOR inhibitor. And so I took the data to my doctors and they prescribed me this mTOR inhibitor called serolimus. It was like a 10-year-old drug at the time?

39:32Been on the market for 15 years. Yeah. Sort of known for a few decades. And yeah, now it's been over 11 and a half years that I've been doing great on this medicine. Wow. No relapses, full health. Yes, let's start knocking on the way. The question I don't want to ask, but I got to ask is, how many of these drugs your body kind of adapts? How long is it going to work for? Yeah, it's the right question. I mean, I think that what's so crazy is how long it's been. Well, to me, 11 is like, you've definitely passed that window where it's tough stuff. But you can imagine that every day that went by afterwards, I used to measure someone and be like, how long have you been in remission for?

40:04And I'd be like 37.29 months. And they're like, what? You're like someone in sobriety. Yeah, I'm like, I can't round up. You don't know what's going to happen tomorrow when you're going through these sorts of things. But I know it's been like 28.29. And so the months added up. I made it to Kayla and I's wedding day, May 24, 2014. 2014. My hair grew back just in time for the wedding. It looked like a buzz cut, but it was back in time. And yeah, the months have just sort of stacked and stacked. Okay. So you come out of this and I don't know in order, but you get a job as a professor at Penn in the medical school.

40:34That's right. And you have a lab. Yep. And you decide to really dedicate yourself to exploring these other 18 ,000 diseases with these 4 ,000 medicines that exist to see what off-label stuff could exist. Are you immediately employing AI? When does AI enter the picture? Because it's got to be almost impossible without AI. Yes, that's right. So the moment that Sierra Lima started helping me, I just remember having these flashbacks to walking past the CVS and being like, wait a minute, it was in there. All those three years that I was dying from this thing and all those five times I said goodbye to my family, it was in that CVS.

41:10And I just never knew it. No one knew it. Stay tuned for more Armchair Expert, if you dare.

41:27Are you kind of like, why didn't all these doctors figure? I'd be mad. You would. Well, I'm just in here doing my own blood and testing. Why aren't these other doctors doing that? I think you have to acknowledge how myopic the field of medicine is. You are an oncologist. His father's a surgeon. You're not in the synthesizing generalist business. You're in the specializing business. And generalizing and synthesizing is so hard. This is why people were freaked out, you know, that Homeland Security was tapping everyone's phones. And so it's like, it's a fucking joke. Nothing can synthesize all this information.

42:01You can gather information all you want. But to actually find patterns within information is so time consuming and nearly impossible for a human to do. I completely agree. And then also the incentives are the other problem for why this doesn't happen. You're not going to launch a new drug. Hopefully you're going to pick up another few patients, but it's going to be a few. So the pharma company is not incentivized to figure this out. That's exactly right. So once I started, oh my gosh, how many drugs are out there? It's like, okay, this worked for me. Are there other drugs out there for other people?

42:28And I'm just thinking about like the patients that I took care of in med school, where we said, this is it, we're out of options. Like, well, maybe we weren't. Maybe there was something else. I think about my mom. Maybe there was something that could have helped her. I'm going to add too, it's not a sexy idea. No, not at all. It's like recycling old drugs. We like inventions and breakthroughs. We don't like hearing the fucking answer was sitting next to us the whole time. Well, unless you have the ailment, then it's really sexy. Like it's already here. Yeah, yeah, of course. It's just our nature is to want the breakthrough and the next thing and the next clinical trial and not, hey, we already had it.

42:58That's exactly right. The people who are doing the work are not incentivized. It's the patients. Like we are incentivized to do it. We can benefit from it, but the people actually doing the work are not going to benefit from it the same way that they would a new drug. So decide that, okay, this is what I want to do with my life. I want to find new uses for the medicines we have. I want to save people with treatments that already exist just in the same way that I was able to be saved. And so joined the faculty at Penn. And of course, we started focusing on Castleman's and other related rare inflammatory diseases, rare cancers, rare autoimmune conditions.

43:25Because there's some weird overlap. That's exactly right. So Castleman's is very similar to multiple myeloma, it's similar to Poeum syndrome. There are these weird inflammatory conditions and cancers that overlap. And so start studying them and we start finding more repurposed drugs. I'm like, wait a minute. know, there's more for Castleman's and there's more for Poem syndrome. Sadly, you had recommended to another guy suffering from Castleman to take what just worked for you and you were so excited to share it with him. And then it worked for a minute, but it didn't work. It worked in some Castleman's patients, not in others.

43:51I remember the first Castleman's patient that I got to see because we treated patients in various parts of the world, but that I actually got to see in person, a young boy named Joey who responded incredibly well to it. So of course, Monica, you're going to laugh with me that here I am again, like we figured it out. Castleman's just taken care of. Look at Joe. We're like, it's working for everyone. We're done with Castleman's. I was directing the sitcom version of this. Like he would always pop champagne. And it's like by the 20th time we saw him pop champagne, we were laughing so hard. I know.

44:15But you need that spirit actually. It takes that. It's essential. Type of mentality. That's right. Thank God. So we start helping these other people and then it's other diseases. And so angiosarcoma, this horrible cancer, we find that there was research that was done three years earlier about a potential drug that could be useful for it, but it was done in the lab and it was never given to a patient. and we treat a patient with it and it works for him. And like he has this uniformly fatal cancer and actually this person is actually my uncle. And so that's even why I was thinking about it. My uncle Michael, he got this horrible diagnosis.

44:45Everyone dies within a year. I hate to be. No. This is too much stuff in your family. You guys all on a well. Like some point I get suspicious of your environment. This is like a definitely disproportionate amount. We've had a lot of suffering. Yes. So figure out that basically this work had been done three years earlier but no one ever tried it in a patient. So we get Michael on this drug. It works incredibly well. Last month, he walked his daughter down the aisle on her wedding nine years later. Wow. This is crazy, incredible. So start giving it to other patients. It turns out it works in about 18 % of patients.

45:15So it's not everyone, but 18 % it works in, it's everything. You're living years instead of weeks. And so that for me was this major eye-opener. The other drugs we've discovered, the repurposed drugs, we did a lot of hard lab work to figure it out. Doing experiments in my blood and other people's samples. But we didn't have to do anything for Michael. We just had to find a paper that someone else had published and everyone had just disregarded because like you can't read millions of papers a year and stay on top of everything. And so here I was like, wait a minute, maybe there's actually breadcrumbs that are already out there.

45:42So we don't even have to do all the crazy hard lab work. And so that was a really important moment for me. And fast forward over these 11 years, we've now advanced 14 repurposed drugs for a number of rare diseases. We've saved thousands of lives, including angiosarcoma patients. But about three years ago was when artificial intelligence was really coming on the scene. And to your point, We could do 14 drugs for rare diseases, saving a few thousand lives. But AI actually would allow us to say, like, instead of looking at these few diseases, we actually can look at all 4 ,000 drugs and all 18 ,000 diseases and let AI actually give us a score globally.

46:17Every drug, every disease in a way that one lab never could, one person never could. And so that was the big unlock. The whole school, if you dedicated the school, no, couldn't do that. It would be impossible for humans to do. So three years ago, my best friend from medical school, Grant and I and Tracy Secor, we co-founded EveryCure, this nonprofit, with the idea being that we want a nonprofit that's on a mission to save lives with the drugs we already have. It's here to unlock the potential of the treatments we have to treat the diseases that ail us. And we use AI to actually quantify every drug to treat every disease.

46:45So there's 4 ,000 drugs, 18 ,000 diseases. That's 75 million possibilities. If you tried every drug and every disease, you do it 75 million times. We get a score from zero to one for every one of them for how likely it is to work. Yeah, so what's the max out of that zero to one range? I read that and I was just curious. what do you see normally or what's outrageous? Like a 0.7 is like, well, we got some. It's a good question. It's a fairly linear scoring system. So there's actually a lot of 0.9999s. The idea being that we want to look at the 0.99s. The whole point of the score is to always say like, what are the things at the top?

47:17Because if you start with Castleman's only, it's like, well, you might find the best drug for Castleman's, but is that the best drug for humanity to use? Is that the best match between a drug and a disease? Probably not. But if you do this all versus all, to your point, like you can look at the things that are the 0.99s and you come across things where like, really? But then you dig into it deeper and you figure out how it might work. This vitamin that you discovered had an impact on nonverbal autistic kids. It seems impossible. Yeah. So a portion of kids that are nonverbal and or have other neurodevelopmental challenges, often in speech delays, they actually can have a antibody against the folate receptor.

47:50So folate is important for brain development. And in order to get folate into your brain, you need this receptor to be functioning. But if you have an antibody against it, basically the vitamin doesn't cross into the brain, these kids can have what's called a cerebral folate deficiency. And so interestingly, there's a derivative of folate called folinic acid. It was made for people that are on methotrexate chemotherapy, and it's been around for decades. But that derivative of folate can actually bypass this blockage at the receptor and can get into the brain. Can leapfrog this whole... Yeah, there's something called the RFC, which is a channel right next to the folate receptor.

48:19And so if the folate receptor is blocked, but if you give the derivative of folate, it can go through this channel. So basically leapfrog, get in the brain. And that was a really important discovery that humans made. Let me just do it really quick. So that makes total sense. There's this thing inhibiting this vitamin required for this part of the brain to function. But in the absence of that, wouldn't that portion have already been so atrophied, it couldn't be brought back? Or it's just there and it needs that as fuel? It's a good question. We don't know the answer to it. All we know is that work's been done to show that some of these kids have too little folate.

48:48We know that the reason they have too little folate is because of the antibody receptor. And then the really interesting thing is that there have been multiple clinical trials now, all relatively small, that have shown that giving this derivative folinic acid can improve verbal communication to these kids. Wow. Is it just a pill? It's just a pill. Yeah, give the example. One kid was nonverbal for five years. That's Ryan. Ryan was basically nonverbal for five years. He could do something called echolokia, where if someone said something to him, he could repeat it back to them, but he could never actually share his own.

49:12He'd never made yet an executive communication where he made the decision. He had receptive communication. So he had a lot of things in his mind that he wanted to say, but he couldn't say them. within two weeks starting lucavorin, he told his dad for the first time ever a statement. And he said, daddy, I love you. Oh, you can't even write down. That would have killed dad. I was like, I cried for the next 15 minutes. I couldn't do anything. Can you imagine? He couldn't even leave the house. Yeah, my kid's first sentence would be like, I want to go to Target, I think. Oh, because he's been stuck wanting to say that.

49:41And also like, should Ryan have had behavioral issues over the years? Of course, if you had all your thoughts and you couldn't fucking get them out to you, I would rage. Could you imagine? But there's been multiple success stories. There have been multiple success stories. And actually, there's another patient, Mason, who within three days of starting it, he said his first word. And just thinking about what my kids would say, his first word was more. And I feel like that's all my kids do is ask me for more. And I was like, that's exactly what my kids do. My kids are like, more, more, more, more, more.

50:07That's very human. Yes, me too. Oh my gosh, that's so incredible. Isn't it incredible? Yeah, and so this is why we wanted to start EveryCure. Because there's things that are out there. And I love that EveryCure and AI can help us discover new treatments and I can share about some that we've discovered. Literally, it's like, oh, wow, this is never been used. That's amazing. But sometimes it just uncovers what us humans know about, but we just don't put into practice. Yeah, I want to hear those two things. I want some more examples. And I also want to know, I keep reading, you guys train this model to do this.

50:34But how the fuck do you take this tool we have and actually get it to go through every single medical journal ever written? How do you construct that? That's its own breakthrough. It is. So we utilize something called biomedical knowledge graph. So a knowledge graph is a way to basically construct and bring together lots and lots of information from disparate places. So imagine a knowledge graph would be if we had on the wall every drug, every disease, every gene. Everything we know about medicine, all is one node each. And then you've got lines connecting all of them based on the relationship between them.

51:03So we use every paper that's ever been written, all data we can find online. Anything that we can find will fill out this graph. So every concept plus all the relationships between them. So it's like, so Tuximab treats Castleman disease, IL-6 elevated in Castleman's. but imagine that for everything on this graph. So now the surgery is the perfect ingredients to then train machine learning algorithms because we can say, you know, this whole graph here, this drug works for this disease. This drug works for that disease. And we train it on the known treatments. And what it'll learn is that there was a paper that was published three years earlier, like an angiosarcoma showing that this drug might work in that disease.

51:34And it did. And so understand these patterns. And then we ask the exact same algorithm now that we've shown it, this drug works for this disease. Now give us a score from zero to one for how likely every other drug is to treat every other disease based on these pattern of connections. And do we owe the Scandinavians the biggest debt of gratitude? Aren't they the ones that have kept the best medical data and made it? It's not public, but it's public. It's obscured, but it's all there. Yes. Northern Europeans have done a great job with electronic medical record data. You need these epidemiological studies in five seconds.

52:02Absolutely. Yes. Everyone's in the same database, which a lot of other countries, we don't have that. I know we all have privacy concerns, but there's got to be a way. Everything I've gone through with this whole psoriatic arthritis thing, I could save someone years if you could access my thing and just not know my name. I feel like we need to move towards that. Yeah. Why is this not happening on its own? Like what's broken about our system? And I think there's a couple of things that have just completely shocked me. So first of all, those 4 ,000 drugs we have, 80 % of them are generic, which means that once a drug comes generic, anyone can make a copy of that drug.

52:32The exact same drug, it's the same name. And when you have 10 people making the exact same drug, the price plummets, which is good for our healthcare system. It's not a cheap drug, but now it's like a penny a pill of profit per sale. And there's 10 different companies all selling what one company used to sell. So you might find that that drug could work for a million people with another disease and no one will make any money off of that. The depressing thing is that that shouldn't matter, but it does matter. It's not that people are hiding. It's just that if you can't make any money off this thing, you can't spend millions of dollars doing clinical trials and then actually raising awareness about it.

53:03Somehow 80 % of the drugs we have, there's no incentive to find a new use for them at all. Even though they're there and they're safe and we know how they work and we know everything about them and they're the things that are perfect for a knowledge graph because we've got a lot of knowledge about them. Of course, everyone's using AI to find new uses for medicines, but no one's using AI to find new uses for old medicines. And so that financial problem is huge. So real quick, before you move on to the next one, what's the solution for that one? We feel that the solution is to create a nonprofit that doesn't have to be driven by profit.

53:33So we've got this financial problem, which is that it's not profitable to find a new use for an old medicine. And then on top of that, we have an issue that somehow no entity has taken responsibility to be like, I know that there's this market problem over here, but we're the NIH or the FDA or we're some entity. We're just going to do this. We're just going to find new uses for medicines. And so there's just been this huge gap. And then to your point earlier, there's also never really been the technological capability to really do this at scale. So maybe we can't blame the system too much because it's only recent that the system could even address this.

54:01But when you bring those three things together, we have this horrible situation where there's all these drugs that could help people, all these people that are suffering and no one doing the work to bring them together. But you're here now. Thank God. Yeah, until every cure. Okay, so give us a couple more. I read an article maybe in The New Yorker about Joseph Coates. Joseph was diagnosed with a rare cancer called Poem Syndrome. He actually was initially thought to have Castleman disease. And so that's how we initially got connected. He came to a conference and I got a chance to meet him. His diagnosis was changed correctly to Poems.

54:29And a few months went by and I hadn't heard anything about how Joseph was doing or what was going on. And then his girlfriend, Tara, reached out. She said, David, since I saw you guys last, Joseph got really, really bad. He's in the ICU right now and he's on life support. This was a Friday. And by Monday, the doctors are going to take him off of life support and put him into end-of-life hospice care. And I remember just being so shocked. I was like, oh my gosh, I saw him just a few months ago. He has so much life and energy and love and just heartbroken for it. And home syndrome is a condition that I mentioned is in the sort of same family as Castleman's and myeloma.

55:02And so I knew enough about it to where I felt comfortable really digging into see like, are there drugs we could recommend for Joseph? if I know that his doctors are ready to give up, but can we just try something? And so I was able to get in touch with his doctor on that Saturday. And his doctor graciously called me back on a Saturday. I recommended three drugs that are typically used for multiple myeloma, which again is a similar cancer to poem syndrome that doctor hadn't considered. In hindsight, it's like, let's be creative here. Yes, there's nothing for poems, but like, let's look to the side of poems.

55:28Thankfully, he listened to me and he's like, well, I'll talk to the family and I'll talk to my colleagues. Maybe we'll try them. But he was actually very worried about the fact that the chemotherapy that we were recommending was going to kill Joseph. And I talked to him and said, but you're going to take him off life support on Monday. He's going to die from his disease. Let's give him a shot. Let's try this. He made the decision to try these three drugs. And we just sort of waited for the next few days. Like, what are we going to find out? And then within a few days, heard that things started to improve.

55:55And I can't tell you how it's going to be. Oh, no. Exactly. Exactly. Cuts the cigar tips. He responded. He got out of the hospital. And then what's so amazing is that Poem syndrome is a condition where if you can get into remission like we got him into, we did a stem cell transplant for him. And so he's potentially even cured right now. So like I saw him just a few weeks ago and he's got the most incredible energy and he's so positive and he's got his life back. So I should also mention this is an example. And at every cure, the way that we work is so we scan every drug against every disease or our platform.

56:29Our med team finds the best matches and then we move them forward. We do lab studies, we do clinical trials. with this whole systematic approach to fix this system problem. And then also in parallel, we get contacted by patients like Joseph and Tara. I struggle so much because I want to help them. I want to throw the Hail Mary in the same way that we did a Hail Mary for me, right? And at the same time, we have this systematic process where we've got a 50-member team where we're using AI. We have to focus on that. Like we've got this responsibility from a systems level because there's people at the other end of these drugs that we're working on that are waiting for solutions.

56:58But then there's also people who are reaching out to us like Tara and Joseph. And that's probably the biggest struggle that I have is how do I balance the two? Because we've got an amazing team, but our team can't actually pursue every disease that we're contacting. I hate to be crude, but you could be penny wise and pound foolish. I think that's the right analogy here. So what we have to do is we have to say, okay, if you match every drug to every disease, what are the best opportunities? We have nine programs already. We launched this nonprofit three years ago. We built our platform over the first couple of years.

57:25We've only been using the pipeline for 12 months. And we already have nine drug disease matches that we're advancing forward from breast cancer. And there's this lidocaine thing, which is bizarre. Tell Monica about this. Yeah, so amazingly, there's really interesting both laboratory and clinical data on the potential role that lidocaine injection could play in individuals with breast cancer. So lidocaine is the numbing medicine you get when you go to the dentist, right? So injecting it around a breast cancer tumor before surgery, there was a large trial that was done in India of 1 ,600 patients.

57:54And those patients who had it injected around their tumor before surgery had a 29 % reduction in mortality at five years versus people who didn't. but a lidocaine, like this simple substance. And it was published in a major journal called the Journal of Clinical Oncology, one of the best cancer journals in the world. We're looking at it in our platform. It comes through our pipeline and we're like, people must be using this, right? It's like super cheap and it's widely available. But then we learned that no one is using this. The paper's out there, the study's done. And the general consensus from a lot of folks is like, well, you guys should do another study, another seven-year study and see how people are doing.

58:24The question is, do we need to do another seven-year study? This one's already proven. A randomized controlled trial. It's already going to be used in the surgery. And so we are doing more lab work now because the other thing that doctors like is to understand why something might work. Because like, oh, we injected lidocaine and people died less. It's like, well, why? So we are doing lab work to try to figure out the mechanism. We've got some hypotheses. One is there's a lot of evidence to suggest that during the actual act of surgery to cut out a tumor, whether it's breast cancer or you name the tumor, that that's apparently a moment when a number of cancer cells become very migratory.

58:51They basically try to escape from the region. And it's partly because there's decreased blood flow because there's trauma that's occurring in the area. So the thought is that there's actually metastases that occur while you're operating. It's actually migration. And of course, this is a hypothesis, but it's something we're studying. So the idea for how lidocaine may work is that lidocaine is very good at making cells non-migratory. It numbs it. It freezes. It stops it from moving. The thought is that maybe we prevent what would have been a future metastasis to your liver or you name it, from being able to get out of the space before the surgery happens.

59:21You're like kind of paralyzing. Paralyze it. And you actually do the injection eight to 10 minutes before surgery. So you're like paralyzing it, then you cut it out. And at least in these patients in India, it was a game changer. We trust India. Yeah, we like that. So these are the kinds of things that we would have never thought to look for. One that blew my mind is Botox in the frowning. Because that is a cycle, as we know, the people that were famously documenting all the face shapes were giving themselves emotions. And this is a two-way street. And just numbing the ability to frown can have an impact on depression, maybe.

59:52Crazy. Yeah, so this idea with Botox is there's actually, have been clinical studies that for about three or four months after a Botox injection right here between your eyebrows, there's improvement in mood. It's crazy. We got to figure this stuff out. We actually just talked through two of our nine programs, but one of my favorite ones is this rare condition called Bachman-Bopp. Kids are born on feeding tubes. They're unable to move. It's a horrible condition. It's because they have too high of levels of an enzyme called OCE1. What's so interesting is that African sleeping Sleeping sickness is a condition that involves elevated levels of OCE1.

1:00:27So there's a drug called DFMO that blocks OCE1 for African sleeping sickness. Well, it turns out that OCE1 is also too high in these poor kids that are bed bound on feeding tubes. If you give that drug DFMO to these kids, and there's now been about 10 kids treated, the earlier you give it to them in life, the more likely they might have their feeding tube taken out. They might sit up. They can even walk. I keep saying this is why we started every year. Every one of these is why we started every year. But this is it, right? It's like this super rare disease, this super cheap drug that's been around for decades.

1:00:53No one's ever going to do the work to get it to every patient possible. But we at EveryCure, we can do that. We can get involved in trying to diagnose more kids to make sure that more kids get DFMO. This is, for us, why we did this. Well, okay. So if people want to support EveryCure, what should they do? Go to everycure.org slash donate to donate to us. Also, a big part of this is awareness raising. So thinking about some of the drugs we've talked about and even others that we're working on, part of it is doing really good science, great lab work, great clinical trials. But another part is actually just getting the word out.

1:01:19If you know someone who might be able to have this blood test, it might be helpful for someone in their family. So go into our website, learn about our organization, help us spread the word. I did a TED Talk that came out about a month ago. Spread the word about that. These are the kinds of things that actually patients will benefit because we tweeted something. The work's already been done. The drugs are there. So just get in the word. Yeah, Mary Hoff, as your wife comes, it's like, we got to eat kale now. And you're like, how did you find that out? My whole diet is based on whatever someone's told my wife that is good for us now.

1:01:45Exactly. And then, of course, people should read your book, Chasing My Cure. It's wonderful. It's rare that I can say this to somebody, but I'm so happy you didn't make it in the NFL. Oh, my God. Congratulations on not going to the NFL. We needed you way more. And not getting CTE. I knew we wouldn't make it through. I was waiting. We're just lucky that you didn't get it because you wouldn't be able to do all this. Very true. Maybe there's a drug to repurpose. Exactly. David, this has been a delight, and I hope everyone does check out your book and checks out the website and totally grateful this is the work you're doing.

1:02:20And every time we're getting really negative and pessimistic about AI, it's also doing this. It's like doing this shit humans could never do. Can't comb through all that stuff. Thank you so much. Good luck with everything. Well, thanks guys for having me. This has been so special. Thanks, guys. Stay tuned for the fact check. It's where the party's at.

1:02:42Okay, so I have huge Aaron updates. Okay. Okay. So Aaron was there for, I think, five days. He already went? He flew home this morning. Oh, wow. So he didn't fall down? Well, listen, in order, you know, each evening, I would FaceTime him. Okay. Even before he started. And I said, look, what's the game plan for this, like, the second story? Eve on the roof, you know. I said, do you need to rent like a bucket? If you want to rent a bucket, you know, let me know. I'll figure that out. And he said, no, I think I'm going harness and ropes. Okay, I like that. But what's that mean? You put yourself in kind of a diaper.

1:03:30Yeah, you put yourself in a leather dipe or a nylon dipe. You use a carabiner. Yeah, and then you hook off onto the roof. What? To what? Exactly. So the issue with the house in Nashville is it has a metal roof. So you can't do what he would have done when he was a roofer, which is like anchor to the top, just screw into the wood. Oh. So he had to lasso the chimneys. What? Yes. But this plan wasn't he, I think, wisely like I would have done. He just kept putting off the height. Sure. The really tall work. The hard part. He just kept, like, working in the yard and doing trees and doing, like, fences and stuff and just, I think, eyeing all week.

1:04:12And so each night, but he's up and down a ladder. You know, he's doing a lot of ladder stuff. Oh, my God. And then I would look at the cameras at the house just to see if he was lying anywhere on the ground, you know. And then I would FaceTime him every night, which was so fun. A, just have an excuse to have to FaceTime every single night. It's a good, I want to make up a reason why I have to do that. I think you can just, friendship can be the reason. I know, but there's something more organic about it. It was like, okay, good, you're alive. And then I'd hear about everything he did that day.

1:04:41and um all right did you look at the pictures okay i see him on top wow This is so dangerous. Chris. Yes. Aaron looks, he looks like an ant on top of the roof. Who's taking these picks? Chris, the contractor happened to stop by for something else. He sees Aaron way on the top. Look at the one of Aaron crawling up. I know. That's so scary. Dax. I want him to almost be a decoration. Like, wouldn't it be funny if there was a person, we had a person, like a dummy up there putting it on. Yeah. Okay, now if you go to the last picture in that group, do you see Aaron lying on the roof? Okay, so he did fall.

1:05:26No! No, no, no, no. Aaron, and by the way, he's not wearing the helmet, so he does not get$500 from me. Okay, but look how happy he is. Zoom in on his face. This is textbook Aaron. So Aaron, he had this long rope, but the problem was the chimney is not centered to where he needs to be on the high point. So he's using this rope kind of diagonally. And in his mind, he's like, oh yeah, I mapped this out perfectly. Like if I fall, it's gonna catch me on the second story. Well, no, the rope was longer than he anticipated. And he fell down to the first story, but he did land right before he would have gone on the edge.

1:06:06On the ground, yeah. He has taught. I said, are you hurt? I was talking to him on my ride to my meeting last night. I said, you get hurt. He goes, oh, my God. No, I feel great. No problem. Then he sent me this picture about an hour later from the shower. I'm going to send it to you. And this is this is from his harness. No, it's not. That's from his fall. Well, yeah, the harness tightening when he fell. That looks horrible. He's hurt. I know, but he just doesn't care. But I also know what it's like to be him, which is like this. this stuff just doesn't even register. It's like, I wanted to get those lights up there.

1:06:41I got them up there. I don't really care about the thing. Okay, now watch the video coming into the house. And I'm going to watch it with you. That's in fast forward. He's not really driving 100 in my neighborhood. He just wanted you to see what the neighbors have going before you saw what we have going. They do. Wait, that's yours? Yes. The yellow and the blue? Look at this place. It's like the Sconso Gardens. Oh, my God. It's truly Clark Griswold. Wow, Aaron. Can you believe this? He did such an amazing job. It's like an amusement park. Chris is like, you should charge$20 for people to walk through your yard this Christmas.

1:07:24Can you believe it? I'm like, Aaron, no one has ever over-delivered this much. My expectations versus what he did. That looks so good. It looks stylized. Like he like he didn't just throw a bunch of shit everywhere. Right. He put some real thought into it. Yeah. Wow. Good job, Aaron. So for people who don't remember our custom for Thanksgiving with our friendship group, we do something called Secret Turkey. Yes. I presume you've been assigned somebody. Yes. And have you been working on it yet? Yes. You have. I have. I finalized my idea yesterday and I put it a little bit into action, but there's a lot more steps and I'm nervous about running out of time.

1:08:06Because it's next week? Yeah, it's a week from Thursday. Okay, I got to get cooking on mine too. I have the base of mine, but then I need to get artistic on top of it. I, you know, the rule is you have to make it. Okay. Right? Yeah, yeah, yeah. And I feel like... Or customize something you want to do. So I feel like I'm blurring the line a little bit this year on that. Me too. A little. Okay, you too, too. Okay. Yeah. I want to know who you have, but I don't want to know. Yeah, I don't want to know either. You like spoilers or not? Lincoln loves spoilers. Yeah, she loves that. I don't like it.

1:08:45I don't either. And she'll ask me, like, we're watching a movie I've already seen. She's like, what happens? And I'm like, I don't want to tell you. I know. You really want to know. Yeah. And she really wants to know. Yeah, it must be anxiety in a movie or something maybe. Yeah, or just impatience. I think more impatient. That's interesting. Yeah, I mean, that's a quality of mine, impatience, that I definitely think I passed on. But you don't want to know. I don't. And that might be a product of getting older, which is there's so few surprises anymore in life. You've got to really kind of protect them.

1:09:17So, like, I never want to know. I mean, I virtually don't even want to ever open presents on Christmas. What I love is the anticipation of presents I know, it is exciting Yeah, post-presence is Sad It's sad, yeah It's time to make up an excuse for why You're going to Staples You gotta go home Why you gotta go to Staples Yeah, because yesterday I walked in the house And Lincoln was there And she was working on something And she was like, oh, I wanna show you And she showed me And it was her secret turkey Yeah And she was like, I have And she said, and she said, who do you have? Like with no like I know we're not supposed to say No Like she just feels like We're gonna say it That's right I did tell her You did Yeah because I felt Kind of weird being like No I'm not I'm not telling you Yeah she cornered you I told her And I told her my whole idea Oh you did Yeah Okay Well I'll make sure To not ask her I'll make sure To not find out from her Yeah don't let her Tell you about mine Was it No it couldn't have been done Because when I got home Last night from my meeting She was just kind of finishing and it was mind-blowing.

1:10:24Like, I don't know what career exists in making dioramas, but boy, that is her crazy superpower. She makes so many dioramas. She's very artsy. And the tree has lighting in it and stuff. I know, it's beautiful. Yeah. Yeah. I mean, her and Erin, they could get together and really start a business. They could. She could make a model of your house, what it'll look like when it's done, and then Erin could execute it, and then you get the model afterwards. I was just thinking that. Then you have a small version of it. And it's like 55 ,000 instead of. Instead of five. Because of the model. Oh. Do you guys take down everything the day after Christmas?

1:11:02Oh, God, no. Okay, yeah. Some people are like, it's over and we're done. Good for those people. No, you got to go after New Year's, man. That's how I feel. You're going to be entertaining and having people over. Okay, so I have a correction to make. Okay. And this is, I'll take responsibility, even though I think we were on the same page with what the lyrics were. Dax, I was screaming in my car. The Nair lyrics are, who wears short shorts? We wear short shorts. If you dare wear short shorts, Nair for short shorts. Nair for. And they're using Nair as a verb there, even though it is a, it is a noun because it's a proper noun in the name of a product.

1:11:46They are using it as a verb. Nair for short shorts, It's Nair yourself. Or. Or sure. I guess it works both ways. Yeah, it could still be the product. So it's not Nair wears short shorts. Okay, well, I guess I'm happy because that didn't make any sense to us. I'm sad. I liked it more when it was Nair wears short shorts as if Nair wears shorts. Yeah, I mean, I do think it's cute if there's little shorts on the bottle. Big time. That's adorable. But I do appreciate Taryn Graydell correcting us. I like that. Do we think Nair is still on the market? Rob? Checking. Still on the website. Yeah, it looks like it.

1:12:29Okay. Oh, great. I kind of feel like allegedly it had some stuff in it that was like not so great. Well, if it's interesting, it burns your hair off your body, but it doesn't hurt your skin. What a product. You got to tip your hat to the folks at Nair that they figure out how to burn hair off your body without hurting your skin. I guess the question is, but does it hurt your skin? I remember using it once and it hurt my skin. Do you know what's so interesting about my unibrow? Oh, yeah. What? I think it started coming in when I was like in high school unibrow. What do you say? I mean, it is. Uni-brow?

1:13:08No, you're right. But it sounds cute the way you're saying it. I think I'm like, oh, she has. Have you seen her? She has a unibrow. I say unibrow But that doesn't make sense, right? Because there's no A in uni That's how I say it too You say unibrow? Yeah, unibrow Okay And I want you guys to continue to say it that way But I do think in this rare case I'm saying it correctly And you guys are saying it incorrectly Okay, the point is But I think it's funny Okay, go Okay, my unibrow started coming in Probably ninth grade or something I started getting insecure about it Yeah And I started shaving it Oh Which is dicing And a lot of boys shaved it They did?

1:13:43In my school and you can see them be stubble and it looks, it's terrible. So I was like, this doesn't work. Right. Because you see it grow in. Yeah, yeah. And then I used Nair, I think. You did? Yeah, I think I did. And I remember in between my brows being very red and irritated. And me thinking, oh, Jesus, do I have a burn now between? That's not better. You got a chemical burn. Chemical burn, yeah. Because this skin is so sensitive. Very fan. Face skin is extremely sensitive. It's like silk, they say. Is that what they say? They say, and you don't want to be pouring chemicals on silk. Never, never.

1:14:15Almost never. I never put nair on my silk, even if I have a tough, stubborn stain on my silk. Yeah, you don't want to. Now, you never, I guess like the boys in ninth grade weren't even thinking about plucking. No, so then I switched to plucking. Yes. In my, probably by the time I'm a senior or 20s or whatever. All this to say, Monica, I don't do anything to it now. And it's gone. It's fucking gone. Yeah. And it's been gone for a while. Yeah. And I'm so confused because hair is just proliferating all over my body in the most offensive way. Right. I told you, it's like when I work out, half my workout is seeing different hairs because the light's coming from behind me and I'm in front of a mirror.

1:14:58Sure. I'm like, my God, I'm turning into a werewolf. Yeah. But for whatever reason, the uniture, the middle part of the unibrow. Yeah. Went away in an era of great, great hair growth. So I agree, though, even for me. Have you had that experience? Yeah. I mean, every now and then I'll have to pluck a little bit, especially on the sides. But the middle is done. And it used to have some action? Yeah. Yes. I think there is something to when you pluck a lot. They give up. An area. Yeah. They give up. They give up. That's why people were so worried, you know, girls of my gen would over pluck our eyebrows like crazy.

1:15:44And it was just this like teeny tiny thin line. That was what was in. Yeah. And then there was a lot of fear once bushier eyebrows were back in, they would never come back. Right. But they did. They kind of did. Yeah. For me anyway. But yeah, the uni is... Retired. It'll retire. It retires. I wonder why it thinks you need it in your youth and not in your old age. Must have been a very attractive thing at some point. Maybe. It showed your virility or something. Well, testosterone. Sure. Tea. Very virile. Yeah. Interesting. But mine's gone. Do you think, yeah, at one point, like the female unibrow was considered hot?

1:16:26Yeah. I guess Frida. Frida. She was hot. Yeah. May almost had it and she looked great. Like she would, she would on parenthood, she had bushy eyebrows and she would comb them towards each other. Oh, yeah, yeah, yeah. And it looks so cute. Yeah, yeah. You just, I mean, you really, the power to decide you're cute and it's infectious is really one of the miracles on earth. What if they start doing like implants? Yeah, merkins. Stay tuned for more Armchair Expert, if you dare.

1:17:07Okay, we got to talk about it. Okay. Skims has a merkin. Yeah, tell me more. Tell me all about it. Skims has a thong. The front is covered in hair. Okay. And then there's different colors and there's different textures. There it is. Interesting. So blue is an option. Well, I think that's black. Is it? Yeah. Photographed a little blue, but that's okay. It did. And the other one looks like camel hair. Yeah. One's red. I don't really understand that. Well, that's red on the head, fire in the hole. Oh, that's a red head. Do the curtains. Match the carpet. See how they're different textures? Like one's curly, one's straight, one's like fuzzies.

1:17:49Yes. By the way, you can't get any of these. Oh, you can't? No, they're all sold out, which I find I have to be, I love Skims. And I want them to send this to me. Yeah, send it to Monica. I was going to say, I want to see someone in them. Obviously not you. That would be in the realm of, what was that? What were you going to have to put your thumb in my butt to save my life as a co-worker?

1:18:17the things we talk about yeah yeah um so yeah i want to see someone in this maybe rob okay to see rob in this i think you should see kristin in it yeah because that's the best case to know if like it actually is erotic yeah yeah it says it's an actual pair of underwear i mean anything's erotic it's called faux hair micro string thong it's totally sold out I would like Skims to send me one Now, I do have a question Like, I've never seen a red-headed pube Would it possibly be that red? No It wouldn't, right? Well, I've had some red-headed lovers And I've had the great pleasure and joy of seeing red pubis They're lovely But aren't they more orange?

1:19:10Yeah Okay, that would be my guess. Even red hair isn't that color. No, unless it's been augmented. Okay, the one I would be, I think I should try is. Well, blonde though, that's kind of mixed messages. It's like fun mixed messages. Yeah, yeah. They have like a white blonde one. They also have, let me look. Let me see what I want. Okay. I want two. I want, I want three. Okay, great. I want the cocoa blonde straight. Mm-hmm. That's this. Oh, yeah. Great. Exciting. Okay. Then I want Coco Ginger Curly. Oh, sure. Okay. Okay. Then I'm interested in Coco Brown Straight. That's the bottom one there. Yeah.

1:20:00That one looks a little coarse, doesn't it, though? Like horse hind? It does, but to me that looks the most real. But it's not my coloring, so I think that'd be interesting. Yeah, that could be fun for people. Keep them guessing. And I, this one is closest to me, that middle one, Coco Black Curly. Uh-huh, so that's what you want. Ew. Oh, wow, Rob. We have a real extra close-up of the. The brown hair. It looks beautiful. It looks itchy. It looks like hay. It looks itchy. Stabby. It really looks like pointy. Well, you'll have to send those to Monica and then we'll get a full update on how they worked out.

1:20:40Please send me these. Cocoa black curly I would like because I want to see how realistic it is. Well, there's got little hints of gray hair in there. I know. That's fun. No. That will depress me. That will depress me. People's pubic hair does turn gray. I know. I've heard that. Mine hasn't. Me either. Yeah, luckily. Still look youthful. Wow. Will you let us know when yours starts to turn? Turn gray? Yeah. It'll be a sad day. I'll report it. There's that old allegory. There's a very famous story, right, about a king with one gray hair. As soon as you get a gray hair, you can no longer be king. Do you know this?

1:21:14It's a very famous story. I don't know. I don't know it. What happens? He's either, well, he can't be king anymore, and he might even have to die. I don't know. Or turns it over to his son immediately when there's a gray hair. So he's living in this great fear of one gray hair. Oh. Yeah, and it teaches you some kind of lesson, but I don't know what it is. It feels like you should be afraid if you're going to get killed or dethroned. Yeah, it's a legitimate fear. But it's supposed to teach you an important lesson. We just don't know. It's the messenger of death sent by the god of death. And the king immediately understands the implication is youth, middle age, and old age are coming to an end.

1:21:49And death is imminent. Ooh. I still don't understand the lesson. The core moral of the story is that even a long life is too short to waste on mere worldly pleasures and power. One must recognize the signs of aging and mortality And dedicate oneself to a life of wisdom and righteousness Ah Interesting Okay, wow, this is a ding ding ding This is really ringing a bell Ooh, okay Okay, so my weekend Now I'm going to violate it But I'm not really violating it You might think I'm violating it But I swear I'm not Okay Because I'm not telling any of the people involved Okay And that's the key Okay And no one involved in this will listen to this Nor will it get to them so my weekend was 100 of service great we had a thing on friday night i had to drive to sit through i had a volleyball game then i had a birthday party i had to drive someone out there and then i sit in my car for an hour and a half while someone was at a birthday party then there was a show a thing i mean just it was the whole weekend and i i found myself wanting to call attention to what a sacrifice i had been making that was my instinct and that i i wanted it to be known that I hadn't done anything I wanted to do this weekend.

1:22:59Right. And I remembered my great therapist, Mark, telling me, listen, as a man, you can think this, but you shan't say this. You shan't ever say, well, what about me? And that's solid advice for a man. I like that. Yeah. It's the path we need to walk, us men. And it should be walked. And I just kept hearing the voice in my head all weekend, like, you're not going to do going to mention at all that you haven't done anything but drive people around on your limited two days off. Yeah. And I achieved that goal. And then on the flip side of the coin was I had done something abnormally generous for me for virtually a stranger.

1:23:43Okay. And then I was like, and you can't tell anyone. And I was like, I'm going to call my mom and tell her. That's what I wanted to do great like i'm not gonna tell you my friends i did this great i don't want my children to know christen had to know because we share finances um and i had to talk myself out of uh telling your mom telling my mom and i decided it's you're old man it's time to stop doing anything looking for and so that you'll be observed doing it applause validation yeah we love you you're so good When is it just going to be for you? Why don't you just do things that you know give you a steam and leave it at that?

1:24:28That's a hard challenge for me. I'm embarrassed to admit. Yeah. Like to do things secretly that only fill me up and only I know we're good. Right. Is the, I think, the last chapter I should hope to achieve. Yeah, that's great. On my evolution on this planet. But that reading just made me think of that entirely. Like it's time for wisdom. It's time for other things. Oh, that came. And for me in my life, it's time to just do things quietly for me. Yeah. And it's almost, it feels pointless, which is crazy. That's how deep the exhibitionism of my soul is. It feels pointless to help. If I only know.

1:25:13Oh, wow. I mean, it doesn't feel pointless to the person that I helped. Right. Of course. Yeah, exactly. That should be enough. But opening my imagination to a world where no one ever knows if I did something good is shockingly absent of the normal reward I'm used to getting or just the operation. Yeah. I don't know. It's really tripping me out. Yeah. That's a great goal. Yeah. And it's harder than I want it to be. Yeah, this kind of circles back to something we talked about a few weeks ago, the give for fun and for free. Like, that's what it is about. I know. I know. I guess, like, I don't feel very judgmental of myself because, like, look, again, we're like this super social animal and our reputation is everything in a group.

1:26:07Yeah. Are you benevolent? Are you selfish? Like, these are key things we need to know about each other if we're going to trust each other. So naturally, we want people to see when we're benevolent. I know. And we pray they don't see when we're selfish and shitty. Yes. Because we have to keep our standing in our group. I know, but I guess the... It's like life or death. The catch-22 of it, though, and this isn't fair, but this is true, is displaying you're benevolent or generous, like stating it, has the opposite effect. Uh-huh, yeah. It makes people think like, no, you're not because you had to do that.

1:26:45Like it takes away from the act itself. I think people, I think. Well, there's some artistry to it. There is a way for people, for you to let people find out stuff you've done that's good that isn't overtly braggy. Like if someone's overtly braggy, yeah, it's immediately distasteful. But if you find out that Eric put a kid through college. Yeah. You're like super proud of Eric. That's amazing. Yeah. Yeah, and you would want to say to him, like, that was rad, dude. I'm glad you did that. And so there's a way for Eric to get that out that's not gross. But I don't think so. Like, I think if he has a hand in saying it, it does take away.

1:27:25I think, though, I think people do find out, whether you say it or not, people will find out other people's level of generosity, Whether they are affected or not or told or not. It's, I don't know. I think it's clear. Yeah. And it way more clear when the person is keeping it to themselves. Yeah. It's just, it's a really powerful force. Yeah. To do things secretly. Yeah. It's a good goal. It is. I like it. And it's, but again, so me saying that there seems to be no reward on the other side of it is also me saying like, oh, this is interesting because I know there is a reward, but I can't even imagine it.

1:28:12Yeah. Which is interesting and fun because I'm so locked into this architecture of like people approve of you. Yeah. That's how you know you're doing the right thing. It's like people approve of you. Yeah. The reward is that you know you're good. Right. And that's where But I think the growth is that why don't I value it all if I think I'm good? Yeah, exactly. Why do you need other people to think it if you know it's true? Yes. Why doesn't my opinion about myself matter at all? Unless it's negative, then I think it's very important. Right, right, right. Like when I'm self-flagellating, I think I'm the most astute observer of me in the world.

1:28:52Right. And so, yeah, I think I am going into it with a blind faith that one day I'll wake up and go, oh, this is the reward. And I love it. But it is a bit of a blind faith pivot. Yeah, I like that. I think I've been slowly moving in that direction. But for whatever this weekend just was like compounded, two things I would have normally done. I was like, call my mom. Yeah. Mommy, I was a good boy. I mean, I think it's cute to be. I turned out to be good like you hoped I would be. I think of all the people to tell, your mom is safest. Yeah. Which is why it was hard to talk myself out of. Right.

1:29:33Yeah. Yeah, I think you could have done that. No, I'm not gonna.

1:29:40Well, that's great. All right, let's do some facts. Okay, David Fagenbaum, I only have one fact. He was extremely factual. He sure was. The only thing I did look up was, does glioblastoma affect women more than men? Oh, yeah. It's more common in men than women. Oh, my God. Well, this is why anecdotal info is misleading. That's true. It just so happens in my life I've known a lot of women. Yeah. And none men. Men are about 60 % more likely to develop the tumor. While the exact reasons are still being researched, this disparity is not believed to be solely due to sex hormones. Anyway, it's not fully understood.

1:30:26It's horrific. I know that part. I know. I know. it's because so our unfortunately one of our very good friends has had multiple people affected by this died of it she once taught me that like it's like the shape of the tumor it has like kind of spikies um which make it hard to remove oh what are those kind of they look like call flowers but they're pointy at the end you know they're beautiful yeah um They're green normally. Yeah. They're beautiful. Romanesco cauliflower. Romanesco what? Cauliflower. Cauliflower. God, is that impossibly gorgeous. Nature, let's all give it a round of applause for nature.

1:31:13Isn't that impossibly beautiful? It looks like tiny Christmas trees. Tiny Christmas trees, also coral, sea coral. It is wild that nature made that. Yeah. And like nature makes pineapples. Like that's crazy. Oh, and the symmetry you see and crystals and all these things, like the shapes it can make. Yeah. It's pretty cool. I'm really grateful for you, nature. I hope you're a listener.

1:31:39Oh, one other thing I did look up because he talked about folic acid for nonverbal autism. So when I got diagnosed with epilepsy, he told me, so I got put on the Keppra. My doctor, my neurologist, great man, Dr. Stephen Sykes, love him. Beautiful man. Beautiful man. He said if I'm thinking about getting pregnant ever that I should take folic acid being on this medication and having epilepsy. Okay. I didn't really know why. He probably told me, but my brain was a little fucked up. So then I just looked. Should you take folic acid if you have epilepsy? Yes. People with epilepsy, especially women of childbearing age, should take folic acid.

1:32:24but the appropriate dose must be determined with a doctor, prevents neural tube defects and other birth defects in children, and can also be deficient in those taking certain anti-epileptic drugs. I take it and I don't have epilepsy. Oh, you do? Yeah. It's part of my regime. You like the taste? No, I don't like any of it. I constantly am complaining at night. It takes me like 30 minutes extra to go to bed because of all the stuff I'm doing to try to stay alive longer. And I lament it. I'm like, God, it's a lot of work to stay. And you're actually taking time out of your life. What if we added up the amount of time you're taking?

1:33:00It was a push. I would have rather had the TV time. All right, love you. All right, love you.

1:33:35you go, tell us about yourself by completing a short survey at wondery.com slash survey.