Using Existing Drugs in New Ways to Treat & Cure Diseases of Brain & Body

00:00:00.000 | My doctor explained to me that we were out of options.

00:00:02.360 | He said, David, we've tried everything.

00:00:03.620 | We tried these chemotherapies.

00:00:05.020 | We tried this one experimental drug.

00:00:06.700 | There's nothing more that we can do.

00:00:08.720 | There was a few-minute period where my dad and my sisters and my girlfriend around me,

00:00:13.340 | and we were just bawling our eyes out.

00:00:16.480 | This is the world's expert.

00:00:18.240 | And I kept probing him, like, is there any cell type or signaling pathway?

00:00:22.100 | Is there something we can target?

00:00:23.380 | Like, and he said, David, there's nothing.

00:00:25.420 | Is there anything in the early stage develop?

00:00:27.280 | David, there is nothing.

00:00:29.580 | I heard what he was saying, but then I thought to myself,

00:00:32.300 | you just gave me seven chemotherapies that were made for lymphoma and my multimyeloma.

00:00:37.600 | And they've saved my life now three times.

00:00:40.520 | They're not, it's not long-term.

00:00:41.800 | Like, I know I keep relapsing, but, like, if these seven chemotherapies are working,

00:00:46.180 | how do we know there's not an eighth chemotherapy or a ninth drug for something else?

00:00:50.600 | Like, you can't tell, we haven't tried all 4,000 drugs.

00:00:53.020 | We've just tried the drugs that maybe we've thought to try.

00:00:55.780 | And so I just locked in right then, and I turned to my family,

00:00:59.540 | and just sort of wiped away my tears and said, I'm going to dedicate the rest of my life,

00:01:03.040 | however long that's going to be.

00:01:03.960 | It might be a couple days.

00:01:04.840 | Maybe it'll be a couple months.

00:01:05.880 | But however long I've got to trying to find out, is there a drug out there that could help

00:01:10.040 | me and other patients with my disease that's made for another condition?

00:01:13.060 | I just believe that the 4,000 drugs we have today should help all the patients who can benefit

00:01:17.480 | from them, period.

00:01:19.280 | Like, no one should suffer if there's a drug at your CVS that could help you.

00:01:23.120 | Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for

00:01:28.600 | everyday life.

00:01:32.620 | I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford

00:01:37.700 | School of Medicine.

00:01:38.540 | My guest today is Dr. David Fagenbaum.

00:01:40.940 | Dr. David Fagenbaum is a professor of translational medicine and human genetics at the University

00:01:46.500 | of Pennsylvania.

00:01:47.300 | His work focuses on finding novel cures to both rare and common human diseases by using drugs

00:01:53.200 | and other treatments that already exist and that are approved for use in humans for other

00:01:57.860 | purposes.

00:01:58.280 | As it turns out, most approved drugs impact at least 40 different pathways and mechanisms

00:02:03.080 | across the human brain and body, but these drugs are generally approved for use in just

00:02:07.680 | one or two of those pathways.

00:02:09.420 | David shares with us the many commonly unknown yet powerful benefits of drugs that are already

00:02:14.500 | approved for things like heart health, combating cancer, neurodegeneration, and more.

00:02:19.440 | From his own near-death experience with Castleman's disease, David discovered that the medical profession

00:02:24.420 | already has in hand excellent treatments and perhaps even cures for many of the childhood

00:02:29.260 | and adult diseases that the medical profession deems uncurable or untreatable.

00:02:33.560 | In addition to running his laboratory where they search for novel treatments and cures using

00:02:37.760 | already approved drugs, David has started a not-for-profit called Every Cure, which helps people find

00:02:43.180 | treatments and cures to diseases that the medical field has essentially deemed untreatable.

00:02:47.820 | And that work has already saved countless lives.

00:02:50.580 | Our discussion today is about how to navigate your health journey and how to approach the

00:02:55.080 | treatment of any illness that you or a relative may face.

00:02:57.960 | It's also about the fact that while the fields of medicine and science are truly incredible and

00:03:02.260 | well-intentioned, they do have a giant blind spot built into them, which is that many effective

00:03:07.260 | treatments and in some cases cures exist to diseases that we are told are hopeless to treat.

00:03:12.580 | And that even the best trained and well-meaning MDs are often unaware of those treatments, not

00:03:17.580 | because they are lazy or that they have some other agenda, but simply because of how medications

00:03:21.640 | are studied, patented, and categorized.

00:03:24.320 | As you'll soon learn, Dr. Fagenbaum is on a mission to educate doctors, scientists, and most

00:03:28.760 | importantly, you, the general public about these facts.

00:03:32.060 | He has lived them directly.

00:03:33.700 | He's an MD who got very sick with what he was told was a terminal disease.

00:03:37.980 | And when the existing system left him at a cliff, he went about curing that disease using

00:03:42.220 | old medications in new ways.

00:03:44.340 | And he is now helping others who need to do the same.

00:03:47.520 | Before we begin, I'd like to emphasize that this podcast is separate from my teaching and

00:03:50.860 | research roles at Stanford.

00:03:52.540 | It is however, part of my desire and effort to bring zero cost to consumer information about

00:03:56.480 | science and science related tools to the general public.

00:03:59.680 | In keeping with that theme, today's episode does include sponsors.

00:04:03.240 | And now, for my discussion with Dr. David Fagenbaum.

00:04:07.040 | Dr. David Fagenbaum, welcome.

00:04:08.480 | Dr. David Fagenbaum: Thanks so much for having me.

00:04:10.620 | These days, people are very concerned about their health, even if they're healthy.

00:04:15.180 | And I think the reason for that is ever since 2020, I think people have started to realize

00:04:21.180 | that they need to do more self-advocacy in terms of their health, whether or not it's behaviors

00:04:26.660 | to take care of their health, learning how to explore medical and health information online

00:04:34.180 | more effectively.

00:04:36.140 | No one knows who to trust.

00:04:38.560 | And yet people are realizing that they are a critical element in their health.

00:04:43.940 | And should they encounter challenges to their health, they realize they can no longer be passive

00:04:49.720 | participants and just go to their doctor, that doctors are human too.

00:04:55.180 | So you have a very unique health story and we'll get into that.

00:04:59.280 | But maybe we just start off by educating people a little bit about some of the common misperceptions

00:05:04.760 | in order to give them more sense of agency about what they can do.

00:05:10.720 | One of the things that you've been very vocal about is that you believe through experience

00:05:15.640 | and observation that many of the treatments or even potential cures for the things that

00:05:21.600 | challenge people may already exist in the form of medicines that are prescribed or available,

00:05:27.580 | maybe even over the counter.

00:05:29.480 | But that people, including doctors, are not aware of that.

00:05:32.460 | Could you just elaborate on that?

00:05:33.880 | What we're basically saying is the answers may already be here.

00:05:38.020 | Sure.

00:05:39.020 | Well, first of all, I love that you're talking about agency in health and in medicine.

00:05:42.760 | Because I think oftentimes we talk about agency, you know, I can get a good night's sleep or

00:05:46.520 | I can exercise and eat well in the sense of wellness.

00:05:49.520 | But oftentimes when people get really sick with a horrible disease, whether it's cancer

00:05:52.980 | or Castleman's, feel like, well, we're just going to do whatever our local doctor tells us to do.

00:05:58.140 | But you're right.

00:05:59.140 | I think that there's so much more that we can do and there's so much agency that we can take.

00:06:03.240 | And part of it, to your point, is that there are drugs that we have.

00:06:06.500 | There's 4,000 FDA approved drugs that are approved for about 4,000 diseases.

00:06:10.460 | But we know from laboratory work and also from clinical trials that many of those drugs can

00:06:14.540 | be used in more diseases.

00:06:16.160 | But unfortunately, the system really isn't set up to find new uses for old medicines.

00:06:20.260 | And so that's the work that I do.

00:06:22.380 | But I also think it gives all of us really a sense of responsibility that if we're diagnosed

00:06:27.420 | with a bad disease, that we find out what's the disease organization advocacy group.

00:06:32.040 | Maybe they're aware of a drug being used in one part of the world, but others aren't.

00:06:35.380 | Who's the leading expert?

00:06:36.680 | Can you go drive to see the leading expert?

00:06:38.340 | And can you make sure that once the expert tells you what to take, you ask questions

00:06:42.300 | like, is there potentially something else?

00:06:44.300 | Yeah.

00:06:45.300 | I think of aspirin, for instance.

00:06:46.260 | Yeah.

00:06:47.260 | Most people think of aspirin as a pain reliever.

00:06:49.260 | Yeah.

00:06:50.260 | Aspirin is now used as a way to offset heart attacks for its blood thinning effects, among

00:06:56.540 | other effects.

00:06:58.260 | Just off the top of your head, I'm not trying to test you here.

00:07:02.660 | You're the MD, I'm the PhD, as we were talking about before, I'm not going to test

00:07:06.980 | you on medicine.

00:07:07.980 | I'm not equipped to.

00:07:10.340 | But are there other uses for aspirin that we perhaps haven't heard of, or similar drugs

00:07:14.500 | that might surprise people?

00:07:15.900 | Yeah.

00:07:16.900 | Aspirin also has been shown to reduce risk of recurrence of colon cancer.

00:07:20.020 | Particularly individuals with colon cancer have a mutation actually in the mTOR pathway.

00:07:24.700 | But because it's aspirin, because it's sort of widely available and it doesn't have maybe

00:07:30.500 | the same sort of system behind its use, it's really not actually utilized by all the patients

00:07:35.380 | that have colon cancer to reduce the risk of recurrence of colon cancer.

00:07:38.600 | That's sort of mind-blowing in itself.

00:07:40.720 | There are other great examples.

00:07:43.260 | Many folks have probably heard about how Viagra was repurposed from heart disease.

00:07:47.360 | It's well-known use.

00:07:48.360 | People are aware of erectile dysfunction, but most people don't realize that it's also

00:07:51.640 | been repurposed for a rare pediatric lung disease.

00:07:54.040 | Kids were dying because they weren't getting enough blood flow to their lungs.

00:07:57.040 | And if they take Viagra, they can actually get blood flow to their lungs and live full lives

00:08:00.880 | on Viagra.

00:08:01.880 | And that fortunately was discovered early on in the patent life of Viagra.

00:08:06.040 | So there was really a way to push it forward.

00:08:08.320 | A lot of times these happen after drugs are generic.

00:08:10.720 | Isn't it that the cousin of Viagra, Cialis, was initially Tadalafil used to encourage prostate

00:08:16.720 | health, circulation to the prostate.

00:08:18.720 | And then only later was it discovered to have these other effects related to sexual function.

00:08:22.320 | That's right, yeah.

00:08:23.320 | And, you know, we talked about the side effect of a drug.

00:08:25.600 | It can be bad or can be good.

00:08:28.000 | We were chatting earlier, you know, the average small molecule is a drug that's approved for

00:08:31.840 | a condition, combined between 20 and 30 different proteins in the body.

00:08:35.840 | So we call a drug, you know, we say it does one thing, but actually it's doing a lot of other

00:08:40.480 | things in the body.

00:08:41.600 | And unless that drug company began working on it early on for that condition, oftentimes those

00:08:48.080 | insights and those other roles for the medicine just fall through the cracks.

00:08:50.960 | So the idea that a drug is useful for other things aside from what it's best known for is

00:08:57.680 | seldom discussed, whereas side effects are being discussed more and more nowadays.

00:09:02.400 | Tell us about lidocaine.

00:09:04.800 | Sure.

00:09:05.280 | This is fascinating.

00:09:06.720 | Sure.

00:09:08.160 | So, yeah, I couldn't believe it when we came across this.

00:09:10.800 | So I run a nonprofit called Every Cure.

00:09:12.800 | We scan the world's knowledge of every drug and every disease to find

00:09:15.840 | new uses for the medicines we have.

00:09:17.920 | And when we came across lidocaine, we were just sort of blown away.

00:09:20.800 | So lidocaine, of course, the numbing medicine you get if you go to the dentist and, you know,

00:09:24.640 | it's used all over the body for numbing all kinds of things.

00:09:29.680 | There's interesting data, actually, a large trial that was done in India

00:09:34.400 | of 1,600 patients where women who had localized breast cancer, if they had lidocaine injected

00:09:40.000 | around the tumor before surgery, eight to 10 minutes before surgery, there was a 29%

00:09:45.120 | reduction in mortality of five years versus those who did not have lidocaine injected.

00:09:49.520 | Now, lidocaine is already going to be used during the surgery.

00:09:52.000 | It's used at the site of the incision.

00:09:53.600 | It's widely used, you know, in so many cases.

00:09:56.640 | And what's so interesting, it was published in a great journal, the Journal of Clinical Oncology,

00:10:00.400 | yet there's still been barely any uptake all around the world.

00:10:03.280 | And so this is just sort of another example for us for why you've got to have an entity

00:10:08.720 | that's looking for these great opportunities and then actually doing the work to make sure that they

00:10:12.560 | get into patients. Because there's close to no downside of something like lidocaine.

00:10:16.880 | And if the upside is as high as a 30% reduction in mortality, I don't know how it's not being used

00:10:21.200 | all over the place.

00:10:22.080 | Is lidocaine an expensive drug?

00:10:24.320 | It's a very inexpensive drug.

00:10:26.160 | It's, you know, pennies in injection.

00:10:27.920 | And that doesn't mean anyone's hiding lidocaine.

00:10:30.640 | I'm of the belief that drug companies do such important work to develop brand new drugs.

00:10:34.960 | And they're so good at it.

00:10:35.920 | They do a great job getting those drugs to be used for the uses that they're intended for.

00:10:39.840 | And it's no one's fault.

00:10:40.960 | But once that drug becomes generic, like lidocaine has been generic for decades,

00:10:45.120 | that means that there's a number of other companies that make the exact same drug.

00:10:48.560 | And the profit for each of those doses becomes close to, you know, pennies in injection.

00:10:54.240 | And so, again, it's not that anyone's hiding it, but it's just that no entity is incentivized to

00:10:58.640 | actually go call on doctors and say, "Hey, did you do the lidocaine before your surgery?"

00:11:02.080 | Or to like to really push to get them into guidelines.

00:11:04.320 | And I will say this was a really major study, this study that was published or that was done in India.

00:11:09.200 | It was published in a great journal.

00:11:10.560 | There's interesting laboratory data.

00:11:12.320 | But we at EveryCure actually feel responsible to better understand the potential mechanism for

00:11:16.800 | how it might work and also to review the evidence wholly before we actually go out and start,

00:11:21.360 | you know, encouraging everyone to do it.

00:11:22.640 | So there's still steps that have to be taken.

00:11:24.880 | But our belief is that when you come across something, you know, that looks promising like this,

00:11:28.880 | we need to have some group that's actually pushing and pushing to make sure that it actually

00:11:33.360 | gets to patients once you feel comfortable with the data.

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00:14:15.760 | There are a couple avenues that we could explore given what you've said so far, but the one I'd like

00:14:21.680 | to drill into a bit is this thing related to drug companies and patents. I don't want to set up the

00:14:26.560 | idea that everything is conspiratorial. And yet years ago, when my laboratory was working on eye diseases,

00:14:35.360 | glaucoma in particular, I spent a lot of time around people working at companies that develop drug

00:14:40.080 | treatments for eye diseases. They've developed great drugs for the treatment of over vascularization

00:14:46.000 | of the eye, for instance, that can cause blindness or it's related to some blinding diseases. And I

00:14:50.880 | learned that many of these drugs go to market. They are quote unquote blockbuster drugs. People,

00:14:58.800 | symptoms improve. These drug companies make a lot of money. And then the patent is headed toward

00:15:05.680 | expiration. And at that point, the cost of the drug drops markedly. So the drug companies are heavily

00:15:13.200 | incentivized, I learned, to find new uses for that drug, to renew the patent under this new application,

00:15:22.800 | to basically keep the generics away. And on the one hand, it makes sense because the research and

00:15:30.000 | development for a drug is exceedingly expensive. And so if they can repurpose a drug and maintain

00:15:35.040 | the patent for two diseases, essentially, one drug, two diseases, this is kind of the bread and butter of

00:15:42.400 | how drug companies get and remain very wealthy. It has two, what I consider kind of darker sides to it.

00:15:51.760 | One is that the generic cheaper drugs don't arrive on market for a much longer period of time.

00:15:57.040 | The other side of the coin, however, is that, you know, people suffering from a different disease

00:16:05.120 | now can take this drug. But that second darker piece is that drug companies are not very incentivized to go

00:16:12.640 | look for new molecules to treat new conditions. They are heavily incentivized to use old molecules to treat

00:16:19.760 | new conditions and maintain control. There's a lot in this statement, but my understanding is this is

00:16:26.560 | how it works. And so how do you reconcile that? I mean, how is it that we should be exploring existing

00:16:33.200 | drugs for new conditions, but do it in a way that's really driven toward curing and disease as opposed to

00:16:40.640 | just kind of finding a new purpose so we can keep the generics out for a while?

00:16:43.840 | Yeah, it's such a good question. So you're absolutely right that as drugs begin to reach their patent

00:16:49.760 | cliff, oftentimes the dose might be changed slightly, the formulation might be changed slightly to create

00:16:56.320 | new intellectual property. So that way, this sort of new version can be used in that same initial disease.

00:17:02.960 | which to your point, there's, you know, I wouldn't say pros and cons. There's, you know, side effects of

00:17:08.160 | that sort of a system. But what is pretty clear is that companies will typically not, as it's getting

00:17:14.880 | close to patent exclusivity, find a new disease to go after with that drug. It's usually the same disease,

00:17:20.480 | it's just a new formulation. So that way they can keep working that disease. And what that means

00:17:25.520 | is that though that drug might be able to be used for a different disease, that's rarely explored.

00:17:30.480 | And so especially to your point, once it's generic, I mean, all of research and development discontinues.

00:17:35.840 | And even I mentioned earlier that there's 4,000 FDA approved drugs, they work for 4,000 diseases,

00:17:42.560 | that's incredible. But there's still 14,000 diseases that don't have a single treatment right now.

00:17:47.680 | And of the 4,000 drugs we have, 80% of them are already generic, which means that there is no incentive

00:17:53.600 | to find a new use for those medicines. So like, every time I walk past the CVS, all I think about

00:17:58.000 | is how many drugs are in there that are used for one condition, but could actually help so many more

00:18:02.560 | kids or adults with other conditions. And we're hearing a lot these days about lithium as a potential

00:18:08.960 | protectant for Alzheimer's or other forms of dementia. I don't know that the data are so solid

00:18:16.000 | that I'm ready to run out and take lithium. So I'm not suggesting that to anybody. But I know a few

00:18:19.920 | psychiatrists that tell me for years, they've been taking low dose lithium for a couple months

00:18:24.320 | out of the year, based on their understanding of the data. So you've got doctors doing things,

00:18:29.280 | people don't often talk about this, but doctors often will do things that based on their read of

00:18:33.440 | the literature that they're not talking to their patients about, because they're not in a position

00:18:36.880 | to do it ethically. There's too much liability there. Where and how should the typical person,

00:18:43.680 | without any training in medicine or science, or even a little background in science,

00:18:47.920 | go to find information about existing drugs, generic or otherwise, that could help them treat

00:18:54.560 | their ailments, be it a skin condition or something as serious as cancer.

00:19:00.080 | What I'd recommend is the first is to make sure that you're connecting with whatever the disease

00:19:05.040 | group is for your condition. They oftentimes are so well connected physicians all over the world,

00:19:09.360 | they hear about what things are being tried. So connect with whatever your condition, whatever

00:19:12.560 | that disease organization is.

00:19:13.680 | Dr. Justin Marchegiani: Could you explain disease organization?

00:19:15.520 | Dr. Justin Marchegiani: Sure. So like the Castleman Disease Collaborative Network is

00:19:17.840 | the group that's come together to support Castleman's patients. And to physicians and researchers,

00:19:22.400 | there's an ALS Association, for example. There's Michael J. Fox for Parkinson's disease. So

00:19:28.080 | find that group that has coalesced around your condition, because they'll oftentimes have,

00:19:32.960 | to your point, understanding about, "Hey, I heard this one patient's using this one thing." So

00:19:36.800 | Dr. Justin Marchegiani: I'd go there first. The second is I would figure out where is the world's

00:19:40.880 | expert? Who is that person that really is the guru? They'll oftentimes have insights on these things.

00:19:46.480 | And then the third is to really keep asking questions. So like even when they say this is

00:19:52.240 | the first thing that's recommended, well, is there something else that's like used somewhere else?

00:19:55.920 | And I'll share one example of this. It's a bit heartbreaking, but also

00:20:02.080 | really powerful and informative. And that's that there's a rare condition called data2. Basically,

00:20:07.360 | kids are born with a mutation in a gene that results in them having dozens and dozens of strokes from

00:20:13.200 | the time they're born until they usually pass away in their teenage years because of the accumulated

00:20:16.720 | effect of literally dozens of strokes. It's horrible. Well, about 20 years ago, a doctor apparently was

00:20:22.800 | treating a patient with data2 and also treating a patient with a form of vasculitis and treated that

00:20:28.240 | patient with vasculitis with what's called a TNF inhibitor. It inhibits this one cytokine called TNF.

00:20:32.480 | And he apparently had left TNF inhibitor in his vial. And he was like, "You know what? We've got this kid

00:20:36.400 | 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

00:20:41.920 | stopped having strokes. And that was amazing. And so this doctor, the next few patients he had with data2,

00:20:47.440 | he treated them for their strokes. But about 10 years went by. Meanwhile, hundreds and thousands of kids

00:20:53.120 | around the world are dying from data2 where the word wasn't being spread until this amazing doctor

00:20:58.800 | named Chip Chambers sadly had two children born with data2. And he started looking around to figure

00:21:03.680 | out and learned about, oh my gosh, TNF inhibitors. I was honored to be able to help Chip and his team to

00:21:08.800 | basically bring data together on the effectiveness of TNF inhibitors, also even come up with treatment

00:21:13.440 | guidelines for how do you treat data2. And it turns out that if you start kids on a TNF inhibitor,

00:21:18.640 | they stop having strokes all over the world. Literally, it's a life changer. And so the reason

00:21:24.480 | I share this as an example is that the world knew, someone in the world knew that you could save kids

00:21:30.720 | lives with a TNF inhibitor, but the world didn't know. And we hadn't gotten the word out about it. And

00:21:35.200 | to me, that's so heartbreaking. It's almost like a travesty. It's one thing if you have a horrible disease

00:21:40.640 | and everyone dies from it and there's nothing out there. But I think it's so much more heartbreaking when

00:21:46.160 | you think that, oh my gosh, there was something there. We just, we as a system, hadn't done the

00:21:50.720 | work to make sure people get the medicine. Yeah, I think it's a harsh reality that one's knowledge

00:21:57.360 | network really has a big impact on outcomes to disease. I mean, I sit surrounded by MDs and PhDs

00:22:05.680 | and people working on disease and treating disease. And I'll tell you, there's no question in my mind that,

00:22:12.720 | because I've experienced it when a friend's spouse or kid is dealing with something.

00:22:16.800 | I'm just one example of somebody who knows who to call, because I don't know the answer,

00:22:23.440 | but I know who might know the answer. And within two or three calls, that person is in touch with

00:22:27.760 | somebody who is in communication with the five or six people who are best at this around the world.

00:22:34.560 | But most people don't have access to that. I mean, it's one of the reasons I started this podcast,

00:22:38.880 | frankly, to get people like you on here, people like Eddie Chang, who's a lifetime friend and

00:22:44.080 | chair of neurosurgery at UCSF. Like I would say, may you never need his help.

00:22:47.440 | Yes. Right. You know, but these are the people that I call when friends have questions about things

00:22:52.160 | unrelated to neurosurgery, for instance. So it seems to me there's a pretty straightforward solution

00:23:01.040 | that in addition to these groups that are centered around certain diseases, there should be databases.

00:23:07.600 | There should be ways that people can not just go online and ask a question, but go to a database and

00:23:14.400 | say, you know, I was just diagnosed with, or I'm having symptoms that are the following. And what are the

00:23:21.600 | existing prescription and non-prescription meds known to treat this? What are the side effects? But also

00:23:26.960 | what are the potential pathways that overlap with other approved drugs that are prescription or over

00:23:32.720 | the counter? And then it should feed into a pipeline of how to get a hold of the people that could help

00:23:37.440 | treat that. It should be that straightforward. I mean, this is 2025. I mean, there's no reason why

00:23:44.160 | people should have to know somebody in the medical or scientific field at a major institution

00:23:49.120 | in order to be able to navigate this. I totally agree. And I think that the more I've got into

00:23:52.640 | this, the more surprised I've been that there hasn't been something like that. This nonprofit

00:23:56.720 | I mentioned every cure. So we use this, they're called biomedical knowledge graphs, basically mapping

00:24:02.320 | out what the world knows about human biology. We use an AI platform and machine learning models to

00:24:07.280 | quantify how likely every drug is to treat every disease. And then we start at the top to go,

00:24:11.440 | you know, what match looks promising. We've got nine active programs. And from those,

00:24:15.440 | we're moving them forward to reach patients. And the idea is that, you know,

00:24:18.400 | let's hope all nine of them end up being effective in helping patients. That's sort of the start of

00:24:23.120 | this hopefully master list of additional uses for medicines that we already have. But to your point,

00:24:28.560 | it's not just that they are speculative, but really that the work's been done to really prove that they

00:24:34.080 | actually work. I can't help but ask of some other examples of drugs that have been shown to treat

00:24:40.640 | things other than what most people associate that drug with. Sure. A few come to mind. So the first

00:24:45.920 | one's thalidomide. You probably have heard about the horrible birth defects that thalidomide

00:24:50.320 | caused 50 plus years ago. Originally designed as an anti-miscarriage drug. Well, it was originally

00:24:55.680 | designed as anti-nausea for pregnant women. So the thought was that it could help them with their nausea,

00:25:01.440 | but it ended up causing horrible birth defects. I see. Children were born without limbs and so it was

00:25:06.400 | taken off the market. But then about 20 years later, researchers figured out that it could be effective for

00:25:11.840 | leprosy. So it's FDA approved for leprosy. And then what's crazy is that shortly thereafter,

00:25:17.040 | it got FDA approval for multiple myeloma, a rare or somewhat rare hematologic blood cancer. And the

00:25:23.600 | reason that it can work for leprosy and multiple myeloma and also the reason that it causes birth

00:25:29.280 | defects is it has a major anti-angiogenic effect. So it reduces blood vessel growth. So in the same way that

00:25:35.200 | you need blood vessel growth to grow limbs, you also need blood vessels or you need over

00:25:41.040 | production or increased blood flow for multiple myeloma cells to survive and also in leprosy.

00:25:48.240 | And so the same compound that causes birth defects, helps treat leprosy, also treats multiple myeloma.

00:25:54.320 | It saved thousands and thousands of lives in multiple myeloma patients. Again, the reason that that

00:25:58.880 | in particular has been utilized in multiple ways was that it had a full patent life when the work was

00:26:05.600 | first begun for leprosy and then myeloma was discovered shortly thereafter. But if a drug like

00:26:11.040 | thalidomide was discovered for leprosy and then 20 years later someone figured out it could be useful for

00:26:16.400 | multiple myeloma, patent is gone. And so there wouldn't have been an incentive to then figure out that

00:26:22.160 | oh thalidomide could also be useful for multiple myeloma. The list sort of sadly goes on and on.

00:26:28.880 | I mean one of my favorite examples is a drug called pembrolizumab that is now used for dozens of cancers.

00:26:36.240 | But initially it was first developed for melanoma and for lung cancer and actually the work that we did in

00:26:43.280 | my lab I guess this is 2016 and it was actually simple work. A patient came to us in 2016 with

00:26:52.400 | metastatic angiosarcoma which is a horrible form of cancer and his doctors told him that he was out of

00:26:58.240 | options and we did something really simple. We went on PubMed and looked for like angiosarcoma treatment.

00:27:03.040 | I mean it was that simple and we came across a paper from 2013 where a researcher had looked at five

00:27:11.120 | tumors from five different patients angiosarcoma and four out of the five tumors had increased

00:27:15.280 | expression of PD-L1 which is a marker that you might respond to a PD-1 inhibitor. And so even

00:27:21.120 | though the paper was published in 2013 and this gentleman came to us in 2016 and of course hundreds

00:27:26.880 | of people had died in the previous three years, no one had ever actually tested whether a PD-1 inhibitor

00:27:32.560 | could be useful for angiosarcoma even though again it was just it was a laboratory study published three

00:27:37.280 | years earlier but no one had ever translated that insight into using it in a patient. So we treated

00:27:42.400 | Michael as the first patient ever that we're aware of with a PD-1 inhibitor and he responded

00:27:47.600 | so incredibly well a couple things happened. One is that his doctors started prescribing it to all

00:27:53.360 | patients with angiosarcoma. It turns out it works in about 18 percent of patients so it was a uniformly

00:27:57.840 | fatal cancer within one year. Now about 20 percent of people will live beyond a year and it can be really

00:28:02.000 | transformative. So it changed clinical practice for angiosarcoma. The other thing it did specifically

00:28:08.960 | for Michael is that it has put him into now a nine-year remission. Just last month he walked his

00:28:15.120 | daughter down the aisle on her wedding day in Nashville, Tennessee nine years after he was told

00:28:19.920 | that this is it. And so these drugs are out there and sometimes there's even breadcrumbs. Like it didn't

00:28:25.440 | require any brilliance from my lab. We literally just had to find a study that was published three years

00:28:30.080 | earlier and that again is really what drives us with with this with this work now to say can we find all

00:28:35.680 | these breadcrumbs? Can we put them together and can we make sure people actually benefit from all the

00:28:39.520 | great science that's being done all over the world that's actually translated into patients?

00:28:43.440 | Yeah it seems to me that PubMed and other sources of of science knowledge are great for stacking papers

00:28:51.680 | and and they're pretty decent in terms of how they're organized you know by keyword search. I mean

00:28:57.600 | they're not perfect but you can find stuff. Yeah. And you get suggestions about related articles and

00:29:03.040 | somebody with a little bit of time and energy will get some degree of information there. But it seems to

00:29:09.680 | me that no one has really organized that the enormous database of information about science as it relates to

00:29:16.640 | disease. It occurred to me a moment ago there should be a database where one can enter

00:29:24.960 | whatever knowledge they have about how old their grandparents were when they died and of what

00:29:28.960 | how old their parents are or were maybe they're alive maybe they're deceased any knowledge any

00:29:35.440 | any kind of family history this is the first thing a doctor would ask you if i come in and you're the md

00:29:39.920 | and if i say hey listen you know i've got like this swollen lymph node on the left hand side i don't i don't

00:29:44.000 | think you're going to say hey like go get it scanned you'll say any history of blank and blank in your

00:29:47.920 | family first thing right one should be able to do this from home and then enter any symptom profiles

00:29:54.640 | they might be having and with the appropriate cautionary notes get some ideas back about what

00:29:59.360 | might be going on and that might sound like oh this is people playing their own doctor but i'll tell

00:30:03.520 | you right now if i put in uh left armpit lymph node pain yeah or swelling into any online search engine

00:30:11.280 | it's going to tell me some of the worst possible outcomes so it's not like we need to shield people

00:30:16.320 | from potential outcomes but it seems to me that this should be pushed through an ai read of pubmed

00:30:22.560 | which already exists right most of the large language models are trained on the entire internet

00:30:27.440 | including pubmed and that it should point somebody in some actionable directions including which of

00:30:32.800 | these groups i meant to ask this earlier excuse me which of the various groups for a given disease is

00:30:37.440 | the best one yeah exactly like if somebody is kid you know god forbid has a has a blood cancer yeah

00:30:43.600 | which group do you go to is there a best one are these rated by anybody i mean i i'm not trying to

00:30:49.520 | throw our arms around all of medicine here and all of the problems in the world but it seems to me that

00:30:55.120 | all of this is tractable someone just needs to get organized about the databases i completely agree i think

00:31:00.560 | that there's such randomness to to health care into our biomedical research system i think that's

00:31:06.000 | probably maybe the the most heartbreaking part of this all is that because it's so random you know

00:31:10.800 | michael gets a drug and he walks his daughter down the aisle nine years later and a bunch of other

00:31:15.040 | people don't get a drug and they they aren't alive and so i i love the idea of that centralized database i

00:31:20.640 | think that there's a company called open evidence which is trying to to basically create a gpt but for

00:31:26.800 | health care um i don't know if it's i don't think it's it's to where you described it where you can

00:31:31.200 | really put in your personal family information and get answers but i'm hopeful that others will um you

00:31:37.040 | know the role that i see our work and and my work fitting into that is basically finding as many of

00:31:43.920 | these connections and proving them out in the lab and in clinical trials as possible so that way when you

00:31:48.080 | type in your disease and your situation that that drug that we worked on you know rises at the top

00:31:53.680 | because it wasn't just a connection in pubmed but it was a connection in pubmed that we've added in the

00:31:58.480 | lab and we did the trial to prove that it works yeah it's kind of wild that on a completely different

00:32:03.120 | end of the spectrum um you know recently everyone's talking about creatine creatine creatine creatine

00:32:08.480 | okay i'm taking creatine since my teens because i heard back then that it would help make me stronger

00:32:12.720 | it'll make you stronger now people are talking about creatine for women for men for older people

00:32:17.040 | under conditions of sleep deprivation for cognitive support let's face it the effects while documented

00:32:23.200 | are fairly mild for cognitive support but they're there and this is not being touted as a treatment

00:32:29.680 | for like dementia although it might help offset some minor dementia or something like that i don't know

00:32:34.560 | but the point is that people are talking about it it's in the news it's covered all the time

00:32:39.040 | but we really should be talking about or also talking about drugs like aspirin that can be very

00:32:45.920 | useful for potentially for colon cancer and heart attack not just for pain and all the other examples

00:32:51.840 | that are out there yeah but i think there's this fear that if you talk about a drug that people are

00:32:56.560 | just going to start taking it yes uh as an uh an attempt at a prophylactic yeah right and i think

00:33:02.320 | that um there's a lot of um caution around that for understandable reasons but i want to know i just

00:33:08.480 | turned 50 i want to know all the things that i could be taking to potentially offset heart attack

00:33:15.440 | because i'm already exercising and trying to get my sleep and doing all that stuff and then i can make

00:33:19.200 | a decision so where is the database of information about as a 50 year old male who does the following

00:33:24.640 | things to support his health no history of heart disease in my family that i'm aware of well what

00:33:30.560 | drugs are on the counter um or molecules that exist in behind a script from a doctor that could

00:33:37.520 | potentially extend my life i want to know that information yeah and what we're talking about

00:33:41.280 | creatine yeah so for once i'm i'm kind of like uh i'm not being disparaging of supplements but like

00:33:46.000 | it doesn't make any sense the conversation is skewed in in the wrong direction yeah i mean i think that

00:33:51.280 | what we're trying to do with with every cure and with our work is trying to start this conversation

00:33:56.240 | and keep the conversation going so that way you can go to your doctor with you know with x drug um you

00:34:01.520 | know i mentioned that we have nine active programs so on the one end of the spectrum really common is is

00:34:06.240 | our program with lidocaine and breast cancer where we're doing laboratory work we're also evaluating

00:34:10.000 | clinical data and i hope at some point in the future that the data is strong enough and if it is then

00:34:14.560 | we'll we'll work to to encourage every woman who's about to go in for breast cancer surgery to talk to

00:34:19.920 | their surgeon beforehand and say hey i want to make sure you do this instead of really empowering them

00:34:23.520 | in that way but all the way through even to the rarest of conditions there's a condition called bachman

00:34:28.400 | bupp syndrome where kids are born with a mutation that caused them to have elevated levels of an enzyme

00:34:33.600 | called oce1 and basically they're on feeding tubes they are wheelchair or bed bound unless you give

00:34:43.520 | them a drug that was made for african sleeping sickness which is a perfect covalent binder to oce1

00:34:49.440 | so that enzyme that's too high in these kids african sleeping sickness medicine actually binds to oce1 and

00:34:55.200 | if you started early enough in life these kids get their feeding tube taken out they might be able to

00:34:58.960 | sit up they can even play with their siblings and so the reason i mentioned this is that there aren't

00:35:04.720 | that many people with bachman bupp in fact it's only been described in 20 kids which means there's

00:35:08.720 | probably hundreds of kids um because the medical uh literature is typically behind reality but let's

00:35:14.320 | say there's hundreds of kids at some point we're going to get the word out so that way you know we

00:35:18.720 | can find every kid possible you know with bachman bupp so they can get this this medication dfmo and so

00:35:24.400 | um that these are microcosms of what you're talking about which is that like no one should suffer from

00:35:29.440 | bachman bupp without being on dfmo no one should have breast cancer without having had lidocaine no

00:35:34.400 | one should be a healthy 50 year old man who might be able to have their risk of heart attack reduced

00:35:38.800 | it might be that colchicine is helpful for um for reducing your risk of heart disease but to your point

00:35:44.720 | how can we get this more proactively so we're not just sort of like hoping and waiting that all these

00:35:50.880 | random things line up we used to use colchicine in the lab so coaching is an interesting one so um

00:35:57.040 | colchicine uh is typically utilized for gout um it's this it's been around forever actually i learned that

00:36:02.960 | it's like 3 000 years ago was when it started being used um because uh gout often occurs in individuals

00:36:09.120 | who consume too much alcohol and so like apparently in like egypt 3 000 years ago some of the um wealthy

00:36:15.680 | people were drinking too much alcohol and somehow they figured out that this molecule uh colchicine of

00:36:20.560 | course i think it was a root at the time could be helpful for reducing gout um and we should fact

00:36:25.440 | check that that statement because i need i don't know the exact details but it's been around a long

00:36:28.480 | time if there were a database you just go to the database that's right you can tell where my mind's

00:36:32.400 | going yeah exactly so so colchicine's around forever it's been used for gout for many for decades um

00:36:38.560 | people have gouty arthritis they get these painful joints to give them colchicine it helps them out

00:36:43.120 | well a researcher a couple decades ago um had a hypothesis that because of its anti-inflammatory properties um and a

00:36:50.240 | few other properties of colchicine that it might be able to reduce the risk of heart attacks in

00:36:53.840 | people who've already had a heart attack or maybe in general but in particular people have already

00:36:57.200 | had a heart attack and um because it's been around forever they couldn't um they really couldn't raise

00:37:03.520 | the funding needed to do all the trials to prove it because um heart disease prevention trials are big

00:37:08.560 | expensive trials you got to follow people for years to prove they didn't get a heart attack versus

00:37:12.080 | people who did who got a placebo so they ended up changing the dose of that medicine of colchicine

00:37:18.080 | so it's a slightly different dose from the one that you use for gouty arthritis but it has a very

00:37:23.520 | substantial reduction in heart disease risk if you had a prior heart attack and in particular if you had

00:37:28.080 | a prior heart attack and you have diabetes a really really meaningful reduction so got fda approval for

00:37:33.840 | for that particular subpopulation but i mention it because if they hadn't changed the dose it would have

00:37:39.600 | been a paper that some academic would have published that i think colchicine could help and no one would have

00:37:43.440 | ever done the big trial and again that's sort of the tragedy here is that people are literally not

00:37:47.920 | having heart attacks right now because they're on colchicine but if not for someone figuring out

00:37:52.160 | a way to make the system work you know they would have had their heart attack we've known for a long

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00:40:38.720 | davidprotein.com slash huberman well i feel like we could spend hours going through the catalog of drugs for

00:40:44.640 | which uh these examples exist um and we may return to a few more but i'm putting in a strong vote for

00:40:51.360 | this database i know you're working hard on this i'd like to talk about your journey into this because

00:40:56.160 | you are not a typical doctor um i think that's apparent to people already uh you care very much

00:41:02.400 | about human health and treating human disease uh but you have a very unusual and interesting trajectory

00:41:10.000 | into medicine and i do believe it's helped lead you to this uh very unique orientation within the

00:41:16.480 | field of medicine and science so tell us that story and uh teach us about castleman's disease

00:41:23.760 | sure um well my story um i think really starts back when i was 18 years old and um i was a freshman at

00:41:30.160 | georgetown um we were talking earlier about i played football at georgetown that for me growing up that

00:41:35.280 | was my dream to be division one college quarterback that's all i could think about i was not quite as

00:41:39.680 | jacked as you but somewhere i saw a photo you were larger than i was yeah we'll put up a link to a

00:41:44.160 | photo i david was 230 you're taller than i am i'm six one so you're probably six two three six yeah i think

00:41:51.120 | you might be six three either that or i'm shrinking um and uh super large fit low body fat i mean you

00:41:59.120 | you look um you clearly you're a quarterback but you're large even for a quarterback i was yeah okay

00:42:05.680 | so you know that was my dream was you know i want to play college football and i got there and i was

00:42:09.440 | had been on campus at georgetown for a couple weeks and um i got a call that changed my life my dad called

00:42:15.120 | and and told me that my mom had brain cancer and uh andrew i went from like all i could think about was

00:42:20.880 | football and like you know i'm finally at this you know goal that i'd always set to oh my gosh this is

00:42:26.080 | just just changed everything my mom uh my mom and i were so close and i was heartbroken for

00:42:32.640 | uh glioblastoma brain tumors are uh uniformly fatal they're horrible um uh you know i was only 18 so i

00:42:39.440 | don't think i knew just how bad it was but i knew it was really bad and um watching her battle with

00:42:45.280 | cancer over the next 15 months um just changed everything in me um it it completely locked me in

00:42:52.080 | and i told her just before she passed away that i would dedicate my life to trying to find treatments for

00:42:55.920 | patients like her and um she she couldn't say many words um at the at the end but she said

00:43:01.680 | unconditional love those were the two words that she said when i told her i would do that and i was

00:43:05.360 | like all right i got to do this you know she she um you know she wants me to do it and for me i i

00:43:10.240 | sort of haven't been able to stop thinking about helping people like her from the moment that i started

00:43:14.800 | seeing this um horrible cancer um uh you know take her life in front of me and um and of course the

00:43:21.600 | promise that i made to her i also learned so much from her in watching her her battle against brain

00:43:27.440 | cancer i mean i'll just tell one one quick story um so i got that call from my dad i immediately came

00:43:33.040 | home to north carolina and within a few days she was having brain surgery to get the tumor resected and

00:43:39.840 | they did a surgery where um they put you to sleep to open up your skull and then they actually wake you

00:43:44.640 | up while your skull's open and um the reason for that which you're very familiar with is that as

00:43:49.840 | they're cutting out particularly in the left side of the brain cutting out parts of the brain tumor

00:43:53.520 | you want to be able to see where how far you want to go um you ask people to speak and sort of when

00:43:58.240 | they start slurring their speech you stop cutting and so they went through this whole surgery it was

00:44:01.760 | like a four and a half hour surgery cut out most of the tumor but not everything and um they you know

00:44:08.560 | woke her back up after after the surgery and um she was in the waiting area and we went back to

00:44:13.360 | see her and i remember my dad i've got two amazing older sisters my dad and i we um went back to see

00:44:18.720 | her and we were you know so nervous like is it going to be our mom who's going to come out it took out a

00:44:22.640 | lot of her brain um as part of the surgery and um so nervous and we walked back andrew and pulled

00:44:28.480 | the curtain back i'll never forget i saw my mom sitting there just about as far away as you are

00:44:32.720 | and she had a wrap around her head um bandages and she had this bulb coming out um that was

00:44:38.560 | collecting fluid and she looked at her at her she looked at us and she pointed up to her head and she

00:44:43.040 | said chiquita banana lady and we just burst into laughter she was saying she looked like the chiquita

00:44:48.640 | banana lady and like that for me was this incredible moment of just like taking agency back from this

00:44:55.200 | like horrible cancer like you just went through surgery but like you're going to find something to

00:44:59.200 | laugh about and something to get your family to laugh at and to show that like you're still there

00:45:03.920 | um and so that was sort of the the first of many lessons that i learned from my mom obviously in her

00:45:09.280 | health but also in her illness and so that set me on this journey which is okay i'm going to dedicate

00:45:15.200 | my life to trying to find treatments for patients like my mom i'm going to try to live um in in the way

00:45:20.800 | that she did and um i was sort of well on my way i um finished medical or sorry finished undergrad at

00:45:27.600 | georgetown i did a graduate degree at oxford and then i was a couple years into med school at penn

00:45:31.920 | when you mentioned castleman disease when i went from being totally healthy i shared earlier i won a

00:45:38.480 | bench pressing contest right around that time i was so healthy to being in icu with all my organs shutting

00:45:43.600 | down the story about your mom is a remarkable one uh my first thought when uh you mentioned the chiquita

00:45:50.480 | banana lady reference is that uh even though she was the patient it seemed like she was uh successfully

00:45:56.560 | taking care of all of you she was she was trying to take care of us yeah i know very little about her

00:46:00.560 | only what you shared but she sounds like a very impressive woman she was amazing i so appreciate

00:46:04.880 | you saying that yeah um that comes through so castleman's i've never heard of it who's castleman

00:46:12.480 | and uh these physicians like to name diseases after themselves um but my guess is that they're not

00:46:17.840 | the ones with the diseases they're the ones that discover the diseases correct that's right yep so

00:46:21.520 | benjamin castleman was a doctor in um boston at harvard he'd been getting these cases of patients

00:46:27.760 | that were thought to have lymphoma and they they appeared like they had lymphoma getting very very

00:46:31.920 | sick very quickly but when he looked under the microscope but then they didn't look like a

00:46:35.440 | typical lymphoma patient and so um maybe as i as i share you know sort of what my progression looked

00:46:40.480 | like i mean i was third year med student i just um finished uh an ob g on rotation i just delivered

00:46:45.520 | babies into the world which is sort of a peak moment in medical school and then within a couple weeks

00:46:51.200 | i noticed that i had enlarged lymph nodes in my neck i felt more tired than i'd ever felt um and you're

00:46:56.240 | tired in med school and grad school you know well but i was more tired than ever had horrible abdominal

00:47:00.800 | pain and i noticed fluid pooling around my ankles and this is so weird what's going on um but the fatigue

00:47:07.200 | got worse and worse and worse um and over the course of it really was just a couple weeks um i got so

00:47:12.720 | bad that i went i took a med school exam then i went down the hall to the emergency department i

00:47:16.720 | basically stumbled down to the er and just told them my symptoms and they ran blood work and um

00:47:21.840 | i remember my my doctor coming back and um and looking at me and saying david your liver your kidneys

00:47:28.480 | and your bone marrow are all shutting down we have to hospitalize you right away and i'm like what do

00:47:32.400 | you mean like i was just like i delivered a baby a couple weeks ago like how all my organs are shutting

00:47:36.960 | down and so they hospitalized me and i deteriorated really rapidly i had a retinal hemorrhage that made me

00:47:42.160 | temporarily blind in my left eye i gained a total of about 100 pounds of fluid because my liver and

00:47:47.200 | my kidneys stopped working you saw that picture where i just flew it everywhere um because of the

00:47:52.160 | multi-organ failure and um i needed daily translusions of red blood cells and platelets just to keep me

00:47:57.680 | alive i was on dialysis at the time as well so basically everything was shutting down and we had no

00:48:02.400 | diagnosis so we didn't know what it was my doctor some doctors thought it was lymphoma others thought

00:48:06.480 | maybe it was autoimmune disease others had no idea what it was um but over the course of about 11

00:48:12.080 | weeks i got worse and worse and worse and at one point i was so sick that um i said goodbye to my

00:48:17.040 | my dad and my sisters and my girlfriend at the time caitlin and um a priest came in my room and read me my

00:48:21.680 | last rites when i was 25 years old fortunately right around the time um of having my last rites read to

00:48:28.320 | me which was really the end i mean i didn't didn't have more than a couple days left that's when the

00:48:32.480 | diagnosis came in of castleman disease um so basically a pathologist looked at my lymph node

00:48:36.560 | and they thought i had lymphoma they figured it was a really aggressive lymphoma which is a form of

00:48:39.920 | cancer but they looked at it and just like benjamin castleman did looked at it and said this doesn't

00:48:44.240 | look like lymphoma this actually looks different it looks like this thing called castleman disease

00:48:48.480 | which is basically um what we call it atypical lymphoproliferous disorder so it's kind of like lymphoma

00:48:53.840 | but it's got features that are more like an autoimmune disease and so basically your immune system

00:48:58.880 | becomes highly activated and starts attacking all your vital organs so the reason that

00:49:02.320 | all my organs were shutting down is because my immune system was producing cytokines and other

00:49:06.320 | factors that were were basically um shutting it down do you think that the um long hours of medical

00:49:12.960 | school plus being athletic they're very driven contributed to the autoimmune flare-up and we don't

00:49:19.200 | often discuss this but anyone that's dealt with an autoimmune issue even if it's like psoriasis or

00:49:24.400 | something um which can be very severe but in most cases it's kind of minor to you know they're

00:49:29.520 | over-the-counter things you can use i think but um it's associated with people who are pushing very

00:49:35.040 | very hard and and uh tend to pull long hours and and as a consequence the immune system understandably

00:49:41.120 | ramps up its activity and then goes past a tipping point where it starts attacking one's native tissue

00:49:46.400 | yeah it's funny no one ever asked that but it's the right question to ask and i think people are always

00:49:50.240 | sort of afraid to you know get into like the whys of these things happening to you i'm glad you asked

00:49:54.240 | because actually there was a paper that was published a couple years ago um i think it was in cell where

00:49:58.560 | mice that were sleep deprived like significantly multi-day sleep deprived what actually killed them

00:50:04.560 | was a cytokine storm due to their immune system producing all these cytokines like they actually so

00:50:09.440 | like because we know the sleep deprivation is deadly right you don't sleep enough you know this very well

00:50:13.680 | but again in these mouse studies this the actual thing that killed them was their immune system

00:50:18.560 | producing cytokines including interleukin 6 which is an important cytokine in castleman's um and by

00:50:23.680 | just trying a couple of medicines that basically block the production of some cytokines you could keep

00:50:27.920 | the mice alive longer really pointed this idea that it's sleep causing some disruption in immune balance

00:50:35.040 | causing excess production of cytokines causing death and and so um i don't know if you had you had you

00:50:41.280 | seen i i can share the paper with you it's it's pretty familiar with that one i just but it connects to

00:50:45.840 | your point right yeah i mean i mean again this is all anecdotal for coming from my side uh anyway is

00:50:51.280 | that you know but growing up in in silicon valley and i've known a lot of people who cancers and who

00:50:57.120 | seem to be dealing with autoimmune things and i know a lot of very ambitious hard driving people it's

00:51:01.040 | baked into the culture i grew up yeah and you know and um and sometimes i've just wondered about these

00:51:07.200 | naturalistic observations again these are not controlled studies where some of the most um hard-working

00:51:16.240 | long-hour athletic academic hybrid founder people are the ones that oftentimes are dealing with

00:51:23.840 | severe health issues and you know like how could that be well maybe there's a relationship and the

00:51:27.440 | more i learn about the kind of general backdrop of supporting health sleep being fundamental and all

00:51:33.440 | the rest and you know natural light exposure but not too much uv and you know this kind of thing

00:51:37.840 | you gotta kind of wonder you you i'm not saying people shouldn't work hard i i otherwise i'm headed

00:51:43.120 | for a quick death because i've always worked very long hours mostly from a place of enthusiasm sometimes

00:51:48.560 | fear um but i guess you know you the immune system is a is a highly uh conditional system yeah

00:51:57.360 | i'm not saying mellow laid-back people don't get cancers but has that ever been looked at whether or not

00:52:02.320 | temperament and and propensity for autoimmune induced diseases uh correlate i haven't seen it there may be

00:52:09.120 | i mean what i have seen and to your point i think there's really strong data that among people who have

00:52:13.440 | autoimmune diseases stress results in flares of their autoimmune diseases and so so so if you have it

00:52:20.080 | stress lack of sleep all this stuff can can result in flares i haven't seen data on whether it's sort of

00:52:24.800 | like at the ideological level of actually causing it but i think that you know this mouse study of these

00:52:29.200 | these mice was sort of you know eye-opening for me and i was you know working crazy hours and as you

00:52:34.160 | heard i was on a mission i'm still on a mission which is to find drugs for patients like my mom

00:52:38.080 | and that you know that meant that i worked crazy crazy hours i teach medical students and um they

00:52:44.960 | work crazy hours it's it's really impressive and and striking and at times a little concerning but um

00:52:52.720 | so you get this diagnosis thank goodness they figured out it wasn't lymphoma and it was castleman's

00:52:59.280 | because that at least gave you a kind of a thin end of the wedge to start exploring various treatments

00:53:05.120 | at the time was there any treatment for castleman's disease known treatment at the time there were no

00:53:09.440 | approved treatments um but sort of as we were talking about earlier about like sort of information

00:53:13.360 | asymmetry um there was a drug that was um uh originally developed in japan uh for castleman's um

00:53:20.880 | but my doctors didn't know to try it they gave a form of chemotherapy to me um which fortunately

00:53:27.040 | chemo sort of saved my life just in time but there was this drug in japan that like it's pretty strong

00:53:31.840 | data that works for castleman's but that just like information hadn't and the drug is available in the

00:53:35.440 | u.s for another condition that information exchange just hadn't happened and actually i'll share a quick

00:53:39.520 | story about that drug it's called tocilizumab and um it was made by a doctor named kazoo yoshizaki

00:53:46.000 | or discovered by a doctor named kazoo yoshizaki and um uh i had heard from a colleague that kazoo had

00:53:54.000 | given it to himself before it was given to any other humans to prove that it was safe and um old school

00:53:59.040 | medicine right this is the 90s and and monoclonal antibodies were a new technology and so apparently

00:54:03.760 | he was afraid to give it to patients because he didn't know what it's going to do so he's like i'll give

00:54:06.240 | it to myself so i heard that and i said kazoo i heard you gave your yourself teslizumab he said no

00:54:11.920 | no i didn't give it to myself the nurse the nurse gave it to me i was like all right all right kazoo

00:54:16.720 | i love the specificity exactly um and so he gave it himself and he didn't die when he got it um but

00:54:22.960 | it was safe enough for him so he studied it in castleman's patients it got approval for castleman's

00:54:27.200 | in japan and then it got repurposed for rheumatoid arthritis here in the u.s and a number of other

00:54:31.520 | autoimmune diseases so it's approved in the u.s for autoimmune diseases but like i said it was

00:54:35.840 | made for castleman's in japan approved and available but my doctors didn't even think to try it um chemo

00:54:41.360 | saved my life um but then i relapsed a few weeks later we tried that drug from from kazoo from japan

00:54:47.280 | it didn't work for me it only works in about a third of patients and so um i ended up needing

00:54:51.760 | a combination of seven different chemotherapies adramycin cytotoxin atoposide velcide

00:54:56.000 | exalitamide rituxan like the worst chemos out there um was what i ended up needing to get my

00:55:00.320 | disease into into remission and just to give you a sense for how sick i was this is now

00:55:04.480 | the third time that i almost died in a six-month period i was so sick that once they started giving

00:55:09.120 | me that combo of seven chemos i started feeling better with every dose and these are like the

00:55:13.280 | worst chemos in the world but because they were killing my immune system which was producing cytokines

00:55:17.600 | which was killing me i actually felt better on chemotherapy and and eventually um i got well

00:55:22.960 | enough to where i could be discharged from the hospital and there's that picture i showed you

00:55:25.600 | from the book which is me a couple weeks after i got out of the hospital um and i was just so thankful

00:55:30.720 | to be alive yeah we'll post a link to that photo as well into your book of course um yeah that photo

00:55:37.680 | if you show that photo to the typical person they're they're not going to say that's a healthy looking

00:55:43.120 | person but you said you were so grateful to be alive because relative to where you were before

00:55:47.440 | i mean 100 pounds of fluid it's crazy accumulating in your legs and body prior to that you were in a

00:55:54.960 | very unique position because you have this um inquisitive mind it's very clear you were motivated

00:56:03.120 | not just from your illness but motivated generally based on the story about your mom um and people would

00:56:09.920 | listen to you is my guess they would at least listen to your questions as i'm reading into this a bit but

00:56:15.280 | i think many patients don't know what questions to ask they don't know whether the person they're asking

00:56:23.200 | has access to the best answers or even the answers um i like to think most doctors are benevolent so let's

00:56:31.120 | just assume that but they're also busy and um they get as confused as anybody i'm not trying to knock on

00:56:37.760 | medicine here but this is just the reality so simple question when a physician

00:56:43.040 | finishes their uh their training all the way through residency and they start practicing let's say an

00:56:50.560 | oncologist or a general practitioner in the united states but perhaps elsewhere is the typical physician

00:56:57.360 | accessing the literature often i know they're required to do some continuing medical education but

00:57:02.480 | it could be the case that their education around a disease is just locked in at the time they

00:57:08.240 | finish their residency plus any major updates that come through how does this work because i want

00:57:13.840 | to know when my physician finished training and i want to know how often they read papers and i want

00:57:17.760 | to know who else is on their uh committee of of of people that they share ideas with i want the most

00:57:24.160 | connected physician in the world to be treating me yeah and and i do too and i think that the problem

00:57:29.440 | is is that given all the constraints and requirements of a typical physician they just don't really have

00:57:34.240 | that much time to do all the things that we want them to be doing so um you're right physicians are

00:57:39.440 | reading the literature but typically it's because they have a patient with something that maybe led them

00:57:43.520 | to it or maybe um someone sent that paper to them it's it's very random and sort of piecemeal you

00:57:49.360 | you know no doctor can can look at millions of papers for example and they can't even look at

00:57:53.920 | the hundreds that they maybe would be relevant for the diseases that they treat and so they get sort of

00:57:59.360 | some watered down summaries they go to a conference and they hear sort of what's being told but it's

00:58:04.640 | very piecemeal and i think the big takeaway from from this whole conversation is that so much of

00:58:09.520 | this is piecemeal and it's not systematic and it is random and it's did your doctor happen to come across

00:58:14.480 | this one paper um as opposed to the world that we should be in which is where um where it shouldn't

00:58:20.480 | matter what doctor you go to see because the data is the data i mean this whole idea of like you know

00:58:25.440 | we talk about getting second opinions from doctors it's like for some reason we call it a second opinion

00:58:30.960 | yet we believe that what's being told is like exactly what should be done and it's like well it's

00:58:35.680 | an opinion right and oftentimes second opinions you know um aren't consistent with the first opinion

00:58:40.640 | because their opinions i mean they're educated they're driven in science and driven and um are

00:58:45.600 | oftentimes grounded in evidence um but it's still you you just don't know if if your doctor is going

00:58:51.600 | to have the information that's needed for you which is sort of scary right like we we sort of we we want

00:58:56.160 | to go to our doctor and believe that like we like you know full trust like you know you've got all the

00:59:00.800 | answers and actually i'd sort of have this concept that i i talked about in my book which um maybe

00:59:05.680 | will resonate with you and what we're talking about now i called it the santa claus theory of civilization which is

00:59:10.160 | before i got sick with castleman's and when i was a medical student i had this sort of idea that there

00:59:16.080 | were like rooms of scientists and doctors collaborating working together to come up with solutions kind

00:59:22.000 | of like santa's you know workshop and the elves are working together and as soon as they as soon as

00:59:26.480 | humanly possible that a drug could be discovered it's at your doorstep like as soon as they can figure

00:59:31.360 | out but then i've sort of realized that actually like there isn't a you know there aren't workshops

00:59:36.080 | there aren't groups of scientists and doctors you know sitting together to figure out solutions

00:59:39.760 | and if they are it's just not necessarily at the pace that you would hope that it would be at and so

00:59:44.880 | i think that that's just you know one of the the many things that's been a bit depressing yeah i mean

00:59:50.000 | i'm going to resist the temptation to editorialize too much on that point uh because i want to get more

00:59:55.120 | information from you but i can't resist saying that one of the things i've really wished for for a long

00:59:59.920 | time is that the the model of how biomedical research is done in the united states would

01:00:04.720 | shift from what we call the independent investigator model where we each have a lab you know huberman

01:00:09.680 | lab is not just a podcast it you know was and to some extent still is a laboratory space although i've

01:00:15.280 | certainly pared down the size of my lab in recent years for the podcast reasons and other reasons but

01:00:20.240 | the point is that in this country you get a phd if you decide to do a postdoc and start a laboratory

01:00:27.600 | you have a laboratory that's named after you you get funding to do things that are really

01:00:33.280 | associated with your name it's like a small startup that can grow into a medium-sized startup

01:00:37.200 | or a large startup but you you stay independent the whole notion of the independent investigator is that

01:00:44.080 | it's a very romantic model of science but i think we've reached the point nowadays where the sharing

01:00:49.040 | of information and collaboration around a particular goal is far more powerful and i don't have a magic wand and

01:00:56.720 | the level of influence i will have over the nih is questionable but what i'm really pushing for

01:01:01.840 | is laboratories named after a puzzle or a disease or a challenge yep and people coming together to try and solve those issues

01:01:11.680 | because it's not just a matter of naming and branding it has everything to do with how willing people are to share ideas

01:01:18.160 | as opposed to feeling like they have to fight for their piece of the pie

01:01:21.680 | that's exactly right so this is perhaps a conversation for another time but um you've done a marvelous job

01:01:27.760 | of not just trying to educate people about castleman's but your story and we'll continue down that path

01:01:33.840 | in a moment of trying to solve a problem that was life or death for you and then taking that knowledge and

01:01:41.200 | instead of just saying hey i'm going to help other people with castleman's which you have

01:01:45.040 | to really say hey let's let's do this for all of disease all of the medicine and it's so admirable

01:01:51.440 | i have to ask are there other physicians doing what you are doing or are you the lone wolf out there

01:01:56.800 | i think i'm i'm probably the lone wolf in the in this uh scope of what we're doing it's all fda

01:02:03.920 | approved drugs all 4 000 and all 18 000 human diseases so i'm not aware of anyone else who's taking

01:02:09.040 | this sort of all versus all systematic like let's find the lowest hanging fruit but there are amazing

01:02:13.920 | colleagues of mine who work within hematology who the doctor named luke chen who calls me up when he's

01:02:18.960 | got patients on death's doorstep to figure out what can we do what can we try we're brainstorming let's

01:02:23.920 | try this or try that and and oftentimes they work and this patient's alive because we tried a combination

01:02:28.960 | of five different chemotherapies that weren't made for that that cancer and so there are certainly you

01:02:33.840 | know really incredible and there's so many incredible doctors all over all over the country

01:02:38.320 | and there are some who are really you know pushing the boundaries of what's possible but i'm not aware

01:02:44.240 | of any other effort that's being made that's really at the system level of like i don't care in particular

01:02:50.400 | the name of the disease or the name of the drug i just believe that the 4 000 drugs we have today

01:02:55.600 | should help all the patients who can benefit from them period like no one should suffer if there's

01:03:00.880 | a drug at your cvs that could help you and so the the problem is that's not the world we're in the

01:03:05.920 | problem is that we got to we got to create that world um and so that's what we're doing yeah and

01:03:11.200 | most scientists are incentivized to find new things and most physicians are not scientists that's right

01:03:17.680 | i'm not saying scientists are better but they the two need each other that's right so anyway i i will now

01:03:23.760 | pull back on my desire to editorialize about how the system could be better um my hope is that some of this

01:03:29.360 | will be implemented going forward but if you would you're sitting here now very very much alive

01:03:36.320 | how did this story progress sure so um you know i mentioned i got that chemotherapy got out of the

01:03:41.920 | hospital um went back to med school at penn um as a third year med student um how much time did you

01:03:49.120 | spent six months in the hospital and then about six months in medical leave just sort of building myself

01:03:53.360 | back up um uh amazingly i had this um girlfriend caitlin by my side through it all um caitlin never

01:03:59.360 | left my side um was just amazing and um got back to med school so it was now a total of a year because

01:04:05.680 | six months of hospital six months um recovering and i was so excited to be back and to really get back on

01:04:11.600 | that path that i had before which is that i'm going to go into oncology i'm gonna help patients like my mom

01:04:16.080 | and i was on an experimental drug uh it's actually a drug that's very similar to the drug that um that

01:04:21.440 | my friend kazoo made and um unfortunately about a year after i got out of the hospital i was back in

01:04:27.600 | the hospital again with a relapse and um that relapse is really tough um for a few reasons one i almost

01:04:34.720 | died again for the fourth time um and i was in the icu for a month um with all of my organs shutting

01:04:41.120 | down but maybe it was even harder than that was that i was on that experimental drug that we had hoped

01:04:46.960 | would keep me in remission and it was helping other patients and um my doctor explained to me that we were

01:04:53.120 | out of options he said david we've tried everything you know we tried these chemotherapies we tried this

01:04:56.960 | one experimental drug um there's nothing more that we can do and um there was a few minute period

01:05:04.240 | where my dad my sisters and my girlfriend around me and we were just um just bawling our eyes out

01:05:09.680 | you know we're this is the world's expert you know to use the santa claus theory like this is santa

01:05:13.600 | claus telling you like there's nothing more and i kept probing him like is there any cell type or

01:05:19.120 | signaling pathway or is there something we can target like anything said david there's nothing is

01:05:23.680 | there anything an early stage about david there is nothing and um so we just you know we just bawled um

01:05:31.680 | and then i had a really sort of moment of a moment of clarity where it was basically i heard what he

01:05:39.280 | was saying but then i thought to myself you just gave me seven chemotherapies that were made for

01:05:44.720 | lymphoma and my multi-myeloma and they've saved my life now three times they're not it's not long term

01:05:50.720 | like i know i keep relapsing but like if these seven chemotherapies are working how do we know there's

01:05:56.400 | not an eighth chemotherapy or a ninth drug for something else like you can't tell we haven't

01:06:00.560 | tried all 4 000 drugs we've just tried the drugs that maybe we thought to try and so i just locked

01:06:06.880 | in right then and i turned to my family and just sort of wiped away my tears and said i'm going to

01:06:10.720 | dedicate the rest of my life however long that's going to be it might be a couple days maybe it'll

01:06:14.160 | be a couple months but however long i've got to trying to find out is there a drug out there that

01:06:18.560 | could help me and other patients with my disease that's made for another condition and um i became

01:06:23.840 | just totally locked in on this and part of it too for why it had to be a repurposed drug is that i

01:06:29.600 | didn't have a billion dollars in 15 years to make a new drug from scratch i mean i wouldn't even know

01:06:33.680 | where to start right but i had examples where my life was saved by drugs that weren't made for me and

01:06:39.600 | so i just said well we should do everything we can to find something else and so i started storing blood

01:06:44.640 | samples on myself every couple weeks um shortly thereafter started doing some work in the lab i

01:06:49.920 | was literally an md who had a master's in public health who knew nothing about the lab um but started

01:06:55.760 | working we call that uh dangerous yeah exactly very dangerous and and with a clock ticking right so you've

01:07:02.880 | got a lack of skills which the clock's ticking down um very dangerous and so um started doing uh

01:07:10.400 | laboratory experiments um did a lot of flow cytometry to characterize immune immune cells

01:07:15.120 | that were activated did something called serum proteomics where i measured a thousand proteins in

01:07:18.480 | my blood who's letting you do all i mean whose lab space are you using so you're breaking no i wasn't

01:07:23.200 | breaking that a colleague was very generous people have done it a very very kind colleague gave me some

01:07:27.840 | space in her lab and so um i was doing this work in the lab and also trying to look at other drugs

01:07:33.600 | that were being used for um related conditions um to see you know what could work for me and um we

01:07:39.760 | were making progress i started a foundation called the castle disease collaborative network we really

01:07:43.120 | were pushing things forward and i was optimistic that we would find something and then i relapsed

01:07:48.560 | fifth time back in the icu organs shutting down doctor explaining to my family that this is it in fact

01:07:55.280 | it was so bad at one point that um i had for some reason over these years i think it was maybe a bit of

01:07:59.360 | denial i'd never put together a will but um this time the fifth time my doctor told family you need

01:08:05.600 | this you need to put down and so um i like had a printer piece of printer paper that the nurse gave

01:08:11.280 | me and i sort of wrote down who i wanted my things to go to and i didn't have much but but um cried

01:08:18.240 | hugged my girlfriend we were my she was my fiancee at that time caitlin like just so disappointed that

01:08:24.720 | like i hadn't figured something out because what i didn't mention is that from that lab work i thought

01:08:28.800 | two drugs might be able to work and we tried both of them we tried cyclosporine we tried ivig and it

01:08:33.040 | didn't work and i got worse and i ended up you know back in the hospital and so the two drugs we tried i

01:08:38.400 | thought i that was like i got my shot and i missed um and uh i felt so disappointed um and i remember

01:08:46.240 | saying goodbye to everyone and um and and starting to sort of have life fade away and i thought that was

01:08:53.360 | it and they gave me all the chemo they gave me the highest dose of topos at this horrible chemo that you

01:08:58.080 | could imagine and um two days later i started to wake up and uh andrew there's this sense i i call

01:09:06.560 | it overtime and it's basically like it's like extra time in a game where like it every second counts and

01:09:13.440 | i can't tell you the joy that comes from like getting like when you start to wake up after you've said

01:09:18.720 | goodbye to the people you love and you're looking at them and like my sister gene is here and caitlin's here

01:09:24.000 | and my dad's there i'm like oh my gosh like when you start getting life back that you thought you've

01:09:30.160 | lost and this is now the fifth time i can't put into words what it was like but i remember like

01:09:35.760 | as soon as i started waking up i saw them and i was like gina i need you to get the lymph node that's in

01:09:42.320 | north carolina to philadelphia caitlin i need you to get my serum samples that are downstairs in little

01:09:47.200 | rock arkansas to philly like i got another shot at this like and i remember like starting to wake up

01:09:52.000 | i'm being like oh my gosh i'm gonna get another shot and so um about three weeks later i was out of the

01:09:58.320 | hospital i was back in philadelphia and um that started about a month-long period where i thought

01:10:03.920 | all those samples i did more flow cytometry i did more serum proteomics i did immunohistochemistry on my

01:10:09.280 | lymph node and when you put all the data together um what i discovered was that a communication line

01:10:15.040 | in your immune system or in all of our immune systems called mTOR um was turned into overdrive and i had

01:10:20.640 | a lymph node that i had resected during my last relapse where i actually looked at it and i stained

01:10:25.680 | it for mTOR activation and it came back blazingly positive and um so i took the data to my doctor

01:10:32.720 | and um you know said what do you think about trying an mTOR inhibitor on me sirolimus had never been

01:10:37.520 | used before rapamycin is the other name for this drug had never been used before for castleman's but

01:10:41.840 | it's approved for organ transplant rejection and um i sort of had nothing else to try and so my doctor

01:10:49.920 | prescribed it to me and um you know rapa at the dose of a transplant dose so i take rapamycin at the

01:10:56.480 | same dose that a kidney transplantation patient would take it's a lot higher than the typical longevity

01:11:01.600 | dosing that people do my dose of rapa for longevity is zero zero yeah i'm not a fan okay we could

01:11:07.360 | talk about that a little later yeah we definitely a lot of people that were taking rapa for off of it

01:11:11.280 | for longevity purposes i don't want to because i'll get it wrong like i don't know what peter t is doing

01:11:16.240 | right now he's a friend we could call him but my understanding is that a number of people who were

01:11:20.880 | very bullish on rapa for longevity are no longer bullish on rapa for longevity yeah i've definitely

01:11:26.480 | seen that that shift and i'm not sure if it's based on human data because i don't think anyone's ever

01:11:30.880 | done the data the study in humans but but the reason that people were bullish on it is that every

01:11:36.000 | organism that you give rapamycin to the earlier you give it to them the longer they live now these

01:11:41.040 | are organisms that are in cage settings that are not getting exposed to viruses and pathogens so that's

01:11:46.160 | probably part of it i mean i think that whatever maybe longevity benefit you get from the metabolic

01:11:50.800 | aspect of rapamycin i think that's counteracted by the fact that we don't live in cages and we actually

01:11:55.520 | get exposed to pathogens and so there's probably a negative effect in terms of survival um because

01:12:01.040 | rapamycin is a very potent immunosuppressant the doses that i take i take such a high dose that if

01:12:05.760 | i were to get your kidney transplanted into me my immune system wouldn't notice your kidney in my body

01:12:09.760 | i mean that's that's the the level of dose i take and so um so uh serolimus is approved for organ

01:12:18.080 | transplant rejection as you mentioned it's used sometimes in the setting of longevity um and it had

01:12:23.840 | never been used before for castleman's in the three and a half years before i started taking it i almost died

01:12:29.360 | five times for my disease i said goodbye to my family on five different occasions and my doctors

01:12:33.600 | were sure i wasn't going to survive since starting rapamycin it's now been 11 and three quarter years

01:12:40.320 | that i've been in remission on this drug and it's just sort of like it feels like such a dream awesome

01:12:46.480 | i mean just no other word for it uh your description of overtime yeah is uh i think a very apt one

01:12:58.080 | um and i find it uh equally apt that when you're emerging from near death you're calling plays like

01:13:08.640 | like a quarterback you're telling your sister what she's gonna do with the lymph node she's gonna run

01:13:12.160 | the lymph node downfield right you're calling plays and like to me like you know you're the quarterback

01:13:19.280 | playing quarterback again and i can't help but ask you know the past that you had as an athlete uh do you

01:13:24.880 | you think it served you i mean the the level of drive and determination to say like oh these eight

01:13:29.520 | drugs helping for a while they're no longer helping there's got to be a ninth try the ninth doesn't work

01:13:33.760 | okay let's try something else almost dead come out of near death all right you run the lymph node this

01:13:38.960 | way i mean it's almost impossible to not wonder whether or not you learned some of that resilience

01:13:44.400 | playing sport a lot from playing sports i mean i think that uh

01:13:49.440 | your listeners may not know georgia even has a football team but we do have a football team um

01:13:53.840 | is that any good uh it depends on who you ask i'm sure it's very good good enough to be in in

01:13:58.960 | that's right some league yeah it's division we play ivy league schools so it's like patriot league ivy

01:14:03.280 | schools um but the reason i mentioned that is that um we lost a lot of football games um so uh you know

01:14:09.600 | certainly there's a bunch of things i learned from football i mean first off i decided when i was eight

01:14:14.640 | years old that i want to be division one college quarterback i decided as an eight year old and

01:14:18.480 | andrew i literally had poster boards all over my walls with how far i could throw a football how

01:14:23.680 | accurate i was how fast my 40-yard dash time was how fast my mile dash for the next 10 years and that's

01:14:29.760 | literally that's all i could think about i was just locked in and that sort of like 10 years of like

01:14:35.120 | working towards a mission is sort of the same sort of approach you need to take to solve a massive

01:14:40.480 | problem in healthcare you know to discover a drug it's that same sort of you know just constant

01:14:46.000 | drive so i think one part was that it was the first of what's now been a few of these like sprints that

01:14:51.040 | i've gone on so i think that was part of it another is um mentioned sort of loss and resilience you know

01:14:57.520 | we lost a lot of football games you get back up and you just sort of keep fighting um but also um

01:15:02.960 | physical pain and um and challenges you know broken both my collarbones broken both my hands

01:15:10.320 | um at different times i mean i remember there were times when uh for punishment for the team we did

01:15:16.560 | something called rolling where like literally like you just start rolling on your side on the football

01:15:21.760 | field until everyone like gets sick and then like and then you stop rolling and like but that's like

01:15:27.360 | you're rolling for like many like for a long time until everyone gets sick um that's the kind of

01:15:32.240 | like physical like i don't know i wouldn't say use the word abuse but it's the sort of physical like

01:15:36.960 | demands that get put on your body that enable you to then gain 100 pounds of fluid in the hospital and

01:15:43.200 | be in the worst pain you could ever imagine i mean it was way worse pain than breaking my collarbones

01:15:48.640 | but like i'd felt bad pain before and so like i can feel some bad pain now and i think that a lot of that

01:15:54.720 | came from football i also think that when i was in the icu for that first six month period i learned

01:16:00.160 | a lot about myself and i learned a lot about how do you overcome challenging situations and um i think

01:16:06.640 | there were three things that really helped me so the first was that the whole time i was in the icu for

01:16:11.360 | that six month period i had this clear vision for the future which was a family with caitlin who i was

01:16:17.040 | dating at the time and a career discovering drugs for patients in memory of my mom so that like clear

01:16:21.920 | vision for the future helped to deal with what was just horrible excruciating pain because of the

01:16:26.960 | fluid that you gain around your organs it felt like i was getting basically simultaneously stabbed for for

01:16:31.840 | you know months at a time so one is vision for the future two was that i got so much strength from my

01:16:38.000 | family around me like my dad my sisters caitlin like they were holding my hands and i could feel their

01:16:43.360 | strength in my hands and like i i could they were like literally helping me to keep going and i remember

01:16:49.360 | there was a moment um during the when i very first gotten sick so the first time i almost died from my

01:16:55.360 | disease and doctors came in said i wasn't going to make it we had no diagnosis at this time said goodbye

01:17:01.520 | to my family you know just heartbroken and i remember with every breath i took just just the

01:17:07.040 | horrible pain and so when when you have that much pain with every breath you start slowing your breathing

01:17:11.120 | and um i was starting to let go i was i was just i was you know letting go and i thought that i was maybe

01:17:17.840 | going to miss out in a couple days of life but you know i'm in a lot of pain i'm just going to slow

01:17:21.680 | down and let go and i remember hearing my sister gina was on on my left side she was holding my hand i remember

01:17:27.280 | her looking at me and everyone else was crying and sort of like i think it was maybe um

01:17:31.440 | had had an idea for what was going to happen but gina was holding my hand and she said

01:17:37.440 | just breathe dave just breathe and i remember when i heard that i was like all right i'm gonna do one

01:17:42.880 | more breath and it's gonna be really painful but i got this and i did one more and i did another one

01:17:48.000 | and fortunately the medicines that i'd received helped me to to make it a little bit longer and so

01:17:53.200 | the key takeaway for me was that like you can do anything for like one minute or one hour or one day

01:17:59.360 | but you can't do like i if you told me at the beginning david you're going to be in the worst

01:18:03.520 | pain of your life for six months it's going to be horrible you're going to suffer your organs will be

01:18:06.640 | failing no way i would have the strength to survive that but i could survive for one minute and one

01:18:11.360 | hour and one day and i think that i think a lot of that you learn i think i learned some of that from

01:18:17.040 | playing football and i think that um just this sort of like putting your body um uh through a

01:18:22.960 | lot of challenges i think helped me a lot older sister or younger sister two older sisters yeah

01:18:28.240 | lees and jean are seven and five years older than me awesome man as the younger brother of a

01:18:32.160 | older sister they're the best they're the best they're the best the best yeah big big shout out

01:18:37.200 | for the for the sisters older and younger yes the best i'd like to take a quick break and

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01:20:23.520 | again that's functionhealth.com to get early access to function you had an amazing team so another parallel

01:20:31.280 | to to football and um and another signal that for people um combating disease or just general health

01:20:40.560 | issues that that social support piece is so key i mean i mean there's so much data on this and i mean

01:20:46.400 | we've done podcasts about this and we could probably do a hundred more and the message is always the same which

01:20:51.520 | is to the best that you can surround yourself with at least one person you can rely on and be the best

01:20:57.840 | way to do that is to be that person to people yeah you know um should you stay healthy you have that

01:21:02.960 | person should you not be healthy you have that person so um yeah and over and over it's really um

01:21:11.120 | an incredible story because you emerge from it with 11 years of overtime do you still think about

01:21:18.480 | that as overtime fifth overtime yeah do you although i will admit i think to your question i don't have

01:21:24.480 | the same sort of because there's this in overtime there's a there's both fear and clarity and and the

01:21:30.720 | the fear i think drives some clarity i think you'd be able to talk to the science of a lot more than i

01:21:35.040 | would um i will say as 11 years and three three quarters of a year go by um there isn't maybe the same

01:21:43.520 | heightened sense of like i'm in overtime but you know every once in a while i have a port where i

01:21:48.560 | get my infusion every few months on my chest i've got scars on my neck from where lymph nodes got taken

01:21:54.480 | out and every once in a while i just sort of put my hand here and here and it reminds me okay like

01:21:58.320 | i'm in overtime like i got to be really thankful um because you know we we don't know how much time we

01:22:03.120 | have the brand's wild in this way we had a guest on this podcast michael easter he wrote the book

01:22:08.480 | the comfort crisis it's an incredible book really about how to navigate life generally and and doing

01:22:13.680 | really hard things um voluntarily and uh and he go do really hard expeditions and then come back from

01:22:21.360 | them with a renewed sense of gratitude for like the smallest things the smallest things and i asked

01:22:26.320 | him you know how long does that gratitude last and i think he said about two months oh you know

01:22:32.400 | and then it resets and of course those weren't life or death circumstances of the sort that you're

01:22:37.040 | describing so he just goes on more of these things right great um and it's a wonderful book and an

01:22:42.160 | important dare i say an important book for people healthy uh and certainly healthy or sick i think this

01:22:48.320 | this notion that you're on borrowed time or overtime it's hard to hold on to because you also have to

01:22:53.760 | just live your life but clearly you're making the most of that and and as i mentioned earlier you

01:22:59.440 | know in service to others so your background as a as an athlete helped you navigate this health

01:23:06.640 | challenge then the health challenge dovetails with your work as a physician and you're really a

01:23:11.520 | physician scientist because you you hold both titles and uh formally and um and as a practitioner so

01:23:20.240 | nowadays do you get contacted by people all the time whose kid or themselves are dealing with it with

01:23:26.320 | a challenging disease with the question is there a drug that's approved that can help me or combination

01:23:32.640 | of drugs we do we get contacted a lot and um to share sort of what the these last 11 and a half years

01:23:38.560 | have looked like so um i after medical school i actually um enrolled in business school in part because

01:23:44.560 | i um realized that the greatest barriers to progress did not appear to be scientific or medical they had

01:23:50.240 | to do with things like getting people to collaborate with one another efficient use of resources coming

01:23:54.800 | up with a strategy to solve a disease so it was actually in business school that i discovered

01:23:59.120 | serolimus to save my life and after business school i joined the faculty at penn and set up a lab and um

01:24:04.880 | we got started out first focus on castleman's and you know first it was better understanding how does mTOR play

01:24:10.480 | a role in castleman's he started treating other patients with the drug that i'm on serolimus and so

01:24:15.040 | i'll never forget um we treated a patient in brazil and then treated patient in new zealand and then

01:24:20.000 | but i just heard about them i wasn't physically with them but then the fourth patient we treated

01:24:23.360 | was a patient named joey who was a child um he was a 13 year old boy at children's hospital philadelphia

01:24:28.800 | and um it completely turned his disease around he was he was literally dying in the children's hospital

01:24:35.280 | we used serolimus and i would come in every day to see him and i'll never forget um you know seeing

01:24:40.400 | the blood work seeing him the couple days after we started serolimus and it was just andrew it was so

01:24:46.080 | incredible to like see this boy who was on death's doorstep start to turn around because of the drug

01:24:51.120 | that saved me and now we're saving other people and again we'd use it in brazil use in new zealand but

01:24:55.200 | i hadn't seen them i hadn't like felt like what his family was feeling i actually just saw joey a couple

01:24:59.520 | days ago and his parents a couple days ago as well um he's a he's a college student at temple

01:25:04.400 | university now but so that for me was this huge moment it's like oh my gosh like the drug i'm on

01:25:09.280 | is helping other people it's not just this sort of one-off thing and then we found a drug that's used

01:25:14.800 | for bone uh for a bone marrow condition called myelofibrosis um that we thought could also treat

01:25:19.280 | castleman's patients so there's a young girl named kyla in a hospital in chicago wasn't responding to

01:25:23.840 | anything and she didn't respond to my drug either serolimus and we recommended her doctor um try uh

01:25:29.360 | ruxolitum first time ever for castleman disease and she responded incredibly well she's in college now

01:25:33.920 | marquette university she's going to be a nurse and um that was amazing i was like okay not only did we

01:25:38.480 | find this drug for me and give other people but now we find another drug for castleman's like wow maybe

01:25:43.120 | there's even more we can do so our lab kept working and working and that's when michael the patient with

01:25:47.840 | angiosarcoma came to us back in 2016 and we found out that this drug for melanoma could actually treat

01:25:54.800 | his angiosarcoma cancer and then it's oh my gosh we can find for another disease and this over the course of

01:26:01.200 | uh of the last 11 years has totaled 14 drugs for diseases they weren't intended for and with every

01:26:08.080 | one of them we get so excited and then we also think to ourselves how many more drugs are there out there

01:26:12.960 | that are made for one disease that could actually treat more diseases and so that meant that three

01:26:18.480 | years ago um as artificial intelligence was really continuing to move forward at an incredible pace

01:26:24.480 | my co-founders grant mitchell and traces of core grant was utilizing artificial intelligence to support

01:26:31.120 | drug companies with finding new uses for their medicines to find subpopulations that might benefit

01:26:34.880 | from their medicines but we thought what if instead of using ai one drug company at a time to find you

01:26:40.480 | know one new use for medicine what if we could utilize artificial intelligence to scan across all drugs and

01:26:45.120 | all diseases to find the best opportunities so we started every cure three years ago and since starting

01:26:50.720 | every cure um you're absolutely right we get contacted by lots of patients and families and we try to help

01:26:55.120 | them any way that we can and i'll share a couple really exciting examples and at the same time that

01:27:00.560 | we're having all these incomings about people that are on death's door what we keep focusing on is can we

01:27:07.040 | find these matches like lidocaine for breast cancer or dfmo for bachman buff that syndrome i mentioned

01:27:13.680 | can we find these matches and do the work so that way people don't get to death's doorstep do the work

01:27:18.960 | to do the clinical studies get the word out so doctors are prescribing them so they're not coming to

01:27:22.960 | us for a hail mary but we're actually getting the work done ahead of time so that way the drug is just

01:27:27.040 | being used can we match every drug to every disease that they can treat and do the work to get it to

01:27:32.080 | people um because that's really the i think the way that we really solve problems at scale as opposed to

01:27:37.120 | this sort of that one-off hail mary approach but i'll share a couple um one-off approaches that i'm

01:27:41.680 | really really proud of one of them is a patient um named al in vancouver who wasn't responding to any

01:27:47.600 | medicines he also has castleman's and the subtype that i have the really deadly one and um the number

01:27:53.360 | one ranking uh number one ranked drug in our machine learning algorithm for castleman disease when we

01:27:59.120 | ran it for the first time two years ago um was uh a tnf inhibitor actually mentioned tnf earlier and

01:28:06.000 | based on some other work in our lab we thought that maybe we could try it for him um he received

01:28:11.840 | the drug he responded really well castleman for castleman tumor necrosis factor yeah tnf inhibitor

01:28:17.440 | yeah so sorry not tnf directly the inhibitor of tnf exactly so we give him adalimumab and he responded

01:28:23.360 | incredibly well he's been doing great now for two years published in the new england journal of medicine

01:28:27.600 | earlier this year can i ask you forgive me for interrupting sure okay so so an inhibitor of tumor

01:28:31.760 | necrosis factor alpha tnf alpha is involved in inflammatory response earlier you said that this

01:28:38.000 | inhibitor can help treat this condition of multiple strokes yes in childhood okay strokes are basically

01:28:44.400 | bleeding out in in brain areas essentially right okay i'm sure there's a mechanistic pathway that can be

01:28:51.360 | you know uh connected connected to that right um involving any number of things uh and i'm sure

01:28:59.280 | there's a mechanistic pathway that can be linked to this other observation does it matter to you

01:29:06.160 | like does it matter that uh like i i think i actually have seen papers where you know tnf alpha is

01:29:11.760 | involved in the kind of like endothelial neural interface and then you have inflammation and then you have

01:29:16.960 | some shearing and then you're bleeding and okay so like i can it's a just so story in my mind um that

01:29:22.080 | works right um does it matter or is the goal to screen drugs in patients um as these hail mary passes

01:29:30.000 | and figure out things that work and then worry about mechanism later i mean this is typically not the way

01:29:34.400 | science and medicine is done especially in this country people don't like the notion of eating a plant

01:29:40.480 | or eating a seed and then seeing benefits and not knowing what the molecules are i mean we like

01:29:44.720 | reductionist science in this country this is changing somewhat but that's been the pattern

01:29:49.120 | to you for a patient that's suffering is all that matters that they get better i could understand why that

01:29:55.600 | might be the case yes 100 all ever since i saw my mom die from brain cancer all i've wanted to do is

01:30:03.920 | think about how can we help people with these horrible conditions and then when i went through my own

01:30:08.320 | experience i realized that oh my gosh helping people with these horrible conditions may not be

01:30:12.640 | spending my whole career to develop one drug it might actually be spending my whole career finding

01:30:16.800 | out all the uses for all these other drugs and to use a football analogy it's like we've got all these

01:30:20.800 | drugs that are on like you know the one yard line um that could be useful for a new condition but there's

01:30:25.440 | no incentive to do that so can we just push them in so yes it's all about can we help patients and i

01:30:30.240 | think it goes bi-directionally so when a drug helps a patient like like that tnf inhibitor helped help help

01:30:34.880 | al we believe it's because uh t cells in castles patients cd4 positive t cells are producing too

01:30:40.640 | much tnf when they become activated and we've shown that in the lab so you can actually start working

01:30:45.200 | backwards so like when a tnf inhibitor helps a patient so let's look at their blood and let's

01:30:48.240 | figure out why and then maybe i can learn something for the we can learn something for the next patient

01:30:51.840 | so i think it should be bi-directional clinical observations and in the lab and let's go in both

01:30:56.320 | both directions and then i also want to share about another patient named joseph who um has a rare

01:31:00.800 | cancer called poem syndrome and so his uh girlfriend tara reached out to us in one of

01:31:06.080 | these sort of hail mary attempts um because his doctors were getting ready to take him off life

01:31:10.160 | support because he was dying from his poem syndrome and um we recommended three drugs that are typically

01:31:16.640 | used for multiple myeloma we mentioned myeloma earlier myeloma and poems are really really similar

01:31:21.840 | so again it wasn't rocket science to recommend three drugs that are used for a really similar form of

01:31:26.960 | cancer for um for his condition um but he was dying his doctors were afraid to try chemotherapy

01:31:34.240 | they were worried that that it would kill him the drugs himself but they were gonna take him off life

01:31:37.520 | support so they tried it and he responded incredibly well he's been doing great it's been over a year

01:31:42.400 | and a half of remission and i mentioned all these examples because like each one of them sort of

01:31:47.040 | teaches us something else about this and that's that like they're similar conditions yet they weren't being

01:31:52.480 | you know but we weren't thinking creatively yes there were no treatments for poem syndrome

01:31:57.520 | but there were treatments for myeloma and so you know and there's shared mechanisms between the two

01:32:01.920 | so i think that um some doctors are doing this but we have to create a system where we uncover these

01:32:07.600 | and then we can get it out to the masses so they use them the fear is that you try one of these novel

01:32:13.840 | drug applications drugs aren't sorry existing drug used in a novel way yeah be very specific with the

01:32:20.640 | language here and a patient gets sick or dies yep you know it wasn't but gosh maybe a decade and a

01:32:27.040 | half ago that this kid was given gene therapy and died yes and that delayed setback however you want

01:32:35.920 | to view it uh the whole field of gene therapy by a very long time all it takes is one patient death

01:32:41.440 | yep i mean even and then in the supplement realm i don't know if you remember this but like um because

01:32:46.160 | we're about 10 years apart you're younger than i am um is uh tryptophan the amino acid to induce sleep

01:32:54.320 | because you know it's in the serotonin synthesis pathway and um but the binders used in a particular

01:33:01.200 | batch of tryptophan that i think was sold out of japan although um ended up being contaminated and

01:33:06.320 | somebody got very ill and died you couldn't buy tryptophan for a long time now tryptophan not as

01:33:12.480 | critical as life-saving drugs in my opinion except the naturally occurring yeah of course but all it

01:33:17.280 | takes is one bad situation and the whole thing gets vaulted for a very long time so how do you mitigate

01:33:26.240 | that risk is it by only focusing on patients that are really it you know kind of at the end of their

01:33:31.520 | rope in terms of possibilities and it seems to me that the medical community has been pretty

01:33:36.240 | um open to what you're doing uh but i have a little bit of a like a kind of like traditionalist

01:33:44.640 | fear voice in the back of my head like like what if you start giving aspirin to kids with this other

01:33:50.080 | condition and kids start getting really really sick and you can't pull those symptoms back because

01:33:53.920 | it's one thing to halt a drug symptoms stop it's another to to halt a drug and and those

01:34:00.480 | side effects symptoms whatever you want to call them persist and god forbid a kid dies yeah you know

01:34:06.720 | so what you're doing is is extremely exciting but um it's also risky yeah you're asking all the right

01:34:13.760 | questions i mean i think that there's a couple ways that we think about this and one is that we really

01:34:19.200 | do try to avoid the hail marys as you mentioned and as you as you thought lots of people are reaching

01:34:24.400 | out to us and unless we have solid evidence about a drug for that disease we are we don't want to just

01:34:29.520 | speculate because to your point speculation can actually lead to harm so and if there's a you know

01:34:34.960 | fine line between you know speculation that could save a life and harm and of course we are only doing

01:34:40.000 | what we're doing to help people um it's a non-profit organization we literally just exist just to help

01:34:44.720 | people there's nothing else here to it so um we definitely don't want to cause harm um so one part

01:34:50.320 | is that we focus on you know we look across everything versus everything every drug versus

01:34:55.920 | every disease to find the best opportunities and then we move them forward in a really rigorous way

01:35:00.400 | we do laboratory studies we do clinical trials we evaluate the results of those trials we look in

01:35:04.560 | observational data so we can be really rigorous about the things that we do at the end of the day say

01:35:08.960 | we are advocating for this use that's one way to do it the other thing to consider is that there's

01:35:16.000 | always a physician that's prescribing the medicine to the patient and so the best thing we can do is to

01:35:21.280 | educate those physicians and those patients on what it is that maybe we found in a clinical trial or in the lab

01:35:27.280 | works but it's still got to be decision between the patient and and their physician and what about

01:35:32.800 | outside the domain of disease in the domain of health very brief anecdote uh colleagues of mine

01:35:39.760 | some don't like when i tell this story but i'm gonna tell it anyway love it because um many years ago i

01:35:45.600 | went to visit columbia university school of medicine right so like columbia meds fantastic place and there's

01:35:51.360 | a nobel prize winning neuroscientist there met with him to discuss his work he happens to be an md

01:35:57.120 | he's a researcher and um i noticed he chewed six pieces of nicorette inside of the 45 minutes we met

01:36:04.240 | so i asked him like what are you doing guy was in his late 60s then now he's in his late 70s

01:36:08.480 | very very sharp nobel prize wasn't an accident he looked at me like this and he said nicotine is

01:36:15.200 | protective against alzheimer's and parkinson's he said smoking and there wasn't really vaping then but

01:36:22.640 | smoking will kill you but nicotine isn't carcinogenic nicotine despite raising blood pressure

01:36:28.880 | um protects dopaminergic neurons and cholinergic neurons so that's why i do it and he said that he

01:36:33.280 | used to smoke and he was much sharper now he uses nicorette and i thought should i use nicorette so i

01:36:37.440 | said should i be doing this he said you're young you probably want to wait until you're in your 60s

01:36:40.800 | or 70s he said but it's protective against parkinson's and alzheimer's and he also said don't get your head

01:36:45.600 | hit don't play football you know this kind of thing okay so i took that and um i decided all right

01:36:51.920 | someday i'll chew nicorette now nicotine is all the rage i actually don't suggest that most people

01:36:56.560 | take nicotine because of the blood pressure effects yeah he's a constrictor there could be other things

01:37:00.960 | it's very very popular but very very habit forming slash addictive so i want to be very clear about that

01:37:05.760 | but i realized there are really smart people inside of my profession who have medical degrees who are

01:37:10.880 | doing things to promote their health like take lithium not continuously but for one or two months per year

01:37:20.000 | i know a colleague doing that colleague like taking nicotine is now in his late 70s and still very very

01:37:25.680 | sharp now you can't run the the other you can't be the control experiment for yourself but what i want

01:37:30.800 | to know is do you think that there are things that are of value that people can and should explore to

01:37:38.560 | maintain or promote their health to avoid disease in the same kind of framework that you're approaching

01:37:44.160 | the treatment of disease absolutely and i think we need to be as rigorous in this realm as in you know

01:37:50.400 | in the in the world of treating disease i think that the challenge is that there's such limited data

01:37:54.880 | right like you said you know you your one friend is doing really well but it's hard to know was it

01:37:58.880 | because of the nick red or is it you know that he was going to be fine um either way i just think we

01:38:03.680 | got to figure out ways and i think you've done such a great job of spotlighting these opportunities so

01:38:07.360 | that way people will think about it more and actually will do further investigation um you know

01:38:12.800 | i was thinking in terms of this um prevention side of things of course about glp1s and so of course

01:38:18.240 | there's interesting evidence emerging and you'll know better than i will um but around uh improvement

01:38:23.360 | in parkinson's symptoms in patients that are on glp1s and have parkinson's disease improvements or

01:38:27.920 | reduction in risk of alzheimer's and also breast cancer people who are on glp1s and so there's likely a very

01:38:34.480 | complex interplay between weight loss and maybe it's the glp1s are reducing risk of these things

01:38:40.320 | because of metabolic effects maybe there's direct effects maybe it's anti-inflammatory so these are

01:38:45.120 | you know preventative concepts um with pharmaceutical products that um that i think we we need to be

01:38:51.520 | thinking about and to your point you know there really isn't an actual line between natural and

01:38:57.280 | pharmaceutical i mean think about the drug i'm on sirolimus it's called rapamycin because it was found

01:39:01.760 | on the island of rapinui in the soil of i don't know if you know that story it was found in so

01:39:06.240 | rapamycin or serolimus the other name for it was found in the soil of the island of rapinui and there

01:39:11.760 | was a researcher at wyeth pharmaceuticals who was going all around the pacific ocean to a bunch of

01:39:16.320 | different islands and picking up soil samples and he thought that you know maybe i could find some drugs

01:39:21.920 | in the soil and he eventually found this molecule now called rapamycin where they synthesized a bunch of

01:39:27.520 | of it it's completely naturally occurring from from and the other name for rapinui is easter island

01:39:32.000 | it's from the island you know from easter island so synthesized it and they initially thought that

01:39:36.880 | it might be a good drug for um as an antifungal but it's a lousy antifungal and so they're trying to

01:39:41.840 | figure out like what else could it do and they found out that it's a really potent immunosuppressant

01:39:46.000 | and um and in fact the research into the immunosuppressor role ended up you know really

01:39:50.640 | accelerating understanding of how the mTOR pathway works in the first place and it actually is an

01:39:55.600 | amazing story um that was it was done on on radiolab about how um it eventually um or at one point it was

01:40:02.240 | shelved wyeth and pfizer decided not to study it and then it sort of got taken off the shelf and it got

01:40:06.800 | approved for organ transplant rejection but i just think about something like that i mean if that

01:40:12.480 | scientist hadn't picked up the soil sample in rapinui i'm not sitting here with you talking to

01:40:16.640 | you right um and of course there's thousands of people all over the world who aren't sitting here

01:40:20.640 | talking to anyone because you know that drug wouldn't have been discovered and and it was in

01:40:24.720 | the soil and it's not some you know pharmaceutical synthetic thing you know this is a totally naturally

01:40:28.800 | occurring compound so i think our our the line that we put between creatine and you know sirolimus

01:40:36.720 | and glp1s there's a lot of overlap here and yes some of these molecules are very much

01:40:41.840 | synthesized and you think about the chemos that i've gotten are like horrible compounds that like

01:40:46.000 | 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

01:40:50.080 | i think the term is bioprospecting uh when people from pharmaceutical companies go out and look for

01:40:56.800 | things in nature and then develop drugs from them we had a guy on here very impressive guy chris mccurdy

01:41:02.480 | who's down in florida he studies kratom and kratom leaf products kratom is a is a it's being sold as

01:41:11.200 | a kind of natural opioid replacement i just should anytime it comes up i have to be very careful

01:41:16.720 | because you all cut clips and you take them out of context i'm going to just i've learned how to guard

01:41:21.120 | that against that forgive me but kratom products and the kratom leaf have been used by some former

01:41:30.240 | prescription opioid addicts to get off those prescription drugs however it's very clear that

01:41:38.480 | a lot of these products which are sold over the counter in convenience stores um corner stores

01:41:43.040 | 7-eleven etc cvs can also be highly addictive alone and they're sold to kids it's a serious serious issue

01:41:52.080 | but the kratom leaf kratom i think is the way it's the traditional um uh pronunciation uh contains a bunch

01:41:59.840 | of different plant alkaloids and the synthesized purified kratom is the one that has this pain pain relief

01:42:06.880 | aspect that's also can be very addictive um and we discussed the coca plant and cocaine but also

01:42:11.920 | other elements within the coca plant that his he runs a laboratory that are being isolated and being

01:42:16.480 | tested for different pain relief and psychoactive properties that can be very beneficial to people so

01:42:22.080 | bioprospecting is something that drug companies don't really discuss a lot but the way they're doing

01:42:27.040 | this is going into nature looking at the crap the kratom leaf the uh coca plant um micuna purines is this

01:42:35.120 | velvety bean that um is 99 l-dopa oh really wow yeah which you can buy this over the counter so we think

01:42:43.920 | so the line between supplementation and prescription drug is very very fine it's just that there's no

01:42:48.720 | control over the the over-the-counter stuff and so this is where it runs into problems and gets a bad

01:42:54.400 | reputation and understandably so we don't want people harming themselves with this i'm beginning

01:42:59.280 | to think that what's really needed and people in the current administration do listen um to the podcast

01:43:07.280 | i don't know if they what they do with the information but um i think we need more thoughtful safe

01:43:12.880 | bioprospecting to develop drugs that they can be tested in pre-clinical models animals pre-clinical means

01:43:18.560 | animals folks um and then eventually clinical trials but i don't know that we have the time

01:43:26.480 | for clinical trials on all these bioprospective molecules or even the molecules that you're talking

01:43:31.840 | about which are already fda approved it sounds like a lot of it just has to be run in real time

01:43:36.480 | in people like the experiment in some sense has to be done in humans i just don't see otherwise it's

01:43:42.960 | going to be you know another 50 years before we have a cure for alzheimer's or or we solve some of

01:43:48.480 | the most serious like psychiatric illnesses i i agree it the answer comes from actually testing these

01:43:55.680 | things in humans there are so many things that cure mice and they don't ever translate to humans and and

01:44:00.080 | vice versa so um i think that i'm really bullish on the idea of leveraging the world's biomedical

01:44:07.920 | knowledge and using artificial intelligence to help to prioritize among all these different

01:44:12.160 | things and so at the end of the day you know we talk about the 4 000 drugs the 18 000 diseases

01:44:16.400 | the reason we do the scoring on everything versus everything is so that we can just know where to

01:44:20.800 | start because you know i mean we rank everything versus everything and and maybe the fifth highest

01:44:25.280 | scoring thing is is the thing to go after maybe the 10 000th highest scoring thing is the point being

01:44:30.320 | is that ai can at least help us to to focus in on where do you start because to your point there's so

01:44:35.120 | many opportunities of the existing drugs we have of the molecules that are already available in nature

01:44:39.840 | but you need you need somewhere to start and i think ai is really well positioned to direct us

01:44:44.320 | humans to where to start amen to that um because in theory with ai you could um develop i guess they

01:44:51.840 | call it in silico you could say uh let's run a 10 000 cell cultures in parallel the graduate student

01:44:58.800 | cost is nothing they don't need to sleep it's ai after all and um with all the properties of of you

01:45:06.320 | know this immune cell type different concentrations of drug and while it's not a real world experiment

01:45:12.480 | you can get an indication of what the outcome might be and what might be worth taking a better look at

01:45:17.280 | is that is that what you're imagining that's right and also um that that's a true simulation where the

01:45:23.120 | work hasn't been done what also is the case is that as you know there are labs all over the world

01:45:27.680 | running experiments all the time on various uh cell lines and animal models and in humans all of that's

01:45:34.640 | happening and so what i really am bullish on using ai for is not to simulate something that hasn't been

01:45:40.240 | done yet but it's actually to find connections between what has been done so um we know you know the

01:45:46.560 | example earlier that one lab found increased pdl1 expression in this one form of cancer and this drug

01:45:52.400 | inhibits pd1 so therefore let's make a connection that no one had made yet so there are two truths

01:45:57.600 | that hadn't been connected you know a you know and b are connected b and c are connected let's connect a

01:46:02.880 | to c and i think that ai is particularly well suited um to to find these patterns of things that we know so

01:46:10.000 | so it's not a total it's not a simulation it's actually just connecting um really like breadcrumbs

01:46:16.240 | into into one story you're a parent i am uh how do you navigate health care for a kid knowing what

01:46:24.480 | you know about medicine and knowing what you know about what medicine doesn't know i'm a very rigorous

01:46:31.920 | parent of two kids when it comes to health care yeah i've got a seven-year-old and a three-year-old which

01:46:36.960 | um it feels like a dream to be here talking to you 15 years after i went through um all that

01:46:42.080 | i've gone through definitely feels like a dream that i'm able to tell you i've got a seven-year-old

01:46:45.840 | and a three-year-old i'm just i'm so lucky but like you said um i'm really rigorous you know uh you know

01:46:53.360 | one of my doctors suggests you know try this for for my daughter um i you know ask a lot of questions

01:46:58.400 | i mean i try to really stay on top of things and it um sort of gets me thinking about something i was

01:47:03.600 | hoping to ask you about and uh it's that over the course of my challenges and sort of ups and downs

01:47:08.640 | that i've had in my health um and and the work that i've done to find treatments i've found that i think

01:47:14.080 | there's this circuit that again i'd love to get your thoughts on so i find that it starts with hope so i'm

01:47:21.200 | hoping for some future so maybe it's that my child's health condition will be improved or my health

01:47:25.280 | condition but you know you start with some sort of hope that you hope something will happen and then

01:47:29.040 | that drives some amount of action so like maybe in my case you know i run experiments on my own

01:47:33.120 | blood samples and then that results in some impact that um you know maybe i get learn something maybe

01:47:39.280 | that drug is going to work for me and that impact gives me more hope and then it creates this this

01:47:44.480 | circuit so it's hope action impact which gives you more hope action impact and i haven't figured out

01:47:50.080 | exactly like if there's some some some neuroscience behind this but i found that for me and just thinking

01:47:56.400 | about you know your question around whether that's you know helping your child with the medical issue

01:48:00.320 | that they're facing or again my own that that circuit has just been a game changer for me i don't know if

01:48:05.600 | there's if there's some neuroscience behind that that you can help me to understand this this hope

01:48:09.760 | action impact uh there absolutely is and uh the person who deserves credit for um revealing this

01:48:17.120 | circuit is my colleague joe parvizzi at stanford who's a neurosurgeon wow who was in the brain of awake

01:48:22.880 | patients uh stimulating different brain areas uh in anticipation of a neurosurgery like you described

01:48:28.400 | earlier and had electrodes in a structure called the uh mid-cingulate cortex um it's part of a larger

01:48:35.680 | network of course as is every brain structure uh and he noticed when he stimulated a sub-region called the

01:48:41.760 | anterior mid-cingulate cortex that patients would report in real time that they felt like there was some

01:48:50.240 | challenge kind of bearing down on them like going into a storm each one described it differently but

01:48:55.600 | that the stimulation also made them feel as if they wanted to lean into that challenge now here's where

01:49:00.640 | it gets really interesting if he marches the electrode back a millimeter or less completely

01:49:06.560 | different set of effects laterally completely different set of effects so the anterior mid-cingulate

01:49:11.040 | cortex seems to be the seat of some sort of sense of tenacity to lean into challenge wow it gets really

01:49:16.560 | interesting when you start looking at the data of kind of volumetric imaging of this structure in

01:49:22.560 | people that for instance successfully overcome obesity through exercise and diet or people who

01:49:29.040 | decide to undertake some other challenge like a cognitive challenge or learning how to dance

01:49:34.160 | something that's challenging yeah and then you look at the literature on longevity and you look at this

01:49:40.240 | group of so-called super agers which is a misnomer because they actually age very slowly right yeah

01:49:45.840 | uh and what you find is that psychologically they report a very strong will to live and their anterior

01:49:54.080 | mid-cingulate cortex is the one of just several areas that seems to maintain volume as they age

01:50:00.640 | relative to these age match cohorts now none of these are perfect experiments on their own but when you start to

01:50:06.880 | put these together as a collection of things you realize that all the things that are the reverse

01:50:11.120 | of depression so what's major depression a lack of positive anticipation of the future um uh lack of

01:50:18.400 | understanding or belief rather lack of belief that uh changing one's behavior could change circumstances

01:50:24.160 | like get a job or new relationship or overcome something and you see the exact inverse of that in people

01:50:30.160 | with a kind of naturally large or perhaps um self-fertilized uh anterior mid-cingulate cortex

01:50:39.040 | these people report a lot of positive anticipation about some hopeful future event wow and it's not

01:50:45.680 | always a big monumental thing sometimes these are you know closer milestones sometimes it's a bigger thing

01:50:51.920 | and they live longer and they have this incredible will to live so it seems that you know taking this to

01:50:57.440 | its kind of extreme conclusion that the will to live sits somewhere in the network of this structure

01:51:02.640 | it's not just this structure and it's intimately related to dopamine uh networks so reward reinforcement

01:51:10.640 | and learning networks and all the rest yeah um but you know it's hard to pinpoint one structure but if i

01:51:15.840 | had to you know put a pin in one structure would be joe parvizzi's discovery of the anterior mid-cingulate

01:51:20.080 | cortex and it has all the elements of you described hope yeah plan yep and action exactly repeat yes and

01:51:28.000 | so for people who are not ill or who are ill having that um sequence a good friend who is in uh tier one

01:51:34.960 | special operations uh in the seal teams he described this as um when there's a challenge you have to

01:51:42.080 | shorten the horizon get a forward center of mass but think duration path and outcome

01:51:50.640 | what path how long outcome iterate and it's the same way you work down a football field is the way you

01:51:56.720 | work you you know kind of lay through these challenges so um again i'm i'm creating a tapestry from a bunch

01:52:03.520 | of disparate things here but but none of is it is outside the realm of a peer-reviewed science it all sits

01:52:09.520 | there um so we haven't scanned your brain i don't think we need to to know that your anterior mid-cingulate

01:52:14.800 | cortex is clearly um very robust and i would wager the hypothesis that it was probably um built and

01:52:22.560 | reinforced through your postering up of athletic goals on the wall of your childhood bedroom i think

01:52:29.760 | you're right i think you're right yeah the the more you work you know the better your times get the

01:52:34.240 | better those numbers get and then you know as you said it it becomes a true circuit you know the thing

01:52:39.280 | you're hoping for when you get closer to that thing you're hoping for it drives you to take more action

01:52:43.360 | and then and then you can you can keep going in that circuit well clearly you are living in that

01:52:48.240 | circuit and it lives in you could you tell us about ways that people can get involved with every cure

01:52:54.800 | i have to imagine more information is better than less sure what can people do sure so um anyone can

01:53:02.720 | go to everycare.org ideas and tell us about maybe there's a drug that you were prescribed off label

01:53:07.520 | by your doctor or maybe you're a researcher and you think that a drug could be used in a new way so you

01:53:11.600 | can go to everycare.org ideas tell us about that medicine and we'll look into it we'll compare it next

01:53:16.720 | to our ai predictions and we'll determine whether maybe it can be moved forward um if you're an expert

01:53:21.920 | say in neuroscience or you name the the area you can go to everycare.org experts and you can sign up so

01:53:27.360 | that if we find a drug that might be useful for a condition that you're an expert in you might be able to

01:53:31.760 | give us advice and guidance on you know maybe what the right development path is and anyone who's

01:53:36.480 | watching can help us to raise awareness about the work that we're doing so you can follow us on social

01:53:40.640 | media at everycare.org and beyond i did a ted talk recently you can help spread the word and check that

01:53:46.080 | out and finally of course people can support our work financially we're a non-profit organization

01:53:49.760 | clinical trials are expensive you can go online everycare.org/donate and donate to our work and

01:53:55.040 | we're just so excited for this opportunity we have to help people with the drugs that we have but we

01:53:58.800 | realize that it we can't do it alone we actually really need the whole community to get behind us

01:54:03.040 | where is funding currently derived from is it just public support so right now um about half of our

01:54:10.240 | funding actually comes from the u.s government from an agency called arpa h they're one of our earliest

01:54:14.400 | supporters and the other half comes from individuals who decided that this is important

01:54:18.480 | um it may be that they have a loved one that has a condition that they would love for us to work on or

01:54:24.080 | maybe it's that they just want to see um you know us be able to help patients with with the drugs that

01:54:28.720 | we already have and um we are just so excited of that opportunity to match the drugs we have to the

01:54:33.520 | patients who need them fantastic and i should ask um if a drug application is discovered is there a

01:54:40.160 | feedback mechanism for you guys to derive income from it or this is a completely non-profit it's completely

01:54:46.080 | non-profit so i think by the end of you know let's say the next few years i will guess that nearly all

01:54:52.400 | of the opportunities that we advance forward are the same dose the same formula no one makes any money

01:54:58.320 | off of them whatsoever i think there'll be rare cases where let's say the drug looks like it'll be

01:55:03.040 | effective but it needs to get into the brain where a tweak will have to be made where a different dose

01:55:07.200 | or formulation will be needed i think they'll probably be rare cases where probably a company will be

01:55:11.680 | need it to be spun out to do it but for the vast majority we're non-profit we just want to take

01:55:16.160 | the drugs we already have to use them for the disease that could benefit from them terrific we'll

01:55:20.720 | put a link to it in the show that'd be awesome david thank you so much for coming here today to share

01:55:26.560 | your story with us and just a ton of actionable knowledge for people that are healthy continue to

01:55:31.840 | explore options safely yeah think about what's possible understand there are things that are known there

01:55:36.560 | are a lot of unknowns and again explore safely for people that are ill find a disease-related group

01:55:43.680 | that really has um an eye on what's new what's existing who the best people are search for a few

01:55:49.760 | of those is kind of what i took away from that and um thank you for doing the work you do it's amazing we

01:55:56.000 | need more people like you uh you're truly one of a kind so we're immensely grateful uh that you've taken

01:56:02.320 | hardship and transmuted it into so much good and love to have you back sometime to talk about all

01:56:07.760 | the millions of other things we didn't have time to talk about but this has been incredibly enriching

01:56:12.080 | for me and i'm certain it has for everyone else well thanks so much for having me thanks for all that you

01:56:16.080 | do to advance the public health and also to get the word out about the work we're doing through every

01:56:19.920 | cure thank you for joining me for today's discussion with dr david fagenbaum to learn more about his

01:56:25.280 | laboratory's work and his non-profit every cure please see the show note captions if you're learning from

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01:57:05.600 | you that haven't heard i have a new book coming out it's my very first book it's entitled protocols an

01:57:10.800 | operating manual for the human body this is a book that i've been working on for more than five years

01:57:15.040 | and that's based on more than 30 years of research and experience and it covers protocols for everything

01:57:20.800 | from sleep to exercise to stress control protocols related to focus and motivation and of course i

01:57:27.840 | provide the scientific substantiation for the protocols that are included the book is now available

01:57:33.360 | by presale at protocolsbook.com there you can find links to various vendors you can pick the one that you

01:57:39.680 | like best again the book is called protocols an operating manual for the human body and if you're

01:57:45.200 | not already following me on social media i am huberman lab on all social media platforms so that's

01:57:50.400 | instagram x threads facebook and linkedin and on all those platforms i discuss science and science related

01:57:56.720 | tools some of which overlaps with the content of the huberman lab podcast but much of which is distinct

01:58:01.440 | from the information on the huberman lab podcast again it's huberman lab on all social media platforms

01:58:07.040 | and if you haven't already subscribed to our neural network newsletter the neural network newsletter is

01:58:11.440 | a zero cost monthly newsletter that includes podcast summaries as well as what we call protocols

01:58:16.480 | in the form of one to three page pdfs that cover everything from how to optimize your sleep how to

01:58:21.280 | optimize dopamine deliberate cold exposure we have a foundational fitness protocol that covers

01:58:26.080 | cardiovascular training and resistance training all of that is available completely zero cost you

01:58:31.280 | simply go to hubermanlab.com go to the menu tab in the top right corner scroll down to newsletter

01:58:36.160 | and enter your email and i should emphasize that we do not share your email with anybody thank you once

01:58:41.280 | again for joining me for today's discussion with dr david fagenbaum and last but certainly not least

01:58:47.040 | thank you for your interest in science

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

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