The Peter Attia Drive - #06 - D.A. Wallach: music, medicine, cancer screening, and disruptive technologies

Episode Date: July 23, 2018

D.A. Wallach is a true polymath: recording artist, songwriter, essayist, investor, and so much more. In this episode, among the highlights, D.A. provides compelling and colorful insight into how the music industry works today vs the past, liquid biopsies, how to approach healthspan, cancer screening, and how we can reach a “singularity” in medicine. We discuss: How to learn music as a kid and an adult [7:30]; Chester French’s early struggles and ultimate success [16:45]; Learning to learn, fostering curiosity in kids, and balancing creativity with structure [31:30]; D.A.’s musical inspirations [44:30]; History of the music industry, Spotify, and other disruptive technologies [50:00]; The past, present, and future of medicine, hospitals, and healthcare [1:05:30]; Investing in health [1:16:30]; What D.A. is most excited about in the future of medicine [1:22:00]; Liquid biopsies, how to make sense of the morass of sensitivity, specificity, positive predictive value, negative predictive value, true negatives, false positives, false negatives, and true positives in cancer screening...and the swiss cheese metaphor [1:33:00]; The immune system, inflammation, and allergies [2:05:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratia-md.com.

This podcast, I'll be speaking with my good friend, DA Wallach. I've known DA for maybe five years now, maybe four I can't recall, but he is truly a Renaissance man. I have been accused of being a Renaissance man on occasion, but I am not. DA, however, is. And if you look up Renaissance man in the dictionary, I think you'll just see his picture with his curly hair sitting there. He is a recording artist, a songwriter, an investor, an essayist. He was discovered while an undergrad at Harvard by Ferrell, among others who signed him to a deal. He went on to

become one half of the band Chester French. They released three full-length albums and he also has a solo album called Time Machine which was released in 2016. We'll link to all of that stuff. Well with Chester French, they toured with a number of legendary bands and artists such as Lady Gaga, Weezer, and perhaps my favorite of them all, Blink 182. Beyond music however, DA is sort of in a class of his own in terms of his intellectual curiosity and his ability to assimilate information that seems so far outside of his area of expertise. In fact, some of the most interesting discussions I remember ever having with DA is sort of what prompted this podcast. I remember one day he came over, he was passing through San Diego on his way down from LA, came by and we were sitting out at a park on the swings

having a discussion about liquid biopsies. And I was thinking to myself, how is it that I'm sitting here with this guy, my body, who's a musician, and a very good investor, having this discussion about liquid biopsies at a level of detail, but I don't get to have with pretty much anybody else outside of people who are knee deep in this field. And that was sort of when it clicked in my mind. I was like, you know, D.A. would be a great guy to have on the podcast. He's advised a number of startup companies, including SpaceX, Dr. Undemand, Ripple, Emulate, and of course, he was an artist in residence for Spotify.

And we talk actually quite a bit about Spotify on this episode for anyone who's kind of interested in how it came to be. The other things that we talk about, of course, is his background in music and his start. My daughter is a great drummer for a little kid and I've always been interested in how one can continue to encourage kids to be involved in music. We talk about some fun times that we've had when he's been over and has jammed with her. We talk a lot about cancer screening, which anybody who's kind of ever heard me talk about this stuff privately, I really think that when it comes to the major metabolic diseases, cardiovascular disease and the other atherosclerotic diseases, cancer

and neurodegenerative diseases, the big tool that is really missing is these liquid biopsies. By the time cancer becomes visible on an imaging study, you can make the case you've lost the war. I don't know that that's true, but I do believe that if we can catch these things when they are not yet fully determined to be cancers, based on either looking at a DNA signature and RNA signature or even a protein signature, that we might have a shot.

We also get into some really kind of nerdy stuff that I think is very important for anybody thinking about screening, such as positive predictive value, negative predictive value, sensitivity, and specificity, and we'll link to some information here that we use internally in our practice to help patients navigate that. So if you're interested in music,

if you're interested in liquid biopsies, cancer prevention, general cancer screening, and just interested in listening to a really smart dude who seems to know a lot about a lot of things and can speak very articulately about them, I think you'll really enjoy this podcast. You'll be able to find the show notes for this at peteratiamd.com forward slash podcast and we'll link to a lot of the stuff that we talk about that will hopefully allow those of you

who are interested to follow up and learn a little bit more. So without further delay, here is my conversation with the amazing DA Wallet. [♪ OUTRO MUSIC PLAYING [♪ DR. BELL RINGS DR. BELL RINGS DR. BELL RINGS DA. Peter.

Thanks for having me over to your lovely place. Uh, you're welcome. You're welcome here anytime. I like how you saw that I was in the driveway before I got here and I was kind of just hanging out. Well, we have this thing called the doorbird, which is kind of the evolved version of a ring. And you, since you're interested in all

esoteric technical things, would be interested in know that this is the only web-enabled cloud recording doorbell system that can look into a electric strike, a strike being the thing that opens a gate remotely. And so I'm able to see who rings the doorbell, and then if I want to let them in, press a button from the same app that opens the game. Remarkable technology. Yes.

Technology as Ali G would say. Yes. So we have known each other. I don't even remember how we met. I actually I think we met through Gary Tobs, didn't we? We met through Gary Tobs, and I met Gary Tobs because I called emailed him, which is how most things started my life. Yes.

And I called emailed him because I became sort of obsessed with obesity and nutrition research. This was maybe six years ago, or there about six, seven years ago. And then I had gotten coffee with Gary up in Berkeley, and he thought it would be worth our meeting. And now I talk to you more than I talk to Gary. Yeah, no, it became a, it was a love at first sight actually. And you know, one thing that's really funny, we're gonna talk so much about sort of your musical career

and things like that, but I will forever be grateful to that one night that you and Adam were over for dinner. This was just after my daughter Olivia started to play the drums and you guys got up, Adam's played the piano, you played the drums, Olivia then played the drums, and it was really exciting to see, she got to see an action what like improvise music can look like, and I really think that that's part of the reason she still loves the drums. Well, that's good. I mean, part of the drums that's fun is that you don't necessarily need to know the musical material as well as other instrumental don't necessarily need to know the musical material

as well as other instrumentalists do in order to play along with people. You don't need to sort of learn the song. You can kind of, as long as you can learn the beat of the song or figure it out quickly, you can play, which is as someone who doesn't necessarily love practicing something that's always drawn me to drums. And I remember her teacher when she was five and I started saying, you know, it's going to be really hard because the music is really hard to read. So the only shot she'll have at starting this young is if she sort of has an intuitive

feel for the music, in which case she can get by on that until she learns to actually figure out that, you know, two sixteenths is actually an eighth and that kind of stuff. Right. That's a good point. And I think the best way to learn instruments or to learn music in general is kind of to start without any framework, play around and explore yourself, and then learn a little theory, because what you don't want to do is become imprisoned by theory, but it does answer some important questions

that you'll arrive at if you allow yourself to get lost in the first place. And so I've always said that when we have kids, my vision for piano training would be, you just have to sit there for half an hour every day, and you can do whatever you want. You don't have to touch the piano if you don't want, but of course anyone's sitting at a piano for 30 minutes will. And you can figure out how it works.

And then theory, if you have spent, you know, tens of hours messing around is like an amazing gift because it goes, Oh, okay, well, that makes sense. That's how it works. It's just like if you were trying to reinvent mathematics with no orientation. Like Ramanujan. Yes, like Ramanujan, which, you know, I'm not. You're almost a Ramanujan of music. I wish. So speaking of which, how did you get started in music?

Were you always musicals a child? Were you playing instruments when you were young? I don't think I was particularly musical. I always liked listening to music, and my dad would take me to jazz shows occasionally when I was young, which sort of infected me with an interest in jazz. The first instrument I tried playing was the saxophone because I thought it looked cool. I remember we rented one. This was in the middle school band, so it might have been fifth grade.

This would have been an alto sax or a tenor. I don't even remember. And in any event we rented it, I brought it home and I tried to learn how to just make a sound with it, which is not trivial because with a read, you have to purse your lips in a particular way and all this. And I was so frustrated in the first hour of trying to play the saxophone that I gave up

and became a drummer. And then played drums throughout middle school and high school. And I had sort of bands with high school friends and that sort of thing. And then in college, became a singer, which was something I had never done. Oh, so I didn't realize that you had never sung until you got to college. I had never sung and I met some cool guys in the dining room at my college. And then they said, do you want to try out

for this band we're thinking about starting? And I said, sure. And I tried out as the drummer, but I got beaten by my friend Damian, who then became our drummer. And as a consolation prize, they asked me if I wanted to be the singer. And I said, well, I've never sung before, but I'll try.

And I've been trying ever since. So I didn't realize that. So you went into what became Chester French as the drummer. Trying to be the drummer, and then Damien, who became the drummer, later quit, and became a filmmaker and is now one like 10 Academy Awards. He did Whiplash and then he did Lala Land

which I have a small cameo in. But Whiplash, if you've seen it as about a drummer and it's somewhat autobiographical about Damian. Oh, I didn't, I didn't realize. I mean, Whiplash is, there's only probably five movies I have stored on my iPad, because, you know, it's just, they take up a lot of room, right? So, but the five that I have are like, such that if I'm on an airplane and everything goes to hell on a hand basket and the Wi-Fi is broken and I don't feel like doing work,

boom, boom, boom, and Whiplash is one of those five. It's great, which means it's a movie I've seen more times than I can count, but I especially like the last scene. Well, it's a high octane movie. I mean, it's a movie I've seen more times than I can count, but I especially like the last scene. Well, it's a high octane movie. I mean, it's about human performance, basically. So I get why you like it. It is unbelievable. Yeah. But I had no idea about this notion that it was not just purely fictional, and that there was some autobiographical component to it. A little bit. I mean, I don't think there was anyone as sinister in Damien's life as the teacher in the movie, but Damien both has a drummer and now as a filmmaker is incredibly self-critical and hardworking and perfectionistic. And so I think those elements are definitely a

reflection of his personality. I'm always amazed when you look back at sort of the Anil's A Rock and Roll, how many musicians didn't come into it as singer. So for example, I remember hearing about Bob Dylan and Jimmy Hendrix and people who really never thought of it as their voice was what was going to do things. And yet we still think of them as completely iconic. Can anybody learn to sing? I don't know if anyone can learn to sing.

I mean, you need a certain amount of physical instrumentation that you just can't escape. I mean, so there's things I wish I could do with my voice that I'll never be able to do, just like I wish I could dunk a basketball. That being said, I think there's probably an enormous range of refinement that can be pursued because I started as a pretty bad singer and I think I've become an okay singer. And a lot of that, just like any physical activity, is about learning how to mentally control a part of your body to get it to do what you want it to do. It's just that controlling your vocal folds and the way that you express air is a relatively

fine-tuned set of physical processes. And so the sort of detailed control that you need to physically command over your anatomy is kind of difficult to obtain. But I became a much, much better singer. I think the thing that is probably more natural that you either have or you don't have is an ability to know when you're making a noise whether it is on pitch. And some people clearly don't have this, but I think most people have a decent sense of pitch.

And if they didn't, then they wouldn't be pleased by harmonious music. I mean, we have a natural ability to hear whether someone's hitting a sour note in a chord or something or whether someone's singing off tune. That bothers most of us. So if you can be bothered by that, then chances are you can hear the difference between that and the right thing. And that's what a lot of it comes down to. When you're singing, it's very important that you hear yourself because that's the feedback loop.

Yeah. So do you remember the first time you sang on stage in front of people besides your bandmates? Well, it would have been freshman year in college and we began by doing sort of weekly performances in the student commons at Harvard and you know the audience was 20 or 30 of our friends. And the band always had a sense of humor to the music, although that trailed off in our final album, which was not really funny. But earlier we had always kind of been humorous at some level. always kind of been humorous at some level. And I think that masked how poor my musicianship was for a long time, because we could kind of play it off

as a bit of a joke band. So sort of like bear naked ladies, like what was he? Not that they were a joke band, but you know what I mean? Like they were always having fun. They were silly. We were irreverent and somewhat subversive in the notion that what we did was meant to almost

be ironic. So we would do songs about medieval nights. We would do totally absurdist music. And I think totally possible to hear it and either think that it was self-consciously funny or to think that it was totally clueless. And so that made it easier to sort of cut the tension a little bit and break the ice or so to speak, it wasn't like you were scared to death getting up there. For me, like if you said to me, Peter, you have to either go and climb Mount Everest or K2.

And there's like a 30% chance you're gonna die or you have to sing in front of a thousand people. I'm trekking, I'm going to the mountain. Like the thought of actually singing in front of any human being. Right. Including people, my kids, there's no way I'm singing. Yeah, I don't know why there is some sense of shame that attends singing.

I mean, I know what you're saying. I don't feel it, but I know what you're saying. But I wish I could. I know what you're saying. Part of it is, I think realizing that singing is just a musical speaking. So we're really singing all the time when we're talking, we're just not using tonality

and as deliberate away. I mean, there's a pitch to every time you speak. So singing is just controlling that pitch, which is actually a helpful thing that I learned from vocal coaches who when I went to go touring, I went to see literally because it became more of a sport for me. It was now something that I was going to have to do for an hour or two every day, and I didn't have the physical endurance and the muscle control to endure that without hurting myself. So I would go to some coaches to sort of get ready to tour. And they would make this point that singing

is just musical speaking. And it really changed the way I thought about singing and made it quite a bit easier. So let's talk to the transition. So you guys start this band. Tell me about the name Chester French. Where did it come from? Chester French was the name of a sculptor,

Daniel Chester French, who did the Lincoln Memorial. And then he also did the John Harvard statue, which is in the center of Harvard's main quad. And we didn't know that when we chose the name, but we had a dining hall there that all freshman eight and that sort of looks like the Hogwarts dining hall in Harry Potter, big wood paneled room with soaring ceilings and busts all around the walls. So we were going into lunch and we saw one of these busts and it had a little plaque under it

that was, we thought the name of the person who had been sculpted. And so we said, oh, Chester French, that's kind of a cool name. And we picked it then and there. And then we later of course learned that that was the sculptor of not only that bust but also these other great American sculptures.

Got it. So when did you guys start to get some traction? And I mean, because most college bands don't end up going on tour. So what was that transition like? We basically got no traction doing what we initially set out to do, which was to build a live performance following. So the conventional wisdom, if you started a band on the East Coast in college, which a lot of people did, actually, if they were musicians, was start playing on your campus, start playing at surrounding campus parties and sorority cackers and whatever, and then ultimately get a van and start driving

around the East Coast and going to other colleges, and you can build a following among college students. And we tried to do this, but we just totally ate shit. I mean, we could barely get people to come to our shows on campus. And then I remember booked a gig at a club called Great Scott in Boston, which was kind of the, or Harper's Ferry,

was the specific one that I'm thinking of here. Great Scott was another club. We booked a show at this Harper's Ferry, and we both tried to recruit our friends from campus to make a 10-minute journey to this club. I think three of them came, and then we also, for the three nights prior to the show, went and stood on the street in front of the club, figuring that people who lived in the area probably walked by the club or people who went to the club might come and see multiple shows, handing out flyers, trying to promote ourselves. And when we got there to do the gig on a Thursday night or something,

I think there was an audience of like five or seven people. And you know, that's particularly depressing when you've spent two and a half hours setting up and sound checking and hauling all your gear. So, anyways, that strategy failed. I'm not sure why. Maybe we just weren't good live or something. But we took a turn at the end of sophomore year in strategy, and our focus became just making recordings. And the thought was ultimately the product is a recorded music product. That's what we're really making.

We're songwriters and we're producers. And so our focus shifted to essentially just living in the recording studio, making stuff. And the idea became, let's try and make an album that we think is a great, complete representation of our musical ideas. And if we do that and it's really good, it will speak for itself. And no one in the record industry will care whether we have this big live following or not. Luckily, that turned out to work. I mean, it was not certain by any means,

but we made this record over the subsequent two and a half years. And then in the middle of senior year started sending out that album to as many people as we could send it out to. And ultimately, it got to Kanye West who gave us our big break and flew us out to Los Angeles and offered us a record deal. And then that spurred a number of other people attempting to sign us to record deals.

We ultimately chose to work with Farrell and did a deal with him and a guy named Jimmy Iving who ran inner scope records. And as soon as we graduated, we moved out to LA and that became our career. I mean, just put that in context for a moment. That strikes me as like a fairy tale, right? I mean, what's the probability that Kanye West, I mean, how many times is he getting something pitched

and having to pick a knee lot of a haystack? Is that how that works? I think it was a little atypical that other artists supported us. And now that I'm sort of not doing music full-time in retrospect when I look at the band's career, it's kind of clear to me that we were an artist's artist. In other words, our fans tended to be people who were quite musical, whether they were famous musicians or whether they were just random people who played guitar at home. But we were making a style of music

that I think spoke to musicians specifically. Part of that was the result of trying to make music that we wanted to listen to. And so we were our own customer in a kind of weird way. So it certainly wasn't typical that other artists would be the ones to jumpstart our career. On the other hand, it was at a time

when the music industry was changing. And so all of the paradigms by which artists got discovered were being destabilized. There used to be these armies of A&R people who worked at record companies and they went to concerts and scouted. And what was changing when we came onto the scene was that the internet was becoming

the primary distribution channel for music. And also the primary place where people discovered new artists. This is what like 2003 2007. 2007, okay. And so, you know, Facebook was a couple years old. My space was kind of at its height, and we were one of the first artists to primarily build our audience online. So, you know, that was unique. And was Facebook a better channel for that than, say, having your own site that you're hosting,

like, how, how were you? Facebook was and remains a bad channel for that, but my space was an amazing channel for that. And my space had all of these features that allowed culture to kind of virally permeate civilization. So. Tell me what my space did better than Facebook with respect to that or what had enabled.

Well, there were, let's say, two or three distinctive things about it. The first was that it essentially was a place where spam was totally legal and standardized. And so it was kind of like, my space felt almost like time square in the 80s or something. You know, it was like a little unsavory. There were all these weird people on there. People had avatars so you didn't know if it was really them or not, identity had not been formalized

in the way that Facebook ultimately made it. So on the one hand, you could spam people. So for us, we could go on there and just randomly send our music to random people who we thought might like it. That was highly useful. The second thing was that they had this thing top eight. So on everyone's my space page, you could pick your top eight friends. And that became kind of like a prize

to be one of the top eight of a famous person or one of the top eight of a famous band or something. And so you could kind of go on my space and try and find artists who you thought would share an audience or whose audience you wanted to steal essentially. It's not stealing because it's not a zero-something. People can like a lot of artists. But we would identify these artists who we wanted to steal the fans of. And then we'd try and get our music to them to get in their top eight, because then tons of people would discover you.

And then the third thing was that MySpace allowed each user an incredible amount of freedom in designing their page. So you could go in and change the HTML or the CSS on your MySpace page, and this from a user experience standpoint made it a very difficult place to navigate. But I think what it brought out was that everybody when you give them a creative canvas likes to paint on it.

And what you saw was that ordinary people who were just MySpace users, consumers of content, themselves would really wear their identity on their page. And so you could kind of navigate this universe of my space and understand the cultural orientation of every person on it. And it made it really easy to figure out who were your people. You know, I mean, if you were like a goth band or some, they're a metal band, it was very clear who the metal people were.

And so for us, we could really take advantage of this and kind of hack the system to find our people quickly. I don't want to go too down the rabbit hole in this, but it's so interesting because I've never, I haven't thought about Myspace in probably 10 years or something like that. When the history books written, and it could probably be written now, I'm assuming, why did Facebook win Myspace lose at the risk of oversimplifying things? I think there are few reasons I perceive, and then there are probably many, I have no idea about like what?

You just strike me as having a better sense than the average person based on a pretty robust understanding of how both of them worked. My space was, even if they maybe thought they were being scientific, it was not a sort of science project. In other words, the people building it were in LA, they were kind of more inclined to understanding culture and to thinking about personal freedom and expression,

whereas what Facebook was built around was the idea that if you created an accurate map of people's real world relationships, then the behaviors that they exhibit in the real world would end up mirrored in this digital environment. So social values like trust were going to be essential in the Facebook universe. Whereas in my space, like I said, it was like Times Square in the 80s. It was like there were CD people on there. You didn't know if people were who they said they were. It was a fake place. And the early internet was much more like that.

Everyone was in chat rooms with aliases and stuff. You never really knew who was who. Facebook became a digital version of the real world. And so it was kind of more valuable from the outset because things that you only previously could do in reality, like talk to someone or share with them photos or something, became something that you could do in a highly managed way through Facebook. That's really interesting. I have never, I would have assumed just as a guy who knows nothing that, you know,

Facebook won because they figured out how to monetize this stuff better than my space. But it sounds like there's much more cultural, emotional, sort of philosophical differences that may have decided which direction was going to have greater mass appeal. I think that's right. And you sort of see this resuscitated in the rise of Snapchat, because Snapchat is also kind of back to that LA mindset. It's much more expressive and irreverent and kind of culturally contextualized. It's got a lot of character and personality.

Its logo is a funny ghost drawing and this sort of thing. So I wouldn't give up yet on the idea that the future of the internet may allow people to be much more expressive than you see them being on Facebook. Facebook is a little bit totalitarian, not necessarily in a bad way. I mean, that's a word that is pretty loaded, But I'm looking for an antiseptic or anodyne or I don't know what the right word is, but it doesn't have a lot of flavor. It's a reflection of the engineering mindset behind it,

which itself is really ingenious, but it as a digital place, lacks culture. Mark Zuckerberg, who I think very highly of and who's a friend, a digital place, lacks culture. Mark Zuckerberg, who I think very highly of and who's a friend is a genius business person and technologist, but he's never, I don't think, been especially interested in culture. And when he talks about Facebook being a community and a global community, I think he is potentially

always, you know, I don't want to put words in his mouth, but I think he's maybe always thought that Facebook shouldn't have too much of a culture that it imposes. It should basically be a blank canvas for all of the diversity that is in the world. And when you allow people to express themselves more, it's unclear whether what you're doing is loading a place with some cultural precepts of your own, even by dint of the way that you design what those expressive tools are, or if you're actually giving people more freedom. And so I think Facebook has always taken the approach of limiting people's expressive capacity, forcing them to make comments or post things in these very structured, linear

formats, whereas some of these other tools have been a lot more liberal in the attitude that they take to personal expression. When you went to college, remind me what you studied. I did African American studies, and I have a minor in Kikuyu, which is a Kenyan language that I no longer speak. Were you thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about

the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about

the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about the money and I was thinking about academia may be interested in me, the arts certainly did. And I think halfway through my freshman year, I decided that the goal I wanted to shoot for was becoming a musician.

But part of that was a response to finding when I got to college that Harvard was essentially a vocational school for investment banking and management consulting. I never, I didn't know that those were jobs in the world. I'd never heard of either of those professions. And when it became clear to me that 40 or 50 percent of my classmates would end up in those jobs, I was kind of horrified and I thought, oh my gosh, is that the adult life that awaits me? And maybe as a bit of a rebellion against that, I went full bore into, I wanna be a musician.

That is hilarious, the vocational school for investment banking and management consulting. I didn't realize it was that high. So, roughly, I don't know. But whatever, even if a third of people end up as investment bankers and management consultants, that's a pretty interesting concentration. And after there's anything wrong,

I mean, I know you were a management consultant at one point, but there was a sense in which I felt that my college and elite universities in general, I've mentioned it a couple times, but I'm not someone who's a big booster. I'm not involved in alumni stuff. I don't take a lot of pride particularly in having gone to Harvard or anything. And part of why is because I'm very suspicious of these institutions, both because they essentially serve a function in the society of reproducing inequality and social hierarchy.

And they've been doing that for hundreds of years. And second, because they homogenize all of these talented young people. So they do an extraordinarily good job of finding interesting, unique people in high school, and then turning them into boring, high-achieving technocrats. And that's kind of a tragedy for the world, because it's a waste of the formidable resources that those universities do have, that what they choose to do with it is essentially pump out functionalities in the financial services. But somewhere along the way you

learn to think, and is it safe to then assume that you learned that before college and that college, if anything, didn't diminish that ability rather than augmented it? I'll tell you where I'm going with this, you know, and we're gonna talk a lot about biology and our mutual interest in hacking and lifespan and all that sort of stuff. I remember even the first day we met, maybe it was after our second meeting or some time, I remember thinking, how does this guy know so much about this stuff? You had more than just a superficial understanding of stuff that suggested you'd read a couple

of things about it, which obviously just suggested to me that you learned how to learn. And as a result of that, when you decided, hey, I really want to understand this area, and I want to understand the science of this stuff. You at least had a toolkit that you could use to do that. Where do you think you got that? I think I've maybe just always been curious, and that is a personality, trait, or disposition. Just wanting to understand things has always driven me to some degree.

When I went to college, I was interested in race and the history of race in America and how this set of ideas about who we are influences what the world is and who we become as people. And I was essentially interested primarily in these very complicated phenomena in the social world. So I wanted to, you know, I remember the first time I read Marx and whatever, it was so engaging

to discover a set of these totalizing ideas about how history works or something. You know, whether I agree with them or not, it's a separate issue. But the idea that one could theoretically describe reality was always compelling to me. And what has happened intellectually, as I've gotten older, is that I've realized that science is essentially the best methodology that we have for describing reality. And I've realized that I think the things

that most interested me, like social phenomena, government, public policy, history, are very difficult to address with the science currently at our disposal. So ultimately, I believe we will be able to have an empirical understanding of some of these sorts of things, but I was going after them back then naively thinking that we already had those tools at our disposal, or that I could by reading a lot about history, develop a accurate picture of how it works.

And one learning how to think is about understanding the limitations of our own biology, our own cognition. But then it's also about figuring out what's knowable and how you can understand things and what processes you can use to understand things. And so when I encounter a subject, I'm instantly tracking on what's the theoretical framework behind it. The details don't really interest me. It's what's the skeleton behind it, what's the structure of it. And for that reason, I don't think, you know, I've never been good at facts. I'm not good at dates. I'm not good at memorizing names of biomolecules. But what sticks in my brain are these kind of theoretical constructs.

Yeah, somebody asked me on Twitter a while ago, and I decided it would be a good question for an AMA at some point, which was if you could change something about the medical school curriculum, what would it be? And I wouldn't describe it probably as eloquently as you, but it's basically, I remember the first day of medical school, they said, you know, the average college graduate has a vocabulary of X words. And I don't actually remember what X is, but I feel like it was about 10,000 or something like that. And they said, you know, in the next two years, which is before you go into

the clinical stuff, you're going to learn, and it was a little more than that. So if it was 10,000 with the college grad, they said, like, you'll learn 12,000 new words. And obviously, you do need to learn a new vocabulary in medicine. But when I look back at medicine, medical school rather, I think the biggest deficit was no attention paid deliberately towards how to think. And that of course becomes relevant because, you know, all facts have a half-life, and some facts like anatomical facts have very long half-life, so in an area like that, it's probably reasonable to know stuff.

But in other things, like by the time you're done medical school, the information is wrong or irrelevant, and yet nothing's really put in place to teach that skill of how do you go about your now out there in the real world, your taking care of patients, and yet maybe what you learned about cholesterol or maybe what you learned about subject XYZ is kind of not right, or at least should be revisited XYZ is kind of not right, or at least should be revisited, or the probability of it being correct is lower. So do you and Liz think you'll have kids? Yeah.

And so how do you, now I'm asking this as a curious parent, but how do you think about creating an environment to produce that type of curiosity and that skill set? What do you think a parent can do deliberately? I'm asking this based on you having been the kid not the parent so far. Well, you certainly have more experience with this because you've got kids. What I've heard people say and what I sense may be real is that you actually don't need to teach

kids this. They're born with a lot of it and what the world tends to do is squeeze it out of them. this, they're born with a lot of it, and what the world tends to do is squeeze it out of them. And so, I guess I would invert the question and frame it as, how do you not kill a child's curiosity and how do you feed it? Certainly, one of the things I think my parents did was not sanction in a negative way asking questions or asking why questions. And by contrast, you can inculcate a child in religious ideologies or strictures about how to live that are so imprisoning that becomes a fundamental part of their brain. And so I think just not making those mistakes is probably the most important thing. I like the example you gave earlier of your piano lesson is 30 minutes of sitting in front

of a piano for some period of time. Before you start to read sheet music and start doing drills and things like that, I like that idea. That's absolutely. I mean, look, there's a balance between the sort of wrote discipline that is required in anything and then the creative and exploratory potential within that area. In my mind, I tend to wait the latter.

And so what's difficult for me is the brutal, repetitive, skill building. And I've had to figure out ways in life of not making my success depend on that aptitude and figure, you know, that's stuff that I look to other people to help me with. You know, my band as an example, my partner Max is an, I mean, he's good at everything. He's a musically brilliant person at a compositional level too. I mean, he can write great music and he's very theoretical, but he also has that OCD capacity to sit there and practice guitar for 10 hours. And that's really, that's his happy place. I'd go crazy doing that. And so I think to come back to your question about children, I think the struggle for me will be figuring out

how to impart to them a greater capacity to do the part that I don't like doing, because if you can really have both, that's the superpower. But it sounds like, to me, at least, maybe part of the secret is knowing how much emphasis to put on each of those two, again, they're not mutually exclusive, but you understand that this is a kid that,

if pushed too hard on the wrote stuff, will actually dampen the creativity versus, sounds like in Max's case, that's not the case. He can live in both of those worlds and be quite successful, and... I think that's right. The one metaphor I used to think about this, because a debate that comes up in all contemporary art,

be it painting or writing or music, is essentially whether amateur work can be just as valid as quote unquote professional works. So if you think about punk rock, the whole idea is screw learning these instruments, I'm just gonna pick up the guitar and express myself. And so, of course, there's a level of vitality that can be produced through that type of artwork,

both the absence of formal rules gives birth to a lot of expressive freedom, and you can get a kind of visceral version of someone, but there are only so many ways to smash a guitar on stage. And so if a hundred people do- None of them are as good as Jimmy Hendrix's at Monterrey. None of them are- and Jimmy Hendrix can- he can still smash a guitar on stage, but he can also do a thousand other things that the Ramones can't do.

And so the metaphor that I've been thinking of lately is almost like granularity or resolution. So if you imagine a photograph of something in low resolution versus high resolution, it's the same thing that's being expressed, but the greater the resolution, the more detail there is. And when someone is making music or singing or writing a poem or doing anything, what you're essentially, they're communicating. And what you're getting is you're getting sort of a photo of their brain. And the more technical skill they have in this metaphor, the greater the resolution of that picture

they can produce. And so I once remember being in the studio with Ferrell and Herbie Hancock came by. And Ferrell is a kind of folk musician. I mean, he's incredibly successful and he's very, very talented, but he's not a trained, he didn't go to music conservatory. He can't play you a boxenata.

He can write amazing stuff. He's a theoretical musician, right? He's a great songwriter and he's got great taste. And Herbie Hancock came and he was showing us a bunch of piano exercises that he and his friends used to do in Chicago in the 60s. And Ferrell kind of expressed that he was scared to learn that stuff because he was worried it would eat into his roughness or his authentic expression. And I remember Herbie Hancock saying, it's just gonna give you more colors to paint with.

It doesn't cost you anything. It just gives you more things that you can say with those ideas you've got. And I thought that was a great argument. You know, I think it was convincing to for all too. When you were in high school, who do you, in retrospect, look back at and say,

yeah, those were really, those musicians shaped my, either my taste or my philosophy or my way of writing or performing, like who, just broadly speaking, who were your influences in that regard? They're a little bit mundane, but they're sort of the obvious suspects, the Beatles, Bob Marley, Curtis Mayfield, those are the big ones, Stevie Wonder, maybe those four, Motown, all the Holland-dozer Holland were the three great songwriters.

You did a lot of the Motown stuff, a lot of the four top songs, the Temptations songs. Any James Brown? Yeah, I Any James Brown? Yeah, I like James Brown, but I would put, I'm more of a songwriter, and James Brown, I think, is most important as both a performer and as a groove guy. So, different music is good at different things,

and there's a tradition in black American music that I think ultimately begins in Africa and in the African diaspora of music that is not really linear. It's not about a narrative story being told through something like a song. It's much more about setting a musical mood and almost being a place that you hang out. Indian music is also like this. If you think about Indian Raga's, for example, it's sort of a tonal place and the piece of music may be half an hour long, it may be two hours long, but you kind of go there and you're just hanging out there in that vibe. Whereas the sort of music that influenced me much more that I

sort of work in is more about, it's again it's kind of more theoretical, it's more about a story, it's a linear story, it's a three-minute song, there's a beginning to middle and an end, it has some conventions about the way that it moves through those places. And people I cited, I think, are emblematic of that style. Now you're a drummer, so what drummer would you have identified with most? I'm sort of now going to double back on what I just said, because the key function of the drums is most highly expressed in those types of music that are essentially

groove music. So Clyde Stubblefield, who played with James Brown, is one of my favorite drummers of all time. That style of music that James Brown made is all about the drummer, you know, give the drummer some. And other people who are, you know, giants of that format are Bernard Perty, who's just, he's still around and he's incredible. I think he claims he's the most recorded drummer of all time, or is maybe played on the most hits of any drummer of all time. And then there are great rock drummers like Keith Moon or John Bonham. In jazz, the drums are much more of an instrument. You can sing through the drums in jazz music because the drummer is not just hitting hard

and fast and loud. The drummer has an incredible dynamic range of tonalities and expressive options. So in jazz drumming, you know, Elvin Jones is probably my favorite who played a lot with John Coltrane, but there are an almost unlimited number of incredible jazz drummers who I look up to. I think in the show notes for this podcast, we should link to some performances that you find particularly notable. Oh, that'd be cool.

I remember once you gave me a nice list of stuff for Olivia, which was like, here are some great Michael Jackson songs, here are some great James Brown songs, here are some great Boombu Boombu and it was like, this is a great way for a kid to start thinking about music. I thought that's such a helpful thing to provide. So, okay, let's go back to LA. So you get to LA, you're living the dream, right? Like it's, you've hit a home run here.

It's hard to imagine given what the denominator is on the number of people that are trying to accomplish what you guys have accomplished. And are you primarily now still a studio band? Or are you, once you've got this break, are you becoming kind of more performance-based as well? Well, by that time the band was just me and my bandmate Max, so it was a duo, really. And we, as we made

music, were a studio thing still, but we quickly realized. And you were playing, so you were doing vocals, you were doing drums, and were you keyboard as well? You know, I was primarily writing the songs with Max and singing them. And Max in the band was the primary instrumentalist. He can play pretty much everything and he can learn new instruments in a week. So Max on the recordings was playing almost all the instruments.

Occasionally we would have studio musicians come in and do stuff that he couldn't do, you know, if we needed a viola player or something. But my function in the band was largely to write the songs with him. I was writing all the lyrics. I was typically writing the vocal melodies of the songs and then singing them. So how did Spotify come into the picture? Was that true true and unrelated? Was that just a... Did Sean start that So how did Spotify come into the picture? Was that true, true and unrelated? Was that just a...

Did Sean start that or how did that... No, so let's fast forward a few years. So we basically... Because there's not a lot, I think, that is super interesting about this period in my life, although you may disagree, but... I don't know a period of your life. It's not interesting. So, in 2007, we get our record deal, we move out here,

and then we spent three years making records and touring. And a lot of stuff happened in the years. Can you tour Blink at one point, right? We toured with all sorts of people. Lady Gaga, Blink 182, Weezer, huge number, really cool artists. And then I concluded that I didn't like touring. And it was around that time that I discovered Spotify. I think at the time I already had an interest in investing, but I didn't really know which direction to go.

I had met Ashton Kutcher, who became a really good friend, and he and I got along, I think, right away, because we were both from the Midwest, we were both artists, and we both had an interest in business and technology. But he was a decade ahead of me in terms of being a famous entertainer, and he was three or four years ahead of me in terms of thinking that Silicon Valley venture capital could be an interesting canvas

for his artwork. And so he gave me a little bit of a template for an artist who was going to get into the technology business. And the question became for me, you know, how do I go from being a musician who neither has capital nor investing experience and become a professional investor. experience and become a professional investor. And Spotify ended up being in retrospect to the pivot that allowed me to do that. You know, historically, the music industry has not birthed many good businesses. And so it was a pretty happy accident that right at this time that I wanted to make this transition, this company that would become now a $28 billion

public market behemoth, was starting to become ubiquitous in Sweden, and I had friends who knew about it. And when they told me about it, the appeal of that product, of this idea that you could install a thing on your computer and have all of the world's songs ever at your instant recall was an incredibly cool thing to me. And I was just thinking of it as the customer basically. I was someone who collected tons of music, had hard drives full of it, was always struggling to manage the data. I'd get a new computer, now I have to copy all the songs, and I have to put them in folders.

And it was such a pain in the ass that when someone showed me this, I thought, whoa, this is what I've always wanted. And was Pandora on the scene at that time? Pandora was really popular. And it was just streaming. Pandora was streaming, but it was streaming algorithmic radio. Right. In other words, you couldn't choose the song. What was so cool about Spotify was that it recreated the experience of having bought

every song ever. You had MP3s that you'd buy through the iTunes store, for example, and they'd be on your computer, but maybe you'd bought 200 of them. That was your library of music. Whereas when I first saw Spotify, I thought, wow, for $10 a month, it's as if I bought everything ever. I mean, that was such a shocking value proposition to me that I thought this is almost certainly what everyone should have if the powers that be allow it. And the business question, which was much more difficult than the product design question, was can this company get everyone who owns music

to be a part of delivering this experience to the consumer? And so was the hardest cell with the artists or with the studios? Everything was a hard sell. Spotify was, I'm not going to take much credit for it because there were thousands of people working on this from the beginning almost, but everything about building that business was difficult. The first thing that was difficult was that record companies and music publishing companies own the rights to the music. And they had seen their business destroyed in the 90s.

The record industry went to a quarter of its former size in the 90s because of piracy. And so you'll remember the record labels were suing. Is that because CDs had become so ubiquitous that it was easier to copy a CD than say a vinyl or a cassette? I mean, not that it's not hard to copy a cassette, but the quality's not as good, is that? Well, it was coincidental with CD-ROMs. So two things happened. One, sites like Napster arose that allowed people

to trade music freely without paying for it. And then what they did with that music after they traded it on the internet, which was so difficult to control or put a lid on, was then they would burn CDs and copy the CDs and whatever. So, not only did the format of CDs get unlocked with the ability to write CDs, I mean, you remember getting your first CDR, that was really cool. But also, you had this unfettered digital environment

in which people could share music without anyone getting paid for it. What preceded this in the 80s and 90s, really in the 90s, was the CD revolution. And so not only was piracy painful in its own right, it succeeded a decade during which the music companies resold the entire history of music in a 10-year period. In other words, they not only sold in the 90s on CDs the new music that was being made in the right place, but everything that had been made today. So they sold you an entire library of the world's history of music in a 10-year period. They were rolling in cash. And when they made new music, they would sign an artist, they'd make one hit song that they'd play on the radio, and then you had to go by an 1899 album with 14 other songs you didn't want just to get the one

you liked. So they were raken in the cash by completely controlling the consumer's experience. Piracy blew the lid off that and the consumers rebelled and everyone stopped paying for music. And so the industry that Spotify came into was one that had been eviscerated by piracy. And then to add insult to injury, the legal paid download model that Steve Jobs pioneered with iTunes,

unilaterally recaptured the distribution system of what before then had been fragmented. So the record labels used to in the good old days of the 90s both control the radio stations so they could make things get popular, but then they had a variety of physical retailers, Sam Goodey, Virgin Megastore, all these different CD retailers that they could play off each

other. They had all the leverage. They could make the thing big and then they could tell you at the record store that you had to give them this promotion or else your artist wasn't going to show up there and do a CD signing. Well, when Steve Jobs invented the iTunes store, he became the only retailer that mattered. And so the record labels had this one-two punch they'd been subjected to of the industry disappearing and going to a quarter of its size.

And then this one guy who didn't need them, Steve Jobs, who made all his money selling hardware, gaining total unilateral control over them because he became the only place they could sell music. And so they were desperate, never to let either of these sorts of things happen to them again. They were incredibly paranoid about a new model that they viewed as threatening the paid download business. So Spotify was showing up telling consumers for 10 bucks a month, you get all the music ever. The labels at that point were

still embedded in a model where what you did was you sold people downloads for a dollar a piece. They were used to selling you 10 songs a month for $10. And Spotify came along and said, let's give them 22 million songs for $10. So selling the record labels was incredibly difficult. And then the artists were ardently against this as well, because for them, their lifeblood was selling downloads. They too were in an environment that was severely nutrition restricted from the past decade. And they were struggling to make money. Most

of them were only making money touring and recovering a little bit of income selling their recordings. Spotify came along and what we said was, we're going to fix this problem. We're going to convince most people in the world that they should pay for music. And the way we're going to do it is we're going to give them an experience that is every bit as good as the free, illegal experience, and we're going to get them hooked on it. And then we're going to charge them 10 bucks a month. And if we can get a huge percentage of them paying 10 bucks a month, that is far more than the average consumer at that time was currently spending on music.

I still don't understand the economics of Spotify. So if you're spending that 10, and by the way, I couldn't just sign up for 10 bucks a month today. Could I, aren't those sweet ones? You're done, 10 bucks a month. I thought that was like a student deal or some... You can sign up for $3 a month for the first three months today,

and then it'll go to $10 a month. I'm ashamed to say I still don't use Spotify. I still have a wed to iTunes. You gotta get on there. And I don't know if it's just like the hurdle rate of switching out of iTunes, but it strikes me as ridiculous because I pay a buck 29 per song. I probably buy an average of 10 to 20 songs a month, so I'm obviously spending more money than I would.

But let's just talk about the remuneration for the artist. So when I spend a buck 29 on iTunes, where does the rent go? Thirty percent goes to Apple. Seventy percent goes to the record label. The record label pays out roughly 10 percent of their 70 percent. So seven percent percent of their 70 percent, so 7 percent, to the music publisher, which owns the song, note that the song, which is called publishing, is different from the recording of the song. So if you and I write Happy Birthday and people sing it all over the world, we own the song, no matter who's singing it. But if Tony Braxton records a version of Happy Birthday, she owns the recording. The song owner gets about 10% of the 70%, and the artist will typically get somewhere between 15%

and 20% of what's left after their 15% or 20% cut has fully paid back the record label for all the money that label has spent promoting them. So Apple is getting a straight 30 that's pretty straightforward of the 70 the label is getting the majority of it. The label is getting the majority of it and the artist is getting anywhere from zero to maybe 10 percent something like that. Now that sounds grossly unfair. What makes it less obviously unfair is that the record label is the one taking all of the financial risk in financing the music and very often paying for the artist's life.

So, in this economy, they are still the only companies that take a financial risk making original artwork and they certainly deserve to be paid for taking that risk. So how does it work at Spotify? So now you paid your ten bucks a month. How is that rent spread out? Sure. So what happens is you listen to music all month at the end of the month. Spotify looks at the amount of time that you spent listening to each of those songs, and your $10 gets split pro-rata to the originators of that music. In roughly the same distribution as the 70% out of iTunes got split, how much does Spotify get to keep of the $10?

30%. Okay, so Spotify keeps 30 and the other 70 goes the same way, but now it's pro-rata. Yeah, that's correct and so for a consumer like you who maybe before Spotify was spending more than $10 a month it results in less financial benefit Then it it might have before on the other hand Depends how much you listen to those songs so if on Spotify, you know if you buy the song on iTunes and you listen to those songs. So if on Spotify, if you buy the song on iTunes and you listen to it one time,

you're paying $1.29 for one listen. But a lot of people, when they fall in love with the song, listen to it thousands of times and they listen to it for years. And if you take $1.29 and split it among thousands, effectively, they're paying very little each listen. So the paradigm shift is towards a pay for listen model. It's a consumption-based payment. Now back before

any of this stuff came along, if you had a radio station and you played a song, not satellite radio, just straight FM radio, for example, did you have to pay a royalty for that? The radio station had an agreement with an organization called a Performing Rights Society. These are societies that manage a particular type of right in music. So if you and I write a song, we and record it, we've just generated a whole basket of different types of legal

rights, all of which we begin by owning. And then we can sell those rights off to different third parties that will help us collect the income that attaches to the exploitation of those rights. In the case of songs that get played on the radio or performed at a basketball game or these sorts of things, that right is called a public performance right.

And the radio stations do deals with these rights societies in the US, the two most prominent ones are called ASCAP and BMI, and those organizations are responsible for monetizing that right on behalf of artists. So the radio station at the end of the year will give ASCAP a million dollars, and then ASCAP will do something like Spotify does, which is tabulate what that million dollars corresponded to,

and they'll pay out the royalties to artists pro-rata in accordance with that. And Sean Parker was involved with Spotify and with Napster, right? That's right. So he had kind of a, this was the evolution of what he and Sean Fanning had done, yeah. It was, they had intended Napster to become a legal service. And what they wanted, you know, 20 years ago was to go do deals with the record labels to legalize it. But the industry was so defensive towards them and so aggressive that it couldn't happen.

It took 20 years and it took the industry being decimated for everybody to be desperate enough that they were willing to entertain solutions to the internet. And that's what Spotify was. You know, it's interesting when you look at all of the businesses that have been disrupted by the internet and contrast it with those that have not. You've just given us a very eloquent description of how the music and history was disrupted,

but you also pointed out something interesting, which wasn't just the internet that disrupted. It was the desperation that followed the decimation that permitted the restructuring. Of course, then you can write off all the glib and obvious examples, right? What Amazon has done to retail, what Netflix has done to blockbuster and stores on the side of the street, what Uber has done to taxis, what all of the travel sites have done to travel agents. I mean, it's been incredibly disruptive. And yet, when I think about medicine, it's like one of the least disrupted industries by technology.

And you basically still have hospitals eat all the rent. Payers, although most people generally perceive them as bad guys, generally don't get paid that much. Providers get less and less on a per encounter basis. And it's overall a pretty much similar system to what it was 20 years ago. And that's, I don't know, I mean, I guess I'd have to think about it, but I can't think of too many industries that are as unchanged in the presence of this revolution as healthcare. No, I think you're right.

The appeal of investing in healthcare is exactly what you just expressed, and that's what drew me into it several years ago. And what I've learned since then has been slightly disillusioning, but I'll give you my take on it. The first thing I would say is that healthcare is still an industry that largely gets paid through labor. So most of the money ultimately goes to labor. Goes to doctors, it goes to the healthcare personnel. The hospitals don't make that much money. They're not that great of business. If you look at Kaiser, for example,

which is an integrated payer provider in California, I think they have a 3 or 4% gross margin. It's not a phenomenal business. The payers, to your point, have very low margins. They, in fact, have legally imposed limits on the amount of gross margin that they can generate, which, you know, you can argue about the ethics of. The pharmaceutical companies, who everyone hates, seemingly extract enormous profits. On the other hand, it's a very competitive

industry. And apart from the legalized monopoly given to them via patents on new drugs, they are the only companies, sort of as I said about record labels. They're the only ones who are out here designing new solutions. And taking an enormous risk. Taking an enormous risk, and their shareholders are taking that risk. Now whether they're being overpaid or underpaid to take that risk is totally debatable. The other thing is that it's unclear where technology can deliver dividends in terms of human health.

And so we're thinking about Madison at a moment in which we as a species have already made an enormous progress. I mean, whatever we've doubled or tripled lifespan and, you know, these numbers better than I do. But even if you get rid of the infant mortality factor and these other things that distort the numbers, people are living quite a bit longer on average than they were even seemingly 30 years ago. That's especially true of affluent societies until they get afflicted by the diseases of affluence.

So where can we get more life from or where can we reduce suffering and disease by way of technology? Is a little unclear. There are all sorts of things that we could of course do to make hospitals more efficient and to spend less than we do on things like end of life care that maybe aren't a good use of capital. But there's not so obviously a Spotify

of healthcare waiting to happen. It's more like there are a million little IT operating efficiencies that McKinsey consultants will over the next several decades implement in large health organizations. And then the big promise is around new types of medicine that I think will arise in the biotechnology industry and that's where I'm now spending a lot of my time and attention.

Yeah, it's sort of interesting because I think one of the challenges of healthcare and I think this was most evident during the debates many years ago, not many, but what I call it eight, 10 years ago around the ACA and around complete revisiting a restructuring of healthcare. And one of the things I found a little painful in listening to politicians talk about healthcare was they spoke about it

like there was just one problem to be solved. But the way I sort of think about it is there are at least three completely separate but highly related problems, which is quality of care. And that can be broken down into two levels. You can sort of have it as just keeping people from dying versus like generating alpha. So really improving quality.

There's cost, which is just the cost to the system. And about 90% of the dollars are basically spent by three entities, the government, the employer, and the payer, depending on who's at risk, the consumer is on the hook for about 10% of that cost. So how could you reduce the cost? And then the third leg of that stool is access. How do you ensure access? And so when we talk about technology disrupting healthcare,

it's like, where do you start, right? Because, you know, for me, I can see things where technology can be quite helpful on quality of care. Not entirely obvious to me how to leverage technology to lower cost. People much smarter than me, I'm sure, think about that. And not entirely clear, at least at a practical level, how it can drive access. Although, in theory, that should be the first place you'd want to go after leveraging technology. But I think I'm trying to think about what you said about how Spotify went about it and trying to see is there a parallel there because the thing with Spotify that

was hard was you had multiple constituents, right? You have artists, you have labels, you have consumers, and they all kind of want something a little different. And that speaks of an optimization problem, which is clearly what healthcare is. But going on what you said a moment ago, it sounds like today you're a little less encouraged than you would have been four years ago, and you're thinking on this problem. Well, let me try and recapitulate your three legs of the stool in one simple framework, which is something that we should all be aiming for is to generate universal access to the current best available health care that anyone in the world receives. You know, one of my favorite quotes I always forget whose quote it is, but venture

capitalists talk about it a lot, which is that the future is already here. It's just not evenly distributed. And I think that's almost always true. Look at what rich people are doing and assume that in 20 or 30 years, everybody will have that. And so what are rich people doing right now? Well, they're paying doctors like you a lot of money to do very bespoke types of medicine that leverage all sorts of deep biometric analyses of their bodies, a lot of thinking by you and your team, and a lot of spend on the usage of what are currently expensive machines, MRI machines to do preventative screening for tumors every

year, things like this that if you're really rich, you know, you might as well go get an MRI every year, get a full body MRI every year. I mean, just see if there's anything going on. Why not? And so what stands between today and orphans in Somalia receiving that level of care. And what stands in the way, I think, is, to some degree, a level of technological leverage. What is happening in your head when you look at a patient's blood tests and try to gel that with your biophysiological mental models is something that I believe

computers will be able to do in the future. And so right now, we use physicians for thinking and for bedside manner and for guidance. And then we use some physicians like surgeons for physical procedures that they're essentially athletes at. You want high performing athletes who don't mess up who are very precise who've done it a million times. Well, the roboticization of physical medicine like surgery is something that I believe will just continue to get better and better. It may take longer, it may not be replaceable immediately, but that will, you know, we will

be primarily doing robotic surgeries a hundred years from now. The cognitive work that physicians do will, I believe, largely be replaced by computational systems that can leverage the same types of theoretical frameworks that our minds are utilizing to make good decisions. And what you're left with is all the touchy-feely personal stuff that you as a physician and any other physician knows really matters. It's not superficial.

The ability to help someone make good decisions about their own health, to make someone care about their physical health, to help them navigate difficult decisions that aren't straightforward that involve trade-offs, are the sort of things that physicians right now don't have the time to do that they did when they were taking their medicine bag around to people's houses and hanging out for a couple hours.

And so in a certain way, we may go back to an older style of medicine, but the people who do that may look more like highly skilled nurses than like physicians. So I believe that what you'll see is globally a lot more technology involved in the deployment of medicine and a shift in the composition of the labor market around medicine towards something that looks more like a large population of highly skilled nurses. Fewer overpaid or appropriately paid, but maybe over trained physicians that right now are very scarce, that only rich people can access. And then most excitingly, you're going to see a lot of new medicine.

That's the stuff I'm focused on now as an investor, and that's the stuff that I think is going to be the most game-changing. That's the stuff that's going to buy us years of additional life. So when did you make that transition where you sort of your big foray into this was obviously Spotify as far as like transition one, so DA 2.0 to DA 3.0 and then DA 4.0 doing the investing. So the biotech stuff specifically, when did you make that transition? Well, I'm still making it because it's a hard transition to make, and there's been so much that I've already had to learn

and so much more that I have yet to learn. I think the starting point was this realization that what mattered most in healthcare as a capital allocator, meaning the most useful place that I could help direct money was to what goes through the pipes of the healthcare system as opposed to the healthcare system itself. The healthcare system in America for the reasons we've just discussed is a creaky old infrastructure.

And it's important to fix it, just like it's important to fix the government or the broken bridges that we have all over the country. But it's not the most interesting thing to do. And it also doesn't have a global impact because fixing the US healthcare system doesn't do a lot for folks in Sudan or in Saudi Arabia or in Japan or anywhere else. You're just dealing with a human system where what's broken are the human structures that we've constructed to deliver the thing. So that was my starting point, was realizing that the medicine itself was the thing that

mattered more. And ultimately, despite all of the valuable things that physicians do, the biggest game changers and human health in the past 50 years have been pills. They've been pills that very brilliant people invent and that we can give to people through any number of channels and that actually fix the problem sometimes. And we're moving into an era of medicine that people call preventative medicine or precision medicine or whatever you want, that really boils down to addressing illness at the level

of mechanism. Understanding that diseases have a functional, concrete explanation, and that we can develop interventions that actually fix what's broken in a very precise way and without a lot of collateral damage. And our ability to do that better and better is what's going to give people much more health in the future. And we're in any two or one of that journey. So as an investor, there couldn't be a more exciting place to hang out. And the advances that we're making

on a monthly or yearly basis are staggering. So when I noticed that that was happening in the world, it just became clear to me that this was not only an exciting and interesting place to be, but also one that could be enormously profitable both financially and in terms of the benefit to humanity that delivered. What got you interested in the problem of living longer, personally? Well, I guess I am not primarily preoccupied with living longer or with longevity as I am with the reduction of suffering that already exists. And so people who are really obsessed with longevity, maybe you are one of them,

will make the argument that death is the great tragedy of human life and that, you know, we basically don't realize it's so bad because we take it for granted and can't see any alternative. That may be right, but I also think there's a lot of evidence in nature that death and the turnover of populations has some utility. Steve Jobs talked about famously that this is nature's way of clearing out the old ideas and bringing in new ones. And creating urgency. And creating urgency.

But I don't want to downplay the credibility of the argument for longevity. I just think that there are enough people dying obviously prematurely from things that should be preventable and there are lots of people dying in the second half of their life or Suffering from things that should be preventable that we should start by focusing on those things now it may be the case that longevity is the skeleton key to all of those problems, that the number one risk factor for all diseases is age,

and that if we could just figure out what's happening with aging, then we could get out in front of all these other diseases, as opposed to playing whack-a-mole with all of them. That may be the case, and I think it's a legitimate hypothesis to explore, but it's not the one that I'm starting from or else all of my investing would be in longevity, whereas most of my investing at this point is preoccupied with individual

diseases and whether we can arrest them and detect them earlier. So what are you most passionate about right now? Not necessarily from the investment thesis perspective, but from the technology or promise that the idea holds. Well, the holy grail for me is approaching what I think of as a singularity like moment in biomedicine. People throw around the term singularity, I mean all sorts of things, but I actually believe it's a useful interest. You know, it may have been Kurzweil, Ray Kurzweil, or I'm not sure, but it may have been some of those old cybernetics dudes like I first heard it from

Ray's work. I don't know enough. Why don't you explain briefly what how he's referring to it? Well, I think Ray Kurzweil is referring to the singularity as this moment when human minds merge with machines. And so we, for example, download our brains into computers and then are effectively immortalized because our consciousness exists now in a digital format. That's not the singularity I'm talking about, but the concept of a singularity is that this is a moment at which sort of everything changes and there's an almost infinite acceleration in our capacity to do something. The singularity that I envision in our understanding of biomedicine is the moment at which we can digitally represent complex biology.

And therefore, study it at zero marginal cost. So let me explain this. Right now, what we essentially do in biology and what medicine has always tried to do is understand how the machine of a living system works. And in the work you do on metabolism, for example, the ways that we try to represent how the machine works are incredibly complicated. There are these flow charts with all these arrows and pictures and this connects to this and this connects to this

and this connects to these 10 things. If you pull this lever, these four things happen and how do we even make sense of that? A way station to the singularity I'm talking about is the field of so-called systems biology in which what people do is they observe these biological systems, and then they try to translate the mechanistic connections that they have uncovered into code, into formal representations, into a formal language that captures how something works in a way that a computer can understand, and in a way that a computer can understand and in a way that is unambiguous and not sort of stifled by the inherent ambiguity of human language by which we describe a lot of these things in everyday life. Ultimately, systems biology, I think, will allow us to simulate biological systems

simulate biological systems in their full glorious complexity. And when we can do that, which we might be 20 years away from, or we might be a thousand years away from, I don't know. But once we can do that, then we can effectively run intervention-based experiments on digital systems at zero cost. And that would be the moment at which we will start to understand biology and the ways that we can intervene in it at an extraordinary rate. Until then, unfortunately, we have to do tests on humans

or mice or dogs or monkeys. And unfortunately, we can only learn one thing at a time that way. We do controlled experiments where we hold everything constantly except one variable. And in so doing, we try to understand how that variable works. And this is a very slow way of learning. And it's a very expensive way of learning. And although the people who participate in clinical trials are heroes, to whom we owe most of our medicine, clinical trials are a brutal form of learning that cause many people to die from experimental medicines, or that cause many people to endure enormous suffering without any benefit.

And so that's the thing I'm most excited about. Getting to that singularity of digitally representing complex biology. Most of the things that I'm focused on as an investor, I view as somehow being stepping stones towards that singularity. If you look at other fields that could benefit from the ability to do digital experiments, consider macroeconomics. Wouldn't macroeconomics be even more complicated than biology? In other words, this sounds like the hardest problem I've ever heard of. All of these systems, people put in the same bucket of complex adaptive systems, kind of ground zero for studying these things as the Santa Fe Institute,

an organization which I'm involved and I'm very passionate about. And part of the reason I'm passionate about all of these types of systems is because they share certain characteristics. So in a kind of vague way, they're all complex in just the colloquial sense. Like they're really complicated.

There are a lot of moving parts. But it may turn out that we can come up with theories that actually describe all of these types of systems. So there's some sense in which these problems of economies and the weather and physiological systems are all kind of similar. And we may be able to come up with theories that are predictive, that help us make predictions

about these different types of systems. So that's a kind of intellectual promise land that I think is worth chasing. Whether or not it's gonna happen or not, I think even trying chasing. Whether or not it's gonna happen or not, I think even trying for those sorts of theories is gonna generate useful information. Whether we'll be able to simulate these things or not

is sort of an open theoretical question. But I'm optimistic about it because it seems like it's the logical endpoint of all of our digital technology is to create digital representations of reality. And on the one hand reality is really complex, but on the other, it seems to be driven at the bottom from relatively simple theories. And so, to the extent that the laws of physics are ubiquitous and are driving everything from the bottom up and that everything that happens subsequent to the laws of physics are these emergent phenomena.

It's not clear to me that we won't come up with simple, parsimonious descriptions of these types of systems. And the physics of the universe before Newton probably also appeared intractably chaotic. So the way that anything looks to us before we understand it is I think pretty imposing, which is why when we have breakthroughs, they feel almost like this enormous relief because something that seemed really complicated becomes really simple. Yeah, I mean, the obvious example, right, would be the coding of the human genome, which is now approaching 20 years in its anniversary. Do you feel that that discovery has underperformed, overperformed, or met expectations on what we would have thought prior to that codification.

The pithy aphorism that I think applies to genomics and a lot of things in technology is that it is probably short term overestimated and long term underestimated. So certainly when the human genome project reached its initial milestones in Craig Ventor's genome being sequenced. There was a extreme optimism that was unjustified that now that we've cracked this code, we're going to figure out everything in five or ten years.

Clearly, that has not happened. And so to that extent, those predictions have failed. On the other hand, the sequencing technology that underwrote that is now being used to sequence mRNA to sequence methylation of the genome to sequence neoantigens in cancer patients tumors, this has become an extraordinarily useful set of tools for reading all kinds of biology. And so long-term, I believe the impact of the human genome and our understanding of it is almost impossible to overstate because it represents a basic part of a tool kit that is now integral to everything at the cutting edge of medicine. Yeah, so in other words, the tool might actually be more valuable than the initial application. Absolutely, but the only way that people were able to justify

But the only way that people were able to justify pain for that tool was in this... In the hope. In the hope. That's what I say about Bitcoin and stuff, by the way, as well, because this is now part of my theory of technology, which is that it takes something like Bitcoin and all these blockchains and all of this. I was an early investor in this company, Ripple, about six years ago now. And so I've been interested in all of this for years. But I don't take the view that there's any end point

I predict and know with any level of confidence. All I can tell you is that having the smartest computer science 19 year olds in the world in mass, shift their attention to an area of technology is going to produce something. So whether Bitcoin becomes a replacement for the United States dollar is almost irrelevant, what I'm interested in is what's going to happen now that millions of people are working on

this thing. Similarly, the Human Genome Project was this kind of catalyzing event. It's very vivid. Bill Clinton had a press conference with Craig Venter and it got everyone excited. And that sort of moment is what inspires a lot of 18-year-olds, or a lot of 15-year-olds,

to go into molecular biology undergraduate programs and then to become genetics researchers. You know, so this is how history happens and a lot of things have already come out of genomics and will continue to. Have you been paying a lot of attention? I mean, you alluded to it a moment ago, but have you just, on a personal level, been paying a lot of attention to the liquid biopsy space? A lot.

Yeah. I've been following the liquid biopsy space now for about four years. Yeah, you and I spoke about this a couple of years ago and I wasn't sure how much you'd still been into it. This is something that's very interesting to me. You know, one of the things I talk about with patients is even with my most best attempts at providing the most bespoke insights into how to prevent diseases. When you take a big step back and say,

let's look at the three main diseases that are going to kill most people in a civilized society, where you're basically taking care of the blocking and tackling that you've alluded to earlier. It's atherosclerotic diseases, it's cancers and neurodegenerative diseases. And my personal viewpoint is that the atherosclerotic disease is in the neurodegenerative diseases. We have much more insight into how to prevent. Cancer's

tough and I sort of explained to people when you look at a blood test and let's talk about the best blood test money can buy. It's probably offering you 70 to 80% of your predictive value on the atherosclerotic side, probably offering you 60 to 70% of your predictive value on the neurodegenerative side. It probably isn't offering you even 30% of insight on cancer, because of course, the mutations that kill are somatic, not germline, so we're not measuring those. We don't have great assays for measuring adoptive immune cell function. We can measure innate immunity, but that's so crude and it's irrelevant in cancer. And so we talk about something else you alluded to, which is how aggressive can we be in screening whilst solving for optimizing around minimizing physical harm and emotional harm,

physical harm from the actual screening tool, emotional harm from risk of false positives, because the harder you look, the more you'll find. And the open gaping open hole in this is we can't do a liquid biopsy. So we got interested in this together, UNI mutually, around this ENOX2 protein, which was quite interesting, but unfortunately that company, that technology, doesn't really seem to exist right now. It also had a number of issues with it, but basically it was a Western bloc. It was a protein assay. They were looking at a protein, this Enoch's 2 protein,

and the belief was that that protein was found exclusively on malignant cells, and could only be shed off not just cancer cells, but cancer cells that had the potential to spread and attach to other cells. Now, a company that we both know pretty well, Grail, is taking a different approach that seems slightly more logical. Tell us a little bit about Grail. Grail is an interesting company. It's a spin-out of alumina, which is the behemoth genome sequencing business. They make all the machines that do sequencing that

most people use. And the premise of Grail is that by sequencing peripheral blood, you can find all sorts of cellular refuse from somatic tissues. And that this refuse, if you are able to amplify it, will tell you about the cells that it's coming from. And so one of the proofs of principle of this concept in general was non-invasive prenatal screening. Pregnant women have in their blood, I think, potentially 10% of their peripheral blood is actually coming from the fetus. And so you can detect a lot of things about the fetus by looking at the mother's peripheral

blood. And in that case, maybe what you need to effectively do is separate the 10% from the 90% in order to look at it. When you're talking about early cancers, you might be dealing with sub-half percent or sub-tenth of a percent concentrations of tumor DNA that are showing up in the blood. And so the premise of grail is that if you sequence the blood with enough depth, meaning you sequence it over and over and over again, you can detect just that DNA that's coming from the tumor. And by doing so, you can identify things about it that give you a guide to where the

tumor is and what its genetic characteristics are. And this is much harder than what you just said a moment ago because the problem you described earlier has two things going for it, which is one, you've got much more of it there. Let's just assume the number is 10%. But the other thing is half of that DNA is foreign. That's right. 50% of that DNA is from the father, 50% is from the mother. So you have half foreign greater quantity.

If you have colon cancer and we are lucky enough to get the RNA or DNA of that colon cancer, it might have 20 mutated genes. It's effectively self-DNA. Well, it is self-DNA. Exactly. It's tumor DNA, which is self-tumor. Yeah, exactly. So, I mean, that's a double whammy.

It's not just a needle in a haystack. It's like a needle of hay in a haystack. That's correct. And it's also difficult because- I just came up with that, by the way. I'm really proud. It's like a needle of hay in a haystack. That's correct. It's also difficult because... I just came up with that, by the way. I'm really proud. That's the first smart thing I think I've ever said. That's a good matter.

The needle of hay in the haystack. I like that. You can use that as much as you want. I will. I'm going to start right now. When you're looking for that needle of hay in the haystack, the premise of your search has to be that you know what you're looking for. In other words, you have to identify a series of potential oncogenes in which you're seeking abhorrent genetic variance that would indicate the gene has essentially been co-opted by the

disease and is now working for the cancer as opposed to working for you who want to defeat the cancer. And there are so many different ways that this technology is going to be difficult. That is matched by billions of dollars that people are investing in this because solving this problem is, as the company's name suggests, sort of a grail. I'm not an investor in grail, but I've looked at them, and I've also looked at many of their competitors. There's another approach that's really cool that I'm investing in right now. A company out of Boston called Glimps is a business that was founded by San Gita Batia, who's an extraordinary researcher at MIT. San Gita is a hepatologist, but a bioengineer

whose work has uncovered two really interesting ideas that I think are useful in cancer screening. One is that when cancer is setting up shop in a tissue, it remodels the microenvironment so as to build defenses for itself against the immune system and against the other physiological processes that would stand in its way. And it turns out that there are in the human genome,

550 different endoprodiases that are in some combination utilized in the remodeling of tissues. In different processes, so they're used primarily in healthy processes. But when cancers are beginning, these proteins get recruited, or these enzymes get recruited, rather, to do this remodeling work. They're sort of the construction workers of the disease as it gets set up.

And San Gita's work and the work of several other researchers that she's leveraging has identified what proteases tend to be implicated in the early formation of different diseases ranging from fatty liver disease, to liver cancer, to lung cancer, and a set of others. And if you can, it turns out, identify 10 or 15 enzymes that you basically only see up-regulated enormously when a particular disease is beginning, then there's another way of detecting it that San Gita's working on, which is to engineer nanoparticles that you send into the body, she calls them a synthetic biomarker. You let them circulate, and you design them such

that they break apart if they encounter those enzymes. And when they break apart, they fragment into smaller nanoparticles that can be detected in the urine. So Sangita's approach is rather than look for these trace amounts of refuse in the blood. Why not send essentially a team, a SWAT team into the body to circulate and hunt for a thing? And if that SWAT team finds the thing, get a much larger signal

in the urine. I think that's a very. Well, that have tissue specificity. It'll have tissue specificity. It'll have tissue specificity to the extent that the disease you're looking for has a different enzymatic signature when it's in different tissues. Got it. So in the context of let's say you get the signal and you would have to believe then that you're going to have different

enzymatic pathways in the, you know, mesenchymal system of colon cancer versus lung cancer. Yeah. I see. So it's not, you know, when you were saying this, I wasn't, I'm not familiar with lymphs. So I was, I was wondering if what you're going to say was it got taken up in residence, and then you basically would do, you know, it was labeled with gadolinium or something, and you you do an MRI and you'd see,

well, hey, this stuff is being broken apart in the lung. Therefore, that's where we want to look, but that's not what you're saying. No, these are all happening in the periphery, in the blood itself. The breakup of the nanoparticles is occurring at the site of the disease, but the refuse from that interaction is going through the kidneys and into the urine. It would be interesting if there was a way to see if there's a way to capture the local signature at the tissue site of origin. There may in fact be ways to do this and there are several nanoparticle-based approaches

that follow the lines that you described where it's an imaging agent that is meant to bind specifically to the tissue. What's cool about this, though, is you don't need to target. You just use the circulatory system to get these things everywhere. And if they detect the thing that you're probing, they change. And that's what you measure. I think this is a really clever workaround for some of the problems that I think have been

be devolene liquid biopsy. But I do think liquid biopsy will probably work. And the other reason it may work, and there's a company called Freenom, for instance, that's taking a different angle on it. Freenom's approach is don't look for the tumor DNA in the blood, look at the entire genome and see if there is any sort of smoke from the fire.

If the cancer is the fire, try to detect the body's systemic response to the cancer, and recognize that as aberrant. In other words, even if the cancer itself is sending off a very small signal, maybe the systemic response to it is a much larger signal, and you can detect that. So people are going to try and get after this in many different ways. My prediction is that within a decade, we'll have one or more of these that work quite reliably, and each of us will, at our annual physical, have a routine blood test that is pretty good at detecting cancer. Now, that gets another problem that people have raised, which is, you know, what if we're

all getting cancer all the time, and most of the time the immune system is disposing of it in short order. If that's happening, then we'll have another problem to solve, which is how do we know when we should treat people who are detected early versus when shouldn't we? But that's fine. Problems create solutions, which create more problems, and that's what we do. You know, that's the problem that I probably worry about the most. I mean, I guess the second most.

The problem I worry about the most is, can we crack this? But that problem, I got this glimpse into with with all the deep dive I did into Uncle Blot three years ago, which was I was asked by a company that was interested in acquiring them to help with the due diligence. I actually thought I was complete buffoonery, total quackery, complete and utter nonsense. But after about a year and a half, I thought there really was something there that unfortunately had been sort of bastardized by unsavory characters that were involved in basically creating kind of a profit center around selling alternative products that were complete nonsense. But when we did our own analyses on raw data that they gave us,

we saw something pretty interesting. There's two questions you have to ask, right, when you're doing this is. on raw data that they gave us, we saw something pretty interesting. There's two questions you have to ask when you're doing this is, the first is, and rather than describe them in terms of sensitivity, specificity, negative predictive value, and positive predictive value, just describing this stuff in English, you want to understand something, which is if you do a blood test on a person, and it comes back and says, nothing, how confident are you that they have nothing?

That's the concept of negative predictive value. And then, conversely, if the test comes back and says, you have something, how confident can you be that you have something? That's the idea of positive predictive value. Now, if you look at how OncoBlock was created and you look at how the FDA gave it a type of approval, which is not an FDA approval, but there's, you know, and I don't want to

get into the weeds on that stuff. But basically, it was approved, quote unquote, only for patients presenting with metastatic cancer with an unknown primary, because of its remarkable ability to create a differentiation around 27 different types of tissue. So someone shows up with a lung nodule that's not lung cancer, it's actually important to know, is that breast, is it thyroid, is it what? Because they could have a primary that's occult, but it's still metastatic cancer, and this

is a life and death decision as to how to treat it. And that's where oncoblock was actually very useful. And so, oncoblock became really, really good if someone had cancer and you did a blood test on them, you had about 99.4% likelihood of correctly guessing, not just that they had cancer, but what kind of cancer it was. But the flip side is really important, which is if you take a whole bunch of people that don't have cancer, and you can only do this out of a blood bank prospectively, you can't even do this in the population. What's the likelihood that you're not going to be

over-calling cancer? And when we did an analysis, and it was not a huge analysis, we were limited by the amount of data we had, what we saw was by about 5x, it overestimated the prevalence of cancer at a given age for a given histology. And our interpretation of that was, either this is categorically useless or it's picking up a bunch of cancers

that don't go on to become cancers. They get winnowed out by the immune system, which is exactly what you just described. And that raises a very difficult question as a physician, as a patient, which is, what do you do if it's your annual physical? Now, sometimes you'll get lucky, right? What's getting lucky?

Getting lucky is it says you have colon cancer, and you can go into a colonoscopy, which is a great way to assess that. It's not a great way, though, if a colonoscopy costs the system three or four thousand dollars and you now are giving people a thousand times more colonoscopies than we're giving today because we've got some screening test that suggests this. I'm reading right now a phenomenal book that everyone listening to the podcast and you should read the book of Why by Judea Pearl or Judea Pearl, who's a professor at UCLA, and his area is causal inference. And he goes through in the book some of the fascinating math that corresponds

with diagnostics in particular. And frankly, I'm always confused by sensitivity and specificity measurements, which is the inverse of which. Do you want me to send you my primer on this? Please send me it. I think that. We've put so much work into this. It's our favorite topic. I believe I understand it now.

But for your listeners, I'll just, from the book, give you one example of it, and the conditional probabilities that express it, people will probably remember a few years ago the guidelines on mammography changed to suggest that women, I think, what under 40 should not get mammograms as a screen. And I was always a little bit skeptical of that conclusion because there's a certain intuitive way in which you think, well, if it gives you a false positive kind of who cares, because just go get a CT, whatever, you know, I mean, what's obviously don't go get your breast cut off,

but if all the cost is to a woman is that she goes and gets another test, maybe that's not good for the system from a cost standpoint, but if you're the patient, you certainly don't want to not get screened if you do have breast cancer. And so, Pearl, though, in his book, walks through the actual statistics of this. So, if the incidence of breast cancer in the wild population is one in 700, that means that out of 4,000 women, say, five of them would have breast cancer, is what you'd expect. If the sensitivity of the test is 73%, which sounds high, that means that still

means, which is what the sensitivity is of a mammogram, 73%. It means that if you get a positive test result, you still have a sub one percent chance of having breast cancer. Now, Bayesian statistics adds another level of complication to this in that Bayesian statistics gives us a way of updating probability estimates that we make. And so there's a difference between you being a member of the random population and you being a woman who say has a lack of mutation that radically increases your chances of getting breast cancer.

And so if you are someone who say has a 50% chance of getting breast cancer in your life, then a positive mammogram gives you a much, much higher likelihood because it effectively updates your estimate that you began with of your likelihood of getting the disease. And so what we probably end up with in any of these tests is a way of stratifying populations based on their genetic risk of getting different diseases. And it's only within each of those cohorts of relative risk that we can consider the importance or usefulness of a screening test like a liquid biopsy. Because it's utility to each person

depends upon the extent to which that person is already at risk of the disease you're surveilling. Yeah. The other thing I add to that is the way we think about this problem clinically that person is already at risk of the disease you're surveilling. Yeah, the other thing I add to that is the way we think about this problem clinically is, if I gave you a piece of Swiss cheese and I said, how many pencils could you drop through here? It's a lot. But what if I put four pieces of Swiss cheese on top of each other and rearrange them in such a way that one and only one hole could accept the pencil. And so where I see the real application of the liquid biopsy is as follows.

So let's use them a biography example. So mammograms are good for some things and bad for some things. And let's ignore cost because I think once you layer cost into this, it becomes way too complicated a problem. So it's highly relevant. But as a physician, I'm trying to solve the problem of the patient, not society. That's my cop out. So then it becomes a question of, is the radiation significant?

And the radiation of mammography is trivial. MBI, of course, which is a more elaborate type of mammogram, has very high radiation, but we almost never do that anymore. So now we've taken away physical harm and we've decided to just discount cost. Well, mammography is good for seeing calcified lesions, but it's not good for seeing non-calcified lesions. Conversely, MRI won't pick up a calcified lesion, but if you're using something called diffusion-weighted imaging, it's infinitely better for picking up pretty much everything else.

So then the question becomes, what happens if you layer the mammogram with the DWI MRI, with the liquid biopsy? Those are three pieces of Swiss cheese. And then the fourth layer would be the Bayesian piece, which is what is the woman's probabilistic likelihood of breast cancer based on her family history, known mutations, and known mutations of unknown

clinical significance, which is basically the types of mutations we have. And now all of a sudden, you've got a much smarter way to think about it. So my only take on this one is, if and when the liquid biopsies become viable, I don't think they should ever be leading candidates. I think they should only be used as confirmation. So once you do, you know, X, Y, and Z, you then come back. So for example, if you do, you know, you go and get a whole body MRI and there's a little shadow in the pancreas. Well, what's the next step there? That's a big

step. Are we going to submit that patient to an ERCP or a biopsy of that? That's the real deal. Well, I think you're right to some degree, but I would push back to lead with it. I push back against the a priori assumption that we wouldn't lead with it because that does really hinge on sensitivity and specificity. You know, I mean, if we have 99% specific sensitive and 100% specific liquid biopsies. Over what time frame though? That's, see, I think that that's the challenge with the liquid biopsy is you're right.

I mean, technically there's no test that can have 100% specificity, 100% sensitivity, that's sort of like having a rock receive rocker and characteristic curve that's a square. No such thing exists. What I think is you take something where, can you generate a liquid biopsy that has 100% sensitivity, even if specificity is only 95%, which a lot of people think is

great, but 95%. No, I actually think you want the inverse. I think you never want false negatives. In other words, you want 100% specificity. You never want to take a role. Yeah, yeah, sorry. I misspoke. You want to talk to people. You want negative predictive value to be 100%. You never want someone who has cancer to be told they don't have cancer. You can tolerate some people who don't have cancer being told that they do. That's right. The other dimension here, I mean, I know we put costs aside, but you can't really, because the question is, what are the relative costs of these different surveillance measures?

If liquid biopsies are trivially inexpensive, which is the goal, say this glimpse test, you know, I forget all the health economics of it, just the cost of doing it might be five or $10 or $20 or something, if the sensitivity and specificity are both high enough, then of course you would rather use them as a universal screen and then follow up with much more expensive interventions. Yeah. And with things like fecal called blood testing or fecal DNA as a precursor to colonoscopy. It makes tons of sense because we have a pretty well understood pathway for the tumor. Again, not having an answer to this dilemma.

My big concern with everybody shows up and Willie Nellie gets a liquid biopsy that shows you've got pancreatic cancer is what do you do next? And let's go one step further. That's a question of sensitivity. Yeah, yeah, so you go and you get the MRI and the MRI shows nothing. To me, that's a great outcome. That's the best outcome is the MRI shows nothing.

And if the test is vetted and you're positive, and you can be confident that that was not a false positive, but rather it's a preclinical tumor. Then you're in a pathway of what's the righteous path of surveillance going forward, and equally important, if not more important, is what steps can the patient take in that moment to ward this thing off, to aid their immune system? Is that something, as quote unquote simple as, you got to sleep more, give your immune system a boost, figure out ways to de-stress yourself, which of course is pretty hard given that I just

told you you have pancreatic cancer. But you know what I mean? So anyway, that's the art of how to think about using these things, which I look forward to being able to think about these problems. I mean, I think what we're getting at is a really interesting framework, though, that is almost certainly going to become standard, which is the utility of the genomics and family history, which is, you know, genomics tells part of that story, but it doesn't tell you what happened with your ancestors. Family history remains

incredibly important, but you'll start when a baby is born with a whole genome and a family history. And that will generate for you the prior probabilities of different diseases, being the diseases that afflict that person in the rest of their life. Those prior probabilities will, in a personalized way, determine the utility of a wide array of low-cost screening tools that we're gonna have at our disposal, and will also lead you to make personalized estimates of the sensitivity or rather the diagnostic power

of those tests for that person, which to the Bayesian point is different for every person. This is a fundamentally different way than how we think about using diagnostics today. There's one detail of it that I don't have enough knowledge about that you've made me interested in in your Swiss cheese metaphor, which is what from a probabilities and statistics standpoint is the right way to think about that Swiss cheese metaphor. Does adding tests on top of each other, how do you mathematically combine the sensitivity and specificity of the different tests? And can you even do so without running clinical trials on the combined

usage of the tests to have some ground truth to reference them against. My intuition is, directionally, you can do it, but you will not have a number. In other words, you can't say that mammography plus DWIMRI plus liquid biopsy will have this sensitivity and this specificity calculated from the three pairs that you layered on. But I think philosophically what you're trying to do is arbitrage each strength and weakness of different screening tools. I think that's right. So it's a conceptual model more than it is a theoretical and precise. 100% where it gets interesting though is in the math because that's what you make it very counterintuitive So if you think about the example that I'm citing from Pearl's book

the sensitivity of the 73% test says that if you have breast cancer There is a 73% chance this test is positive this test is positive the much harder probability is what is the chance that you have breast cancer if this test is positive. These are two different conditional probabilities. And the shocking result is that if the test says you are positive, you have less than a 1% chance of having breast cancer. So what's counterintuitive is if we thought, oh, we have a one test that's 73% sensitive, we have one test that's 90% sensitive, we have one test that's 85% sensitive, you would assume that if you layer the three pieces of Swiss cheese, the

possibility that if you are positive on two of those three and you have the disease is quite high, it may turn out though that it's not very high. You know, the thing I always caution people against is you never want to talk sensitivity without remembering the specificity and vice versa. So in our little primer that we use with our patients, we use two extreme and very glib examples. If I mail a letter at random to a thousand women and tell them all that they have breast cancer, I have a hundred percent sensitivity. I have zero percent specificity, but I have a hundred percent sensitivity. I have zero percent specificity, but I have a hundred percent sensitivity. Because let's just assume three of those women have breast cancer. We told them all they have breast cancer. Never mind the fact that, never mind the fact that 997 of them don't

have breast cancer, and I incorrectly told them they do. But you can have a hundred percent sensitivity, and you're still, it's a dog shit test. If the specificity is really low. And similarly, you can send a thousand letters out to women at random and say, you absolutely don't have breast cancer. And you will say that with 100% specificity. Now what's cool about, and this may be true of incumbent diagnostics as well,

but what's kind of cool in the liquid biopsy companies I'm looking at, and I'm here exposing my lack of statistical knowledge, is that because the test is effectively a computer analysis of data, you can manually trade off between sensitivity and specificity. And that's like a PSA. Where do you decide the cutoff is? So for the liquid biopsies, what everyone is doing is they're saying we have to have a 100% specificity.

We can't tell anyone who has the disease that they don't have it. And that's the way it should be. That is how it should be. I think that that's, so what, you know, if you picture one of those and maybe we'll link to this in show notes so people know what we're talking about when we talk about a receiver operating characteristic curve, but that's, you picture pulling to the upper left, tightening that curve, getting it as close to an area under the curve of one. And that was the thing I could never get those onco block eyes to understand, was they

couldn't understand, they thought of this exclusively as a binary yes, no, and it's like, no, no, no, there's no such thing as yes, no. You could say PSA is prostate cancer if it's higher than one, and you will catch every single person who had prostate cancer and a million people who don't. Conversely, you can make the cut off 20 and you'll miss a million people with prostate cancer, but you'll be guaranteed that everyone who you say has prostate cancer has prostate cancer. That's fissitious and not even true, but directionally,

that's the problem that you face. And I like the question you posed, EA, which I've never thought of, which is, could you take my sort of hand waving Swiss cheese approach and mathematically map it out without doing the clinical trial? And that also goes beyond my pay grade. I would have to consult with the statistician.

You could certainly do it retrospectively. The way that these tests are developed is that a researcher gets lots of tissue and blood samples from patients and they know which of those are coming from cancer patients or not, and then they build a set of assays and analytics pipeline that look at the samples and try to class them correctly. And so you could certainly run multiple of those types of tests on the same samples

from the same patients if you had large enough sample volumes, and you could develop these tests in a layered manner, I don't think that the statistics would hold if you developed them separately from one another. But that effectively is a controlled experiment that I'm describing. Yeah, if you did it as a biased and unbiased sample, so you'd have to bifurcate the sample, do all of your learning on the biased piece and then only verified on the unbiased piece. That's correct. And that's how they use it.

And that's how they developed these. They teach an algorithm, essentially, what the differences are between healthy and disease, and then they feed it new samples and they ask whether those new samples can be clashed algorithmically into either of the buckets. I don't know. The liquid biopsy space is so interesting to me. I really, you know, I tell my patients that I think this is the single area that will most influence our care Hopefully in the next five years is right now like I don't right now. We're learning a lot about cardiovascular disease.

We are still learning, especially in the inflammatory side of that disease. We're not learning a hell of a lot around the light but proteins. We're just trying to educate people to actually know what's true and what's not true, but where we're learning geometrically as around inflammation and potentially with these two clinical trials that were published this year, or one that was published this year, one that was halted likely, the methotrexate study was halted early, likely because of a positive effect, and that won't be announced until the fall.

But that's two really interesting proof of concept. So the anti-IL-1 study and then the methotrexate study, where making no change in lipoproteins, you're improving cardiovascular outcomes. In my mind, the next frontier on cardiovascular is what can we do to strengthen the endothelial resilience? Because if you have a strong endothelium and muted inflammatory response and you can control lipoproteins,

you're taking the only inevitable disease our species has ever faced and knocking it on its heels. But cancer, man, like we're no better at curing cancer today than we were 40 years ago with five exceptions. Well, cancer like aging seems to be an enormously resilient set of processes. And you know, biology and evolution have been pretty thrifty. So the mechanisms, as you know, of many cancers are mechanisms that are used in early

fetal development by the body. So these are tools that our organism has for developing in the first place, and unfortunately they run some risk of getting reactivated later in life and doing crazy stuff that's contrary to our interests. And so this trade-off between the apparatus that we've been given to become healthy and mature and the processes that ultimately are undoing seems quite difficult to overcome.

Atherosclerosis is a less obvious one, although the sort of endothelial damage that is at its core and the function of the immune system in the processes that ultimately degrade that juncture are also used for all sorts of good things. I mean, the immune system seems to be at the core of much of this. That, you know that if you do view atherosclerosis ultimately as a sort of auto-inflammatory

disease, then you can think of it as a trade-off against the immune system. Yeah, just allergies. Right, yeah, exactly. And I'm getting allergy shots right now, which funny enough, I guess, have always been referred to as immunotherapy before it was hot. But, you know, I mean, I would still rather have to get allergy shots than be susceptible

to almost certain death if I didn't have this immune system. Do you have any anaphylactic reactions or your allergies, pretty much? Thankfully, no. And thankfully, I haven't had any anaphylactic reactions to the immunotherapy. Which is still witch doctor science. One of the things Sean Parker is working on is allergy. And it's one of the things that led him into immunotherapy because he has horrible allergies. And so has always been fascinated by the immune system.

And when he perceived that there was a crossover between his allergies and cancer biology, he got obsessed with the idea that immunotherapy was going to be the root. But allergies themselves, as mundane as they are, still can't be addressed in a particularly rigorous or precise way. So precision medicine for tree pollen allergies is still beyond the frontiers of current medicine. Although the work that Dr. Nadeau who is the largest sort of recipient of the work that Sean's doing up at Stanford, I mean, she is amazing.

And the work that they are doing. I mean, I've sent multiple patients. their carries always very kind and takes my referrals. I mean, I have seen before my own eyes, people who once would have died from peanut dust and they can eat peanuts again through this sensitization. So it's, yeah, I don't, I, I sometimes wonder if Sean gets enough credit for the amazing stuff he's done both in terms of funding cancer research, but also this incredible center at Stanford that, you know, little by little, we're seeing, you know, Mount Sinai's doing this in New York, Chop is doing it in Philly. I mean, other centers are still are taking this research forward. And I don't

know, I mean, I think for people out there listening to this who have children or who themselves have anaphylactic reactions, I am way more optimistic about this than I was four years ago. Well, and this is, you know, comes back to the earlier point about the futures already here. Yeah. Now, how do you make that accessible to everyone? How do you make it accessible to everybody and how do things that make sense and have been proven in a sense become standard of care. Unfortunately, in the United States, and this is something that I discovered very slowly, it's not as if there's one arbiter of standard of care.

You've got all these different medical societies that govern physicians and standards in clinical guidelines in every specialty area. They have their conferences and their board of directors, and the payers sometimes respect their clinical guidelines and the government sometimes respect their clinical guidelines. So one of the things that in sort of definitive science, do we rapidly

make sure that it becomes standard for every patient, everywhere? And right now, it has to go through this long cascade of human minds and bureaucratic organizations, which is an enormous detriment to patients. I mean, this is something that has nothing to do with science. It just has to do with people. And it's the sort of thing that physicians should care much more about as a community. It's the sort of thing that people like,

I think, a tool Goanday rightly are always reminding us to think more about. It's very easy to get drawn into the science and technology frontiers, but we forget that we could make such an enormous impact with just these simple changes in our own behavior. D.A., I know I could sit here and have this discussion for another two hours, but I want to be respectful of your time and you've been super gracious to open up your home this morning. Where can people learn more about you? I know you've got a huge following on Twitter

so they can obviously see you there. What's your Twitter handle? It's DA Wallick, that's DAWA, L-L-A-C-H. And I have a website which is equally simple, DAWallick.com. And I'm on Instagram, also DAWALIC. I tend not to do that much social media these days, but I still occasionally post pictures.

And I'm very easy to reach to. So I presume that in your audience, there is a mixture of crazy people, geniuses, and smart, nice people who think they're geniuses, but are not. And I'm particularly interested in meeting the geniuses. So, right now, anyone listening, please put yourself in the bucket of crazy genius or smart, not genius.

Correct. And if you're in bucket two, can you reach out to DA? If you're smart, not genius, but do have an interesting novel idea that itself could be deemed genius, I'm also interested. That's great. Do you still perform? Not regularly. The most recent performance I did was after a dinner party, when I was embarrassingly asked to play a song on someone's piano in their living room and got pure pressured into doing it

But most of the time I don't perform because I don't have a great way of performing If someone was gonna buy just one piece of music would it be your most recent album? What would you recommend? I think so I would recommend my my most recent album, which came out in time machine, about three years ago. Yeah. Yeah. To be called time machine. Oh, I thought it was 2016. It came out. Was it 15? It may have been 16. I'm doing it with dates. You told us. I'm terrible with dates. Okay. I think it was six, 2016. I was thinking the other day that it felt like it was a year ago. And then when I sort of realized it was three years ago, I thought, oh, shit, I should probably finish some of these songs. I've been writing, you know, because I can't

go like a decade between now. I don't have the axle rows credibility to wait that long between albums. All right. So time machine it is, which I believe came out in 2016, but I could be wrong. And of course, like a fool, I bought all your stuff on iTunes, so I overpaid for it. I could have just been on Spotify. If you're not listening to it much, I made out like a bandit on that, so thank you. No, I tend to, when I listen to music, I just listen. I'm like a big repeater.

Right. It drives everyone around me nuts. So you've got that OCD focus. Yeah. I can go five songs on a repeat for an entire five-hour flight. Amazing. Yeah, usually could go I can go five songs on repeat for an entire five hour flight. Amazing. Yeah, usually Zeppelin. Right. Yeah. Zeppelin's good. I don't know if I mentioned bottom before. You did. Yeah. I wouldn't have let you get this for on the conversation if you hadn't at least mentioned John Bonham. What's cool about both bottom and Elvin Jones

is that they both played behind the beat. They're always kind of catching up with the song and when you play behind the beat it sounds cool. I don't know why, but just like you can recognize cool, if someone dresses cool or is cool, playing behind the beat sounds cool. I, to this day, listen to Good Times Bad Times at least once every couple of days. And I think to myself, how is it possible that this was the first song on the first Zeppelin album? And Bonham's opening riff, it's like incredible. And I think to myself, what would it have been like to have heard that for the first time on vinyl as like a new sound? I just, I mean, I would have worn that record out.

Well, and they had a level of mystery too. I don't know if you know this, but they were never on the album covers, pictures of them. So people would go to the concert to figure out what they looked like. So this, I do somewhat regret not having been, oh, yeah, I've been around in a time where there was that level of magic around who was making some music you heard. I mean, it must have been even crazier with wax cylinders and stuff like this. People famously thought when they heard the phonograph

that they needed to pull the curtain back and see the source of the audio there, because it sounded so realistic. Now, if you hear a primitive wax cylinder recording, it's like shocking that anyone could have thought that was in the room, because it's so scratchy and simplified, but the magic's happening in people's brains,

so they just couldn't piece together how that was coming out of the speaker if it wasn't there. Do you ever listen to vinyl anymore? Yeah, I love vinyl. I mean, vinyl's great. Vinyl is a peak technology in music reproduction. So you get a level of accuracy with digital music that you don't get with vinyl, but analog media are pretty cool.

Yeah, golly. And last question, just because we're bringing it back to music, if you go back in time and see three or four concerts, actual pick the date, pick the band, pick the venue, that you just otherwise wouldn't have been able to have seen because you weren't old enough or whatever. What do you think they'd be? Well, I would have liked to see,

I saw Prince one time, and it was the most virtuosic live performance I've ever seen. So I might devote two of those concerts to Prince or something. People say Chuck Berry was pretty awesome live and pretty unhinged. I bet, you know, I don't love early rock and roll and I don't love blues, but some of those early rock folks, you know, if you had never seen it before, probably would have been incredibly shocking.

So I would have liked to see that. And watching the documentary on Nina Simone that I saw a few years ago, I concluded that she must have been one of the greatest live performers ever. She's just a virtuosa live performer. So I would have liked to see her. It's like one of my favorite games to play.

In the time machine. Oh yeah. All right, the A. Well, thank you so much. Hey, it's pleasure. It was all in speeder. You can find all of this information and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode.

You can also find my blog and the NerdSafari at peteratiamd.com. What's a NerdSafari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity,

science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, ATA, MD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for

professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and or advise please visit peteratiamd.com-forward-slash-about. splash about.