Ground Truths

Piezo touch and pressure-sensing ion channels are showing up everywhere as the explanation for physiologic phenomena, both at the macro and micro levels. Ardem Patapoutian, my friend and colleague at Scripps Research, discovered these receptors back in 2010 and was awarded the Nobel Prize in 2021 for his work. As you’ll see/hear from our conversation, the field has exploded. And you’ll get to know Ardem, who is such a fun, charismatic, and down-to-earth person. He also recently got a unique tattoo (videos below) and I wonder (unlikely) if any other Nobel laureates have one related to their discovery?!Below is a video clip from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Transcript with links to audioEric Topol (00:07):Well, hello. It's Eric Topol with Ground Truths, and I've really got a special guest today. The first time for the podcast, I've been able to interview a colleague and faculty at Scripps Research, Ardem Patapoutian, who just by the way happens to be the 2021 Nobel Laureate in Physiology or Medicine. So welcome, Ardem. It's so wonderful to have you.Ardem Patapoutian (00:30):Thanks so much, Eric. Looking forward to chatting with you.Eric Topol (00:34):Well, this has been interesting because although I've known you for several years, I didn't research you. I mean, I had to learn about more than I even do. And of course, one of the great sources of that is on the Nobel Prize website where you tell your whole story. It is quite a story and not to review all of it, but I wanted to go back just before you made the call to move to Los Angeles from Beirut, Lebanon and with the scare that you went through at that time, it seemed like that was just extraordinary that you had to live through that.Ardem Patapoutian (01:11):Yeah, so I am of Armenian origin, but I was born in Lebanon and born in 1967, so I was eight years old when the civil war started. So it's a kind of bizarre childhood in the sense that with all the bombs and fighting in Lebanon. So it was tough childhood to have, but it was never personal. It was bombs and such. And so, the event you're talking about is, I happened to be kidnapped while crossing East to West Beirut. They only held me for four or five hours at first asking me questions to see who I am, but I think they pretty soon figured out that I was not a dangerous guy and they ended up letting me go. But before that, that incident really had a huge impact on me so that by the time I got home, I literally said, I'm out of here. I'm going to find a way to leave the country. And so, that's what, very quickly within a few months I packed and came to United States.Eric Topol (02:19):And how did you pick LA to be your destination?Ardem Patapoutian (02:22):Being from the Armenian community, there's a lot of Armenians in Los Angeles. My cousins already had moved there. They also grew up in Lebanon. And my brother, who's a few years older than me, got admitted to USC graduate school in engineering. So he was going to be there. So it made a lot of sense.Eric Topol (02:44):Oh yeah.Ardem Patapoutian (02:45):Unlike him, I came with no school or job prospects because it happened so fast that I kind of just left. One year I was at American University of Beirut for one year, but then just left and came here. So worked for a year in various jobs and then started going back to school to UCLA.Eric Topol (03:07):Yeah, I saw how there was about a year where you were delivering pizzas and before you got into UCLA, and that must have been an interesting off year, if you will. Well, the story of course, just to fast forward, you did your baccalaureate at UCLA, your PhD at Caltech, postdoc at UCSF, and then you came to Scripps Research 24 years ago along with Pete Schultz, and it's been quite an amazing run that you've had. Now, before we get into PIEZO receptors, the background, maybe you could help me understand, the precursor work seems to be all related to the transient receptor potential (TRP) series, also ion channels. They were of course related to whether it was heat and temperature or somatosensory. How do these channels compare to the ones that you discovered years later?Background on these Ion ChannelsArdem Patapoutian (04:09):Yeah, so the somatosensory neurons that innervate your fingertips and everywhere else in your body, their main job is to sense temperature and pressure. And this is very different than any other neuron or any other cell. So when you touch a hot stove that’s burning hot, you need to know about that immediately within milliseconds or something cold. So the opposite side of it is pressure sensing, and it also comes in light touch, which is pleasant or a hammer hitting your finger, which is unpleasant. But all of these have the same characteristic anyway, that is your body has learned at the molecular level to translate a physical stimulus such as temperature and pressure into an electrical signal that neurons use to communicate with each other. But this idea of how you translate physical stimuli into chemical or electrical signal has been a long open question because as you know, most of our cells communicate by chemicals, whether that's hormones or small molecules, we know how that works, receptor bind to ligand, confirmational change and you get a kinase activation and that's enough. But here, how do you sense pressure? How do you sense temperature? It was just, there wasn't much known about that. And that's why our earlier work on TRP channels, which were temperature sensors came before the pressure. And so, they're very related in that sense.Eric Topol (05:52):The structure of these, if you were to look at them, do they look pretty similar? What the TRP as you say, and what you did back in the 2010 Science paper, which we'll link to, of course the classic paper where you describe PIEZO1 and PIEZO2, but if you were to look at this structures, would they look pretty similar?Ardem Patapoutian (06:14):No, that's a good question. And they absolutely don't. That's why finding these receptors were so hard. So if you go back to other sensory receptors, vision rhodopsin G-protein coupled receptor (GPCRs), larger G-protein coupled receptor look the same. So for example, when it was identified by chemically, that smell also works through G-protein coupled receptor. Richard Axel and Linda Buck, who also won the Nobel Prize, found those receptors by homology to visual GPCRs. The ion channels other than the fact that they crossed the membrane a few times or more, they have nothing else in common. If you looked at their structure, you can't even immediately tell they’re ion channels. So you couldn't find these by structural homology or sequence homology. So you had to do something else. And usually that means functional screens and et cetera.Eric Topol (07:09):Well, yeah, and I'm in touch with the screening. We'll get to that and how you dig these up and find them. But the somatosensory ones are really interesting because I don't think a lot of people realize that when you have wasabi or you have Listerine mouthwash and feel the burn and that these are all mediated through these channels, right?Ardem Patapoutian (07:35):Yeah. So there's this whole field of chemesthesis, which means senses in your mouth, for example, that are not explained by taste transduction and olfactory. And these are actually by the same somatosensory neurons that help you sense temperature and pressure. And some of these receptors are the same. Their evolution has taken over and used them for many different things. The prime example of this is the capsaicin receptor that David Julius my co-laureate identified, which is also heat receptors. So all languages describe chili peppers as hot, and that's not a coincidence. It actually activates heat activated channel, and that's why we think of it as hot. And so, the same goes to another one of these TRP channels that you mentioned, which is TRPA1, and this one is also activated, but a lot of spicy foods other than the chili pepper active ingredient includes what's in garlic and onions and everything that has this burning sensation and chemicals of this and wasabi and chemicals of this are used in over the counter products like Listerine that cause that burning sensation.Eric Topol (08:54):So when you're chopping onions and it makes you cry, is that all part of it as well?Ardem Patapoutian (08:59):That’s all TRPA1, yeah.The Discovery, A Test of PerseveranceEric Topol (09:01):It's wild. Now, this was the groundwork. There were these heat temperature and somatic sensory, and then you were starting to wonder what about touch, what about out pressure and proprioception. And so, you went on a hunt, and it's actually kind of an incredible story about how you were able to find out of these cells that you had, screening hundreds or I guess you got to 72 different small interfering RNA blocking that you finally found the one. Is that right?Ardem Patapoutian (09:37):That's right. So in retrospect, looking back at it, I think there's such an interesting scientific message there. And so, many of us were looking for this touch pressure sensors and we were all looking in the DRG sensory neurons that are complicated heterogeneous, they don't divide. It's not easy to do a screen on them. And ultimately after a lot of failures, what worked for us is to take a step back and ask a much more simpler question. And that was, can we find one of these cell lines that you could easily homogeneously grow in a culture dish, if they respond to mechanical force, can we find our channel there? And then go back and look if it's relevant in vivo for what process. So I think the message is ask the simplest question to answer the question you're after. And finding what that is, is actually the challenge lots of times.Ardem Patapoutian (10:36):But yeah, that's what Bertrand Coste in my lab did is found a simple cell line that neuroscientists had been using for a hundred years and somehow found that they over overexpressed this channel because you can record from them, you can push them and record the currents from them. And then it became a simpler question of finding it. It still took a whole year. He made a list and one by one knocking them out and looking at it. And finally, as you say, number 72 was the hit. When he knocked that out, the current was gone. And that's where we started believing that we have what we were looking for.Eric Topol (11:12):Were you all ever about ready to give up at that point?Ardem Patapoutian (11:16):Oh yeah. I mean that's another lesson. These are postdocs doing the work, right? And they're here three, four years and this was coming close to end of two years, and he didn't have anything yet. So we started talking about having a backup project and he started that and we said, okay, we were ordering this oligos 30 at a time because they're expensive. And so, the first 30 nothing, the second 30 nothing. And how many more are we going to do before we potentially give up? And we said, well, let's do at least a third and then decide, thank goodness it was in that last set.Eric Topol (11:54):Wow, that is so wild. Now what's happened since this discovery, which I guess when you published it in 2010, so it means 14 years ago, but we're on this exponential growth of learning that these piezo receptors are everywhere. They're doing everything. In fact, I recently put on Bluesky, PIEZO ion channels are to human physiology as GLP-1 drugs are to treating many diseases because it's just blowing up. And you've published on some of these of course, on itch and bladder function and vascular function. We'll get to maybe malaria, I mean, but even the cover of Science recently was about wet dog shakes and how animals shake because of water. These receptors are so fundamental to our function. So maybe you could comment, 15 years ago when you were doing the work and you're making this discovery, did you ever envision it was going to blow up like this?Ardem Patapoutian (12:57):Not to this level, but I should have. I think that this idea, again, that most of cell communication is through chemicals is of course a lot of it is true.Ardem Patapoutian (13:12):But it would be ridiculous for evolution to ignore all the physical forces, the pressures that cells experience. And once they do, you would think you would put an instructive way of sensing this pressure signal and using it beneficially to the system or the cell. And so, when we used to talk about pressure sensing at the beginning, there were a couple of touch, pain, maybe proprioception, hearing are like the poster children of pressure sensing. But I think what these molecules, as you say is enabling us is finding out the much more wider role that pressure sensing is playing in physiology and in disease that no one had thought seriously about. And this is, I compare sometimes the finding the PIEZO molecules. You're going in a dark room, and you need to find a door to get into there. And PIEZO is kind of that finding the door once you get in, now you use that molecule now to find physiology instead of the opposite way around. So by pursuing PIEZO expression and function, we're finding all these new roles that they play in physiology and in disease that we didn't think about. And because they're so specialized to sense tension, membrane tension, they don't do anything else. So if you see them expressed somewhere or if you see a function for them, you can bet that they are playing a role in sensing pressure. A lot of biology has kind of come from this hypothesis.Eric Topol (15:00):Well, I mean it is so striking to see the pervasiveness, and I do want to go back just for a second because when you name them PIEZO, you named it after the Greek word. How did you come to that name?Ardem Patapoutian (15:13):So Bertrand and I were actually sitting on Google Translate and we were typing pressure and trying to see what it's like in Greek or in Latin or different languages. His native French and my Armenian and píesi in Greek is pressure. And of course, what's really cool is that the word that more people know about this is piezoelectric device.Eric Topol (15:41):Oh, right.Ardem Patapoutian (15:41):Actually, translates physical force into electricity and vice versa. And in a way, this is a little molecular machine that does the same thing, and he uses this piezoelectric device to actually push on the cell. That's his assay. So it all came together as a very appropriate name for this gene and protein.Call from the Nobel CommitteeEric Topol (16:04):Oh really, it’s perfect. And you get to name it, even that's fun too, right? Now we're going to go to getting the call at 2:00 AM, but it didn't come to you because your phone from the Nobel Committee was on ‘do not disturb’ and your 94-year-old father, Sarkis. How did the Nobel Committee know to get ahold of him? How did they reach him in the middle of the night?Ardem Patapoutian (16:37):Yeah, so I mean, since receiving it, I've had conversations with various committee members, and they are very resourceful folks, and they have assistants who throughout the year collect information on all potential people who might win. They're also doing last minute searches. So they looked for other Patapoutian’s in California. So they just called my dad who initially yelled at them for disturbing him at 2:00 AM.Eric Topol (17:17):And he could get through to you because he was not on your list of ‘do not disturb’ or something like that.Ardem Patapoutian (17:22):I didn't even know this. And I don’t know if the policy has changed, but in some phones the ‘do not disturb’ if it's called by someone who's in your contacts or favorites.Ardem Patapoutian (17:34):After I think they called twice and they get through, and that's how.Getting a Tattoo!Eric Topol (17:39):That's amazing. Wow. Well, that's quite a way to find out that you're getting recognized like this. Now recently you got a tattoo, which I thought was really remarkable, but we're going to put that of course in the post. Tell us about your decision to get the PIEZO channel on your arm.Ardem Patapoutian (18:02):So as you can tell, I'm obsessed about PIEZO and it's been good to me. And I had the idea a while ago, and my very wise wife, Nancy Hong, said that you might be going through midlife crisis. Why don't you wait a year? If you still believe in it, you should do it. And that's what I did. I waited a year, and I was like, I still want to do it. And I guess I could show it. Here it is.Eric Topol (18:32):Oh yeah, there it is. Oh wow.Ardem Patapoutian (18:33):What’s cool is that I can pretty much flex to show the activation mechanism because the channel is like bent like this in the plasma membrane. When it's stretched, it opens and it actually flattens like this. So I feel like other than being a tattoo, this is both performance art and instructional device. When I'm giving talks without PowerPoint slides, I could give a demonstration how this ion channel works.[Below is from a presentation that Ardem recently gave, the Harvey Lecture, at Rockefeller University.]Eric Topol (19:04):It's wild. Now how did you find a tattoo artist that could, I mean, it's pretty intricate. I mean, that's not your typical tattoo.Ardem Patapoutian (19:14):Yeah, I put it up on social media that I was thinking of doing this, and many scientists are into tattoos, so I actually got so many recommendations. And one of them was a local here in San Diego, and she is very popular. I waited six months to get this, I was on a waiting list. The appointment was six months off when we made it. So she's very popular and she's very good.Eric Topol (19:45):Was it painful to get that done?Ardem Patapoutian (19:47):Well, that's actually really cool, right? Because PIEZO2 is involved in pain sensation, and I felt it while it was being tattooed on my arm. The whole day, I was there like six and a half hours.New Prospect for Pain MedicationEric Topol (20:00):Oh my gosh. Wow. Now that gets me to pain because, I'd like you to talk a bit about the people that don't have mutations or loss of function PIEZO receptors and also what your thoughts are in the future as to maybe we could develop a lot better pain medications.Ardem Patapoutian (20:22):Yeah, we're working on it. So you're right. One of the great parts of the science story, and this is mainly the work of Alex Chesler and Carsten Bönnemann at the NIH, where they identified people who came to the clinic for undiagnosed conditions, and they were uncoordinated and had difficulty walking. And when they did whole-exome sequencing, they found that they had mutations in PIEZO2, there were loss of function, as you say. So complete loss on both chromosomes. And when they started testing them, they realized that just like we had described them in animal models, humans without PIEZO2 as well, didn't sense touch, don't have proprioception. This sense of where your limbs are, that's so important for balance and most other daily functions that we take it for granted. So they were completely lacking all of those sensations. They also do not feel their bladder filling.Ardem Patapoutian (21:26):And so, they have learned to go on a schedule to make sure they don't have accidents. And many of these projects that we've done in the lab collaboration with Alex Chesler, et cetera, have come from the observations of what else these individuals experience. And so, it's been a great kind of collaboration communication between mechanistic animal model studies and the clinic. And so, one of the things that these individuals don't sense in addition to touch, is something called tactile allodynia, which is simply when touch becomes painful. You and I experienced this after small injury or sunburn where just touching your shoulder becomes painful, but for peripheral neuropathy and other neuropathic pain conditions, this is one of the major complaints that individuals have. And we know from the NIH studies that these individuals don't have this tactile allodynia. So touch becomes painful and doesn't apply to them, which tells us that if we block PIEZO2, we can actually get interesting relief from various aspects relative to neuropathic pain on other pain related neuropathies. But given everything we talked about, Eric, about how this is important for touch and proprioception, you don't want to make a pill that blocks PIEZO2 and you take it because this will have some serious on target side effects. But we are developing new compounds that block PIEZO2 and hope that it might be useful, at least as a topical medication pain and other indications. And we're actively working on this, as I said.Eric Topol (23:15):Yeah, I mean the topical one sounds like a winner because of peripheral neuropathy, but also I wonder if you could somehow target it to sick cells rather than if giving it in a systemic targeted way. I mean it has tremendous potential because we are on a serious hunt for much better relief of pain than exists today.Ardem Patapoutian (23:41):Absolutely.Eric Topol (23:42):Yeah. So that's exciting. I mean, that's another potential outgrowth of all this. Just going back, I mean the one that prompted me in November to write that about the human physiology in PIEZO, it was about intestinal stem cell fate decision and maintenance. I mean, it's just everywhere. But the work you've done certainly now has spurred on so many other groups to go after these different and many unanticipated functions. Were there any ones, of course, you've been pretty systematically addressing these that actually surprised you? You said, oh, are you kidding me when you read this? I never would've guessed this, or pretty much they followed suit as things were moving along.Ardem Patapoutian (24:33):So one of them is this role in macrophages that I found fascinating that we found a few years ago. So again, this came from human studies where PIEZO1 gain-of-function mutations. So in relation to loss of function, their gain-of-function where there's more activity given a certain amount of pressure. They have dehydrated red blood cells, which I'm not going to talk about right now. But they also have shown that in these patients, individuals, it's not really that pathological. They also have age-onset iron overload. What does that have to do with pressure sensing? And we brought that information into animal models, and we found that macrophages, their rate of phagocytosis depends on PIEZO, so that if you have too little PIEZO, they don't phagocytosis as much. If you have too much PIEZO, the phagocytosis too much. And this increased rate of phagocytosis in the long term because it's constantly eating red blood cells and the iron is circulating more causes long-term effects in iron overload. And again, as you kind of set that up, who would've thought that mechanical sensation is important for this basic hematology type?Eric Topol (25:52):Yeah, I mean, because we've been talking about the macro things, and here it is at the cellular level. I mean, it's just wild.Ardem Patapoutian (25:59):If you go back and look at a video of a macrophage eating up red blood cells, then you go, oh, I see how this has to do with pressure sensing because it is like extending little arms, feeling things letting go, going somewhere else. So again, I want to bring it back by this simple cell biological function of a cell type, like macrophage, exploring its environment is not just chemical, but very mechanical as well. And so, in retrospect, it is maybe not that surprising, that pressure sensing is important for its physiology.Career Changing?Eric Topol (26:33):Yeah, that's extraordinary. Well, that gets me to how your life has changed since 2021, because obviously this a big effect, big impact sort of thing. And I know that you're the first Armenian, first person from Lebanon to get this recognition. You recognized by the Lebanese Order of Merit. There's even a stamp of you, your picture characterized in 2022.Eric Topol (27:04):So if you were to sum up how it's changed because I see no change in you. You're the same person that has a great sense of humor. Often the tries to humor relaxed, calming. You haven't changed any to me, but how has it affected you?Ardem Patapoutian (27:26):Thank you, Eric. That's very kind of you. I try very hard for it not to change me. I do get a little bit more attention, a ton more invites, which unfortunately I have to say no to a lot of them because, and I'm sure you're very familiar with that concept and a lot of things are offered to you that I feel like it's so tempting to say yes because they're wonderful opportunities and an honor to be asked. But the end of the day, I'm trying to be very disciplined and not taking things on that I can do as an opportunity. But things that I really want to do. I think that's so hard to do sometimes is to separate those two. Why am I doing this? Is this really important for the goals that I have? So in one way, the answer for that is that I just want to stay in the lab and do my research with my students and postdoc, which is what I enjoy the most. But on the other hand, as you said, being the first Armenian who's received this, literally after the Nobel, I got this whole elementary school, all Armenian kids write to me multiple letters.Ardem Patapoutian (28:39):And they said, you look like me. I didn't think I could do this, but maybe I can. So in a sense, to ignore that and say, no, I just want to do my science, I don't want to be involved in any of that is also wrong. So I'm trying to balance being engaged in science outreach and helping to make science understood by the general public, realize that we're just regular people and at the same time how awesome science is. I love science and I like to project that, but leave plenty of time for me to just be a scientist and be in my lab and interact with my colleagues at Scripps, including you.Immigrant ScientistsEric Topol (29:21):Well, we're so lucky to have that chance. And I do want to mention, because you're prototyping in this regard about great immigrant scientists and other domains of course, but every year the Carnegie Foundation names these great immigrants and one year you were of course recognized. And in recent years, there have been more difficulties in people wanting to come to the US to get into science, and they wind up going to other places. It seems like that's a big loss for us. I mean, what if we weren't able to have had you come and so many hundreds, thousands of others that have contributed to this life science community? Maybe you could comment about that.Ardem Patapoutian (30:10):Yeah, I think it is tragic, as you say. I think in some circles, immigrants have this negative image or idea of what they bring, but at every level, immigrants have contributed so much to this country. It's a country of immigrants, of course, to start with. And I think it is important to put up a positive image of immigration and science is the ultimate example of that, right? I mean, I think when you go into any laboratory, you probably find if there's a lab of 16 people, you probably find people from 10 different countries. And we all work together. And the idea of also immigrant and especially about science is that I'm a big believer of changing field, changing things because just like that, immigrants have changed their whole life. So they come to a new culture, they bring with them their own way of thinking and their way of seeing things. And then you come into a new environment, and you see it a little bit differently. So that kind of change, whether it's because of physical immigration or immigrating from one field to another in science is really beneficial for science and society. And I think positive examples of this are an important part of highlighting this.Eric Topol (31:40):I couldn't agree with you more really.Bluesky vs Twitter/XEric Topol (31:41):Now, speaking of migration, there's been recently a big migration out of X, formerly Twitter to Bluesky, which I like the metaphor you liken to the Serengeti. Can you tell us about, now I know you're posting on Bluesky and of course so many others that you and I are mutual contacts, and our different networks are. What do you think about this migration outside of what was the platform where a lot of this, we shared things on X or before Musk took over known as Twitter? Thoughts about Bluesky?Ardem Patapoutian (32:27):Yeah, I think I use social media for a few reasons. The number one reason should be is to see new science by colleagues. My main point is that, but also, again, having fun in science is a big part of my draw to this. And as you can see from my posts, it's a bit lighthearted, and that's really me.Eric Topol (32:52):Right. Yeah.Ardem Patapoutian (32:52):I think on Twitter, things start getting a little bit dark and too many negative comments, and it was just not productive. And I just felt like after the elections, I felt like it was time to migrate. And I find Bluesky a great scientific community, and it's remarkable how quickly people have migrated from Twitter to Bluesky. But the counter argument for this is that you should stay in a place where majority of people are, because being in a bubble surrounding yourself by people like you doesn't help society. And so, I get that perspective as well. It just depends on what you're using the platform for and it's a difficult issue. But yeah, I've taken a break probably long-term break from Twitter. I'm on Bluesky now.Eric Topol (33:48):Yeah, no, the point you're bringing up about the echo chamber and is there going to be one for people that are leaning one way and they're thinking, and another with a whole different, often politically charged and even extreme views? It's really unfortunate if it does wind up that way. But right now, it seems like that migration is ongoing and it's substantial. And I guess we'll see how it settles out. I share your concern, and so far, I've been trying to keep a foot in both areas because I think if we all were to leave, then we're just kind of caving into a, it's tricky though. It really is because the noxious toxic type of comments, even when you try to avoid comments, you say, only followers can make a comment, they’ll of course, quote your thing and then try to ding you and whatever. It's just crazy stuff, really.Ardem Patapoutian (34:53):I mean, what I think is that, that's why I said depends on why. I mean, your presence on social media is such an important part of science education. And I could almost say you can't afford to do what I do, which is I'm just putting my goofy posts and having fun. So we have different purposes in a way, and yeah, that affects what you use and how you use it.Eric Topol (35:17):Yeah, no, it's tricky it really is. We covered a lot of ground. Is there anything I missed that you want to get out there? Any part of this, your story and the PIEZO story, science and everything else that I didn't bring up?The Essentiality of Basic ScienceArdem Patapoutian (35:42):I just think that the basic science community is really suffering from decreasing amounts of funding and appreciation of doing basic science. And one of my goals, in addition to this immigrant scientist thing, is to remind people that all medicines start with basic science work. And funding this has mainly been through NIH and it's getting harder and harder for basic scientists to secure funding and I'm really worried about this. And we need to find ways to be okay for people to do basic science. And I'll give you one example. Whenever we make a publication and there's a journalist talking to us or some kind of press coverage, they ask, how is this directly affecting patients? And my work actually is very much related to patients, and I answer that question, but I also say, but it's also important to do science for the science sake because you don't know where the applications are going to come from. And we need to, as a society, encourage and fund and support basic science as the seeds of all these translational work. And I think doing that just kind of highlights that this is important too. We should support it, not just things that right now seem very related to translational that directly helps patients.Eric Topol (37:16):Well, I'm so glad you emphasized that because I mean, the PIEZO story is the exemplar. Look what's come of it, what might still come of it. In many respects here you are maybe 15 years into the story and there's still many parts of this that are untold, but if it wasn't for the basic science, we wouldn't have these remarkable and diverse insights. And recently you cited, and I think so many people read about the ‘crown jewel’ NIH, front page New York Times, and how it's under threat because the new NIH director doesn't have a regard for basic science. He's actually, he's confirmed, which is likely, he's an economist, physician economist, never practiced medicine, but he doesn't really have a lot of regard for basic science. But as you point out, almost every drug that we have today came out of NIH basic work. And I mean, not just that, but all the disease insights and treatments and so much.Eric Topol (38:25):So this is really unfortunate if we have not just an NIH and other supporting foundations that don't see the priority, the fundamental aspect of basic science to then lead to, as we call translational, and then ultimately the way to promote human health, which is I think what we're all very much focused on ultimately. But you can't do it without getting to first base, and that's what you have done. You served it up and it's a great example. Well, Ardem, it's always a pleasure. This is a first time talking through a podcast. I hope we’ll have many, many visits informally that will complement the ones we've already had, and we will follow the PIEZO work. Obviously, you have had just an exceptional impact, but you're still young and who knows what's next, right? I mean, look what happened to Barry Sharpless. He won here. He won two Nobel prizes, so you never know where things are headed.Ardem Patapoutian (39:36):Thank you, Eric, and I really appreciate what you do for the biomedical community. I think it's wonderful through your social media and this podcast, we all appreciate it.***********************************************************************************Please take a moment to complete the poll above.Thank you for reading, listening and subscribing to Ground Truths.If you found this informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary and of course appreciated. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to each of them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.And Happy New Year! Get full access to Ground Truths at erictopol.substack.com/subscribe

American healthcare is well known for its extreme cost and worst outcomes among industrialized (such as the 38 OECD member) countries, and beyond that to be remarkably opaque. The high cost of prescription drugs contributes, and little has been done to change that except for the government passing the Affordable Insulin Now Act at the end of 2022, enacted in 2023. But in January 2022 Mark Cuban launched Cost Plus Drugs that has transformed how many Americans can get their prescriptions filled at a fraction of the prevailing prices, bypassing pharmacy benefit managers (PBMs) that control 80% of US prescriptions. That was just the beginning of a path of creative destruction (disruptive innovation, after Schumpeter) of many key components American healthcare that Cuban is leading, with Cost Plus Marketplace, Cost Plus Wellness and much more to come. He certainly qualifies as a master disrupter: “someone who is a leader in innovation and is not afraid to challenge the status quo.” Below is a video clip from our conversation dealing with insurance companies. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Transcript with External links to Audio (00:07):Hello, it's Eric Topol with Ground Truths, and I have our special phenomenal guest today, Mark Cuban, who I think you know him from his tech world contributions and Dallas Mavericks, and the last few years he's been shaking up healthcare with Cost Plus Drugs. So Mark, welcome.Mark Cuban (00:25):Thanks for having me, Eric.Eric Topol (00:27):Yeah, I mean, what you're doing, you’ve become a hero to millions of Americans getting them their medications at a fraction of the cost they're used to. And you are really challenging the PBM industry, which I've delved into more than ever, just in prep for our conversation. It's just amazing what this group of companies, namely the three big three CVS Caremark, Optum of UnitedHealth and Express Scripts of Cigna with a market of almost $600 billion this year, what they're doing, how can they get away with all this stuff?Inner Workings of Pharmacy Benefit ManagersMark Cuban (01:03):I mean, they're just doing business. I really don't blame them. I blame the people who contract with them. All the companies, particularly the bigger companies, the self-insured companies, where the CEO really doesn't have an understanding of their healthcare or pharmacy benefits. And so, the big PBMs paid them rebates, which they think is great if you're a CEO, when in reality it's really just a loan against the money spent by your sickest employees, and they just don't understand that. So a big part of my time these days is going to CEOs and sitting with them and explaining to them that you're getting ripped off on both your pharmacy and your healthcare side.Eric Topol (01:47):Yeah, it's amazing to me the many ways that they get away with this. I mean, they make companies sign NDAs. They're addicted to rebates. They have all sorts of ways a channel of funds to themselves. I mean, all the things you could think of whereby they even have these GPOs. Each of these companies has a group purchasing organization (I summarized in the Table below).Mark Cuban (02:12):Yeah, which gives them, it's crazy because with those GPOs. The GPO does the deal with the pharmacy manufacturer. Then the GPO also does the deal with the PBM, and then the PBM goes to the self-insured employer in particular and says, hey, we're going to pass through all the rebates. But what they don't say is they've already skimmed off 5%, 10%, 20% or more off the top through their GPO. But that's not even the worst of it. That's just money, right? I mean, that's important, but I mean, even the biggest companies rarely own their own claims data.Mark Cuban (02:45):Now think about what that means. It means you can't get smarter about the wellness of your employees and their families. You want to figure out the best way to do GLP-1s and figure out how to reduce diabetes, whatever it may be. You don't have that claims data. And then they don't allow the companies to control their own formularies. So we've seen Humira biosimilars come out and the big PBMs have done their own version of the biosimilar where we have a product called Yusimry, which is only $594 a month, which is cheaper than the cheapest biosimilar that the big three are selling. And so, you would think in a normal relationship, they would want to bring on this new product to help the employer. No, they won't do it. If the employer asks, can I just add Cost Plus Drugs to my network? They'll say no, every single time.Mark Cuban (03:45):Their job is not to save the employer money, particularly after they've given a rebate. Because once they give that loan, that rebate to the employer, they need to get that money back. It's not a gift. It's a loan and they need to have the rebates, and we don't do rebates with them at all. And I can go down the list. They don't control the formula. They don't control, you mentioned the NDAs. They can't talk to manufacturers, so they can't go to Novo or to Lilly and say, let's put together a GLP-1 wellness program. All these different things that just are common sense. It's not happening. And so, the good news is when I walk into these companies that self-insured and talk to the CEO or CFO, I'm not asking them to do something that's not in their best interest or not in the best interest of the lives they cover. I'm saying, we can save you money and you can improve the wellness of your employees and their families. Where's the downside?Eric Topol (04:40):Oh, yeah. Yeah. And the reason they can't see the claims is because of the privacy issues?Mark Cuban (04:46):No, no. That's just a business decision in the contract that the PBMs have made. You can go and ask. I mean, you have every right to your own claims. You don't need to have it personally identified. You want to find out how many people have GLP-1s or what are the trends, or God forbid there's another Purdue Pharma thing going on, and someone prescribing lots of opioids. You want to be able to see those things, but they won't do it. And that's only on the sponsor side. It's almost as bad if not worse on the manufacturer side.Eric Topol (05:20):Oh, yeah. Well, some of the work of PBMs that you've been talking about were well chronicled in the New York Times, a couple of major articles by Reed Abelson and Rebecca Robbins: The Opaque Industry Secretly Inflating Prices for Prescription Drugs and The Powerful Companies Driving Local Drugstores Out of Business. We'll link those because I think some people are not aware of all the things that are going on in the background.Mark Cuban (05:39):You see in their study and what they reported on the big PBMs, it's crazy the way it works. And literally if there was transparency, like Cost Plus offers, the cost of medications across the country could come down 20%, 30% or more.Cost Plus DrugsEric Topol (05:55):Oh, I mean, it is amazing, really. And now let's get into Cost Plus. I know that a radiologist, Alex Oshmyansky contacted you with a cold email a little over three years ago, and you formed Cost Plus Drugs on the basis of that, right?Mark Cuban (06:12):Yep, that's exactly what happened.Eric Topol (06:15):I give you credit for responding to cold emails and coming up with a brilliant idea with this and getting behind it and putting your name behind it. And what you've done, so you started out with something like 110 generics and now you're up well over 1,200 or 2,500 or something like that?Mark Cuban (06:30):And adding brands. And so, started with 111. Now we're around 2,500 and trying to grow it every single day. And not only that, just to give people an overview. When you go to www.costplusdrugs.com and you put in the name of your medication, let's just say it's tadalafil, and if it comes up. In this case, it will. It'll show you our actual cost, and then we just mark it up 15%. It's the same markup for everybody, and if you want it, we'll have a pharmacist check it. And so, that's a $5 fee. And then if you want ship to mail order, it's $5 for shipping. And if you want to use our pharmacy network, then we can connect you there and you can just pick it up at a local pharmacy.Eric Topol (07:10):Yeah, no, it's transparency. We don't have a lot of that in healthcare in America, right?Mark Cuban (07:15):No. And literally, Eric, the smartest thing that we did, and we didn't expect this, it's always the law of unintended consequences. The smartest thing we did was publish our entire price list because that allowed any company, any sponsor, CMS, researchers to compare our prices to what others were already paying. And we've seen studies come out saying, for this X number of urology drugs, CMS would save $3.6 billion a year. For this number of heart drugs at this amount per year, for chemotherapy drugs or MS drugs this amount. And so, it's really brought attention to the fact that for what PBMs call specialty drugs, whether there's nothing special about them, we can save people a lot of money.Eric Topol (08:01):It's phenomenal. As a cardiologist, I looked up a couple of the drugs that I'm most frequently prescribed, just like Rosuvastatin what went down from $134 to $5.67 cents or Valsartan it went down from $69 to $7.40 cents. But of course, there's some that are much more dramatic, like as you mentioned, whether it's drugs for multiple sclerosis, the prostate cancer. I mean, some of these are just thousands and thousands of dollars per month that are saved, brought down to levels that you wouldn't think would even be conceivable. And this has been zero marketing, right?Mark Cuban (08:42):Yeah, none. It's all been word of mouth and my big mouth, of course. Going out there and doing interviews like this and going to major media, but it's amazing. We get emails and letters and people coming up to us almost single day saying, you saved my grandma's life. You saved my life. We weren't going to be able to afford our imatinib or our MS medication. And it went from being quoted $2,000 a month to $33 a month. It's just insane things like that that are still happening.Eric Topol (09:11):Well, this is certainly one of the biggest shakeups to occur in US healthcare in years. And what you've done in three years is just extraordinary. This healthcare in this country is with its over 4 trillion, pushing $5 trillion a year of expenditure.[New CMS report this week pegs the number at $4.867 trillion for 2023]Mark Cuban (09:30):It's interesting. I think it's really fixable. This has been the easiest industry to the disrupt I've ever been involved in. And it's not even close because all it took was transparency and not jacking up margins to market. We choose to use a fixed margin markup. Some choose to price to market, the Martin Shkreli approach, if you will. And just by being transparent, we've had an impact. And the other side of it is, it's the same concept on the healthcare side. Transparency helps, but to go a little field of pharmacy if you want. The insane part, and this applies to care and pharmacy, whatever plan we have, whether it's for health or whether it's for pharmaceuticals, there's typically a deductible, typically a copay, and typically a co-insurance.Insurance CompaniesMark Cuban (10:20):The crazy part of all that is that people taking the default risk, the credit risk are the providers. It's you, it's the hospital, it's the clinics that you work for. Which makes no sense whatsoever that the decisions that you or I make for our personal insurance or for the companies we run, or if we work for the government, what we do with Medicare or Medicare Advantage, the decisions we all make impacts the viability of providers starting with the biggest hospital systems. And so, as a result, they become subprime lenders without a car or a house to go after if they can't collect. And so, now you see a bunch of people, particularly those under the ACA with the $9,000, the bronze plans or $18,000 out-of-pocket limits go into debt, significant medical debt. And it's unfortunate. We look at the people who are facing these problems and think, well, it must be the insurance companies.Mark Cuban (11:23):It's actually not even the insurance companies. It's the overall design of the system. But underneath that, it's still whoever picks the insurance companies and sets plans that allow those deductibles, that's the core of the problem. And until we get to a system where the providers aren't responsible for the credit for defaults and dealing with all that credit risk, it's almost going to be impossible to change. Because when you see stories like we've all seen in news of a big healthcare, a BUCA healthcare (Blue Cross Blue Shield (BCBS), UnitedHealth, Cigna, and Aetna/CVS) plan with all the pre-authorizations and denials, typically they're not even taking the insurance risk. They're acting as the TPA (third party administrator) as the claims processor effectively for whoever hired them. And it goes back again, just like I talked about before. And as long as CMS hires or allows or accepts these BUCAs with these plans for Medicare for the ACA (Affordable care Act), whatever it may be, it's not going to work. As long as self-insured employers and the 50 million lives they cover hire these BUCAs to act as the TPAs, not as insurance companies and give them leeway on what to approve and what to authorize and what not to authorize. The system's going to be a mess, and that's where we are today.Academic Health System PartnershipsEric Topol (12:41):Yeah. Well, you've been talking of course to employers and enlightening them, and you're also enlightening the public, of course. That's why you have millions of people that are saving their cost of medications, but recently you struck a partnership with Penn Medicine. That's amazing. So is that your first academic health system that you approached?Cost Plus MarketplaceMark Cuban (13:00):I don't know if it was the first we approached, but it was certainly one of the biggest that we signed. We've got Cost Plus Marketplace (CPM) where we make everything from injectables to you name it, anything a hospital might buy. But again, at a finite markup, we make eight and a half percent I think when it's all said and done. And that saves hospital systems millions of dollars a year.Eric Topol (13:24):Yeah. So that's a big change in the way you're proceeding because what it was just pills that you were buying from the pharma companies, now you're actually going to make injectables and you're going to have a manufacturing capability. Is that already up and going?Mark Cuban (13:39):That's all up and going as of March. We're taking sterile injectables that are on the shortage list, generic and manufacturing them in Dallas using a whole robotics manufacturing plant that really Alex created. He's the rocket scientist behind it. And we’re limited in capacity now, we're limited about 2 million vials, but we'll sell those to Cost Plus Marketplace, and we'll also sell those direct. So Cost Plus Marketplace isn't just the things we manufacture. It's a wide variety of products that hospitals buy that we then have a minimal markup, and then for the stuff we manufacture, we'll sell those to direct to like CHS was our first customer.Eric Topol (14:20):Yeah, that's a big expansion from going from the pills to this. Wow.Mark Cuban (14:24):It's a big, big expansion, but it goes to the heart of being transparent and not being greedy, selling on a markup. And ourselves as a company, being able to remain lean and mean. The only way we can sell at such a low markup. We have 20 employees on the Cost Plus side and 40 employees involved with the factories, and that's it.Eric Topol (14:46):Wow. So with respect to, you had this phenomenal article and interview with WIRED Magazine just this past week. I know Lauren Goode interviewed you, and she said, Mark, is this really altruistic and I love your response. You said, “how much f*****g money do I need? I'm not trying to land on Mars.” And then you said, “at this point in my life, it’s just like more money, or f**k up the healthcare industry.” This was the greatest, Mark. I mean, I got to tell you, it was really something.Mark Cuban (15:18):Yeah.Eric Topol (15:19):Well, in speaking of that, of course, the allusion to a person we know well, Elon. He posted on X/Twitter in recent days , I think just three or four days ago, shouldn't the American people be getting their money's worth? About this high healthcare administration costs where the US is completely away from any other OECD country. And as you and I know, we have the worst outcomes and the most costs of all the rich countries in the world. There's just nothing new here. Maybe it's new to him, but you had a fabulous response on both X and Bluesky where you went over all these things point by point. And of course, the whole efforts that you've been working on now for three years. You also mentioned something that was really interesting that I didn't know about were these ERISA lawsuits[Employee Retirement Income Security Act (ERISA) of 1974.] Can you tell us about that?ERISA LawsuitsMark Cuban (16:13):Yeah, that's a great question, Eric. So for self-insured companies in particular, we have a fiduciary responsibility on a wellness and on a financial basis to offer the members, your employees and their families the best outcomes at the best price. Now, you can't guarantee best outcomes, but you have to be able to explain the choices you made. You don't have to pick the cheapest, but again, you have to be able to explain why you made the choices that you did. And because a lot of companies have been doing, just like we discussed earlier, doing deals on the pharmacy side with just these big PBMs, without accounting for best practices, best price, best outcomes, a couple companies got sued. Johnson and Johnson and Wells Fargo were the first to get sued. And I think that's just the beginning. That's just the writing on the wall. I think they'll lose because they just dealt with the big pharmacy PBMs. And I think that's one of the reasons why we're so busy at Cost Plus and why I'm so busy because we're having conversation after conversation with companies and plenty of enough lawyers for that matter who want to see a price list and be able to compare what they're paying to what we sell for to see if they're truly living up to that responsibility.Eric Topol (17:28):Yeah, no, that's a really important thing that's going on right now that I think a lot of people don't know about. Now, the government of the US think because it's the only government of any rich country in the world, if not any country that doesn't negotiate prices, i.e., CMS or whatever. And only with the recent work of insulin, which is a single one drug, was there reduction of price. And of course, it's years before we'll see other drugs. How could this country not negotiate drugs all these years where every other place in the world they do negotiate with pharma?Mark Cuban (18:05):Because as we alluded to earlier, the first line in every single pharmaceutical and healthcare contract says, you can't talk about this contract. It’s like fight club. The number one rule of fight club is you can't talk about fight club, and it's really difficult to negotiate prices when it's opaque and everything's obfuscated where you can't really get into the details. So it's not that we're not capable of it, but it's just when there's no data there, it's really difficult because look, up until we started publishing our prices, how would anybody know?Mark Cuban (18:39):I mean, how was anybody going to compare numbers? And so, when the government or whoever started to negotiate, they tried to protect themselves and they tried to get data, but those big PBMs certainly have not been forthcoming. We’ve come along and publish our price list and all that starts to change. Now in terms of the bigger picture, there is a solution there, as I said earlier, but it really comes down to talking to the people who make the decisions to hire the big insurance companies and the big PBMs and telling them, no, you're not acting in your own best interest. Here's anybody watching out there. Ask your PBM if they can audit. If you can audit rather your PBM contract. What they'll tell you is, yeah, you can, but you have to use our people. It's insane. And that's from top to bottom. And so, I'm a big believer that if we can get starting with self-insured employers to act in their own best interest, and instead of working with a big PBM work with a pass-through PBM. A pass-through PBM will allow you to keep your own claims, own all your own data, allow you to control your own formulary.Mark Cuban (19:54):You make changes where necessary, no NDA, so you can't talk to manufacturers. All these different abilities that just seem to make perfect sense are available to all self-insured employers. And if the government, same thing. If the government requires pass-through PBMs, the price of medications will drop like a rock.Eric Topol (20:16):Is that possible? You think that could happen?Mark Cuban (20:19):Yes. Somebody's got to understand it and do it. I'm out there screaming, but we will see what happens with the new administration. There's nothing hard about it. And it's the same thing with Medicare and Medicare Advantage healthcare plans. There's nothing that says you have to use the biggest companies. Now, the insurance companies have to apply and get approved, but again, there's a path there to work with companies that can reduce costs and improve outcomes. The biggest challenge in my mind, and I'm still trying to work through this to fully understand it. I think where we really get turned upside down as a country is we try to avoid fraud from the provider perspective and the patient perspective. We're terrified that patients are going to use too much healthcare, and like everybody's got Munchausen disease.Mark Cuban (21:11):And we're terrified that the providers are going to charge too much or turn into Purdue Pharma and over-prescribe or one of these surgery mills that just is having somebody get surgery just so they can make money. So in an effort to avoid those things, we ask the insurance companies and the PBMs to do pre-authorizations, and that's the catch 22. How do we find a better way to deal with fraud at the patient and provider level? Because once we can do that, and maybe it's AI, maybe it's accepting fraud, maybe it's imposing criminal penalties if somebody does those things. But once we can overcome that, then it becomes very transactional. Because the reality is most insurance companies aren't insurance companies. 50 million lives are covered by self-insured employers that use the BUCAs, the big insurance companies, but not as insurance companies.Eric Topol (22:07):Yeah, I was going to ask you about that because if you look at these three big PBMs that control about 80% of the market, not the pass-throughs that you just mentioned, but the big ones, they each are owned by an insurance company. And so, when the employer says, okay, we're going to cover your healthcare stuff here, we're going to cover your prescriptions there.Mark Cuban (22:28):Yeah, it's all vertically integrated.Mark Cuban (22:36):And it gets even worse than that, Eric. So they also own specialty pharmacies, “specialty pharmacies” that will require you to buy from. And as I alluded to earlier, a lot of these medications like Imatinib, they'll list as being a specialty medication, but it's a pill. There's nothing special about it, but it allows them to charge a premium. And that's a big part of how the PBMs make a lot of their money, the GPO stuff we talked about, but also forcing an employer to go through the specialty mail order company that charges an arm and the leg.Impact on Hospitals and ProceduresEric Topol (23:09):Yeah. Well, and the point you made about transparency, we've seen this of course across US healthcare. So for example, as you know, if you were to look at what does it cost to have an operation like let's say a knee replacement at various hospitals, you can find that it could range fivefold. Of course, you actually get the cost, and it could be the hospital cost, and then there's the professional cost. And the same thing occurs for if you're having a scan, if you're having an MRI here or there. So these are also this lack of transparency and it's hard to get to the numbers, of course. There seems to be so many other parallels to the PBM story. Would you go to these other areas you think in the future?Mark Cuban (23:53):Yeah, we're doing it now. I'm doing it. So we have this thing called project dog food, and what it is, it's for my companies and what we've done is say, look, let's understand how the money works in healthcare.Mark Cuban (24:05):And when you think about it, when you go to get that knee done, what happens? Well, they go to your insurance company to get a pre-authorization. Your doctor says you need a knee replacement. I got both my hips replaced. Let's use that. Doctor says, Mark, you need your hips replaced. Great, right? Let's set up an appointment. Well, first the insurance company has to authorize it, okay, they do or they don't, but the doctor eats their time up trying to deal with the pre-authorization. And if it's denied, the doctor's time is eaten up and an assistance's time is eaten up. Some other administrator's time is eaten up, the employer's time is eaten up. So that's one significant cost. And then from there, there's a deductible. Now I can afford my deductible, but if there is an individual getting that hip replacement who can't afford the deductible, now all of a sudden you're still going to be required to do that hip replacement, most likely.Mark Cuban (25:00):Because in most of these contracts that self-insured employers sign, Medicare Advantage has, Medicare has, it says that between the insurance company and the provider, in this case, the hospital, you have to do the operation even if the deductibles not paid. So now the point of all this is you have the hospital in this case potentially accumulating who knows how much bad debt. And it's not just the lost amount of millions and millions and billions across the entire healthcare spectrum that's there. It's all the incremental administrative costs. The lawyers, the benefits for those people, the real estate, the desk, the office space, all that stuff adds up to $10 billion plus just because the hospitals take on that credit default risk. But wait, there's more. So now the surgery happens, you send the bill to the insurance company. The insurance company says, well, we're not going to pay you. Well, we have a contract. This is what it says, hip replacement's $34,000. Well, we don't care first, we're going to wait. So we get the time value of money, and then we're going to short pay you.Mark Cuban (26:11):So the hospital gets short paid. So what do they have to do? They have to sue them or send letters or whatever it is to try to get their money. When we talk to the big hospital systems, they say that's 2%. That's 2% of their revenue. So you have all these associated credit loss dollars, you've got the 2% of, in a lot of cases, billions and billions of dollars. And so, when you add all those things up, what happens? Well, what happens is because the providers are losing all that money and having to spend all those incremental dollars for the administration of all that, they have to jack up prices.Eric Topol (26:51):Yeah. Right.Mark Cuban (26:53):So what we have done, we've said, look for my companies, we're going to pay you cash. We're going to pay you cash day one. When Mark gets that hip replacement, that checks in the bank before the operation starts, if that's the way you want it. Great, they're not going to have pre-authorizations. We're going to trust you until you give us a reason not to trust you. We're not short paying, obviously, because we're paying cash right there then.Mark Cuban (27:19):But in a response for all that, because we're cutting out all those ancillary costs and credit risk, I want Medicare pricing. Now the initial response is, well, Medicare prices, that's awful. We can't do it. Well, when you really think about the cost and operating costs of a hospital, it's not the doctors, it's not the facilities, it's all the administration that cost all the money. It's all the credit risks that cost all the money. And so, if you remove that credit risk and all the administration, all those people, all that real estate, all those benefits and overhead associated with them, now all of a sudden selling at a Medicare price for that hip replacement is really profitable.Eric Topol (28:03):Now, is that a new entity Cost Plus healthcare?Mark Cuban (28:07):Well, it's called Cost Plus Wellness. It's not an entity. What we're going to do, so the part I didn't mention is all the direct contracts that we do that have all these pieces, as part of them that I just mentioned, we're going to publish them.Eric Topol (28:22):Ah, okay.Mark Cuban (28:23):And you can see exactly what we've done. And if you think about the real role of the big insurances companies for hospitals, it's a sales funnel.Getting Rid of Insurance CompaniesEric Topol (28:33):Yeah, yeah. Well, in fact, I really was intrigued because you did a podcast interview with Andrew Beam and the New England Journal of Medicine AI, and in that they talked about getting rid of the insurers, the insurance industry, just getting rid of it and just make it a means test for people. So it's not universal healthcare, it's a different model that you described. Can you go over that? I thought it was fantastic.Mark Cuban (29:00):Two pieces there. Let's talk about universal healthcare first. So for my companies, for our project dog food for the Mark Cuban companies, if for any employee or any of the lives we cover, if they work within network, anybody we have the direct contract with its single-payer. They pay their premiums, but they pay nothing else out of pocket. That's the definition of single-payer.Eric Topol (29:24):Yeah.Mark Cuban (29:25):So if we can get all this done, then the initial single-payers will be self-insured employers because it'll be more cost effective to them to do this approach. We hope, we still have to play it all through. So that's part one. In terms of everybody else, then you can say, why do we need insurance companies if they're not even truly acting as insurance companies? You're not taking full risk because even if it's Medicare Advantage, they're getting a capitated amount per month. And then that's getting risk adjusted because of the population you have, and then there's also an index depending on the location, so there's more or less money that occurs then. So let's just do what we need to do in this particular case, because the government is effectively eliminating the risk for the insurance company for the most part. And if you look at the margins for Medicare Advantage, I was just reading yesterday, it's like $1,700 a year for the average Medicare Advantage plan. So it's not like they're taking a lot of risk. All they're doing is trying to deny as many claims as they can.Eric Topol (30:35):Deny, Deny. Yeah.Mark Cuban (30:37):So instead, let's just get somebody who's a TPA, somebody who does the transaction, the claims processing, and whoever's in charge. It could be CMS, can set the terms for what's accepted and what's denied, and you can have a procedure for people that get denied that want to challenge it. And that's great, there's one in place now, but you make it a little simpler. But you take out the economics for the insurance company to just deny, deny, deny. There's no capitation. There's no nothing.Mark Cuban (31:10):The government just says, okay, we're hiring this TPA to handle the claims processing. It is your job. We're paying you per transaction.Mark Cuban (31:18):You don't get paid more if you deny. You don't get paid less if you deny. There's no bonuses if you keep it under a certain amount, there's no penalties If you go above a certain amount. We want you just to make sure that the patient involved is getting the best care, end of story. And if there's fraud involved as the government, because we have access to all that claims data, we're going to introduce AI that reviews that continuously.Mark Cuban (31:44):So that we can see things that are outliers or things that we question, and there's going to mean mistakes, but the bet was, if you will, where we save more and get better outcomes that way versus the current system and I think we will. Now, what ends up happening on top of that, once you have all that claims data and all that information and everybody's interest is aligned, best care at the best price, no denials unless it's necessary, reduce and eliminate fraud. Once everybody's in alignment, then as long as that's transparent. If the city of Dallas decides for all the lives they cover the 300,000 lives they cover between pharmacy and healthcare, we can usually in actuarial tables and some statistical analysis, we can say, you know what, even with a 15% tolerance, it's cheaper for us just to pay upfront and do this single-pay program, all our employees in the lives we cover, because we know what it's going to take.Mark Cuban (32:45):If the government decides, well, instead of Medicare Advantage the way it was, we know all the costs. Now we can say for all Medicare patients, we'll do Medicare for all, simply because we have definitive and deterministic pricing. Great. Now, there's still going to be outlier issues like all the therapies that cost a million dollars or whatever. But my attitude there is if CMS goes to Lilly, Novo, whoever for their cure for blindness that's $3.4 million. Well, that's great, but what we'll say is, okay, give us access to your books. We want to know what your breakeven point is. What is that breakeven point annually? We'll write you a check for that.Eric Topol (33:26):Yeah.Mark Cuban (33:27):If we have fewer patients than need that, okay, you win. If we have more patients than need that, it's like a Netflix subscription with unlimited subscribers, then we will have whatever it is, because then the manufacturer doesn't lose money, so they can't complain about R&D and not being able to make money. And that's for the CMS covered population. You can do a Netflix type subscription for self-insured employers. Hey, it's 25 cents per month per employee or per life covered for the life of the patent, and we'll commit to that. And so, now all of a sudden you get to a point where healthcare starts becoming not only transparent but deterministic.Eric Topol (34:08):Yeah. What you outline here in these themes are extraordinary. And one of the other issues that you are really advocating is patient empowerment, but one of the problems we have in the US is that people don't own their data. They don't even have all their data. I expect you'd be a champion of that as well.Mark Cuban (34:27):Well, of course. Yeah. I mean, look, I've got into arguments with doctors and public health officials about things like getting your own blood tested. I've been an advocate of getting my own blood tested for 15 years, and it helped me find out that I needed thyroid medication and all of these things. So I'm a big advocate. There's some people that think that too much data gives you a lot of false positives, and people get excited in this day and age to get more care when it should only be done if there are symptoms. I'm not a believer in that at all. I think now, particularly as AI becomes more applicable and available, you'll be able to be smarter about the data you capture. And that was always my final argument. Either you trust doctors, or you don't. Because even if there's an aberrational TSH reading and minus 4.4 and it's a little bit high, well the doctor's going to say, well, let's do another blood test in a month or two. The doctor is still the one that has to write the prescription. There's no downside to trusting your doctor in my mind.Eric Topol (35:32):And what you're bringing up is that we're already seeing how AI can pick up things even in the normal range, the trends long before a clinician physician would pick it up. Now, last thing I want to say is you are re-imagining healthcare like no one. I mean, there's what you're doing here. It started with some pills and it's going in a lot of different directions. You are rocking it here. I didn't even know some of the latest things that you're up to. This seems to be the biggest thing you've ever done.Mark Cuban (36:00):I hope so.Mark Cuban (36:01):I mean, like we said earlier, what could be better than people saying our healthcare system is good. What changed? That Cuban guy.Eric Topol (36:10):Well, did you give up Shark Tank so you could put more energy into this?Mark Cuban (36:16):Not really. It was more for my kids.Eric Topol (36:19):Okay, okay.Mark Cuban (36:20):They go hand in hand, obviously. I can do this stuff at home as opposed to sitting on a set wondering if I should invest in Dude Wipes again.Eric Topol (36:28):Well, look, we're cheering for you. This is, I've not seen a shakeup in my life in American healthcare like this. You are just rocking. It's fantastic.Mark Cuban (36:37):Everybody out there that's watching, check out www.costplusdrugs.com, check out Cost Plus Marketplace, which is business.costplusdrugs.com and just audit everything. What I'm trying to do is say, okay, if it's 1955 and we're starting healthcare all over again, how would we do it? And really just keep it simple. Look to where the risk is and remove the risk where possible. And then it comes down to who do you trust and make sure you trust but verify. Making sure there aren't doctors or systems that are outliers and making sure that there aren't companies that are outliers or patients rather that are outliers. And so, I think there's a path there. It's not nearly as difficult, it's just starting them with corporations, getting those CEOs to get educated and act in their own best interest.Eric Topol (37:32):Well, you're showing us the way. No question. So thanks so much for joining, and we'll be following this with really deep interest because you're moving at high velocity, and thank you.**************************************************Thank you for reading, listening and subscribing to Ground Truths.If you found this fun and informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to each of them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.FootnoteThe PBMS (finally) are under fire—2 articles from the past week Get full access to Ground Truths at erictopol.substack.com/subscribe

A leader for conducting rigorous randomized trials of humans along with animal models for understanding nutrition and metabolism, Dr. Kevin Hall is a Senior Investigator at the National Institutes of Health, and Section Chief of the Integrative Physiology Section, NIDDK. In this podcast, we reviewed his prolific body of research a recent publications. The timing of optimizing our diet and nutrition seems apropos, now that we’re in in the midst of the holiday season!Below is a video snippet of our conversation on his ultra-processed food randomized trial.Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Note: I’ll be doing a Ground Truths Live Chat on December 11th at 12 N EST, 9 AM PST, so please mark your calendar and join!Transcript with links to publications and audioEric Topol (00:05):Well, hello. This is Eric Topol with Ground Truths, and I'm really delighted to have with me today, Dr. Kevin Hall from the NIH. I think everybody knows that nutrition is so important and Kevin is a leader in doing rigorous randomized trials, which is not like what we usually see with large epidemiologic studies of nutrition that rely on food diaries and the memory of participants. So Kevin, it's really terrific to have you here.Kevin Hall (00:34):Thanks so much for the invitation.Ultra-Processed FoodsEric Topol (00:36):Yeah. Well, you've been prolific and certainly one of the leaders in nutrition science who I look to. And what I thought we could do is go through some of your seminal papers. There are many, but I picked a few and I thought we'd first go back to the one that you published in Cell Metabolism. This is ultra-processed diets cause excessive caloric intake and weight gain. (Main results in graph below.) So maybe you can take us through the principle findings from that trial.Kevin Hall (01:10):Yeah, sure. So that was a really interesting study because it's the first randomized control trial that's investigated the role of ultra-processed foods in potentially causing obesity. So we've got, as you mentioned, lots and lots of epidemiological data that have made these associations between people who consume diets that are very high in ultra-processed foods as having greater risk for obesity. But those trials are not demonstrating causation. I mean, they suggest a strong link. And in fact, the idea of ultra-processed foods is kind of a new idea. It's really sort of appeared on the nutrition science stage probably most prominently in the past 10 years or so. And I first learned about this idea of ultra-processed foods, which is really kind of antithetical to the way most nutrition scientists think about foods. We often think about foods as nutrient delivery vehicles, and we kind of view foods as being the fraction of carbohydrates versus fats in them or how much sodium or fiber is in the foods.Kevin Hall (02:17):And along came this group in Brazil who introduced this new way of classifying foods that completely ignores the nutrient composition and says what we should be doing is classifying foods based on the extent and purpose of processing of foods. And so, they categorize these four different categories. And in the fourth category of this so-called NOVA classification scheme (see graphic below) , they identified something called ultra-processed foods. There's a long formal definition and it's evolved a little bit over the years and continues to evolve. But the basic ideas that these are foods that are manufactured by industries that contain a lot of purified ingredients made from relatively cheap agricultural commodity products that basically undergo a variety of processes and include additives and ingredients that are not typically found in home kitchens, but are typically exclusively in manufactured products to create the wide variety of mostly packaged goods that we see in our supermarkets.Kevin Hall (03:22):And so, I was really skeptical that there was much more about the effects of these foods. Other than that they typically have high amounts of sugar and saturated fat and salt, and they're pretty low in fiber. And so, the purpose of this study was to say, okay, well if there's something more about the foods themselves that is causing people to overconsume calories and gain weight and eventually get obesity, then we should do a study that's trying to test for two diets that are matched for these various nutrients of concern. So they should be matched for the macronutrients, they should be matched for the sugar content, the fat, the sodium, the fiber, and people should just be allowed to eat whatever they want and they shouldn't be trying to change their weight in any way. And so, the way that we did this was, as you mentioned, we can't just ask people to report what they're eating.Kevin Hall (04:19):So what we did was we admitted these folks to the NIH Clinical Center and to our metabolic ward, and it's a very artificial environment, but it's an environment that we can control very carefully. And so, what we basically did is take control over their food environment and we gave them three meals a day and snacks, and basically for a two-week period, they had access to meals that were more than 80% of calories coming from ultra-processed foods. And then in random order, they either received that diet first and give them simple instructions, eat as much as little as you want. We're going to measure lots of stuff. You shouldn't be trying to change your weight or weight that gave them a diet that had no calories from ultra-processed foods. In fact, 80% from minimally processed foods. But again, both of these two sort of food environments were matched for these nutrients that we typically think of as playing a major role in how many calories people choose to eat.Kevin Hall (05:13):And so, the basic idea was, okay, well let's measure what these folks eat. We gave them more than double the calories that they would require to maintain their weight, and what they didn't know was that in the basement of the clinical center where the metabolic kitchen is, we had all of our really talented nutrition staff measuring the leftovers to see what it was that they didn't eat. So we knew exactly what we provided to them and all the foods had to be in our nutrition database and when we compute what they actually ate by difference, so we have a very precise estimate about not only what foods they chose to ate, but also how many calories they chose to eat, as well as the nutrient composition.And the main upshot of all that was that when these folks were exposed to this highly ultra-processed food environment, they spontaneously chose to eat about 500 calories per day more over the two-week period they were in that environment then when the same folks were in the environment that had no ultra-processed foods, but just minimally processed foods. They not surprisingly gained weight during the ultra-processed food environment and lost weight and lost body fat during the minimally processed food environment. And because those diets were overall matched for these different nutrients, it didn't seem to be that those were the things that were driving this big effect. So I think there's a couple of big take homes here. One is that the food environment really does have a profound effect on just the biology of how our food intake is controlled at least over relatively short periods of time, like the two-week periods that we were looking at. And secondly, that there's something about ultra-processed foods that seem to be driving this excess calorie intake that we now know has been linked with increased risk of obesity, and now we're starting to put some of the causal pieces together that really there might be something in this ultra-processed food environment that's driving the increased rates of obesity that we've seen over the past many decades.Eric Topol (07:18):Yeah, I mean I think the epidemiologic studies that make the link between ultra-processed foods and higher risk of cancer, cardiovascular disease, type 2 diabetes, neurodegenerative disease. They're pretty darn strong and they're backed up by this very rigorous study. Now you mentioned it short term, do you have any reason to think that adding 500 calories a day by eating these bad foods, which by the way in the American diet is about 60% or more of the average American diet, do you have any inkling that it would change after a few weeks?Kevin Hall (07:54):Well, I don't know about after a few weeks, but I think that one of the things that we do know about body weight regulation and how it changes in body weight impact both metabolism, how many calories were burning as well as our appetite. We would expect some degree of moderation of that effect eventually settling in at a new steady state, that's probably going to take months and years to achieve. And so the question is, I certainly don't believe that it would be a 500 calorie a day difference indefinitely. The question is when would that difference converge and how much weight would've been gained or lost when people eventually reached that new plateau? And so, that's I think a really interesting question. Some folks have suggested that maybe if you extrapolated the lines a little bit, you could predict when those two curves might eventually converge. That's an interesting thought experiment, but I think we do need some longer studies to investigate how persistent are these effects. Can that fully explain the rise in average body weight and obesity rates that have occurred over the past several decades? Those are open questions.Eric Topol (09:03):Yeah. Well, I mean, I had the chance to interview Chris van Tulleken who wrote the book, Ultra-Processed People and I think you might remember in the book he talked about how he went on an ultra-processed diet and gained some 20, 30 pounds in a short time in a month. And his brother, his identical twin brother gained 50, 60 pounds, and so it doesn't look good. Do you look at all the labels and avoid all this junk and ultra-processed food now or are you still thinking that maybe it's not as bad as it looks?Kevin Hall (09:38):Well, I mean I think that I certainly learned a lot from our studies, and we are continuing to follow this up to try to figure out what are the mechanisms by which this happen. But at the same time, I don't think we can throw out everything else we know about nutrition science. So just because we match these various nutrients in this particular study, I think one of the dangers here is that as you mentioned, there's 60% of the food environment in the US and Great Britain and other places consist of these foods, and so they're unavoidable to some extent, right? Unless you're one of these privileged folks who have your backyard garden and your personal chef who can make all of your foods, I'm certainly not one of those people, but for the vast majority of us, we're going to have to incorporate some degree of ultra-processed foods in our day-to-day diet.Kevin Hall (10:24):The way I sort of view it is, we really need to understand the mechanisms and before we understand the mechanisms, we have to make good choices based on what we already know about nutrition science, that we should avoid the foods that have a lot of sugar in them. We should avoid foods that have a lot of saturated fat and sodium. We should try to choose products that contain lots of whole grains and legumes and fruits and vegetables and things like that. And there's some of those, even in the ultra-processed food category. I pretty regularly consume a microwavable ready meal for lunch. It tends to be pretty high in whole grains and legumes and low in saturated fat and sugar and things like that. But to engineer a food that can heat up properly in a microwave in four minutes has some ultra-processing technology involved there. I would be pretty skeptical that that's going to cause me to have really poor health consequences as compared to if I had the means to eat homemade French fries every day in tallow. But that's the kind of comparison that we have to think about.Eric Topol (11:36):But I think what you're touching on and maybe inadvertently is in that NOVA class four, the bad ultra-processed foods, there's a long, long list of course, and some of those may be worse than others, and we haven't seen an individual ranking of these constituents. So as you're alluding to what's in that microwave lunch probably could be much less concerning than what's in these packaged snacks that are eaten widely. But I would certainly agree that we don't know everything about this, but your study is one of the most quoted studies ever in the ultra-processed food world. Now, let me move on to another trial that was really important. This was published in Nature Medicine and it's about a plant-based diet, which is of course a very interesting diet, low-fat versus an animal-based ketogenic diet. Also looking at energy intake. Can you take us through that trial?Plant-Based, Low Fat Diet vs Animal-Based, Low Carbohydrate Ketogenic DietKevin Hall (12:33):Sure. So it's actually interesting to consider that trial in the context of the trial we just talked about because both of these diets that we tested in this trial were relatively low in ultra-processed foods, and so both of them contained more than a kilogram of non-starchy vegetables as a base for designing these, again, two different food environments. Very similar overall study design where people again were exposed to either diets that were vegan plant-based diet that was really high in starches and was designed to kind of cause big insulin increases in the blood after eating the meals. And the other diet had very, very few carbohydrates of less than 10% in total, and we built on that kind of non-starchy vegetable base, a lot of animal-based products to kind of get a pretty high amount of fat and having very low carbohydrates. Both diets in this case, like I mentioned, were pretty low in ultra-processed foods, but what we were really interested in here was testing this idea that has come to prominence recently, that high carbohydrate diets that lead to really large glucose excursions after meals that cause very high insulin levels after meals are particularly obesogenic and should cause you to be hungrier than compared to a diet that doesn't lead to those large swings in glucose and insulin and the prototypical case being one that's very low in carbohydrate and might increase the level of ketones that are floating around in your blood, which are hypothesized to be an appetite suppressant. Same sort of design, these minimally processed diets that one was very high in carbs and causes large swings in insulin and the other that's very low in carbs and causes increases in ketones.Kevin Hall (14:22):We ask people, again, while you're in one food environment or the other, don't be trying to gain weight or lose weight, eat as much or as little as you'd like, and we're going to basically measure a lot of things. They again, don't know what the primary outcome of the study is. We're measuring their leftovers afterwards. And so, the surprise in this particular case was that the diet that caused the big swings in glucose and insulin did not lead to more calorie consumption. In fact, it led to about 700 calories per day less than when the same people were exposed to the ketogenic diet. Interestingly, both food environments caused people to lose weight, so it wasn't that we didn't see the effect of people over consuming calories on either diet, so they were reading fewer calories in general than they were when they came in, right. They're probably eating a pretty ultra-processed food diet when they came in. We put them on these two diets that varied very much in terms of the macronutrients that they were eating, but both were pretty minimally processed. They lost weight. They ended up losing more body fat on the very low-fat high carb diet than the ketogenic diet, but actually more weight on the ketogenic diet than the low-fat diet. So there's a little bit of a dissociation between body fat loss and weight loss in this study, which was kind of interesting.Eric Topol (15:49):Interesting. Yeah, I thought that was a fascinating trial because plant-based diet, they both have their kind of camps, you know.Kevin Hall (15:57):Right. No, exactly.Immune System Signatures for Vegan vs Ketogenic DietsEric Topol (15:58):There are people who aren't giving up on ketogenic diet. Of course, there's some risks and some benefits and there's a lot of interest of course with the plant-based diet. So it was really interesting and potentially the additive effects of plant-based with avoidance or lowering of ultra-processed food. Now, the more recent trial that you did also was very interesting, and of course I'm only selecting ones that I think are particularly, there are a lot of trials you've done, but this one is more recent in this year where you looked at vegan versus ketogenic diets for the immune signature, immune response, which is really important. It's underplayed as its effect, and so maybe you can take us through that one.[Link to a recent Nature feature on this topic, citing Dr. Hall’s work]Kevin Hall (16:43):Yeah, so just to be clear, it's actually the same study, the one that we just talked about. This is a secondary sort of analysis from a collaboration we had with some folks at NIAID here at the NIH to try to evaluate immune systems signatures in these same folks who wonder what these two changes in their food environment. One is vegan, high carbohydrate low-fat diet and the other, the animal-based ketogenic diet. And again, it was pretty interesting to me that we were able to see really substantial changes in how the immune system was responding. First of all, both diets again seem to have improved immune function, both adaptive and innate immune function as compared to their baseline measurements when they came into the study. So when they're reading their habitual diet, whatever that is typically high in ultra-processed foods, they switched to both of these diets.Kevin Hall (17:39):We saw market changes in their immune system even compared to baseline. But when we then went and compared the two diets, they were actually divergent also, in other words, the vegan diet seemed to stimulate the innate immune system and the ketogenic diet seemed to stimulate the adaptive immune system. So these are the innate immune system can be thought of. Again, I'm not an immunologist. My understanding is that this is the first line defense against pathogens. It happens very quickly and then obviously the adaptive immune system then adapts to a specific pathogen over time. And so, this ability of our diet to change the immune system is intriguing and how much of that has to do with influencing the gut microbiota, which obviously the gut plays a huge role in steering our immune system in one direction versus another. I think those are some really intriguing mechanistic questions that are really good fodder for future research.Eric Topol (18:42):Yeah, I think it may have implications for treatment of autoimmune diseases. You may want to comment about that.Kevin Hall (18:51):Yeah, it's fascinating to think about that the idea that you could change your diet and manipulate your microbiota and manipulate your gut function in a way to influence your immune system to steer you away from a response that may actually be causing your body damage in your typical diet. It's a fascinating area of science and we're really interested to follow that up. I mean, it kind of supports these more anecdotal reports of people with lupus, for example, who've reported that when they try to clean up their diet for a period of time and eliminate certain foods and eliminate perhaps even ultra-processed food products, that they feel so much better that their symptoms alleviate at least for some period of time. Obviously, it doesn't take the place of the therapeutics that they need to take, but yeah, we're really interested in following this up to see what this interaction might be.Eric Topol (19:46):Yeah, it's fascinating. It also gets to the fact that certain people have interesting responses. For example, those with epilepsy can respond very well to a ketogenic diet. There's also been diet proposed for cancer. In fact, I think there's some even ongoing trials for cancer of specific diets. Any comments about that?Kevin Hall (20:10):Yeah, again, it's a really fascinating area. I mean, I think we kind of underappreciate and view diet in this lens of weight loss, which is not surprising because that's kind of where it's been popularized. But I think the role of nutrition and how you can manipulate your diet and still you can have a very healthy version of a ketogenic diet. You can have a very healthy version of a low-fat, high carb diet and how they can be used in individual cases to kind of manipulate factors that might be of concern. So for example, if you're concerned about blood glucose levels, clearly a ketogenic diet is moderating those glucose levels over time, reducing insulin levels, and that might have some positive downstream consequences and there's some potential downsides. Your apoB levels might go up. So, you have to kind of tune these things to the problems and the situations that individuals may face. And similarly, if you have issues with blood glucose control, maybe a high carbohydrate diet might not be for you, but if that's not an issue and you want to reduce apoB levels, it seems like that is a relatively effective way to do that, although it does tend to increase fasting triglyceride levels.Kevin Hall (21:27):So again, there's all of these things to consider, and then when you open the door beyond traditional metabolic health markers to things like inflammation and autoimmune disease as well as some of these other things like moderating how cancer therapeutics might work inside the body. I think it's a really fascinating and interesting area to pursue.Eric Topol (21:55):No question about it. And that also brings in the dimension of the gut microbiome, which obviously your diet has a big influence, and it has an influence on your brain, brain-gut axis, and the immune system. It's all very intricate, a lot of feedback loops and interactions that are not so easy to dissect, right?Kevin Hall (22:16):Absolutely. Yeah, especially in humans. That's why we rely on our basic science colleagues to kind of figure out these individual steps in these chains. And of course, we do need human experiments and carefully controlled experiments to see how much of that really translates to humans, so we need this close sort of translational partnership.On the Pathogenesis of Obesity, Calories In and Calories OutEric Topol (22:35):Yeah. Now, you've also written with colleagues, other experts in the field about understanding the mechanisms of pathogenesis of obesity and papers that we'll link to. We're going to link to everything for what we've been discussing about calories in, calories out, and that's been the longstanding adage about this. Can you enlighten us, what is really driving obesity and calories story?Kevin Hall (23:05):Well, I co-organized a meeting for the Royal Society, I guess about a year and a half ago, and we got together all these experts from around the world, and the basic message is that we have lots of competing theories about what is driving obesity. There's a few things that we all agree on. One is that there is a genetic component. That adiposity in a given environment is somewhere between 40% to 70% heritable, so our genes play a huge role. It seems like there's certain genes that can play a major role. Like if you have a mutation in leptin, for example, or the leptin receptor, then this can have a monogenic cause of obesity, but that's very, very rare. What seems to be the case is that it's a highly polygenic disease with individual gene variants contributing a very, very small amount to increased adiposity. But our genes have not changed that much as obesity prevalence has increased over the past 50 years. And so, something in the environment has been driving that, and that's where the real debates sort of starts, right?Kevin Hall (24:14):I happen to be in the camp that thinks that the food environment is probably one of the major drivers and our food have changed substantially, and we're trying to better understand, for example, how ultra-processed foods which have risen kind of in parallel with the increased prevalence of obesity. What is it about ultra-processed foods that tend to drive us to overconsume calories? Other folks focus maybe more on what signals from the body have been altered by the foods that we're eating. They might say that the adipose tissue because of excess insulin secretion for example, is basically driven into a storage mode and that sends downstream signals that are eventually sensed by the brain to change our appetite and things like that. There's a lot of debate about that, but again, I think that these are complementary hypotheses that are important to sort out for sure and important to design experiments to try to figure out what is more likely. But there is a lot of agreement on the idea that there's something in our environment has changed.Kevin Hall (25:17):I think there's even maybe a little bit less agreement of exactly what that is. I think that there's probably a little bit more emphasis on the food environment as opposed to there are other folks who think increased pollution might be driving some of this, especially endocrine disrupting chemicals that have increased in prevalence. I think that's a viable hypothesis. I think we have to try to rank order what we think are the most likely and largest contributors. They could all be contributing to some extent and maybe more so in some people rather than others, but our goal is to try to, maybe that's a little simple minded, but let's take the what I think is the most important thing and let's figure out the mechanisms of that most important thing and we'll, number one, determine if it is the most important thing. In my case, I think something about ultra-processed foods that are driving much of what we're seeing. If we could better understand that, then we could both advise consumers to avoid certain kinds of foods because of certain mechanisms and still be able to consume some degree of ultra-processed foods. They are convenient and tasty and relatively inexpensive and don't require a lot of skill and equipment to prepare. But then if we focus on the true bad guys in that category because we really understand the mechanisms, then I think that would be a major step forward. But that's just my hypothesis.Eric Topol (26:43):Well, I’m with you actually. Everything I've read, everything I've reviewed on ultra-processed food is highly incriminating, and I also get frustrated that nothing is getting done about it, at least in this country. But on the other hand, it doesn't have to be either or, right? It could be both these, the glycemic index story also playing a role. Now, when you think about this and you're trying to sort out calories in and calories out, and let's say it's one of your classic experiments where you have isocaloric proteins and fat and carbohydrate exactly nailed in the different diets you're examining. Is it really about calories or is it really about what is comprising the calorie?Kevin Hall (27:29):Yeah, so I think this is the amazing thing, even in our ultra-processed food study, if we asked the question across those people, did the people who ate more calories even in the ultra-processed diet, did they gain more weight? The answer is yes.Kevin Hall (27:44):There's a very strong linear correlation between calorie intake and weight change. I tend to think that I started my career in this space focusing more on the metabolism side of the equation, how the body's using the calories and how much does energy expenditure change when you vary the proportion of carbs versus fat, for example. The effect size is there, they might be there, but they're really tiny of the order of a hundred calories per day. What really struck me is that when we just kind of changed people's food environments, the magnitude of the effects are like we mentioned, 500 to 700 calories per day differences. So I think that the real trick is to figure out how is it that the brain is regulating our body weight in some way that we are beginning to understand from a molecular perspective? What I think is less well understood is, how is that food intake control system altered by the food environment that we find ourselves in?The Brain and GLP-1 DrugsKevin Hall (28:42):There are a few studies now in mice that are beginning to look at how pathways in the brain that have been believed to be related to reward and not necessarily homeostatic control of food intake. They talk to the regions of the brain that are related to homeostatic control of food intake, and it's a reciprocal sort of feedback loop there, and we're beginning to understand that. And I think if we get more details about what it is in our foods that are modulating that system, then we'll have a better understanding of what's really driving obesity and is it different in different people? Are there subcategories of obesity where certain aspects of the food environment are more important than others, and that might be completely flipped in another person. I don't know the answer to that question yet, but it seems like there are certain common factors that might be driving overall changes in obesity prevalence and how they impact this reward versus homeostatic control systems in the brain, I think are really fascinating questions.Eric Topol (29:43):And I think we're getting much more insight about this circuit of the reward in the brain with the food intake, things like optogenetics, many ways that we're getting at this. And so, it's fascinating. Now, that gets me to the miracle drug class GLP-1, which obviously has a big interaction with obesity, but of course much more than that. And you've written about this as well regarding this topic of sarcopenic obesity whereby you lose a lot of weight, but do you lose muscle mass or as you referred to earlier, you lose body fat and maybe not so much muscle mass. Can you comment about your views about the GLP-1 family of drugs and also about this concern of muscle mass loss?Kevin Hall (30:34):Yeah, so I think it's a really fascinating question, and we've been trying to develop mathematical models about how our body composition changes with weight gain and weight loss for decades now. And this has been a long topic, one of the things that many people may not realize is that people with obesity don't just have elevated adiposity, they also have elevated muscle mass and lean tissue mass overall. So when folks with obesity lose weight, and this was initially a pretty big concern with bariatric surgery, which has been the grandfather of ways that people have lost a lot of weight. The question has been is there a real concern about people losing too much weight and thereby becoming what you call sarcopenic? They have too little muscle mass and then they have difficulties moving around. And of course, there are probably some people like that, but I think what people need to realize is that folks with obesity tend to start with much higher amounts of lean tissue mass as well as adiposity, and they start off with about 50% of your fat-free mass, and the non-fat component of your body is skeletal muscle.Kevin Hall (31:45):So you're already starting off with quite a lot. And so, the question then is when you lose a lot of weight with the GLP-1 receptor agonist or with bariatric surgery, how much of that weight loss is coming from fat-free mass and skeletal muscle versus fat mass? And so, we've been trying to simulate that using what we've known about bariatric surgery and what we've known about just intentional weight loss or weight gain over the years. And one of the things that we found was that our sort of expectations for what's expected for the loss of fat-free mass with these different drugs as well as bariatric surgery, for the most part, they match our expectations. In other words, the expected amount of fat loss and fat free mass loss. The one outlier interestingly, was the semaglutide study, and in that case, they lost more fat-free mass than would be expected.Kevin Hall (32:44):Now, again, that's just raising a little bit of a flag that for whatever reason, from a body composition perspective, it's about a hundred people underwent these repeated DEXA scans in that study sponsored by Novo Nordisk. So it's not a huge number of people, but it's enough to really get a good estimate about the proportion of weight loss. Whether or not that has functional consequences, I think is the open question. There's not a lot of reports of people losing weight with semaglutide saying, you know what? I'm really having trouble actually physically moving around. I feel like I've lost a lot of strength. In fact, it seems to be the opposite, right, that the quality of the muscle there seems to be improved. They seem to have more physical mobility because they've lost so much more weight, that weight had been inhibiting their physical movement in the past.Kevin Hall (33:38):So it's something to keep an eye on. It's an open question whether or not we need additional therapies in certain categories of patients, whether that be pharmacological, there are drugs that are interesting that tend to increase muscle mass. There's also other things that we know increase muscle mass, right? Resistance exercise training, increase this muscle mass. And so, if you're really concerned about this, I certainly, I'm not a physician, but I think it's something to consider that if you go on one of these drugs, you might want to think about increasing your resistance exercise training, maybe increasing the protein content of your diet, which then can support that muscle building. But I think it's a really interesting open question about what the consequences of this might be in certain patient populations, especially over longer periods of time.Dietary Protein, Resistance Exercise, DEXA ScansEric Topol (34:30):Yeah, you've just emphasized some really key points here. Firstly, that resistance exercise is good for you anyway. And get on one of these drugs, why don't you amp it up or get it going? The second is about the protein diet, which it'd be interesting to get your thoughts on that, but we generally have too low of a protein diet, but then there are some who are advocating very high protein diets like one gram per pound, not just one gram per kilogram. And there have been studies to suggest that that very high protein diet could be harmful, but amping up the protein diet, that would be a countering thing. But the other thing you mentioned is a DEXA scan, which can be obtained very inexpensively, and because there's a variability in this muscle mass loss if it's occurring, I wonder if that's a prudent thing or if you just empirically would just do the things that you mentioned. Do you have any thoughts about that?Kevin Hall (35:32):Yeah, that's really a clinical question that I don't deal with on a day-to-day basis. And yeah, I think there's probably better people suited to that. DEXA scans, they're relatively inexpensive, but they're not readily accessible to everyone. I certainly wouldn't want to scare people away from using drugs that are now known to be very effective for weight loss and pretty darn safe as far as we can tell, just because they don't have access to a DEXA scanner or something like that.Eric Topol (36:00):Sure. No, that makes a lot of sense. I mean, the only reason I thought it might be useful is if you're concerned about this and you want to track, for example, how much is that resistant training doing?Kevin Hall (36:13):But I think for people who have the means to do that, sure. I can't see any harm in it for sure.Continuous Glucose Sensors?Eric Topol (36:19):Yeah. That gets me to another metric that you've written about, which is continuous glucose tracking. As you know, this is getting used, I think much more routinely in type one insulin diabetics and people with type 2 that are taking insulin or difficult to manage. And now in recent months there have been consumer approved that is no prescription needed, just go to the drugstore and pick up your continuous glucose sensor. And you've written about that as well. Can you summarize your thoughts on it?Kevin Hall (36:57):Yeah, sure. I mean, yeah, first of all, these tools have been amazing for people with diabetes and who obviously are diagnosed as having a relative inability to regulate their glucose levels. And so, these are critical tools for people in that population. I think the question is are they useful for people who don't have diabetes and is having this one metric and where you target all this energy into this one thing that you can now measure, is that really a viable way to kind of modulate your lifestyle and your diet? And how reliable are these CGM measurements anyway? In other words, do they give the same response to the same meal on repeated occasions? Does one monitor give the same response as another monitor? And those are the kinds of experiments that we've done. Again, secondary analysis, these trials that we talked about before, we have people wearing continuous glucose monitors all the time and we know exactly what they ate.Kevin Hall (37:59):And so, in a previous publication several years ago, we basically had two different monitors. One basically is on the arm, which is the manufacturer's recommendation, the other is on the abdomen, which is the manufacturer's recommendation. They're wearing them simultaneously. And we decided just to compare what were the responses to the same meals in simultaneous measurements. And they were correlated with each other thankfully, but they weren't as well predictive as you might expect. In other words, one device might give a very high glucose reading to consuming one meal and the other might barely budge, whereas the reverse might happen for a different meal. And so, we asked the question, if we were to rank the glucose spikes by one meal, so we have all these meals, let's rank them according to the glucose spikes of one device. Let's do the simultaneous measurements with the other device.Kevin Hall (38:53):Do we get a different set of rankings? And again, they're related to each other, but they're not overlapping. They're somewhat discordant. And so, then the question becomes, okay, well if I was basically using this one metric to kind of make my food decisions by one device, I actually start making different decisions compared to if I happen to have been wearing a different device. So what does this really mean? And I think this sort of foundational research on how much of a difference you would need to make a meaningful assessment about, yeah, this is actionable from a lifestyle perspective, even if that is the one metric that you're interested in. That sort of foundational research I don't think has really been done yet. More recently, we asked the question, okay, let's ignore the two different devices. Let's stick to the one where we put it on our arm, and let's ask the question.Kevin Hall (39:43):We've got repeated meals and we've got them in this very highly regimented and controlled environment, so we know exactly what people ate previously. We know the timing of the meals, we know when they did their exercise, we know how much they were moving around, how well they slept the night before. All of these factors we could kind of control. And the question that we asked in that study was, do people respond similarly to the same meal on repeated occasions? Is that better than when you actually give them very different meals? But they match overall for macronutrient content, for example. And the answer to that was surprisingly no. We had as much variability in the glucose response to the same person consuming the same meal on two occasions as a whole bunch of different meals. Which suggests again, that there's enough variability that it makes it difficult to then recommend on for just two repeats of a meal that this is going to be a meal that's going to cause your blood glucose to be moderate or blood glucose to be very high. You're going to have to potentially do this on many, many different occasions to kind of figure out what's the reliable response of these measurements. And again, that foundational research is typically not done. And I think if we're really going to use this metric as something that is going to change our lifestyles and make us choose some meals other than others, then I think we need that foundational research. And all we know now is that two repeats of the same meal is not going to do it.Eric Topol (41:21):Well, were you using the current biosensors of 2024 or were you using ones from years ago on that?Kevin Hall (41:27):No, we were using ones from several years ago when these studies were completed. But interestingly, the variability in the venous measurements to meal tests is also very, very different. So it's probably not the devices per se that are highly variable. It's that we don't really know on average how to predict these glucose responses unless there's huge differences in the glycemic load. So glycemic load is a very old concept that when you have very big differences in glycemic load, yeah, you can on average predict that one kind of meal is going to give rise to a much larger glucose excursion than another. But typically these kind of comparisons are now being made within a particular person. And we're comparing meals that might have quite similar glycemic loads with the claim that there's something specific about that person that causes them to have a much bigger glucose spike than another person. And that we can assess that with a couple different meals.Eric Topol (42:31):But also, we know that the spikes or the glucose regulation, it's very much affected by so many things like stress, like sleep, like exercise. And so, it wouldn't be at all surprising that if you had the exact same food, but all these other factors were modulated that it might not have the same response. But the other thing, just to get your comment on. Multiple groups, particularly starting in Israel, the Weizmann Institute, Eran Segal and his colleagues, and many subsequent have shown that if you give the exact same amount of that food, the exact same time to a person, they eat the exact same amount. Their glucose response is highly heterogeneous and variable between people. Do you think that that's true? That in fact that our metabolism varies considerably and that the glucose in some will spike with certain food and some won’t.Kevin Hall (43:29):Well, of course that's been known for a long time that there's varying degrees of glucose tolerance. Just oral glucose tolerance tests that we've been doing for decades and decades we know is actually diagnostic, that we use variability in that response as diagnostic of type 2 diabetes.Eric Topol (43:49):I'm talking about within healthy people.Kevin Hall (43:53):But again, it's not too surprising that varying people. I mean, first of all, we have a huge increase in pre-diabetes, right? So there's various degrees of glucose tolerance that are being observed. But yeah, that is important physiology. I think the question then is within a given person, what kind of advice do we give to somebody about their lifestyle that is going to modulate those glucose responses? And if that's the only thing that you look at, then it seems like what ends up happening, even in the trials that use continuous glucose monitors, well big surprise, they end up recommending low carbohydrate diets, right? So that's the precision sort of nutrition advice because if that's the main metric that's being used, then of course we've all known for a very long time that lower carbohydrate diets lead to a moderated glucose response compared to higher carbohydrate diets. I think the real question is when you kind of ask the issue of if you normalize for glycemic load of these different diets, and there are some people that respond very differently to the same glycemic load meal compared to another person, is that consistent number one within that person?Kevin Hall (45:05):And our data suggests that you're going to have to repeat that same test multiple times to kind of get a consistent response and be able to make a sensible recommendation about that person should eat that meal in the future or not eat that meal in the future. And then second, what are you missing when that becomes your only metric, right? If you're very narrowly focused on that, then you're going to drive everybody to consume a very low carbohydrate diet. And as we know, that might be great for a huge number of people, but there are those that actually have some deleterious effects of that kind of diet. And if you're not measuring those other things or not considering those other things and put so much emphasis on the glucose side of the equation, I worry that there could be people that are being negatively impacted. Not to mention what if that one occasion, they ate their favorite food and they happen to get this huge glucose spike and they never eat it again, their life is worse. It might've been a complete aberration.Eric Topol (46:05):I think your practical impact point, it's excellent. And I think one of the, I don't know if you agree, Kevin, but one of the missing links here is we see these glucose spikes in healthy people, not just pre-diabetic, but people with no evidence of glucose dysregulation. And we don't know, they could be up to 180, 200, they could be prolonged. We don't know if the health significance of that, and I guess someday we'll learn about it. Right?Kevin Hall (46:36):Well, I mean that's the one nice thing is that now that we have these devices to measure these things, we can start to make these correlations. We can start to do real science to say, what a lot of people now presume is the case that these spikes can't be good for you. They must lead to increased risk of diabetes. It's certainly a plausible hypothesis, but that's what it is. We actually need good data to actually analyze that. And at least that's now on the table.Eric Topol (47:04):I think you're absolutely right on that. Well, Kevin, this has been a fun discussion. You've been just a great leader in nutrition science. I hope you'll keep up your momentum because it's pretty profound and I think we touched on a lot of the uncertainties. Is there anything that I didn't ask you that you wish I did?Kevin Hall (47:23):I mean, we could go on for hours, I'm sure, Eric, but this has been a fascinating conversation. I really appreciate your interest. Thank you.Eric Topol (47:30):Alright, well keep up the great stuff. We'll be following all your work in the years ahead, and thanks for joining us on Ground Truths today.**************************************Footnote, Stay Tuned: Julia Belluz and Kevin Hall have a book coming out next September titled “WHY WE EAT? Thank you for reading, listening and subscribing to Ground Truths.If you found this fun and informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.Note on Mass Exodus from X/twitter:Many of you have abandoned the X platform for reasons that I fully understand. While I intend to continue to post there because of its reach to the biomedical community, I will post anything material here in the Notes section of Ground Truths on a daily basis and cover important topics in the newsletter/analyses. You can also find my posts at Bluesky: @erictopol.bsky.social, which is emerging as an outstanding platform for sharing life science. Get full access to Ground Truths at erictopol.substack.com/subscribe

Below is a brief video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! This one has embedded one of my favorite TikTok’s from Will. There are several links to others in the transcript. The audios are also available on Apple and Spotify.Transcript with links to both audio and videos, commencement addresses, NEJM article coverageEric Topol (00:06):Hi, it's Eric Topol from Ground Truths, and I've got an amazing couple with me today. It's Will Flanary and Kristin Flanary, the Glaucomfleckens. I've had the chance to get to know them a bit through Knock Knock, Hi! which is their podcast. And of course, everyone knows Dr. Glaucomflecken from his TikTok world and his other about 4 million followers on Instagram and Twitter and all these other social media, and YouTube. So welcome.Will Flanary (00:43):Thanks for having us.Kristin Flanary (00:44):Thank you. Happy to be here.By Way of BackgroundEric Topol (00:45):Yeah. Well, this is going to be fun because I'm going to go a quick background so we can go fast forward because we did an interview back in early 2022.Kristin Flanary (00:56):Yes.Eric Topol (00:57):And what you've been doing since then is rocking it. You're like a meteoric, right. And it was predictable, like rarefied talent and who couldn't love humor, medical humor, but by way of background, just for those who are not up to speed. I guess you got your start, Will, as a class clown when your mother was a teacher in the sixth grade.Will Flanary (01:22):Yep, yep. I misbehaved a little bit. It helped that I still made good grades, but I cut up a bit in class.Eric Topol (01:32):And then you were already in the comedy club circuits doing standup in Houston as an 18-year-old.Will Flanary (01:40):It was all amateur stuff, nothing, just dabble in it and trying to get better. I was always kind of naturally funny just with my friend group and everything. I loved making people laugh, but doing standups is a whole different ball game. And so, I started doing that around Houston as a high school senior and kept that going through college and a little bit into med school.Kristin Flanary (02:02):Houston was a good training ground, right? That where Harris Wittels was also coming up.Will Flanary (02:07):Yeah. A lot of famous comedians have come through Houston. Even going back to Bill Hicks back in the, was that the 80s, I think? Or 90s?Eric Topol (02:17):Well, and then of course, it was I think in 2020 when you launched Dr. Glaucomflecken, I think. Is that right?Will Flanary (02:28):That's when it really started to take off. I was on Twitter telling jokes back in 2016.Kristin Flanary (02:39):GomerBlog before that, that's actually where it was born.Will Flanary (02:41):I was doing satire writing. I basically do what I'm doing now, but in article form, trying to be The Onion of medicine. And then the pandemic hit, started doing video content and that's really with lockdown. That's when, because everybody was on social media, nobody had anything else to do. So it was right place, right time for me and branching out into video content.On to Medical School Commencement AddressesEric Topol (03:11):Alright, so that's the background of some incredible foundation for humor. But since we last got together, I'll link the Medicine and the Machine interview we did back then. What has been happening with you two is nothing short of incredible. I saw your graduation speeches, Will. Yale in 2022, I watched the UCSF in 2023 and then the University of Michigan in 2024. Maybe there's other ones I don't even know.Kristin Flanary (03:45):There’s a few others.Will Flanary (03:45):There's a few. But I feel like you've done, I'm sure your fair share of commencement addresses as well. It's kind of hard to come up with different ways to be inspirational to the next generation. So fortunately, we have together, we have some life experiences and learned a thing or two by doing all of this social media stuff and just the things we've been through that I guess I have enough things to say to entertain an interest.Eric Topol (04:18):Well, you're being humble as usual, but having watched those commencement addresses, they were the best medical commencement addresses I've ever seen. And even though you might have told us some of the same jokes, they were so great that it was all right. Yeah, and you know what is great about it is you've got these, not the students, they all love you of course, because they're probably addicted to when's your next video going to get posted.(04:44):But even the old professors, all the family members, it's great. But one of the things I wanted to get at. Well, I'll start with the graduation speeches, because you were such an inspiration, not just with humor, but your message. And this gets back to you as a couple and the tragedies you've been through. So you really, I think, got into this co-survivor story and maybe Kristin, since you are the co-survivor of two bouts of Will’s testicular cancer, and then the sudden cardiac death. I mean, people don't talk about this much, so maybe you could help enlighten us.Tragedies and Being a Co-SurvivorKristin Flanary (05:26):Yeah, it’s funny because the experience of being a co-survivor is nothing new. It’s as long as we've had human beings, we've had co-survivors. But the concept around it and giving it a name and a label, a framework to be able to think about it, that is what I think is new and what people haven't talked about before. So co-survivor is just this idea that when a medical trauma happens to a patient, the patient has their experience and if they survive it, they are a survivor and they have a survivor experience. And also, most people are closely attached to at least one other person, if not many. And those people are co-surviving the medical event along with the survivor. That event is happening in their lives as was happening to them too. If someone comes in with a patient to the hospital, that person, you can just assume by default that their lives are pretty intimately or profoundly intertwined or else why would that person be there? And so, thinking of it as there's the patient and then there's also a co-patient, that family members in the past have only been thought of as caregivers if they've been thought of at all. And that is certainly one aspect of the role, but it's important to remember that whatever it is that's happening to the patient is also affecting the family members' lives in a really deep and profound way.Eric Topol (07:04):That's really helpful. Now, the fact that you recognize that in your graduation speech, Will, I think is somewhat unique. And of course, some of the other things that you touched on like playing to your creativity and the human factors, I mean, these are so important messages.Will Flanary (07:23):Well, in the discussion about co-survivorship and because I talk about that whenever I do my keynotes and when I do the commencement addresses, but all credit goes to Kristin for really being the driving force of this idea for me and for many others because as a physician, we take care of patients. Our focus is always on the patient. And it really wasn't until this happened to me and my family and Kristin in particular that I started to understand exactly what she's talking about and this idea. And so, Kristin gets a lot of credit for just really bringing that term and that idea to the forefront.Eric Topol (08:09):Yeah, well, you saved his life. It's just not many have that bond. And then the other thing I just want to mention now, you've been recognized by the American Heart Association and a whole bunch of other organizations awarded because of your advocacy for CPR. And you even mentioned that I think in one of your commencement addresses.Will Flanary (08:31):Yeah, I tried to get the crowd to do CPR. Like team up, partner up, and it kind of fell flat. It wasn't quite the right time, I think, to try to do a mass class on CPR. So maybe next time.Eric Topol (08:47):Right. Well, so you had this foundation with the Glaucomflecken General Hospital and taking on 37 specialties and all these incredible people that became part of the family, if you will, of spoof on medicine and your alter ego and these videos that you would do. And sometimes you have three or four different alter egos in there playing out, but now you've branched into new things. So one which is an outgrowth of what we were just talking about. You've been on this country tour, Wife & Death.“Wife and Death,” A Nationwide TourKristin Flanary (09:28):Yes.Eric Topol (09:29):Wife and death. I mean, yeah, I guess we can make the connect of how you named it that, but what is it you've been selling out in cities all over the country, and by the way, I'm really upset you haven't come to San Diego, but tell us about wife and death.Will Flanary (09:44):Yeah. Well, we have this amazing story and all these medical challenges we've been through, and then developing the Glaucomflecken brand and universe, and we've done keynotes together for years, and then we thought, let's have more fun with it. Let's do keynotes. They're great. We can get our message out, but sometimes they're just a bit stuffy. It's an academic environment.Kristin Flanary (10:15):They're usually at seven in the morning also, so that's the downside.Will Flanary (10:21):So we thought, let's just put together our own live show. Let's put together something that we could just creatively, we can do whatever we want with it. I could dress up as characters, Kristin, who has these beautiful writing and monologues that she's put together around her experience and just to create something that people can come into a theater and just experience this wide range of emotions from just laughter to tears of all kinds, and just have them feel the story and enjoy this story. Fortunately, it has a happy ending because I'm still alive and it's been so much fun. The audiences have been incredible. Mostly healthcare, but even some non-healthcare people show up, and we've been blown away by the response. Honestly, we should have done bigger theaters. That's our lesson for the first go round.Eric Topol (11:21):I saw you had to do a second show in Pittsburgh.Will Flanary (11:24):We did.Kristin Flanary (11:26):That one sold out too. Something about Pittsburgh, that was a good crowd, and there was a lot of them.Will Flanary (11:33):It was almost like in Pittsburgh, they rarely ever get any internet comedian ophthalmologists that come through. I don't know.Eric Topol (11:41):Well, I see you got some still to come in Denver and Chicago. This is amazing. And I wondered who was coming and I mean, it's not at all surprising that there'd be this phenomenal popularity. So that's one thing you've done that's new, which is amazing. And of course, it's a multidimensional story. The one that shocked me, I have to tell you, shocked me, was the New England Journal partnership. The New England Journal is the most stodgy, arrogant, I mean so difficult. And not only that.Kristin Flanary (12:17):You said that. Not us.Partnering with the New England Journal of Medicine!Eric Topol (12:19):Yeah, yeah. They'll get this too. They know we don't get along that well, but that's okay. You even made fun of journals. And now you're partnering with the New England Journal, God's greatest medical journal, or whatever. Tell us about that.Will Flanary (12:39):Well, so one thing that I really enjoy doing, and I've done it with my US healthcare system content is almost like tricking people into learning things. And so, if you make something funny, then people will actually sit there and listen to what you have to say about deductibles and physician-owned hospitals and all these inner workings. DIR fees and pharmacy, all these things that are really dry topics. But if you can make them funny, all of a sudden people will actually learn and listen to it. And the New England Journal of Medicine, they approached me with an idea. Basically just to take one or two of their trials per month. And I just make a skit out of that trial with the idea being to help disseminate some of the research findings that are out there, because I guess it's getting harder and harder for people to actually read, to sit down and read a journal article.(13:43):And so, I have to credit them for having this idea and thinking outside the box of a different way to get medical information and knowledge out to the masses. And you're absolutely right, that I have been critical of journals, and particularly I've been critical of the predatory nature of some of the larger journals out there, like Elsevier. I've specifically named Elsevier, Springer, these journals that have a 40% profit margin. And I certainly thought about that whenever I was looking into this partnership. And the reason I was okay with doing it with the New England Journal is because they're a nonprofit, first of all, so they're run by the Massachusetts Medical Society. That's the publisher for that journal. And so, I feel okay partnering with them because I feel like they're doing it in a much better way than some of the bigger journal corporations out there.Kristin Flanary (14:54):Well, and also part of the deal that we negotiated was that those articles that you make skits about those will be available open access.Will Flanary (15:03):Oh yeah. That was a prerequisite. Yes. It was like, if I'm going to do this, the articles that I'm talking about need to be free and readily available. That's part of it.Eric Topol (15:14):I think you've done about five already, something like that. And I watched them, and I just was blown away. I mean, the one that got me where I was just rolling on the floor, this one, the Belantamab Mafodotin for Multiple Myeloma. And when you were going on about the Bortezomib, Dexamethasone. We'll link to this. I said, oh my God.Will Flanary (15:40):Yeah. The joke there is, you don't have any idea how long it took me to say those things that quickly. And so, I was writing this skit and I'm like, wouldn't it be funny if somehow that triggered a code stroke in the hospital because this person is saying all these random words that don't have any meaning to anybody. Man, I tell you, I am learning. Why would I ever need to know any of this information as an ophthalmologist? So it's great. I know all this random stuff about multiple myeloma that I probably would never have learned otherwise.Kristin Flanary (16:21):It's the only way, you won't read a journal either.Eric Topol (16:23):Well, and if you read the comments on the post. These doctors saying, this is the only way they want to get journal information from now on.Will Flanary (16:33):Which is double-edged sword, maybe a little bit. Obviously, in a 90 second skit, there's no way I'm going to cover the ins and outs of a major trial. So it's really, in a lot of ways, it's basically like, I call it a comedy abstract. I’m not going much further than an abstract, but hopefully people that are actually interested in the topic can have their interest piqued and want to read more about it. That's kind of the idea.Eric Topol (17:06):Yeah. Well, they're phenomenal. We'll link to them. People will enjoy them. I know, because I sure did. And tenecteplase for stroke and all that you've done. Oh, they're just phenomenal.Will Flanary (17:20):Every two weeks we come out with a new one.Eric Topol (17:24):And that is basically between the fact that you are now on the commencement circuit of the top medical schools and doing New England Journal videos on their articles. You've crossed a line from just making fun of insurance companies and doctors of specialties.Kristin Flanary (17:44):Oh, he has crossed many lines, Dr. Topol.Eric Topol (17:46):Yeah. Oh yeah. Now you've done it, really. Back two years ago when we convened, actually it's almost three, but you said, when's it going to be your Netflix special?Will Flanary (18:02):Oh, gosh.Eric Topol (18:02):Is that in the works now?Will Flanary (18:04):Well, I'll tell you what's in the works now.Kristin Flanary (18:06):Do you know anyone at Netflix?Will Flanary (18:09):A New Animated SeriesNo. We're working on an animated series.Eric Topol (18:12):Oh, wow. Wow.Will Flanary (18:13):Yeah. All these characters. It's basically just this fictional hospital and all these characters are very cartoonish, the emergency physician that wears the bike helmet and everything. So it's like, well, what do we have together? What do we, Kristin and I have time for? And it wasn't like moving to LA and trying to make a live action with actors and do all, which is something we probably could have tried to do. So instead, we were like, let's just do an animated series.Kristin Flanary (18:48):Let's have someone else do the work and draw us.Will Flanary (18:51):So we've worked with a writer for the first time, which was a fun process, and putting together a few scripts and then also an animator. We learned a lot about that process. Kristin and I are doing the voiceovers. And yeah, it's in process.Kristin Flanary (19:10):We're the only actors we could afford.Will Flanary (19:12):Right, exactly.Eric Topol (19:13):I can't wait to see it. Now when will it get out there?Will Flanary (19:17):Well, we're hoping to be able to put it out on our YouTube channel sometime early next year. So January, February, somewhere around there. And then we can't fund the whole thing ourselves. So the idea is that we do this, we do this pilot episode, and then we'll see what kind of interest we can generate.Eric Topol (19:37):Well, there will be interest. I am absolutely assured of that. Wow.Will Flanary (19:42):Let us know if you know anybody at the Cartoon Network.Kristin and Will Flanary (19:45):Yeah, we're open to possibilities. Whatever, Discovery channel. I don't know.Eric Topol (19:51):You've gotten to a point now where you're ready for bigger things even because you're the funniest physician couple in medicine today.Kristin Flanary (20:05):Well, that's a very low bar, but thank you.Will Flanary (20:08):There are some funny ones out there, but yeah, I appreciate that.Eric Topol (20:11):Well, I'm a really big comedy fan. Every night I watch the night before, since I'm old now, but of Colbert and Jimmy Kimmel, just to hear the monologues. Trevor Noah, too. And I can appreciate humor. I'll go to see Sebastian Maniscalco or Jim Gaffigan. That's one of the things I was going to ask you about, because when you do these videos, you don't have an audience.Will Flanary (20:39):Oh yeah.Eric Topol (20:40):You're making it as opposed to when you are doing your live shows, commencement addresses and things like that. What's the difference when you're trying to be humorous, and you have no audience there?Will Flanary (20:55):Well, whenever I'm filming a skit, it's just all production. In fact, I feel like it's funny. I think it's funny, but it's really not until I see the response to it, or I show Kristin, or what I have is where I really know if it's going to work. It's great to put the content out there and see the responses, but there's nothing like live interaction. And that's why I keep coming back to performing. And Kristin's been a performer too in her life. And I think we both really enjoy just the personal interaction, the close interaction, the response from people to our story.Kristin Flanary (21:36):We do most of our work alone in this room. I do a lot of writing. He does a lot of playing.Will Flanary (21:44):Dress up.Kristin Flanary (21:44):All the people in his head, and we do that very isolated. And so, it's very lovely to be able to actually put names to faces or just see human bodies instead of just comments on YouTube.Will Flanary (21:59):Meet people.Kristin Flanary (21:59):It's really nice.Will Flanary (22:01):We’ve been doing meet and greets at the live shows and seeing people come up wearing their costumes.Eric Topol (22:07):Oh, wow.Will Flanary (22:11):Some of them talk about how they tell us their own stories about their own healthcare and talk about how the videos help them get through certain parts of the pandemic or a difficult time in their life. And so, it reinforces that this means something to a lot of people.Kristin Flanary (22:29):It's been really fun for me, and probably you too, but to get to see the joy that he has brought so many people. That's really fun to see in person especially.Eric Topol (22:42):No question. Now, when you're producing it together, do you ever just start breaking into laughter because it's you know how funny this is? Or is it just you're on kind of a mission to get it done?Will Flanary (22:54):Well, the skits I do by myself. And sometimes when I'm writing out the skit, when I'm writing the skit itself, I will laugh at myself sometimes. Not often, but sometimes they're like, oh, I know that's really funny. I just wrote a skit that I'm actually going to be debuting. I'm speaking at the American Academy of PM&R, so the big PM&R conference. I'm writing a skit, it's How to Ace your PM&R residency interview.Will Flanary (23:28):I was writing up that skit today and kind of chuckling to myself. So sometimes that happens, but whenever we do our podcast together, we definitely have outtakes.Kristin Flanary (23:38):Oh yeah, we've got some.Will Flanary (23:40):We crack each other up.Kristin Flanary (23:41):We do.Will Flanary (23:42):Sometimes we're getting a little punchy toward the end of the day.Eric Topol (23:47):And how is the Knock Knock, Hi! podcast going?Will Flanary (23:51):It's awesome. Yeah.Kristin Flanary (23:52):Yeah. It's a really fun project.Will Flanary (23:54):We still enjoy. You can work with your spouse and in close proximity and still be happily married. So it's doable everyone.Kristin Flanary (24:06):That's right. And we're in that phase of life that's really busy. We've got kids, we've got a gazillion jobs. House, my parents are around, and so it's like the only time all week that we actually get to sit down and talk to each other. So it's actually kind of like a part of our marriage at this point.Will Flanary (24:28):We’re happy to involve the public in our conversations, but we couldn't do it because we have all these things going on, all our hands and all these little places. We can't do it without a team.Kristin Flanary (24:41):Yeah, absolutely.Will Flanary (24:41):And that's the thing that I've learned, because I've always been a very loner type content creator. I just wanted to do it all myself. It's in my head and I have trouble telling others, describing what's in my head. And Kristin and our producers have helped me to be able to give a little bit of control to others who are really good at what they do. And that's really the only way that we've been able to venture out into all these different things we've talked about.Eric Topol (25:12):Well, I think it comes down to, besides your ability to get to people in terms of their laughter receptors, you have this incisive observer capability. And that's one of the things I don't, I can't fathom because when you can understand the nuances of each specialty or of each part of healthcare, and you haven't necessarily interacted with these specialists or at least in recent years, but you nail it every time. I don't know how you do it, really that observational, is that a central quality of a comedian, you think?Will Flanary (25:52):There's definitely a big part of that. You got to get the content from somewhere. But for the specialties, it's really first about just getting the personalities down. And that doesn't change over time.Kristin Flanary (26:08):Or around the world.Will Flanary (26:09):Or around the world. We hear from people from all over the world about, oh, it's the same in Guatemala as it is in the US.Kristin Flanary (26:18):Surgeons are the same.Will Flanary (26:19):Yeah.Kristin Flanary (26:20):Emergency is the same.Will Flanary (26:21):Which has been really cool to see. But so, I draw on my experience interacting with all these specialties back in my med school and intern days. You're right, as an ophthalmologist, we don't get out very much.Eric Topol (26:33):No.Will Flanary (26:35):So very few people have ever seen an ophthalmologist. We do exist. But then beyond that, I do have to include some actual medical things. And so, I actually, I do a lot of research. I find myself learning more about other fields sometimes than I do in my own field. So especially the further out I get from med school, I know less and less.Eric Topol (27:00):Yeah, that's what I was thinking. But you're always spot on. It's interesting to get that global perspective from both of you. Now you're still doing surgery and practicing ophthalmology. Have you reduced it because this has just been taking off so much more over the recent years or keeping it the same?Will and Kristin Flanary (27:21):Nope, I’m still. Do you know how many years I had to come along on all of this medical training? He is not allowed to give this up.Will Flanary (27:29):I know there's something called a sunk cost fallacy, but this is no fallacy. There's enough of a sunk cost. I got to stick with it. No, I still enjoy it. That's the thing. It actually, it informs my comedy, it grounds me. All of the social media stuff is built upon this medical foundation that I have. And if I stopped practicing, I guess I could maybe cut back. But I'm not planning on doing that. If I stop practicing medicine, I feel like it would make my content less.Kristin Flanary (28:07):Authentic.Will Flanary (28:08):Less authentic, yeah. That's a good way to put it.Eric Topol (28:09):Yeah, no, that makes a lot of sense. That's great you can get that balance with all the things you're doing.Will Flanary (28:17):And if I stop practicing medicine, they're not going to invite me to any more commencement addresses, Dr. Topol. So I got to draw the line somewhere.Eric Topol (28:28):One of the statements you made at some point earlier was, it was easier to go to become a doctor than to try to be a comedian. And yeah, I mean you proven that.Will Flanary (28:38):A lot of ways. That's true.Eric Topol (28:40):Wow. I am pretty awestruck about the rarefied talent that you bring and what you both have done for medicine today. And the thing is, you're so young, you have so much time ahead to have an impact.Will Flanary (28:57):You hear that Kristin, we're young. Look at that.Kristin Flanary (29:00):That's getting less and less true.Will Flanary (29:01):Kristin, she just turned 40. It's right around the corner for me. So I don't know.Will Flanary (29:11):We got some years left.Eric Topol (29:12):You're like young puppies. Are you kidding? You're just getting started. But no, I think that what you brought to medicine in terms of comedy, there's no other entity, no person or people like you have done. And just the last thing I want to ask you about is, you have a platform for advocacy. You've been doing that. We talked about co-survivor. We talked about nurturing the human qualities in physicians like creativity and also taking on the insurance companies, which are just monstrous. I'll link a couple of those, but the brain MRI one or the Texaco.Will Flanary (29:54):Texaco Mike.Eric Topol (29:55):Yeah, that one is amazing. But there is so many. I mean, you've just taken them apart and they deserve every bit of it. Do you have any other targets for advocacy or does that just kind of come up as things go?Will Flanary (30:08):It kind of comes up as things go. There's things I keep harping on. The prior authorization reform, which I've helped in a couple of different states. There's a lot of good people around the country doing really good work on prior authorization and reforming that whole process. And I've been able to just play a small part in that in a couple of different ways. And it's been really fun to do that. And so, I do plan on continuing that crusade as it were. There's certain things I'd like to see. I've been learning more about what pharmacists are dealing with as well as a physician. Unfortunately, we are very separate in a lot of ways and just how we come up in medicine. And so, I have had my eyes opened a lot to what community pharmacists are dealing with. For all the terrible things that we have to deal with as physicians in the healthcare system. Pharmacists have just as much, if not more of the things that they're doing that are threatening their livelihoods. And so, I had love to see some more reform on the PBM side of things, pharmacy benefit managers, Caremark, Optum, all of them. They're causing lots of problems.Eric Topol (31:24):I couldn't agree with you more. In fact, I'm going to have Mark Cuban on in a few weeks and we're going to get into that. But the pharmacists get abused by these chains.Will Flanary (31:33):Oh, it's bad. It's really bad.Eric Topol (31:35):Horrible, horrible. I feel, and every time I am in a drugstore working with one of them, I just think what a tough life they have to deal with.Will Flanary (31:45):I guess from an advocacy standpoint, the good news is that there's never a shortage of terrible injustices that are being foisted upon the public and physicians and healthcare workers.Kristin Flanary (31:59):Yes. The US healthcare system is ripe for advocacy.Will Flanary (32:01):Yes. And that's a lesson that I tell people too, and especially the med students coming up, is like, there's work to be done and get in touch with your state societies and there's always work to be done.Eric Topol (32:18):Now you've stayed clear of politics. Totally clear, right?Will Flanary (32:24):For the most part, yeah. Yeah. It depends on what you consider politics. It depends on what you consider politics.Eric Topol (32:32):It being election day, you haven't made any endorsements.Will Flanary (32:36):I haven't. And I don't know. I can only handle so much. I've got my things that I really care about. Of course I'm voting, but I want to talk on the things that I feel like I have the expertise to talk about. And I think there's nothing wrong with that. Everybody can't have an opinion on everything, and it means something. So I am happy to discuss the things that I have expertise about, and I'm always on the side of the patient and wanting to make life better for our patients. And that's the side I'm on.Kristin Flanary (33:25):I think also he never comes out and explicitly touches on certain topics, but it's not hard to tell where he falls.Will Flanary (33:34):If you really want read into it all.Kristin Flanary (33:38):It's not like it's a big secret.Eric Topol (33:40):I thought that too. I'm glad you mentioned it, Kristin. But it doesn't come out wide open. But yeah, it's inferred for sure.Eric Topol (33:49):I think the point being there is that because you have a reach, I think there's no reach that it has 4 million plus people by your posts and no less the tours and keynotes and everything else. So you could go anywhere but sticking to where you're well grounded, it makes a lot of sense. And anyway, I am going to be staying tuned. This is our two-year checkup. I'm hoping you're going to come to San Diego on your next tour.Kristin Flanary (34:21):We're working on 2025 plans.Will Flanary (34:23):Oh, we got more shows coming up. And we'll hit up other parts of the country too.Eric Topol (34:28):I feel like I got to meet you in person, give you a hug or something. I just feel like I'm missing out there. But it's just a joy to have had a chance to work with you on your podcast. And thanks for coming back on one of mine. There's lots of podcasts out there, but having you and joining you is such fun. So thank you.Will Flanary (34:54):This has been great. Thank you for having us.Kristin Flanary (34:55):Yeah, thank you.*****************************************Thank you for reading, listening and and subscribing to Ground Truths.If you found this fun and informative please share it! Yes, laughter is the best medicine.All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.Note on Exodus from X/twitter:Many of you have abandoned the X platform for reasons that I understand. While I intend to continue to post there because of its reach to the biomedical community, I will post anything material here in the Notes section of Ground Truths on a daily basis and cover important topics in the newsletter/analyses. Get full access to Ground Truths at erictopol.substack.com/subscribe