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In this science-focused episode of the Dr. GPCR podcast, we meet Dr. Ian Chronis, a freshly minted PhD from the University of Michigan. While his academic roots started in classical history and ancient Greek, Ian's curiosity pulled him toward chemistry, then pharmacology, and eventually into the complex world of GPCR signaling. His story is a testament to the power of staying open to change and following emerging scientific questions wherever they lead.Ian's doctoral work focused on two key GPCR systems: the well-characterized β2-adrenergic receptor and the lesser-known proton-sensing receptor GPR65. In the former, he explored how PKA phosphorylation modulates receptor interactions and discovered a regulatory role for 14-3-3 proteins. But it's GPR65 — a receptor that constitutively internalizes and signals from acidic endosomes — that has captured Ian's attention and become the centerpiece of his current research. Unlike classical GPCRs, GPR65 uses non-canonical internalization mechanisms, presenting new opportunities to uncover novel biology.The receptor's ability to signal within the tumor microenvironment and immune cells makes it an emerging drug target, especially in cancer immunotherapy. However, there are still major gaps: no selective ligands, little clarity on its internalization machinery, and limited tools to modulate its function. Ian's wish list? A high-affinity agonist and antagonist to begin untangling these questions. Until then, he's carefully optimizing pH-based assays and preparing for next steps in a postdoctoral lab focused on more physiological and therapeutic systems.Whether he's decoding novel trafficking pathways or reflecting on career strategy, Ian brings a balanced perspective that's both ambitious and grounded. His advice to peers? Attend talks outside your field, learn constantly, and surround yourself with people who make science sustainable. This episode is a must-listen for those navigating the intersection of curiosity, technical rigor, and translational potential in the GPCR research community.Watch the video version of this podcast episode:https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-164-with-dr.-ian-chronis---------------------------------Become a #DrGPCR Ecosystem Member---------------------------------Imagine a world in which the vast majority of us are healthy.The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of #GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together.---------------------------------To build our #GPCR Ecosystem, we created various enabling outlets.Premium YearlyPremium Yearly for TeamsDeveloping CountriesAre you a #GPCR professional?Subscribe to the Classified GPCR Weekly NewsListen and subscribe to #DrGPCRPodcast
Ask the Right GPCR Question: A Conversation with Prof. Dmitry VeprintsevIn this episode, Yamina sits down with Prof. Dmitry Veprintsev, a molecular pharmacologist at the University of Nottingham, to discuss his scientific journey, GPCR research, and the intersection of academia and entrepreneurship.Watch the video version of this podcast episode:https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-163-with-dr.-dmitry----------------------------------Become a #DrGPCR Ecosystem Member---------------------------------Imagine a world in which the vast majority of us are healthy.Dr. GPCR is dedicated to fostering a collaborative ecosystem focused on GPCRs. By connecting researchers, sharing knowledge, and facilitating partnerships, the #DrGPCR Ecosystem provides resources to support advancements in GPCR drug discovery.The ecosystem includes a variety of initiatives designed to inform and engage the scientific community, from courses and news updates to networking opportunities.---------------------------------Learn more about Dr. GPCR: https://www.ecosystem.drgpcr.com/ Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricing Dr. GPCR Courses: https://www.ecosystem.drgpcr.com/gpcr-courses GPCR Weekly News: https://www.ecosystem.drgpcr.com/gpcr-news/categories/gpcr-weekly-news
Watch the video version of this podcast episode: https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-162-with-dr-gabriele-kockelkoren---------------------------------Become a #DrGPCR Ecosystem Member---------------------------------Imagine a world in which the vast majority of us are healthy.Dr. GPCR is dedicated to fostering a collaborative ecosystem focused on GPCRs. By connecting researchers, sharing knowledge, and facilitating partnerships, the #DrGPCR Ecosystem provides resources to support advancements in GPCR drug discovery.The ecosystem includes a variety of initiatives designed to inform and engage the scientific community, from courses and news updates to networking opportunities.---------------------------------Learn more about Dr. GPCR: https://www.ecosystem.drgpcr.com/ Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricing Dr. GPCR Courses: https://www.ecosystem.drgpcr.com/gpcr-courses GPCR Weekly News: https://www.ecosystem.drgpcr.com/gpcr-news/categories/gpcr-weekly-news
Watch the video version of this podcast episode.https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-161-with-dr.-brian-hudson---------------------------------Become a #DrGPCR Ecosystem Member---------------------------------Imagine a world in which the vast majority of us are healthy.The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together.---------------------------------To build our #GPCR Ecosystem, we created various enabling outlets. Individuals OrganizationsAre you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode.https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-160-with-dr.-remi-janicot---------------------------------Become a #DrGPCR Ecosystem Member---------------------------------Imagine a world in which the vast majority of us are healthy.The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together.---------------------------------To build our #GPCR Ecosystem, we created various enabling outlets. Individuals OrganizationsAre you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Register for the next Dr. GPCR University course before February 14th https://www.ecosystem.drgpcr.com/event-details-registration/the-practical-assessment-of-signaling-bias Spots are limited! _________ Watch the video version of this podcast episode. https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/ep-159-with-dr.-riccardo-capelli --------------------------------- Become a #DrGPCR Ecosystem Member --------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. --------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. --------------------------------- Become a #DrGPCR Ecosystem Member --------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. --------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts • • Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. --------------------------------- Become a #DrGPCR Ecosystem Member --------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. --------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
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
In this episode of FYI, Brett Winton and Charlie Roberts sit down with Sean McClain, CEO and founder of Absci, and Andreas Busch, Absci's Chief Innovation Officer, to explore how AI is transforming drug discovery and development, particularly in the biologic space. Sean shares how Absci is using AI to tackle the design problem in drug discovery, unlocking new possibilities for "undruggable" targets. Andreas provides insights into the challenges of translating these advancements into real-world therapies, drawing from his deep experience in Big Pharma. Together, they discuss the role of AI in reducing the time and cost of developing new therapies and its potential to reshape the pharmaceutical landscape.Key Points From This Episode:The role of AI in addressing previously "undruggable" targets like GPCRs and ion channels.How Absci's AI-driven approach has shifted from synthetic biology to designing antibodies and biologics for drug discovery.The importance of leveraging partnerships with pharma companies like AstraZeneca and Merck to unlock novel biology.Andreas Busch's transition from Big Pharma to Absci, emphasizing how smaller biotech companies attract top talent and foster innovation.AI's role in shortening drug development timelines and reducing costs, allowing companies like Absci to develop differentiated assets faster.The blend of best-in-class and first-in-class strategies in Absci's portfolio, balancing risks in novel biology and proven therapeutic areas.How AI models are used to design antibodies with specific affinities and predict drug candidates, a first in antibody drug design.The critical role of integrating domain expertise, such as Andreas's experience in drug development, into AI-driven drug discovery.Insights on the future of AI in biology, predicting targets, epitopes, and potential breakthroughs in drug development.The importance of talent and culture in building cutting-edge biotech companies.s.
In this episode, we explore serotonin synthesis within enterochromaffin (EC) cells in the gut, detailing how tryptophan is converted into serotonin through enzymatic processes. We examine the role of gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), in modulating the synthesis of serotonin including impacting tryptophan hydroxylase activity. We explore serotonin's interactions with receptors on enteric neurons and vagal afferent fibers, analyzing how these signaling pathways influence gut motility. Finally, we uncover conditions and symptoms associated with low serotonin production and the importance of the intestinal microbiome. Topics: 1. Introduction to Gut-Produced Serotonin - Serotonin production within the gut. - Serotonin's role beyond mood. - Synthesis, causes of low serotonin, related GI symptoms. 2. Gut Lining Structure and Cell Types - Layers of the gut lining, focusing on the mucosa. - Description of epithelial cells, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells. - Role of enterochromaffin (EC) cells in serotonin production. 3. Serotonin Synthesis in EC Cells - Location and function of EC cells. - How EC cells synthesize serotonin from tryptophan. 4. Biochemical Pathway of Serotonin Production - Step-by-step process: conversion of tryptophan to serotonin. - Enzymes involved, including TPH1 and AADC. - Importance of tryptophan availability in serotonin synthesis. 5. Storage and Release of Serotonin in EC Cells - Role of VMAT1 in serotonin storage within vesicles. - Controlled release. 6. Triggers for Serotonin Release - Physical triggers: mechanical stretch, pressure from food intake. - Chemical triggers: microbial metabolites, bile acids. - Receptors involved (GPCRs, TGR5) and signaling pathways. 7. Release of Serotonin into Intestinal Lining Layers - Serotonin exocytosis and interaction with nearby cells. - Release of serotonin on both luminal and basolateral sides of EC cells. - How luminal and basolateral release affects gut motility and barrier function. 8. Serotonin's Role in Gut Motility - Interaction with 5-HT3 and 5-HT4 receptors on enterocytes and enteric neurons. - Activation of the enteric nervous system (ENS) in the submucosal and myenteric plexuses. - Coordination with pacemaker cells for peristaltic movement. 9. Immune Function and Serotonin in the Gut - Effect on immune cells. 10. Gut-Brain Communication via Serotonin and the Vagus Nerve - Activation of vagal afferent fibers by serotonin. 11. Contributing Factors to Low Serotonin Production - Impact of dysbiosis and reduced SCFA production. - SIBO specifically. - Intestinal inflammation in general. - Imbalanced microbiota and inflammation can disrupt EC cell function. 12. Manifestations of Low Serotonin in the Gut - Effects on motility: constipation, dysmotility... - Common GI symptoms, including bloating, discomfort, and fullness. - Association with conditions like IBS. 13. Supporting Serotonin Production in the Gut - Painting a full picture and identifying root causes. - Strategies to foster a healthy gut microbiome. - Role of sunlight and tryptophan-rich foods in serotonin production. - Stool testing for microbiome imbalances. Thanks for tuning in! "75 Gut-Healing Strategies & Biohacks" Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
In this episode of The Chain, host Nimish Gera, Ph.D., vice president of biologics at Mythic Therapeutics, speaks with Peyton Greenside, CSO and co-founder of BigHat Biosciences, about the role of AI and machine learning in antibody engineering and targeting complex modalities, including bispecifics and ADCs. Greenside also discusses the work her organization does, what BigHat is doing to ensure the quality of data to train their AI models with, the methods of approaching harder targets such as GPCRs, and certain properties that AI can optimize better.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
GPCRs are challenging to understand but crucial to truly knowing how the drugs we use in the ICU and in the anesthesia world work. In this episode we break down this foundational concept, and you can grab the accompanying cheat sheet below! [FREE DOWNLOAD] FOR THE RN OR SRNA: GPCR CHEAT SHEET[FREE DOWNLOAD] FOR THE SRNA: GRAB YOUR FREE SEE/NCE STUDY PLAN HERE [FREE DOWNLOAD] FOR THE RN: GRAB YOUR FREE ICU DRUG CHART HERE
Note: This podcast is a companion to the Ground Truths newsletter “A Big Week for GLP-1 Drugs”Eric Topol (00:06):It is Eric Topol with Ground Truths, and with me today is Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) as we get to know these family of drugs and he's a true pioneer. He's been working on this for decades. So welcome, Daniel.Daniel Drucker (00:43):Thank you.Eric Topol (00:45):Yeah, it's great to have you and to get the perspective, one of the true pioneers in this field, because to say it's blossom would be an understatement, don't you think?Daniel Drucker (00:57):Yeah, it's been a bit of a hectic three years. We had a good quiet 30 plus years of solid science and then it's just exploded over the last few years.Eric Topol (01:06):Yeah, back in 30 years ago, did you have any sense that this was coming?Daniel Drucker (01:14):Not what we're experiencing today, I think there was a vision for the diabetes story. The first experiments were demonstrating insulin secretion and patents were followed around the use for the treatment of GLP-1 for diabetes. The food intake story was much more gradual and the weight loss story was quite slow. And in fact, as you know, we've had a GLP-1 drug approved for people with obesity since 2014, so it's 10 years since liraglutide was approved, but it didn't really catch the public's attention. The weight loss was good, but it wasn't as spectacular as what we're seeing today. So this really has taken off just over the last three, four years.Eric Topol (01:58):Yeah, no, it's actually, I've never seen a drug class like this in my life, Daniel. I mean, I've obviously witnessed the statins, but this one in terms of pleiotropy of having diverse effects, and I want to get to the brain here in just a minute because that seems to be quite a big factor. But one thing just before we get too deep into this, I think you have been great to recognize one of your colleagues who you work with at Harvard, Svetlana Mojsov. And the question I guess is over the years, as you said, there was a real kind of incremental path and I guess was in 1996 when you said, well, this drug likely will inhibit food intake, but then there were gaps of many years since then, as you mentioned about getting into the obesity side. Was that because there wasn't much weight loss in the people with diabetes or was it related to the dose of the drugs that were being tested?Why Did It Take So Long to Get to Obesity?Daniel Drucker (03:11):Well, really both. So the initial doses we tested for type 2 diabetes did not produce a lot of weight loss, maybe 2-3%. And then when we got semaglutide for type 2 diabetes, maybe we were getting 4-5% mean weight loss. And so that was really good and that was much better than we achieved before with any glucose lowering drug. But a lot of credit goes to Novo Nordisk because they looked at the dose for liraglutide and diabetes, which was 1.8 milligrams once daily for people with type 2 diabetes. And they asked a simple question, what if we increase the dose for weight loss? And the answer was, we get better weight loss with 3 milligrams once a day. So they learn that. And when they introduced semaglutide for type 2 diabetes, the doses were 0.5 and 1 milligrams. But in the back of their minds was the same question, what if we increased the dose and they landed on 2.4 milligrams once a week. And that's when we really started to see that the unexpected spectacular weight loss that we're now quite familiar with.Eric Topol (04:16):Was there also something too that diabetics don't lose as much weight if you were to have match dose?Daniel Drucker (04:22):Yeah, that's a general phenomenon. If one goes from either diet to bariatric surgery, and certainly with weight loss medicines, we tend to see maybe two thirds to three quarters of the amount of weight loss in people with type 2 diabetes. We don't really understand it. The brain pathways are probably resistant to some of the pathways that are activated that lead to weight loss, and it's really an interesting observation that needs further study.The Brain EffectEric Topol (04:50):Yeah, it's fascinating really. And it might've at least in part, held up this progress that has been truly remarkable. Now, recently you published a paper among many, you're a very prolific scientist, of course, physician scientist, but back in December in Cell Metabolism was a very important paper that explored the brain gut axis, the ability to inhibit inflammation and the mechanism through Toll-like receptors that you were seeing that. So maybe you could summarize the fact that you saw this, you were quoted in this Atlantic piece by Sarah Zhang, the science behind Ozempic was wrong. The weight loss effects of GLP-1 drugs have little to do with the gut and basically claiming that it's related to the effects on the brain, which of course could be reduced inflammation, reduced or inhibiting centers of addiction craving, that sort of thing. So how do you interpret your recent results and ongoing studies regarding GLP-1's effect on the brain?Daniel Drucker (06:02):Sure, so to be clear, I don't think that was a quote. I never would've said the science behind Ozempic was wrong. I think that was a headline writer doing what they do best, which is catching people's attention. I think what I was trying to say is that where this field started with insulin secretion first and then weight loss second, those are clearly very important pharmacological attributes of GLP-1. But physiologically, if we take GLP-1 away or we take the receptor away, you don't really develop diabetes without GLP-1. You don't really gain a lot of weight without GLP-1. So physiologically it's not that important. Why do we have GLP-1 in the distal gut? I think physiologically it's there to defend against infection and reduce gut inflammation. But we noticed that GLP-1 reduces inflammation in many different places in the heart and blood vessels and in the liver and many organs where you don't see a lot of GLP-1 receptors and you don't see a lot of GLP-1 receptors on immune cells.Daniel Drucker (07:04):So that really led us to the question, well, how does it work and affect all these organs where we don't see a lot of the receptors? And that's where we landed on the brain. Obviously the nervous system can communicate with many different cell types in almost every organ. And we identified neurons that expressed the GLP-1 receptor, which when blocked abrogated or completely eliminated the ability of GLP-1 to reduce inflammation in the periphery in white cells or in lungs. So it's been known for some time that the brain can control the immune system. So this is just the latest piece in the puzzle of how GLP-1 might reduce inflammation.Eric Topol (07:49):And just to be clear, I was quoting the Atlantic headline, not you that you were quoted within that article, but this is something that's really interesting because obviously GLP-1 is made in the brain in certain parts of the brain, it's transient in terms of its half-life made from the gut. But when we give these drugs, these agonists, how does it get in the brain? Because isn't there a problem with the blood brain barrier?Daniel Drucker (08:22):So I don't think the drugs get into the brain very well. We have a lot of data on this, so people have done the classic experiments, they either make radioactive ligands or fluorescent ligands, and they look how much gets in it and not very much gets in beyond the blood-brain barrier. And we also have big drugs that are immunoglobulin based and they work really well, so they don't get into the brain very much at all. And so, the way I describe this is that GLP-1 talks to the brain, but it doesn't directly get into the brain to meaningful extent, it does communicate somewhat there are areas obviously that are accessible in the area of the stream and circumventricular organs, but most of the time we have this communication that's not well understood that results in the magic that we see. And there are some discussions around for the neurodegenerative disease story where GLP-1 is being looked at in Parkinson's disease and in people with Alzheimer's disease. Would you be able to get more benefit if you could get the drugs into the brain to a greater extent, or would you simply increase the adverse event profile and the adverse response? So really important area for study as we begin to go beyond diabetes and obesity.Eric Topol (09:41):Yeah, I mean as you're pointing out, there's two ongoing trials, pretty large trials in Alzheimer's, early Alzheimer's, which may be a little bit too late, but at any rate, testing GLP-1 to see whether or not it could help prevent progression of the disease. And as you also mentioned, diseases and Parkinson's. But I guess, so the magic as you referred to it, the gut -brain axis so that when you give the GLP-1 family of drugs, we'll talk more about the double and triple receptor in a moment, but when you give these drugs, how does the message you get from the gut to the brain would you say?Daniel Drucker (10:27):So pharmacologically, we can give someone or an animal the drug, it does reach some of the accessible neurons that have GLP-1 receptors, and they probably transmit signals deeper into the brain and then activate signal transduction. So one way to look at it, if you use c-fos, the protein, which is an immediate early gene, which is increased when we activate neurons, we see rapid activation of c-fos in many regions that are deep within the brain within minutes. And we know that GLP-1 is not getting directly to those neurons, but it's activating pathways that turn on those neurons. And so, there's probably a very intricate set of pathways that sense the GLP-1 and the accessible neurons and then transmit those signals deeper into the brain.Double and Triple Receptor AgonistsEric Topol (11:18):Okay, well that makes sense. Now, as this has been moving along in obesity from semaglutide to tirzepatide and beyond, we're seeing even more potency it appears, and we have now double and triple receptors adding into glucagon itself and the gastric inhibitory polypeptide, and there's mixed data. So for example, the Amgen drug has the opposite effect on GIP as does the dual receptor, but comes out with the same weight loss I guess. How do we understand, I mean you know these gut hormones inside and out, how do we get such disparate results when you're either blocking or revving up a peptide effect?Daniel Drucker (12:13):Yeah, it's a mystery. I always sort of joke that you've invited the wrong person because I don't fully understand how to reconcile this honestly. There are some theories you could say that tirzepatide may possibly desensitize the GIP receptor, and that would align with what the GIP receptor blocking component is. And so, I think we need a lot of research, we may actually never know in humans how to reconcile these observations. I think we can do the experiments in animals, we're doing them, other people are doing them to look at the gain and loss of function and use best genetics. But in humans, you'd have to block or activate these receptors in very specific populations for a long period of time with tools that we probably don't have. So we may not reconstruct. We may end up with Maritide from Amgen that's producing 15-20% plus weight loss and tirzepatide from Lilly, that's spectacular, that's producing more than 20% weight loss. And yet as you mentioned at the GIP level, they have opposite effect. So I don't think we fully understand. Maybe your next guest will explain it to you and invite me on. I'd be happy to listen.Eric Topol (13:27):Well, I don't know. I don't think anybody can explain it. You've done it as well as I think as possible right now. But then we have the triple receptor, which it seems like if you take that drug, you could just go kind of skeletal. It seems like there's no plateau and its effect, that is I guess is it retatrutide, is that the name of it?Daniel Drucker (13:47):Retatrutide, yeah.Eric Topol (13:48):Retatrutide, okay. And then of course we're going on with potentially oral drugs or drugs that last for a year. And where do you see all that headed?Daniel Drucker (14:00):So I think the way I describe innovation in this field is there are two buckets that we've talked about today. So one bucket is the new molecule, so we're going to have all kinds of different combinations that will be peptides, that will be small molecule orals, the NIH is funding innovative programs to see if we can develop cell-based factories that produce GLP-1. There are gene editing and gene therapy approaches. So there are going to be multiple different molecular approaches to delivering molecules that are better and hopefully easier to take maybe once monthly, maybe every six months. So that's really exciting. And the other obvious bucket is the disease that we're targeting, so we started off with type 2 diabetes. We're now firmly established in the obesity field. In your field, we've seen consistently positive cardiovascular outcome trials. We had a press release a few months ago in October - November saying that semaglutide reduces chronic kidney disease. We have trials underway with peripheral artery disease with Parkinson's disease, with Alzheimer's and a number of neuropsychiatric conditions. So I think we're going to see both innovation on the molecule side as well as expanding if the trials are positive, expanding clinical indication. So it's going to be a pretty exciting next couple of years.Eric Topol (15:21):Right, no question. And as you well know, just in the past week, the FDA gave the green light for using these drugs for heart failure with preserved ejection fraction, which was an important randomized trial that showed that. Now there's got to be some downsides of course there's no drug that's perfect. And I wanted to get your comments about muscle loss, potentially bone density reduction. What are the downsides that we should be thinking about with these drugs?Side EffectsDaniel Drucker (15:54):Sure, so the known side effects are predominantly gastrointestinal. So we have nausea, diarrhea, constipation and vomiting. And very importantly, if those side effects are severe enough that someone can't eat and drink for 24 hours, we need to tell them you have to seek medical attention because some people will get dehydrated and rarely get acute kidney injury. This is rare, but it's described in many of the outcome trials, and we definitely want to avoid that. Gallbladder events are probably one in several hundred to one in a thousand, and that can be anywhere from gallbladder inflammation to gallbladder stones to biliary obstruction. Don't fully understand that although GLP-1 does reduce gallbladder motility, so that may contribute. And then very rarely we're seeing reports of small bowel obstruction in some people difficult to sort out. We don't really see that in the large clinical trials, but we have to take people at there were, we haven't seen an imbalance in pancreatitis, we haven't seen an imbalance of cancer.Daniel Drucker (17:01):There is no evidence for clinically significant bone disease either at the level of reduced bone densities or more importantly at the level of fractures. And we have a lot of real world data that's looked at that. Now muscle losses is really interesting. So when the initial drugs were approved, they didn't produce much weight loss. We didn't think about it. Now that we're getting the 15 20% plus, the question is, will we see clinically significant sarcopenia? And I use the word clinically significant carefully. So we definitely see muscle lean mass loss on a DEXA scan, for example. But what we're not seeing so far are people who are saying, you know what my grip strength is weak. I can't get up off the chair. I have trouble reaching up into the cupboard. My exercise or walking capacity is limited. We're not seeing that. In fact, we're seeing the opposite.Daniel Drucker (17:53):As you might expect, people are losing weight, they're less achy, they can move more, they can exercise more. So the question is buried within that data, are there some individuals with real clinical sarcopenia? And as we get to 25% weight loss, it's very reasonable to expect that maybe we will see some individuals with clinical sarcopenia. So you're very familiar. There are half a dozen companies developing medicines to promote fat mass loss and spare muscle with or without semaglutide or tirzepatide. And this is a really interesting area to follow, and I don't know how it's going to turn out. We really have to see if we are going to see enough clinically significant muscle loss and sarcopenia to merit a new drug category emerge, so fascinating to follow us.Eric Topol (18:46):No, I'm so glad you reviewed that because the muscle loss, it could be heterogeneous and there could be some people that really have some substantial sarcopenia. We'll learn more about that. Now that gets me to what do we do with lifelong therapy here, Daniel, where are we going? Because it seems as though when you stop these drugs, much of the benefit can be not potentially all, but a substantial amount could be lost over time. Is this something that you would view as an insulin and other hormonal treatments or how do you see it?The Question of ReboundDaniel Drucker (19:26):Yeah, so it's fascinating. I think that traditional view is the one that you just espoused. That is you stop the drug, you regain the weight, and people are concerned about the rebound weight and maybe gaining more fat and having less favorable body composition. But if you look at the data, and it's coming very fast and furious. A few months ago, we saw data for a tirzepatide trial, one of the surmount obesity trials, the first author was Louis Aronne in New York and they gave people tirzepatide or placebo for 38 weeks. And then they either continue the tirzepatide or stop the tirzepatide. One year later, so no tirzepatide for one year, more than 40% of the people still managed to keep at least 10% of their weight off, which is more than enough in many people to bestow considerable metabolic health. So I think there are going to be people that don't need to take the medicines all the time for weight loss, but we must remember that when we're excited about heart attacks and strokes and chronic kidney disease, there's no evidence that you can stop the medicines and still get the benefits to reduce those chronic complications.Daniel Drucker (20:46):So we're going to have to get much more sophisticated in terms of a personalized and precision medicine approach and ask what are the goals? And if the goals are to reduce heart attack strokes and death, you probably need to stay on the medicine if the goals are to achieve weight loss so that you can be metabolically healthy, there may be a lot of people who can come off the medicine for considerable amounts of time. So we're just learning about this. It's very new and it's really exciting.Suppressing Inflammation as the Common ThreadEric Topol (21:11):Yeah, no question. And just going back to the inflammation story in heart disease, it was notable that there were biomarkers of reduced inflammation in the intervention trial before there was any evidence of weight loss. So the anti-inflammatory effects here seem to be quite important, especially with various end organ benefits. Would you say that's true?Daniel Drucker (21:35):Yeah, I think that's one of my favorite sort of unifying theories. If we step back for a minute and we come into this and we say, well, here's a drug that improves heart disease and improves liver inflammation and reduces chronic kidney disease and may have some effect on atherosclerosis and is being studied with promising results and neurodegenerative disease, how do we unify all that? And one way is to say all of these chronic disorders are characterized by a component of chronic inflammation. And Eric, it's fascinating. I get reports from random strangers, people who've been on tirzepatide or people who have been on semaglutide, and they tell me, and you'll be fascinated with this, they tell me, my post Covid brain fog is better since I started the drug. They send me pictures of their hands. These are people with chronic arthritis. And they say, my hands have never looked better since I started the drug. And they tell me they've had ulcerative colitis for years on biologics and all of a sudden it's in remission on these drugs. So these are case reports, they're anecdotes, but they're fascinating and quite consistent with the fact that some people may be experiencing an anti-inflammatory effect of these medicines.Eric Topol (22:55):And I think it's notable that this is a much more potent anti-inflammatory effect than we saw from statins. I mean, as you know, well they have an effect, but it's not in the same league, I don't think. And also the point you made regarding this is a very good candidate drug class for Long Covid and for a variety of conditions characterized by chronic inflammation. In fact, so many of our chronic diseases fit into that category. Well, this is fascinating, and by the way, I don't know if you know this, but we were both at Johns Hopkins at the same time when you were there in the early eighties. I was there as a cardiology fellow, but we never had a chance to meet back then.Daniel Drucker (23:41):So were you just ahead of Cricket Seidman and the whole team there, or what year was that?Eric Topol (23:46):Just before them, that's right. You were there doing, was it your internship?Daniel Drucker (23:50):I was doing an Osler internship. I think Victor McKusick loved to have a Canadian every year to recognize Osler, one of the great Canadians, and I was just lucky to get the slot that year.Eric Topol (24:04):Yeah, it's wild to have watched your efforts, your career and your colleagues and how much of a profound impact. If you were to look back though, and you were to put this into perspective because there were obviously many other hormones along the way, like leptin and so many others that were candidates to achieve what this has. Do you think there's serendipity that play out here or how do you kind of factor it all together?Daniel Drucker (24:38):Well, there there's always serendipity. I mean, for decades when people would write review articles on the neuropeptides that were important for control of hunger and satiety and appetite circuits, I would open the article, read it, and I'd say, darn, there's no GLP-1 on the figure. There's no GLP-1 or receptor on the figure, but there's leptin and agouti and the POMC peptides and all the melanocortin and so on and so forth, because physiologically, these systems are not important. As I mentioned, you don't see childhood obesity or genetic forms of obesity in people with loss of function mutations in the GLP-1 sequence or in the GLP-1 receptor. You just don't see a physiologically important effect for having low GLP-1 or having no GLP-1. And that's of course not the case for mutations in NPY or the melanocortin or leptin, et cetera.Other EffectsDaniel Drucker (25:36):But pharmacologically, it's been extraordinarily difficult to make drugs out of these other peptides and pathways that we talked about. But fortuitously or serendipitously, as you point out, these drugs seem to work and amazingly GPCRs are notoriously prone to desensitization. We use that in clinical medicine to turn off entire circuits. And thankfully what goes away with GLP-1 are the adverse effects. So nausea, vomiting, diarrhea, constipation, we see those during the first few weeks and then there's tachyphylaxis, and they generally go away in most people, but what doesn't go away through good fortune are the ability of GLP-1 to talk to those brain circuits and say, you know what? You're not hungry. You don't need to eat. You don't need to think about food. And that's just good luck. Obviously pharmacologically that's benefited all of us working in this area.Eric Topol (26:31):It's extraordinary to be able to get desensitized on the adverse effects and not lose the power of the benefit. What about addiction that is, whether it's alcohol, cigarettes, gambling, addictive behavior, do you see that that's ultimately going to be one of the principal uses of these drugs over time?Daniel Drucker (26:55):The liver docs, when I give a talk at a metabolic liver disease meeting, they say we love GLP-1 because not only might it take care of liver disease, but there are still some people that we see that are having problems with alcohol use disorders and it might also reduce that. And obviously there are tons of anecdotes that we see. If you go on social media, and you'll see lots of discussion about this, and there's a hundred or so animal paper showing that addiction related dependence behaviors are improved in the context of these medicines. But we don't have the clinical data. So we have a couple of randomized clinical trials, small ones in people with alcohol use disorder, very unimpressive data. We had a trial in people with smoking, didn't really see much, although interestingly, they noted that people drank less alcohol than they did the smoking trial. So there are dozens and dozens of trials underway now, many investigator initiated trials looking at whether it's nicotine or cocaine or cannabinoids or all kinds of compulsive behaviors. I think in the next 12 to 24 months, we're going to start to learn are these real bonafide effects that are seen in large numbers of people or are these just the anecdotes that we won't get a very good complete response. So it's really exciting neuroscience and we're going to learn a lot over the next couple of years.Eric Topol (28:20):Yeah, no, it's a fascinating area which just extends the things that we've been discussing. Now, let's say over time, over the years ahead that these drugs become because of the competition and various factors, perhaps in pill form or infrequent dosing, they become very inexpensive, not like they are today.Daniel Drucker (28:44):That'd be great speaking as a non-pharmaceutical physician.Eric Topol (28:48):Yeah, yeah, no, these companies, which of course as you well know, it accounts for the number one economy in Denmark and is having a big impact in Europe. And obviously Eli Lilly is now the most valued biopharma company in the world from all these effects are coming from this drug class, but let's just say eventually it's not expensive and the drug companies are not gouging and pleasing their investors, and we're in a different world. With all these things that we've been discussing, do you foresee a future where most people will be taking one form or another of this family of drugs to prevent all these chronic conditions that we've just been discussing independent of obesity, type 2 diabetes, the initial frontier? Do you think that's possible?Daniel Drucker (29:42):Yeah, I'm a very conservative data-driven person. So today we don't have the data. So if I was in charge of the drinking water supply in your neighborhood and I had unlimited free cheap GLP-1, I wouldn't dump it in there just yet. I don't think we have the data, but we have trials underway, as you noted for Alzheimer's disease, a challenging condition for our society with a huge unmet need if like fingers crossed, if semaglutide does show a benefit for people living with early Alzheimer's disease, if it helps for Parkinson's, if it helps for metabolic liver disease, there are also studies looking at aging, et cetera. So it's possible one day if we have a lot more data that we will begin to think, okay, maybe this is actually a useful medicine that should deserve much more exposure, but today we just don't have the data.Eric Topol (30:38):Absolutely. I couldn't agree more, but just wanted to get you kind of speculate on that a bit off script if you will, but what your thoughts were, because this will take a long time, get to that point, but you just kind of wonder when you have an absence of chronic significant side effects overall with these diverse and relatively potent benefits that cut across many organ systems and as you just mentioned, might even influence the aging process, the biologic process.Worsening InequitiesDaniel Drucker (31:10):There's another related sort of angle to this, which is that the accessibility of these medicines is very challenging even in well-developed countries, the United States, Europe, et cetera, and we have hundreds of millions of people in the global south and less well-developed economies that are also challenged by heart disease and diabetes and obesity and chronic kidney disease and liver disease. And I think we need to start having conversations and I think they are happening just like we did for HIV and just like we did for hepatitis and certainly we did very quickly for the Covid vaccines. We need to think out of the box and say we need to help people in other parts of the world who may not have access to the medicines in their current form and at their current pricing. And I think these are really important moral and ethical discussions that need to be happening now because soon we will have small molecules and the price will come down and we need to make sure it's not just people in well-developed countries that can afford access to these medicines. I think this is a great opportunity for pharmaceutical companies and the World Health Organization and other foundations to really think broadly about how we can benefit many more people.Eric Topol (32:29):I couldn't agree with you more and I'm so glad you emphasize that because we can't wait for these prices to come down and we need creative ways to bridge, to reduce inequities in a vital drug class that's emerged to have far more applicability and benefit than it was initially envisioned, certainly even 5, 10 years ago, no less 30 years ago when you got on it. So Daniel, I can't thank you enough for this discussion. Really a candid discussion reviewing a lot of the things we do know, don't know will know someday perhaps. I just want to note, I know so many people are cheering for you and your colleagues to get recognized further like by the Nobel folks in the years ahead. I think it's pretty darn likely and hopefully when we get a chance to visit again in the years ahead, we'll unravel some of the things that we discussed today that we didn't know the answers and that you as a really an authority and pioneer in the field. Also, I could admit that there's a ways to go to really understand the boundaries if there are boundaries here for how these drugs are going to be used in the years ahead.Daniel Drucker (33:51):Yeah, it's another great story for basic science and bench to bedside, and it's just another story where none of us could have predicted the outcomes that we're talking about today to their full extent. And so to the extent that we can convince our governments and our funding agencies to really fund discovery science, the benefits are never apparent immediately. But boy, do they ever come in spades later on in an unpredictable manner. And this is just a great example.Eric Topol (34:20):Yeah, I also would say that this work cracking the case of obesity, which has been a stumbling block, I ran a big trial with Rimonabant, which was a failure with the neuropsychiatric side effects and suicidal ideation that had to get dropped. And there's many others like that as you know, very well Fen-Phen, and a long list. And the fact that this could do what it's doing and well beyond just obesity is just spectacular. And what I think it does, what you just mentioned, Daniel, is the basic science work that led to this is I think an exemplar of why we should put in these efforts and not expect immediate benefits, dividends of those efforts. Because look what's happened here. If you can break through with obesity, imagine what lies ahead. So thanks so much for joining and we'll look forward to continuing to follow your work. I know you're publishing the same pace, exceptional prolific pace over many, many years, and I'm sure that's going to continue.Daniel Drucker (35:34):Well, I have a great team and so it's a pleasure me to go into work and talk to them every day.********************Thanks for listening to/reading Ground Truths.Please share if your found this podcast informative Get full access to Ground Truths at erictopol.substack.com/subscribe
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Today, I sat down with Dr. Brian Kobilka, Professor in the Department of Molecular and Cellular Physiology at Stanford University School of Medicine. Dr. Kobilka is an expert on a class of receptors called G protein-coupled receports, or GPCRs, that are essential in a majority of biological processes including light, flavor, and odor perception and in the activity of adrenalin, dopamine, and serotonin. In fact, currently approximately half of all pharmaceuticals on the market target GPCRs. In the mid 1980s Dr. Kobilka and his colleagues from the Robert Lefkowitz lab were the first to clone the gene for an important GPCR called the beta2-adrenergic receptor, and later he and his collaborators were the first to determine its molecular structure, which served as the basis for understanding all subsequent GPCRs and creating drugs to target them. This work proved to be revolutionary in many areas of science and medicine, such that in 2012, Kobilka was awarded the Nobel Prize in Chemistry for his contributions to understanding GPCRs. In this interview, we talk about these amazing findings and the recent advances in understanding this important class of receptors. Title music: World Is Holding Hands by WinnieTheMoog https://creativecommons.org/licenses/by/4.0/legalcode
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
Watch the video version of this podcast episode. ------------------------------------------- Become a #DrGPCR Ecosystem Member ------------------------------------------- Imagine a world in which the vast majority of us are healthy. The #DrGPCR Ecosystem is all about dynamic interactions between us working towards exploiting the druggability of # GPCRs. We aspire to provide opportunities to connect, share, form trusting partnerships, grow, and thrive together. ------------------------------------------- To build our #GPCR Ecosystem, we created various enabling outlets. Individuals Organizations ------------------------------------------- Are you a #GPCR professional? Subscribe to #DrGPCR Monthly Newsletter Listen and subscribe to #DrGPCR Podcasts Listen and watch GPCR-focused scientific talks at #VirtualCafe.
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