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Obesity Is a Brain Disease, Not a Willpower Problem · The LIVING Room Podcast | Inside The WNDR Lab

• 0:00
  SPEAKER_01: Today I am joined by Professor Metal Strope.
• 0:03
  SPEAKER_01: Professor Strope was the scientist responsible for discovering the GLP1 glucogon dualagonist that we now more commonly know as Mundomaro and Zeppelin.
• 0:13
  SPEAKER_01: But not only then metabolist has gone on to discover the tripolagonist that will be the next blockbuster drug being named as retentritolide.
• 0:21
  SPEAKER_01: In this episode, he's going to tell us about the next generation of drugs, the quintupolagonists.
• 0:26
  SPEAKER_01: If you've ever had any questions on hunger, appetite, body weight, body composition, desire to lose or gain weight, and the effects of these drugs on your short-term and long-term health, this is the episode for you.
• 0:51
  SPEAKER_01: Welcome to the living room.
• 0:53
  SPEAKER_00: Wonderful to be here.
• 0:54
  SPEAKER_00: Thank you for having me.
• 0:55
  SPEAKER_01: I know you've had an incredibly long day.
• 0:57
  SPEAKER_01: Um, so thank you for making time for it.
• 1:00
  SPEAKER_01: Can we start 30 years ago?
• 1:03
  SPEAKER_01: Let's go back when you know obesity, appetite regulation, weight management wasn't a problem that we really had a good solution for.
• 1:15
  SPEAKER_01: Um, you know, millions of people had nowhere to go, hadn't didn't have a really good understanding of how to manage their weight, their body composition, and were actually made to feel like it was a discipline problem, it was all their fault.
• 1:31
  SPEAKER_01: Um and that's when you started researching in this field.
• 1:35
  SPEAKER_01: You know, fast forward to today, things are very, very different, thanks in large part to the work that you've you've done.
• 1:41
  SPEAKER_01: How and why did you get into that in the first place?
• 1:45
  SPEAKER_00: Well, I was a young physician working at university hospital in in Munich.
• 1:50
  SPEAKER_00: And when I was not in the lab, working on neuroendocinology and hormones, I was seeing patients with, you know, frequently um obesity, significant levels of obesity, diabetes.
• 2:05
  SPEAKER_00: And after a while, I just couldn't believe that in our daily routine, all we had to offer for somebody who was uh significantly overweight was um the advice that already Hippocrates gave, you know, eat less and move more.
• 2:22
  SPEAKER_00: It didn't work then and it isn't working today on an epidemiological level.
• 2:26
  SPEAKER_00: That was one version.
• 2:28
  SPEAKER_00: Or we call a surgeon and see if maybe a gastic bypass was an option.
• 2:33
  SPEAKER_00: I said, well, there had to be something else.
• 2:35
  SPEAKER_00: You know, we um we have figured out so many fantastic therapies for so many diseases, and we're sort of capitulating uh with obesity.
• 2:46
  SPEAKER_00: So when I started to think about and talk about, we we need to find something, and how about a hormone-based therapy?
• 2:55
  SPEAKER_00: I was told by everybody this isn't possible, you know, this is too difficult.
• 3:00
  SPEAKER_00: Um, you know, physiology is is based on evolution in the sense that we always needed to save all the calories, get all the calories in and store them because of the long winters we had to survive as a species.
• 3:13
  SPEAKER_00: So it's too important for survival of the species that all our redundant mechanisms are making sure we're gaining weight, we're not losing weight.
• 3:21
  SPEAKER_00: Meaning when you come up with any therapy, you will have massive side effects.
• 3:26
  SPEAKER_00: So it's a non-starter, forget about it.
• 3:29
  SPEAKER_00: So I thought as an endocrinologist, well, you know, we figured out a bunch of things, right?
• 3:34
  SPEAKER_00: We we have figured out contraception.
• 3:36
  SPEAKER_00: You know, reproduction is sort of important for survival of the species.
• 3:40
  SPEAKER_00: And still that that was something that could be accomplished with with hormones.
• 3:43
  SPEAKER_00: So I didn't want to give up and and and started going into research.
• 3:48
  SPEAKER_01: So then what?
• 3:49
  SPEAKER_01: So so you you push back against the notion that this wasn't possible.
• 3:54
  SPEAKER_01: And then but at the time, were were we even using gastric bypass?
• 4:00
  SPEAKER_01: Probably just about to start, right?
• 4:02
  SPEAKER_00: Not not at the level that we are currently using it or we're using it in the last decade or two, but it was there, it was uh something that that could be done and was done in in some cases.
• 4:15
  SPEAKER_00: But you're right, you know, then what is is exactly where I was because I was equally enthusiastic and naive.
• 4:23
  SPEAKER_00: Um there was no signal known, there was no pathway known that would regulate body weight and and and foot intake.
• 4:30
  SPEAKER_00: Um so luckily, um, as it sometimes goes in the life of a scientist through serendipity, there was about the time where Jeff Friedman here in New York discovered lepton.
• 4:43
  SPEAKER_00: Now that was a paper that really transformed the entire field.
• 4:47
  SPEAKER_00: I would say it started the field of molecular obesity research.
• 4:51
  SPEAKER_00: So for the first time, we had a signal, we had a gene, it was regular known to regulate body weight and uh drive satiety.
• 5:02
  SPEAKER_00: Um, and for a young endocrinologist, a hormone specialist, was oh my god, there's a new hormone.
• 5:07
  SPEAKER_00: When that when did that happen the last time, right?
• 5:10
  SPEAKER_01: Could you make you maybe before we go into that, explain to the audience what leptin is?
• 5:15
  SPEAKER_01: Because I think everyone's heard of these, you know, leptin and ghrelin scraps don't know.
• 5:19
  SPEAKER_00: It was discovered was that there was a fat mouse called the Obi Obi mouse.
• 5:24
  SPEAKER_00: Obi-Obi standing for the obese gene, Obi.
• 5:29
  SPEAKER_00: And um, everybody wanted to know why that mouse is fat.
• 5:32
  SPEAKER_00: You know, something must be missing, or that mouse must have something too much.
• 5:36
  SPEAKER_00: And and and Jeff Friedman was the one who figured it out through meticulous genetics work.
• 5:42
  SPEAKER_00: I mean, today you probably would do this in a week.
• 5:44
  SPEAKER_00: Back then it took 10 years of him focused and going into it.
• 5:48
  SPEAKER_00: Positional cloning was what it was called, what he did.
• 5:51
  SPEAKER_00: And he figured out and he found out which gene that was.
• 5:55
  SPEAKER_00: And since that gene coded for a protein, that protein, when injected, decreased body weight, it made you lean.
• 6:04
  SPEAKER_00: Uh so he he called it leptin from leptos thin in Greek.
• 6:09
  SPEAKER_00: Uh and leptin is a hormone that's secreted by fat cells.
• 6:13
  SPEAKER_00: So we not only had a new hormone, we had a new endocrine organ.
• 6:17
  SPEAKER_00: Because, you know, we thought hormones come from like the thyroid, right?
• 6:22
  SPEAKER_00: Or the the pituitary.
• 6:25
  SPEAKER_00: Um, but fat cells, aren't those just sacs that store calories?
• 6:30
  SPEAKER_00: They do something.
• 6:31
  SPEAKER_00: Now, today we know they're actually complicated organs that signal a lot of things.
• 6:36
  SPEAKER_00: Uh but back then that was completely new.
• 6:40
  SPEAKER_00: So a new endocrine organ, a new hormone, the first regulator of satiety and body weight was exciting, a breakthrough.
• 6:47
  SPEAKER_00: I mean, that that paper that came out in Nature in 1994, um, I still see myself sitting there in the hallway outside my lab and reading that and saying, okay, this is it.
• 6:58
  SPEAKER_00: I'm I'm gonna leave clinical medicine.
• 7:00
  SPEAKER_00: I want to study this, I want to understand this, because I did sense there's gotta be more than that.
• 7:06
  SPEAKER_00: There's gotta be more than one hormone.
• 7:08
  SPEAKER_01: It was 1994.
• 7:09
  SPEAKER_01: 1994.
• 7:11
  SPEAKER_01: Tells you how old I am.
• 7:12
  SPEAKER_01: Wow, I know, but relatively that's you know, we didn't know about the hormone that is responsible for making us feel full, essentially, until 1994.
• 7:23
  SPEAKER_01: Okay.
• 7:24
  SPEAKER_01: Talk to me about ghrelin.
• 7:26
  SPEAKER_00: Well, so then that was basically uh the next step of the story because, well, you know, in in science things take a while, right?
• 7:34
  SPEAKER_00: You need to understand what that really means.
• 7:36
  SPEAKER_00: And then there's the second and the third paper, and then um they're the first individuals that are actually making synthesizing leptin and uh understanding the chemistry better.
• 7:48
  SPEAKER_00: And that was happening interestingly at Eli Lilly, a company we now know a lot about, but back then they weren't really in that business, but they were interested in that.
• 7:58
  SPEAKER_00: So they were the first place where they actually made a soluble um active version of Leptin.
• 8:06
  SPEAKER_00: And when I understood that, I said, I want to go there and understand how that's done.
• 8:10
  SPEAKER_00: So back then it was very traditional, the way uh academicians were thinking about a postdoc fellowship.
• 8:17
  SPEAKER_00: They said, you gotta go to Harvard or Oxford or something like that, otherwise you're never gonna be a professor.
• 8:23
  SPEAKER_00: Yeah.
• 8:24
  SPEAKER_00: I said, yeah, well, sure, but I I want to make drugs.
• 8:27
  SPEAKER_00: Uh yeah, I and they seem to be figuring out how you make leptin, and maybe leptin is that drug.
• 8:33
  SPEAKER_00: Um so I um went for a fellowship at Eli Lilly in Indianapolis.
• 8:40
  SPEAKER_00: And um there was then I went at a start, 1997, 1998, and um there was quite a culture shock, by the way, because here's this this young guy from Munich, Germany, coming out of academia, uh, being an avid mountaineer, going to Indianapolis, which is completely flat, and there's nothing going on, and the streets are ABC 123, and you know, there's the Indy 500 once a year, but other than that, there was no.
• 9:09
  SPEAKER_00: So it was perfect for before the postdoc because it was no distraction, there's nothing to do.
• 9:14
  SPEAKER_00: Nothing to do.
• 9:15
  SPEAKER_00: Um, but uh the science was fantastic.
• 9:17
  SPEAKER_00: I had a great mentor in in Mark Hyman back then, and I met um two individuals right out of the gates uh when I started there.
• 9:27
  SPEAKER_00: One of them was Jeff Friedman, and he visited there and gave a talk, and somehow I was the one who went to lunch with him.
• 9:34
  SPEAKER_00: And you know, we connected, and I told him a little bit what I wanted to do, and we became friends uh, you know, over the years.
• 9:42
  SPEAKER_00: Um and the other one was Richard DiMorkey, uh, a peptide chemist, an expert.
• 9:48
  SPEAKER_00: He was already vice president at Ilalili, and I was the postdoc, but we you know started to talk and then later reconnected and um did a lot of research over the last 30 years together.
• 10:01
  SPEAKER_00: But my my job was as a postdoc to find another hormone, uh the hunger hormone.
• 10:10
  SPEAKER_00: And um, we didn't know what it was at the time, and I was looking in the in the wrong tissue.
• 10:15
  SPEAKER_00: I was looking in the brain because I thought, well, hunger hormone now needs to be in the brain.
• 10:19
  SPEAKER_00: Turns out it was uh in the stomach.
• 10:22
  SPEAKER_00: And there was a Japanese group of scientists who discovered this peptide called ghrelin.
• 10:28
  SPEAKER_00: And they they called it ghrelin because they thought it had to do with growth hormone release, um, which it does too, but that's not its main job.
• 10:37
  SPEAKER_00: Um and um because of the receptor we were studying, and it's a complicated signaling world, my postdoc mentor Mark Hyman and I thought, well, we think that peptide might be the Hunger hormone.
• 10:52
  SPEAKER_00: So we did a bunch of experiments really quickly, made ghrelin.
• 10:55
  SPEAKER_00: I still remember I was supposed to go on on um uh Christmas holidays with my fiancee, and I said, Well, you know, I I need to make ghrelin now.
• 11:05
  SPEAKER_00: I I don't have that much time.
• 11:06
  SPEAKER_01: How did that go down?
• 11:07
  SPEAKER_00: Yeah, that was, you know, it gave there were discussions.
• 11:10
  SPEAKER_00: Um, but it was exciting.
• 11:12
  SPEAKER_00: So I learned to make how to make peptides with the chemists, and we tested it, and it turns out, yeah, that that was it.
• 11:18
  SPEAKER_00: And today it's in the textbooks that that's the human hunger hormone.
• 11:22
  SPEAKER_00: If you inject ghrelin, if you infuse ghrelin right now, um you'll get hungry.
• 11:27
  SPEAKER_00: It increases before meals, it decreases after meals, uh and it's certainly um sort of the counterpart to leptin.
• 11:36
  SPEAKER_00: We thought of it as the yin and yang of of appetite regulation, satiety and hunger.
• 11:42
  SPEAKER_00: But it's not the only one, uh, and neither is leptin.
• 11:45
  SPEAKER_00: And that's why, likely that that's why neither of them was the answer for the obesity epidemic, pandemic.
• 11:54
  SPEAKER_00: Um, because leptin, if you give leptin, there's leptin resistance, but it doesn't do a whole lot.
• 12:01
  SPEAKER_01: Um that was going to be my super naive question.
• 12:05
  SPEAKER_01: Why not?
• 12:05
  SPEAKER_00: Why is leptin not turned into like um insulin in type 2 diabetes?
• 12:11
  SPEAKER_00: Um, because there's insulin resistance, right?
• 12:15
  SPEAKER_00: You can still give a bunch of insulin and get something done.
• 12:17
  SPEAKER_00: And you probably can't do that with leptin, but you know, there weren't leptin molecules that were that good at the time.
• 12:24
  SPEAKER_00: And then blocking the ghrelin pathway was a big disappointment.
• 12:28
  SPEAKER_00: First of all, there was very complicated.
• 12:29
  SPEAKER_00: We worked on that for 10 years, and and in the end, it didn't do a whole lot.
• 12:34
  SPEAKER_00: Probably because there's several receptors and there's several other signals, is a redundant system.
• 12:40
  SPEAKER_00: From these frustrating experiences, by the way, the idea was born that then Richard and I followed up later, that you probably need a combination of signals to really be effective in fighting obesity.
• 12:53
  SPEAKER_00: But we learned one thing, and we learned a lot of things, but one thing is the most important thing that we learned.
• 12:59
  SPEAKER_00: Um, leptin and ghrelin have something in common.
• 13:02
  SPEAKER_00: They both act in the brain.
• 13:05
  SPEAKER_00: And they achieve 95% of what they do as a hormone by acting in the brain.
• 13:11
  SPEAKER_00: And that fit very well with everything we started to learn about genetics of obesity, because all of the genes that were associated in the large G Well studies and sequencing studies with obesity seemed to be calling for something that had a function in the brain or was expressed in the brain.
• 13:28
  SPEAKER_00: In other words, science said obesity is a brain disease.
• 13:34
  SPEAKER_00: So if you want to target obesity, you probably have to target the brain.
• 13:39
  SPEAKER_01: But it was really that discovery that made science say that, right, right?
• 13:44
  SPEAKER_01: Because until that point, science didn't say obesity was a brain disease, it said it's a discipline.
• 13:51
  SPEAKER_00: There was there was always the assumption that, of course, you know, appetite probably needs uh central nervous system.
• 13:57
  SPEAKER_01: Yeah.
• 13:58
  SPEAKER_00: But um, I mean, for centuries we thought obesity is a disease of the fat cell, right?
• 14:04
  SPEAKER_00: It's uh the fat belly.
• 14:05
  SPEAKER_00: Well, yeah, that's that's where you need to look.
• 14:08
  SPEAKER_00: What year was that?
• 14:10
  SPEAKER_00: Um, so the our ghrelin paper saying it's the hunger hormone came out in 2000.
• 14:17
  SPEAKER_00: So a couple of years later.
• 14:19
  SPEAKER_00: Um, and then from there, you know, a bunch of ghrelin research uh that, as I said, was academically really interesting, um, but uh didn't give us the answer that we wanted.
• 14:31
  SPEAKER_00: And you know, traditionally a scientist is supposed to follow up once you have a discovery, follow up on that discovery for decades.
• 14:39
  SPEAKER_00: You you know, become a ghrelinologist and become the guy for that.
• 14:45
  SPEAKER_00: Um, and I was just you know getting frustrated and you know, I wanted to go back to my original mission, finding ways to treat obesity, you know.
• 14:55
  SPEAKER_00: So I was very happy that I then um I was already uh out of Ilalili and uh had finished my postdoc and was at the University of Cincinnati, where there was a great metabolism research center, and I knew there was a lot of expertise in how appetite is regulated, etc.
• 15:11
  SPEAKER_00: So uh I reconnected with Richard DiMarkey, who I had met at Lilly, because he also had left Lilly, and he's at Indiana University.
• 15:18
  SPEAKER_00: And the two of us talked and said, well, you know, can we do something together as a chemist and as a whatever physician, physiologist, that usually is only done inside Big Pharma, um, in academia, um, or with a startup company, and find a novel therapeutic that effectively can treat obesity, and it's probably based on a combination of signals.
• 15:46
  SPEAKER_00: Um, the other hypothesis we had was we need to target the brain, but we can't do this directly.
• 15:53
  SPEAKER_00: We shouldn't do this directly.
• 15:54
  SPEAKER_00: Because we had, by the way, in another set of experiments learned, and there was a couple other groups around the world working on this.
• 16:00
  SPEAKER_00: Uh, if you, for example, target cannabinoid receptors, it was an interesting story.
• 16:05
  SPEAKER_00: Cannabinoid receptor antagonists were working quite well, but had side effects.
• 16:11
  SPEAKER_00: Well, you know, the friends tell me when they smoke marijuana, then they get hungry.
• 16:17
  SPEAKER_00: They told me that.
• 16:18
  SPEAKER_00: You could you could think that's your friends say that.
• 16:20
  SPEAKER_01: Yeah, my friends told me that.
• 16:21
  SPEAKER_00: Um, and and and then, you know, you think, okay, you can block that, um, and then you have a look.
• 16:27
  SPEAKER_00: And it's it actually worked to some extent.
• 16:29
  SPEAKER_00: Effects weren't that great compared to what we know today, what we see today.
• 16:33
  SPEAKER_00: But there were effects.
• 16:34
  SPEAKER_00: Now, also, but there was there were side effects, there were cardiovascular side effects, and there were side effects in terms of driving depression.
• 16:41
  SPEAKER_00: Well, you know, turns out my friends don't smoke it to get hungry, they smoke it to be in a in a pleasant state of mind.
• 16:49
  SPEAKER_00: You mess with that pathway.
• 16:51
  SPEAKER_00: Right.
• 16:51
  SPEAKER_00: So, in other words, if you directly target the brain, we don't have the means until today to specifically target only those neurons, those cells, those astrocytes, those signals for specifically appetite only.
• 17:08
  SPEAKER_00: Um, there's always something else we will mess with, and then that's dangerous and and and undesired.
• 17:15
  SPEAKER_00: Uh so we said, Richard and I, why don't we use Mother Nature's toolkit?
• 17:20
  SPEAKER_00: We use these afferent hormones, those are the hormones that come from the periphery and talk to the brain, that are made for this, to report to the brain how much food is coming in and what's going on with metabolism.
• 17:34
  SPEAKER_00: So you have less of a risk for side effects because you find naturally exactly those places where you need to go.
• 17:40
  SPEAKER_00: And then you need to figure out which ones those are and you need to combine them in the in the right manner.
• 17:46
  SPEAKER_00: By then, there were so many already because that field exploded, and it became a question: well, which ones are we gonna uh work on?
• 17:54
  SPEAKER_00: Because this then is a question of how many years do you have, right?
• 18:00
  SPEAKER_00: Making some of them and combining them and testing them in cells and then in mice and in rats and going back and tweaking it a little bit here, a little bit there.
• 18:10
  SPEAKER_00: That's that's you know, you're losing months and months and years and years.
• 18:13
  SPEAKER_00: So it was a wise decision that we started where we started with the hormone glucagon at some point.
• 18:21
  SPEAKER_00: Test a lot of things, but relatively early we focused on glucagon.
• 18:25
  SPEAKER_00: Might have been also that we got really lucky that we started there, right?
• 18:30
  SPEAKER_00: Bit of luck.
• 18:31
  SPEAKER_01: Success is all half chance, right?
• 18:33
  SPEAKER_00: Serendipity is is an under uh rated uh factor in science.
• 18:38
  SPEAKER_01: Right.
• 18:39
  SPEAKER_01: When was the moment you realized you'd stumbled upon upon what ultimately would turn into an absolute blockbuster?
• 18:47
  SPEAKER_00: It was somewhere, I think it might have been March, April of 2006.
• 18:52
  SPEAKER_00: And that I can't remember, that tells you how much of a moment that was.
• 18:57
  SPEAKER_00: So Richard then had figured out how to how to make glucagon molecules that were longer acting, soluble, and specific.
• 19:07
  SPEAKER_00: And that sounds trivial.
• 19:09
  SPEAKER_00: But an important hormone like glucagon, you would think people had made receptor agonists before.
• 19:16
  SPEAKER_00: So to explain what that means, all of these hormones have one problem, they've have a very short half-life, a few minutes.
• 19:23
  SPEAKER_00: So they're not not drugs at all.
• 19:25
  SPEAKER_00: Yeah.
• 19:25
  SPEAKER_00: So then chemistry got better and better, and Richard was always at the forefront of this, making them uh act longer and be more stable and still do what they're supposed to do and nothing else.
• 19:37
  SPEAKER_00: Um, one important clue came from a lizard that you find in the southwestern United States, the so-called Hilly Monster.
• 19:46
  SPEAKER_00: By the way, I own one now because my postdocs gave me one.
• 19:49
  SPEAKER_00: It's somewhere in the zoo in Germany.
• 19:50
  SPEAKER_00: I can I can go and pet it.
• 19:52
  SPEAKER_00: Uh so in the saliva of that lizard, um by a guy by the name of John Eng found that there's a version of a GLP, a glucagon-like peptide that's more stable.
• 20:04
  SPEAKER_00: And that had a chemical modification that we could also use then to make glucagon more uh thing, yeah.
• 20:11
  SPEAKER_00: I have no idea.
• 20:12
  SPEAKER_00: So these these are this is just one thing that was done, right?
• 20:15
  SPEAKER_00: So that tells you a little bit how crazy science sometimes can go with you know inspiration from places where you don't see it coming.
• 20:22
  SPEAKER_00: Um, and uh so uh a long uh acting glucagon was made, and we uh put it in our mice, uh our mouse model, where our mice were like on a McDonald's diet for like six to nine months, and then they wouldn't weigh 25 grams but 50, 55 grams.
• 20:39
  SPEAKER_00: Yeah.
• 20:40
  SPEAKER_00: And with that glucagon, we could make these mice lose weight substantially.
• 20:46
  SPEAKER_00: And that was the goosebump moment because nobody saw that coming.
• 20:49
  SPEAKER_00: Everybody thought at the time, first of all, glucagon is the glucose hormone that increases blood glucose.
• 20:56
  SPEAKER_00: That was in the textbooks.
• 20:58
  SPEAKER_00: So, what do you gotta do if you treat metabolic disease?
• 21:00
  SPEAKER_00: You gotta block glucagon.
• 21:01
  SPEAKER_00: We said, no, no, no, no, you gotta do the opposite because we think glucagon helps you with burning calories, with curbing appetite, etc., if you have a long-acting version.
• 21:13
  SPEAKER_00: We were called crazy more than once, but that experiment showed us we were on the right track.
• 21:19
  SPEAKER_00: Now we needed to do something to counter the glucose effects of glucagon, and the idea was to use GLP1.
• 21:28
  SPEAKER_00: We've heard that before, from the same family uh of hormones.
• 21:33
  SPEAKER_00: And yeah, by the time it started to become known that there may be a small effect on appetite, because these early versions of these hormones didn't have the massive effects we know they can achieve today.
• 21:46
  SPEAKER_00: And of course, GLP1 would trigger insulin secretion and decrease blood glucose.
• 21:50
  SPEAKER_00: So it would override the bad liabilities of glucagon.
• 21:54
  SPEAKER_00: So we wanted to put them together.
• 21:56
  SPEAKER_00: Putting them together, not in the sense of gluing them together or sticking them together.
• 22:00
  SPEAKER_00: But to engineer glucagon by changing a few amino acids so that it became a hormone that could activate both receptors, glucagon and GLP, in a certain ratio.
• 22:11
  SPEAKER_00: And now you have the best of both worlds, synergistic action and get rid of some side effects.
• 22:17
  SPEAKER_00: And again, it took two or three years, but now we have uh drugs uh that are about to be um approved that are glucagon GLP receptor coagonists.
• 22:28
  SPEAKER_00: So Vodut by Beringer Engelheim is one of them, but there are others.
• 22:32
  SPEAKER_00: Um that was the first dual agonist that uh then um uh we discovered, um, and it was published, I think, in 2009.
• 22:42
  SPEAKER_00: Um but it was only the the beginning of the story.
• 22:46
  SPEAKER_01: Yeah.
• 22:47
  SPEAKER_01: A story we we're all kind of familiar with, the ending of right now, or maybe not the ending of where we are today.
• 22:53
  SPEAKER_01: When you're doing that and when you discover that in the little fat mouse, um like are there moments where obviously it's a goosebump moment, you're extremely excited, it's clearly working.
• 23:07
  SPEAKER_01: Do you ever think in that moment this is too good to be true?
• 23:11
  SPEAKER_01: Like, what's gonna go wrong?
• 23:12
  SPEAKER_01: What's the side?
• 23:13
  SPEAKER_01: There's got to be some kind of side effect because you know that is a problem we've been trying to solve for many decades.
• 23:20
  SPEAKER_00: Well, you know, in a scientist's life, there's so much frustration and rejection.
• 23:26
  SPEAKER_00: Uh so when when uh next generation scientists ask me, what do you think it needs to become a great scientist?
• 23:33
  SPEAKER_00: Not that I would really know, but what I usually tell them is one thing you definitely need is you gotta be able to handle frustration and rejection.
• 23:42
  SPEAKER_00: Yeah, you gotta have perseverance.
• 23:45
  SPEAKER_00: Because, you know, everything else, you know, you need some luck, you need some good ideas, but your papers are gonna be rejected, um, your experiments are gonna reject you, and your hypotheses are gonna be wrong, and you still gotta be passionate and excited and carry on.
• 24:00
  SPEAKER_00: So that that was daily business that you know you didn't come out the way you wanted it.
• 24:05
  SPEAKER_00: And so, but these moments that I mentioned, this goosebumps moment, these goosebumps moments where I had maybe only three, four in my life, but they drive you.
• 24:14
  SPEAKER_00: You sort of get addicted to that moment where, like, wow, nobody saw this before me, and and I found something.
• 24:22
  SPEAKER_00: It's like discovery.
• 24:24
  SPEAKER_00: Yeah, it's like you're on Starship Enterprise and you see a new star.
• 24:27
  SPEAKER_00: That's how you feel when you uh see these numbers on your screen.
• 24:30
  SPEAKER_00: You're like, oh my god, this the gorillon levels go up and you fast the the rats.
• 24:36
  SPEAKER_00: I think this is the hunger hormone.
• 24:38
  SPEAKER_00: And you want that moment again.
• 24:40
  SPEAKER_00: So and and then you you go for years and years and you hunt the next discovery.
• 24:45
  SPEAKER_01: So that's 2009.
• 24:48
  SPEAKER_01: How then you know we're in 2026 now?
• 24:51
  SPEAKER_01: It feels a lot like the last four or five years we've seen this insane uh uh adoption of these um GLP agonists.
• 25:00
  SPEAKER_01: Talk to me about that sort of bridge between finding that in the lab and then when you know consumers were then buying into this idea.
• 25:10
  SPEAKER_00: So it may seem to some like overnight there's this revolution, this transformative development.
• 25:18
  SPEAKER_00: But when you really look into the history, uh Jeff Friedman and I, two years ago, uh wrote an article um in Science Translational Medicine reviewing the the history of the peptide hormones and how the obesity drugs then came came to uh be that successful.
• 25:36
  SPEAKER_00: And it turns out, you know, it's at least 120 years of of science that went into that, that is the building.
• 25:46
  SPEAKER_00: It's not that open.
• 25:47
  SPEAKER_00: I mean, of course, the breakthrough moments and there's acceleration.
• 25:50
  SPEAKER_00: Um, but yeah, well, you know, you gotta know about that.
• 25:55
  SPEAKER_00: There has been an incretin hypothesis and the whole GIP was discovered so many years ago and so on.
• 26:01
  SPEAKER_00: And then it builds on that.
• 26:04
  SPEAKER_00: Um but yeah, it started to then accelerate.
• 26:07
  SPEAKER_00: Um, and in parallel to what we did with glucagon and and then GIP and combining with GLP, the GLP1 research was you know uh continuing to improve the quality of these molecules.
• 26:23
  SPEAKER_00: Um, you know, putting a fatty acid on the molecule, making it even more long-acting and more powerful.
• 26:31
  SPEAKER_00: Um it does go back to one breakthrough moment in the mid-80s, where I think mostly Svetlana Moisov at the Rockefeller here here in New York uh discovered the bioactive sequence.
• 26:46
  SPEAKER_00: You know, what is the exact sequence of the pre-proglucagon, the GLP1, that is um that is activating the GLP1 receptor.
• 26:55
  SPEAKER_00: And it took a couple of more years until somebody, and I believe this was Sir Stephen Bloom, uh put it into the brain of a rat and said, well, this does something to food intake.
• 27:07
  SPEAKER_00: And then, you know, step by step, um this became the story that it is today.
• 27:13
  SPEAKER_00: Um, our next step was to, after glucagon and GLP work together, put GIP and GLP together.
• 27:21
  SPEAKER_00: Again, one molecule looks like an endogenous hormone more or less, and that's important because otherwise your immune system is going to reject that stuff.
• 27:28
  SPEAKER_00: Um, just a little bit of change here and there.
• 27:31
  SPEAKER_00: It now we had a molecule that would activate the GLP1 receptor and the GIP receptor.
• 27:36
  SPEAKER_00: GIP, another uh hormone of that family of peptides, which is important chemically because they're relatively similar.
• 27:45
  SPEAKER_00: So, you know, you only need a few changes to make them make it a dual agonist.
• 27:49
  SPEAKER_00: So we discovered the second dual agonist and we saw uh saw that that works even better.
• 27:54
  SPEAKER_00: Well, and and that dual agonist, GIP, GLP, that became the basis for what we now know as tercepatite munjaro and and and sep bound, right?
• 28:05
  SPEAKER_00: Um and of course, uh, that also is a story where then you know small improvements in the chemistry made it more and more powerful.
• 28:12
  SPEAKER_00: But the the concept um and the first version of it, we actually put it in in humans first, the first GIP GLP agonist, um, that uh we published um I think it was in 2011.
• 28:26
  SPEAKER_00: Uh now is that 15 years ago, right?
• 28:29
  SPEAKER_00: And it it it takes a while, but um it is still of the approved drugs the the most potent one, the most efficacious one, and a transformative breakthrough.
• 28:40
  SPEAKER_00: And then when I saw in clinical trials a couple of years ago that this works so well, that was another uh sort of goosebumps moment because I remembered when I started as a young doctor in the early 90s, everybody told me never in our lifetime is there gonna be a drug where you can safely reduce 20-25% of body weight.
• 29:00
  SPEAKER_00: You you're gonna kill people.
• 29:02
  SPEAKER_00: Stop thinking about it.
• 29:03
  SPEAKER_00: You know, go go and do something else.
• 29:06
  SPEAKER_00: And and it's it's possible.
• 29:08
  SPEAKER_00: So um, you know, some sometimes it's worthwhile going against uh everybody's recommendation.
• 29:16
  SPEAKER_01: Well that's a gangster story for a start.
• 29:19
  SPEAKER_01: Not only did it not kill people, it's done the exact opposite, right?
• 29:24
  SPEAKER_01: There must it must have saved hundreds of thousands of lives.
• 29:29
  SPEAKER_01: You know, it's is a problem that you know we're still combating right now, of course, because of the just sheer volume of people that are in that category of overweight and and and obese.
• 29:42
  SPEAKER_01: But what a remarkable accolade, right?
• 29:45
  SPEAKER_01: It works and it works well almost miraculously well for people.
• 29:54
  SPEAKER_01: Do you ever see this being the outcome?
• 29:57
  SPEAKER_01: I mean, obviously that was the ambition.
• 29:58
  SPEAKER_01: Did you ever think it would get adopted and become this just cr absolute revolution in in this field of weight management?
• 30:08
  SPEAKER_00: That was that was the ambition.
• 30:10
  SPEAKER_00: Um, and of course we had hopes, but um time we have here today won't uh suffice for me to tell you all the stories of things that didn't work.
• 30:20
  SPEAKER_00: Because we tried a lot of things and a lot of things didn't work.
• 30:23
  SPEAKER_00: So and and it kind of gets blurry and when you look back in in its 30 years of research, 35 years, and you tend to then um remember it as a narrative of success, but um all the hours, all the molecules, all the months, um all the grad students that worked on something else and didn't have the success they want to have, they yeah, it's they they're still there.
• 30:49
  SPEAKER_00: And and um as I said earlier, serendipity and luck play an important role.
• 30:56
  SPEAKER_00: And while you gotta have good hypotheses, and we had the hypothesis to go indirectly and target the brain and combine signals, that was about it in terms of the hypothesis that were right, because we uh thought we could combine with a gallon receptor antagonist, or you know, maybe um there is a version where we could use a growth hormone, and none of that worked, right?
• 31:20
  SPEAKER_00: So um, yeah, I I think the the combination of some solid hypothesis, hard work, and a lot of luck uh led us to where we then were.
• 31:31
  SPEAKER_00: At some point, then you get a feeling for a field where because of things that worked and others don't know about it yet, but you're sort of at the forefront, you get a gut feeling, pun intended, for what would next work.
• 31:47
  SPEAKER_00: So, example, we had a GIP, GLP dual agonist that worked great.
• 31:52
  SPEAKER_00: We had a glucagon GLP agonist that worked great.
• 31:56
  SPEAKER_00: How about a triple receptor or hormone receptor agonist, a GLP, GIP, glucagon triple agonist?
• 32:04
  SPEAKER_00: And that worked, and we saw that coming because that seemed so obvious that now not only you would combine the power of all three, but you could even dose down with that and maybe reduce with that uh some of the side effects.
• 32:20
  SPEAKER_00: And my philosophy was always Mother Nature doesn't do that with one signal.
• 32:26
  SPEAKER_00: So if it's sort of a matrix, a pattern of signals, we want to imitate that.
• 32:31
  SPEAKER_00: Uh, not you know, press on one signal too hard, but combine the right signals and be more physiological about it.
• 32:39
  SPEAKER_00: Because when you eat or or you fast, um, a bunch of signals change and you want to imitate that.
• 32:45
  SPEAKER_00: And um I think the triple agonist is is something that really um uh does that well uh or better than any of our other approaches.
• 32:55
  SPEAKER_00: And I think probably end of this year, next year, I expect the first triple agonist to be approved.
• 33:01
  SPEAKER_00: It's retadritite.
• 33:02
  SPEAKER_00: Retardritite, yeah.
• 33:03
  SPEAKER_00: Uh incredibly difficult name.
• 33:06
  SPEAKER_00: I don't know who came up with that, but that's the Lily version of a triple agonist.
• 33:10
  SPEAKER_00: Um we published it in 2015, and then of course several pharmaceutical companies followed suit.
• 33:16
  SPEAKER_00: I'm sniffing around, yeah, of course.
• 33:18
  SPEAKER_00: And and now, I mean, but again, uh there's there's an art form uh in in big pharma to develop these things well and to make them um the real drugs.
• 33:28
  SPEAKER_00: That's that's a lot of work and the case of retardotite, really well done.
• 33:33
  SPEAKER_00: Um, but that gives you what 30% weight loss?
• 33:36
  SPEAKER_00: Is that what is 30%?
• 33:38
  SPEAKER_00: 29%, right?
• 33:40
  SPEAKER_00: Um, and uh not not more side effects.
• 33:45
  SPEAKER_00: So now we are at a level where with retardotrotide being approved, you can give a once-a-week injection and achieve the same outcome like we did with a gastric bypass, right?
• 33:55
  SPEAKER_00: About 30% weight.
• 33:57
  SPEAKER_01: That's remarkable.
• 33:58
  SPEAKER_01: Feels like there's a a Moore's law of peptides going on here.
• 34:03
  SPEAKER_01: Where does this stop?
• 34:04
  SPEAKER_01: Does it ever stop?
• 34:05
  SPEAKER_01: Is this just the beginning?
• 34:06
  SPEAKER_00: Well, we didn't stop.
• 34:08
  SPEAKER_00: We uh we continued and published a few months ago a nature paper on a quintuple agonist.
• 34:16
  SPEAKER_00: Of course.
• 34:16
  SPEAKER_00: Something that is combining a GIP.
• 34:20
  SPEAKER_00: Yeah, five.
• 34:21
  SPEAKER_00: GIP, GLP, and a triple P par.
• 34:24
  SPEAKER_00: Uh this is small molecules now.
• 34:26
  SPEAKER_00: Now we're going and add small molecules, nuclear hormone receptor agonists to the peptides and have the peptides deliver them like a Trojan horse to sell certain cells.
• 34:37
  SPEAKER_00: Uh you can tell this is way more complex, but also very fascinating.
• 34:41
  SPEAKER_00: I think this is going to be a version of sort of personalized metabolic medicine where you target certain organs in certain cells and not others with different versions of satiety-inducing drugs, uh, which also help burn calories, but also prevent other things like inflammatory pathways and this and that.
• 35:02
  SPEAKER_00: Um, that might be next level.
• 35:05
  SPEAKER_00: The thing that I'm most excited about these days is that we tackled another problem, I believe, which is the side effects that these drugs still have, right?
• 35:15
  SPEAKER_00: Um, and the most well-known, most frequent one are nausea and you know, maybe emesis, vomiting, um, diarrhea, obsipation, stomach pain, indigestion.
• 35:27
  SPEAKER_00: Yeah.
• 35:27
  SPEAKER_00: It's and and it's uh very individual.
• 35:31
  SPEAKER_00: Some folks have less of a problem.
• 35:33
  SPEAKER_00: Um, but most of uh patients have a little bit of that, some level of that.
• 35:39
  SPEAKER_00: That's why dosing up slowly is what's done with any version of a GLP1 receptor atoms, like semaplotite or CEMPIC or or or tesepatite, Munjaro or Seppound.
• 35:50
  SPEAKER_00: Um, so um that helps with getting used to these drugs and not having too much of these gastrointestinal uh adverse effects.
• 36:00
  SPEAKER_00: Now, there are other things you gotta see a physician who prescribes these drugs because you you you can't take them when you had a history of thyroid carcinoma or pancreatitis, and um there are other things.
• 36:15
  SPEAKER_00: Um, there is a little bit of an increase in heart rate with some of them.
• 36:19
  SPEAKER_00: Um, monoagonists as well as stool agonists, um, specifically retrotitude is something where that was seen.
• 36:26
  SPEAKER_00: It increases early in treatment and goes down a little bit, but there's something there with cardiovascular effects.
• 36:33
  SPEAKER_00: So our ambition became uh for the last five to ten years to come up with versions that don't have these side effects.
• 36:42
  SPEAKER_00: And that again was was you know not trivial.
• 36:47
  SPEAKER_00: Everybody in the world is trying this now.
• 36:49
  SPEAKER_00: When we started, we were alone.
• 36:50
  SPEAKER_00: Yeah, now everybody is doing it, right?
• 36:53
  SPEAKER_00: And it's big pharma and they have a lot of manpower and cash.
• 36:57
  SPEAKER_00: Yeah.
• 36:58
  SPEAKER_00: Um, and for us, it's still Richard and I, and and and a few a few folks on the team.
• 37:04
  SPEAKER_00: Um, so um our idea was a lot of what we see here is happening with the monoagonists, semaglotite or sampic has these side effects.
• 37:14
  SPEAKER_00: The dual and triple agonists have it.
• 37:17
  SPEAKER_00: So logically, you would think it has something to do with GLP.
• 37:23
  SPEAKER_00: Um so what if we come up with a version that's GLP1 free?
• 37:28
  SPEAKER_00: Um, how about a GIP glucagon?
• 37:32
  SPEAKER_00: And for that, it's important to know that um these drugs like Munjaro, that's actually not a GLP1 drug.
• 37:38
  SPEAKER_00: Um, it's more of a GIP drug.
• 37:41
  SPEAKER_00: The ratio of GIP to GLP is toward GIP.
• 37:45
  SPEAKER_00: And while everybody has GLP because that was the first one.
• 37:48
  SPEAKER_00: Yeah, that's just what we think they're called, right?
• 37:50
  SPEAKER_00: Munjaro is more of a GIP thing.
• 37:52
  SPEAKER_00: So GIP is really important.
• 37:53
  SPEAKER_00: What if we add glucagon, a little bit glucagon to GIP and get rid of the GLP?
• 37:58
  unknown: Yeah.
• 37:59
  SPEAKER_00: We did that, and Richard made the dual agonist after we did tons of experiments with knockout mice and co-infusing and this and that.
• 38:08
  SPEAKER_00: And it turns out, bottom line, it decreases body weight as much as retardotite.
• 38:14
  SPEAKER_00: It doesn't increase blood glucose, it improves uh metabolism significantly.
• 38:20
  SPEAKER_00: And um we have tested this now in uh mice and rats and in non-human primates in monkey studies, and don't see any sign of these adverse effects in terms of gastrointestinal side effects.
• 38:34
  SPEAKER_00: Um, we're hoping to have this in the in the clinic soon, next next year.
• 38:38
  SPEAKER_01: So we could end up with a version of this that gets us as good a result as the most effective version that we know about today, retadotide, but with no side effects.
• 38:48
  SPEAKER_00: That's what I believe.
• 38:50
  SPEAKER_00: I think we're time to be alive.
• 38:53
  SPEAKER_00: Yeah, and you might be alive longer because of these drugs.
• 38:56
  SPEAKER_01: Let's talk about that.
• 38:58
  SPEAKER_01: Let's talk about that.
• 38:59
  SPEAKER_01: You know, when we remove the the fact that you know they're they're helping to dramatically improve body composition, do we know that there are other benefits?
• 39:10
  SPEAKER_01: We hear a lot about these different mechanisms that might be improving all types of different markers of health.
• 39:17
  SPEAKER_01: Do we know that for sure?
• 39:19
  SPEAKER_00: Now I have mixed feelings about this when like The Economist has on the title page that that title uh the everything drugs.
• 39:30
  SPEAKER_00: Um they're definitely not the everything drugs.
• 39:33
  SPEAKER_00: A lot of the benefits that they do have beyond just decreasing body weight, um, are in my opinion um a consequence of improved metabolism and decreased body weight.
• 39:46
  SPEAKER_00: That you have you know cardiovascular benefits, uh, fewer heart attacks and fewer strokes.
• 39:52
  SPEAKER_00: That's very obvious for a drug that helps you keep the lipids down and keep the glucose in check and um keep the adipose tissue low and the calories stored in the right place.
• 40:04
  SPEAKER_00: Well, of course.
• 40:05
  SPEAKER_00: The same for you know decreased risk of neurodegeneration, the same for several types of cancer, colon cancer and so on.
• 40:14
  SPEAKER_00: There are, however, effects that are likely direct, and most of them have to do with addiction.
• 40:22
  SPEAKER_00: Because, in a sense, you could argue that the main effect of these drugs is they're fighting food addiction.
• 40:28
  SPEAKER_00: If you listen to patients tell you about their experience, um, they would say, well, you know, for my entire life I had these voices in my head that I need to eat and I need to think about food.
• 40:39
  SPEAKER_00: And now I have like five hours more time in my day because these voices are gone.
• 40:44
  SPEAKER_00: So these drugs work on food addiction in a sense in the brain, and they work on addiction to alcohol, nicotine, some say even gambling addiction.
• 40:55
  SPEAKER_00: Yeah.
• 40:55
  SPEAKER_00: Now I'm saying I'm saying this a little bit more carefully because we don't have the prospective studies yet, the long-term studies that we have with obesity.
• 41:04
  SPEAKER_00: Yeah.
• 41:04
  SPEAKER_00: But there seems to be something, something to it.
• 41:06
  SPEAKER_01: Um it would certainly make sense that it impacts all kinds of addiction in the same way.
• 41:12
  SPEAKER_01: Can I ask you a then a sort of follow-on from that?
• 41:15
  SPEAKER_01: You know, obviously, I do think that in the media we conflate some of the benefits of these drugs with just weight loss, but obviously there's more to it than that.
• 41:23
  SPEAKER_01: And it makes it a lot easier to achieve the weight loss.
• 41:26
  SPEAKER_01: So, you know, there is a tremendous upside there because that is one of the most difficult things for the people who are struggling with being overweight.
• 41:35
  SPEAKER_01: I guess one concern that gets voiced, I have this concern myself, is that if you blunt desire in that fashion, you know, or or the the um being compelled to consume, does that blunt the desire to consume and take part in everything?
• 41:55
  SPEAKER_01: Right.
• 41:55
  SPEAKER_01: So will that make people feel less inclined to exercise, to have intimate relations, like all of the things that are beneficial for our health, um, because there's obviously downstream effects of that which are negative.
• 42:10
  SPEAKER_00: It doesn't seem to do that, but that's something that of course we all thought about and and clinicians were worried about.
• 42:16
  SPEAKER_00: You know, basically, does it drive you into depression?
• 42:19
  SPEAKER_00: If if in in a sense all the things that are fun in life are now being covered.
• 42:23
  SPEAKER_00: Cut the joy out of it, yeah.
• 42:25
  SPEAKER_00: Uh um and there are patients that are saying, well, it's a little bit less colorful how I experience life now, but it's it's definitely worth it.
• 42:33
  SPEAKER_00: But you know, there's so much of a trigger for depression in obesity because people being stigmatized, being um, you know, uh deprived of social interactions because of that stigma, et cetera.
• 42:46
  SPEAKER_00: And just the ability to function in daily life.
• 42:49
  SPEAKER_00: And now, for the first time in their lifetime, they're you know, after losing 30, 40, 50 kilograms, uh, they can uh do exercise, move more, uh, be more active and uh more encouraged to take part in social life.
• 43:05
  SPEAKER_00: So that that is such a positive drive that to dissect what are the effects on on mood and quality of life that are positively influenced by these drugs and by the weight loss, or that may also be negatively influenced by what it's is done to uh addiction or levels of of joy.
• 43:26
  SPEAKER_00: Yeah, um, that that is complex.
• 43:28
  SPEAKER_00: Overall, there is no signal uh that this would drive depression uh uh at all.
• 43:35
  SPEAKER_00: And um it also seems that uh folks are in in enjoying their meal, it's just uh that they're not having the second plate or the third, and then they maybe don't have to have dessert.
• 43:49
  SPEAKER_01: Yeah.
• 43:49
  SPEAKER_00: Um, so um in a sense, this this works just as it should.
• 43:55
  SPEAKER_00: And interestingly, it works best in uh massive overweight and the more you lose weight the less effective it is so even though it's abused quote unquote as a lifestyle drug it is not a very good lifestyle drug because it works best on a on a BMI of 45.
• 44:16
  SPEAKER_00: Right so there's it doesn't work that great on a BMI of of 25.
• 44:20
  SPEAKER_00: It does work depending on the dose of course and on on the individual response.
• 44:25
  SPEAKER_01: Use that term abuse I mean I think that's one thing that all of these different talking points we get opposing views on in the media.
• 44:35
  SPEAKER_01: Right?
• 44:35
  SPEAKER_01: You can read one article that says you know a Zen pick or name any of these GLP agonists causes depression.
• 44:44
  SPEAKER_01: And then another one saying it alleviates depression causes lean tissue loss.
• 44:49
  SPEAKER_01: Another one saying you know it's good for um body composition as a whole and that the loss is through fat.
• 44:55
  SPEAKER_01: How is it how do consumers just pass through that noise?
• 44:59
  SPEAKER_01: Because it is very confusing.
• 45:01
  SPEAKER_00: Yeah they need to listen to your podcast that's right okay next question.
• 45:05
  SPEAKER_00: Then they're gonna be informed.
• 45:07
  SPEAKER_00: So let me talk about uh body composition for a moment there because there's a lot of confusion a lot of confusion a lot of misinformation.
• 45:15
  SPEAKER_00: Yep.
• 45:15
  SPEAKER_00: Whichever way you lose weight whenever you lose weight you will lose fat mass and you will lose lean mass.
• 45:22
  SPEAKER_00: And lean mass is you know composed of um muscle mass, water and so on.
• 45:30
  SPEAKER_00: Bone, yeah.
• 45:31
  SPEAKER_00: Bone.
• 45:33
  SPEAKER_00: Now there's nothing that these drugs, the mono and dual agonists are doing directly to muscle that we know of.
• 45:42
  SPEAKER_00: They're not even receptors there of these drugs.
• 45:45
  SPEAKER_00: But you're going into a negative energy balance because fewer calories and the same levels or increased levels of energy expenditure and burning calories so you will lose inner balance fat and lean mass.
• 46:01
  SPEAKER_00: If you are forcing yourself into a diet and do caloric restriction, the exact same thing will happen.
• 46:09
  SPEAKER_00: You could also look at it from a physiological perspective and say, you know, if if you carry around 20 kilograms of fat in a backpack and you suddenly get rid of that backpack, you're losing a level of weightlifting on exercise you need less muscle.
• 46:29
  SPEAKER_00: So is it really that bad that now you have also lost some muscle mass it's a new balance that's probably the right one for you.
• 46:37
  SPEAKER_00: There are of course situations especially when you look at an aging population where it's desirable to maintain or increase muscle mass.
• 46:48
  SPEAKER_00: And that's why in in you know in in the academic labs and in in the the big pharma these days and in biotech a lot of folks are working on combination drugs that also increase muscle mass.
• 47:04
  SPEAKER_00: That is tricky right if if you work on a myostatin inhibitor or something like that.
• 47:13
  SPEAKER_01: Very fascinating but let me point out one issue with that uh our heart is also a muscle you want that to grow um so you know something that um will be complex uh but again uh not not something that may never be solved but something where we're not as close as people think I want to say this because I've said this on other podcasts and now that you're here I want to I don't want anyone to call me out for not bringing it up um but you know this uh the use of these drugs when people are not massively overweight and I don't just mean a little overweight I mean like significantly overweight in this obese uh category when we see people abusing them which I think they do get abused and we see this loss of lean tissue which is measurable right and and and I agree with you by the way I don't I don't think that's the the drug is not to blame it's this huge energy deficit there is a there is a significant loss of lean tissue that becomes pretty difficult to get back once you've lost it in your latter years.
• 48:26
  SPEAKER_01: I think there is going to be for some people I think it will be catastrophic.
• 48:33
  SPEAKER_01: I think it will be it will be extremely difficult if not impossible to gain back.
• 48:40
  SPEAKER_01: If you leave if you are in your 50s, 60s, 70s beyond and you're not overweight, right?
• 48:47
  SPEAKER_01: I don't know why we would risk the loss of the lean tissue.
• 48:50
  SPEAKER_01: I think that is currency of longevity.
• 48:52
  SPEAKER_00: Right.
• 48:52
  SPEAKER_00: So it becomes more difficult to gain muscle back and gain muscle uh at at my age you know I'm I'm I'm 59 so uh I I know what the numbers look like and they're not friendly.
• 49:04
  SPEAKER_00: So a lot of exercise is important and uh I hate it when I have like a flu and I can't exercise oh my God can I catch it catch up again yeah um so you you're right um so these drugs should not be abused um that's why physicians experts should be prescribing prescribing them nobody should order them on the web from uh from China in from some catalog um for scientific purposes and then use them but apparently this is what's happening right people are getting their hands on retardotide already left and right and and they they shouldn't um this should be guided by by uh experts um in from the medical medical business um but uh there is I think a different perspective on that possible um I wouldn't be surprised and I'm not seeing patients anymore I'm just just doing science and look at it from that perspective if there was a future for sort of microdosing with these drugs where you are improving your metabolism just keep keeping it in in a certain uh dimension uh more healthy that makes uh uh that would make an important contribution to your um longevity yeah um well people are doing that now as well right people are microdosing now yeah what what what do you what's your perspective on that do you think that is there's value there I think there might be value there right from everything we know it doesn't seem to hurt anything and it might help yeah um if if you have slightly better lipids and slightly more controlled glucose and um maybe a a little bit of a check on not overdoing it uh when you're at a at a fabulous restaurant too many times a week um and maybe a little bit less alcohol that's a good thing so if you are on 2.5 milligram of of turcepatide um even though you're not clinically obese that might be a good thing we don't have the studies yet right yeah this this needs to be studied carefully I'm not recommending it that you know don't don't do this at home yeah but I mean academically I'm thinking there's likely a chance that that that uh becomes uh relevant in the future if if we remember I mean even back then I think now 20-30 years back we already knew from clinical studies before we had weight loss drugs that even if you lose three to five percent of your body weight uh that had has massive impact on your cardiovascular and metabolic health yeah uh even though you really should lose 20% just a little bit so if you translate that now into uh these drugs today a little bit of these drug effects that may actually have a disproportional impact on on your chances for you know um health span.
• 52:16
  SPEAKER_01: To straw man my own argument as well I think if you start seeing these marginal gains in the in the way that you feel, in the way that you look and perform, it is encouraging, it's motivating.
• 52:26
  SPEAKER_01: And so there is a certainly a subset of people that that would drive them to go on to then get more healthy habits and then maybe spend more time doing exercise and the things that then can contribute to building there is something that sort of keeps me awake at night that is that it's it's possible to abuse these drugs especially when the more powerful versions now become available.
• 52:50
  SPEAKER_00: When I was uh early in the in the ghrelin days and studied ghrelin I was um investigating if ghrelin itself or a long-acting version of ghrelin could be used to fight anorexia anorexia nervosa and because basically there was no treatment and there's still isn't a real treatment for that and it's a horrible condition.
• 53:13
  SPEAKER_00: And uh turns out that it wasn't the answer until until today it doesn't seem like ghrelin is the answer there because really not not being hungry is not the main problem of most of these patients because they actually have hunger but but um they're overriding that.
• 53:31
  SPEAKER_00: Now that the drugs we discovered and that are helping millions of people and they're saving millions of lives can be abused by patients that are fighting anorexia nervosa and then making their condition even worse.
• 53:47
  SPEAKER_00: That worries me.
• 53:49
  SPEAKER_00: And that is why these drugs need to be really controlled and shouldn't be available freely.
• 53:56
  SPEAKER_01: Can we talk about this for a minute because this is a something that is a concern for me and our patients and you know discussions that I've had in this room that um we are now seeing not just these research versions of those drugs but of any other number of peptides and the the sort of floodgates have opened there where we're seeing this reclassification of half a dozen of them under this current administration your your drugs collectively have decades of research and data.
• 54:32
  SPEAKER_01: These do not right and and so now um I feel like I always feel like a villain for saying this because they've become so popular online and people are using them and people swear by them but at what cost?
• 54:47
  SPEAKER_01: We because we don't know yet.
• 54:49
  SPEAKER_01: It's way too early we don't know what's in these vials we have no lit little to no human clinical data on any of them to be clear for the audience and yet we can not only buy them online through catalogues but now we have in New York right here licensed physicians that are prescribing them.
• 55:12
  SPEAKER_00: And so you know we've always been told you know before you do or take anything you should be getting this approved by a licensed physician but now what does that even mean if people are doing that without having that data and I think that's unfair on the abundance of incredible physicians who are not willing to cross that line you know I I get worried when I hear people these days all be fascinated suddenly about peptides even though I've been dealing with peptides and uh promoting peptides uh my all my professional life as a matter of fact when I started um as a young researcher peptides were sort of the thing of yesterday people like oh you gotta if you want to make a drug you need a small molecule one of the drivers for that was small molecules are not sort of um taken apart by the stomach acid so you can use them orally peptides are going to be destroyed in the stomach so you got to inject them.
• 56:10
  SPEAKER_00: So everybody thought well this is a thing of the past.
• 56:13
  SPEAKER_00: Now look at where peptides are today.
• 56:16
  SPEAKER_00: But peptides that is that is talks about a chain of amino acids of a certain length and if they're longer than that certain length then they're gonna be called proteins.
• 56:28
  SPEAKER_00: Nobody's excited about proteins well in a different way but uh for for for nutrition.
• 56:33
  SPEAKER_00: But peptides folks that are excited about peptides are a great thing they need to realize there is deadly toxins uh you know poisons those are peptides right um if you eat a dangerous mushroom and you die that was a peptide so we we gotta be careful that that we're not you know generalizing too much um it turns out that some of these drugs are are are based on a peptide structure but that doesn't make peptides a good or a bad thing um and that that whole excitement is is a little bit misleading and dangerous.
• 57:11
  SPEAKER_01: Tim the cart has got ahead of the horse there a little a little bit yeah it's I mean what what about when we we when they are we do have the capacity to compound them safely right and so I I and that's part of the reason for this reclassification because you know some of them are showing promise in animal models in the same way that that yours were two decades ago.
• 57:36
  SPEAKER_00: But that's why we have this long path of of complicated challenging expensive studies to make sure um we're not overlooking something um and and uh we we know from horrible examples in history what happens maybe a laundry list of examples yeah maybe in in in in pregnancy and to to your babies um if if we're overlooking something so all of these things make a lot of sense to be tested uh thoroughly and intensely before we go uh and and um approve it or or use it broadly and we we we can't overlook that that's that's really really important um I I trust that the system works and protects everybody from uh their their own enthusiasm for peptides um but I think a little bit of that is driven by this combination of the success of these drugs and limited access to them uh because not everybody can afford them right um they're expensive they're really expensive yeah and um I know a lot of folks even you know friends of mine who would like to be on it and um it's not covered by their insurance and they they can't afford it uh long term um so that's why I'm very much looking forward to and and um wherever I can pushing for these drugs becoming more affordable soon and it will happen more and more competition and some of them will go off patent and in a couple of years we will see much more affordable versions.
• 59:19
  SPEAKER_00: They still need to be prescribed by responsible doctors that have expertise in that area but I think that will hopefully then uh take away some of that sort of black market uh um activity that that is really dangerous.
• 59:36
  SPEAKER_00: And you think they become really affordable?
• 59:38
  SPEAKER_00: Yeah yeah absolutely I mean the the the the cost for synthesis for a month of these rocks is is significantly less than$10, right?
• 59:47
  SPEAKER_00: Wow the cost for developing all of them that there were billions and billions and that's what needs to come back.
• 59:56
  SPEAKER_00: Looking at you know how how well these companies are doing I think they got it back.
• 1:00:01
  SPEAKER_01: They're making a few dollars a few more yeah can I ask you a question about the efficacy just for us as individuals I don't know if this is true but I'm gonna say it anyway.
• 1:00:12
  SPEAKER_00: These drugs don't work for a percentage of the population I heard that's around you know 20 to 30% is that right different numbers around um but there are certainly patients where it doesn't work.
• 1:00:26
  SPEAKER_00: Some of them stop or it doesn't work because of the side effects and this is something we're tackling now.
• 1:00:32
  SPEAKER_00: But for some of them it doesn't seem to show the same impact on weight loss the same you don't take it the same weight loss benefits.
• 1:00:42
  SPEAKER_00: Now with almost every drug for every disease you sort of have have a Gaussian distribution of you know most of them have solid effects some have super effects and some seem to be sort of resistant biology is complicated.
• 1:00:59
  SPEAKER_00: We all have different genetic makeup and polymorphisms and react a little bit better a little bit less um and then there will be some patients that don't respond because they have a specific um genetic um composition where for example they don't have a functioning GIP receptor or the GIP receptor functions only to 10% and we we start to know about these cases.
• 1:01:25
  SPEAKER_00: It's not that frequent but it explains some of these phenomena and for those then you need different versions right those then need uh a GLP with an amylin or or something like that.
• 1:01:38
  SPEAKER_00: And luckily now there's so many versions coming of future combinations that we will be able to offer that personalized medicine where we will be screening uh quicker and quicker and in more depth and with AI-based analysis get quick results and say you need this version because you will not respond to this.
• 1:01:59
  SPEAKER_00: Right.
• 1:02:00
  SPEAKER_00: That's something um you know biomedical researchers are talking about for 20 years now hasn't happened yet.
• 1:02:06
  SPEAKER_00: Yeah um basically it's at the level from you can get your whole genome sequence at the end your doctor's gonna tell you you know eat an apple and go do some more box go for a run.
• 1:02:16
  SPEAKER_00: Oh well that was worth it yeah um but we we'll get there yeah those those genetic tests are getting better now that we can we can deduce more from them than we used to be able to what do what do you think that screening looks like uh uh beyond genetics do you do you think that that is uh you know an assay uh uh subjective measures a combination of those things I think I'm just trying to get you out of the lab eventually because otherwise you're gonna have to keep developing these I think um there's gonna be a whole other uh you know dimension of a combination of proteomics and uh exosomes and metabolomics going in there I personally am not a a big fan of of um and overinterpreting the microbiome there was a lot of hype about the microbiome being so important for metabolism but then there were clinical studies done where the entire gut microbiome was killed with antibiotics for months.
• 1:03:23
  SPEAKER_00: And you know what happened to metabolism and weight?
• 1:03:26
  SPEAKER_00: Absolutely nothing.
• 1:03:28
  SPEAKER_00: Which you know makes me question how how important it really is for that part of medicine.
• 1:03:34
  SPEAKER_00: But there's um even so much more that we don't know about and one version that made me think about this is uh a friend of mine Ferenc Kraus uh at Ludwig Maximilians University where I'm now in Munich he is a is a physicist who uses his laser-based methods now to to um analyze blood samples and um he doesn't even want to know is this uh proteins or peptides or he just gets physical signals out and combines those with large amounts of data predicting diseases and he's showing first success that goes beyond anything I've ever seen which just tells us there's there's so much other stuff that we haven't understood yet that he you know just ignores and just goes with his methods helps that he already has a Nobel Prize in physics that he's a pretty smart guy.
• 1:04:31
  SPEAKER_00: That would do it and and um I I think you know this is just the tip of the iceberg uh even though we have more data than we can analyze no with AI we start to be able to but this is weirdly enough this is still early days.
• 1:04:49
  SPEAKER_00: Yeah there's a lot of unanswered questions can we can we touch on some that are answered what are the things that you do if you're open to talking about it to protect your own health your own health span longevity whatever buzzword we want to use to to talk about that tell me about the things that you believe in enough to weave into your own life I don't do enough I do crazy things like flying across the Atlantic uh waiting in immigration uh going on a taxi uh ride for two hours only to talk to you that's not good for my health I feel like it is but um so I don't do anything miraculous that others won't do I try to exercise um five six times a week try to get in my seven eight hours a week um what type of exercise are we talking and uh you know um weight uh um exercise but mostly sort of calisthenics and functional training um I used to train completely different heavy weights in the past like many of us I guess uh But some cardiovascular, some tennis, some fun needs to be in there as well.
• 1:06:08
  SPEAKER_00: I try to look after my diet.
• 1:06:10
  SPEAKER_00: Unfortunately, I have a sweet tooth, and it is a constant fight against ingesting too much sugar.
• 1:06:20
  SPEAKER_00: But there's nothing miraculous that I do beyond that.
• 1:06:24
  SPEAKER_00: I you know don't overdo it with supplements, some healthy levels of vitamins and um some fish oil.
• 1:06:34
  SPEAKER_00: Um but yeah, nothing, not nothing, nothing too fancy.
• 1:06:40
  SPEAKER_00: Um used to stopped mostly because I'm lazy and forget to buy it.
• 1:06:45
  SPEAKER_00: Yeah.
• 1:06:46
  SPEAKER_00: But I've got busy days, and um, no, that's an interesting question.
• 1:06:51
  SPEAKER_00: Um when I look at folks that you know have had a full life of positive stress, they they tend to be getting pretty old.
• 1:07:02
  SPEAKER_00: Um I'm not so sure that stress in a general sense, uh in terms of hard work, is is um is standing against a a you know um long health span or something like that.
• 1:07:19
  SPEAKER_00: Uh I love to work and um my feeling is that if you're excited about what you do, uh you can do a lot of hours.
• 1:07:28
  SPEAKER_00: Uh yeah.
• 1:07:29
  SPEAKER_00: Not saying that my my job is always just fun and games, but um I I I I work long hours and uh just fit in that exercise um if I force it in in the early mornings.
• 1:07:45
  SPEAKER_01: Your morning workout guy.
• 1:07:47
  SPEAKER_01: Yeah, I am too.
• 1:07:49
  SPEAKER_01: Otherwise it's too easy to find excuses tomorrow.
• 1:07:53
  SPEAKER_01: Yeah, exactly.
• 1:07:54
  SPEAKER_01: Uh so I I do it first thing in the morning.
• 1:07:57
  SPEAKER_01: Can I ask you, and you don't have to answer this.
• 1:07:59
  SPEAKER_01: Do you take GLB agonists of any kind?
• 1:08:04
  SPEAKER_00: I've uh I've tried, of course, dual agonists because after 30 years of research, I wanted to know how it feels, and it was really interesting.
• 1:08:11
  SPEAKER_00: Um how does it feel?
• 1:08:13
  SPEAKER_00: It's a it's a it's a fun story.
• 1:08:15
  SPEAKER_00: Um because I um I don't know why, uh, but it worked out that way.
• 1:08:19
  SPEAKER_00: That I started taking it for the first time on vacation.
• 1:08:24
  SPEAKER_00: And and we're in Italy and big big family, and and uh so and suddenly I'm like, first of all, I didn't like the tiramisu anymore, and uh uh I have one plate of pasta, well, maybe half a plate is fine enough.
• 1:08:38
  SPEAKER_00: And then I didn't want alcohol anymore.
• 1:08:41
  SPEAKER_00: Actually, that went away after a while.
• 1:08:43
  SPEAKER_00: But in the beginning, it was like, oh, I don't know, I don't want to drink, I don't like that gin tonic.
• 1:08:48
  SPEAKER_00: And what do I do then?
• 1:08:50
  SPEAKER_00: I went to bed early and I felt great.
• 1:08:53
  SPEAKER_00: Uh, but my brother-in-law uh talks to me two weeks later and says, you know what?
• 1:08:58
  SPEAKER_00: You used to be more fun.
• 1:09:00
  SPEAKER_00: Uh so that was interesting, but it's it's it's really amazing how it felt.
• 1:09:05
  SPEAKER_00: I did this for a while and I stopped, but I'm you know, I'm I'm considering going back on a on a microdosing uh version of this.
• 1:09:13
  SPEAKER_01: Um I've never tried it, but I would consider it.
• 1:09:17
  SPEAKER_01: I one thing I I always sound like a bit of a nay, I find myself sounding like a bit of a naysayer and major in the majors and do all the things we know to work.
• 1:09:26
  SPEAKER_01: One thing that is for certain, I I have seen and and continue to see some people whose some people whose life is night and day different because of this and have been trying for many years, if not decades, to manage their weight.
• 1:09:42
  SPEAKER_01: And you know, we have we're we're almost gaslit into being told that it wasn't possible or it was a desire problem or a a discipline problem.
• 1:09:51
  SPEAKER_01: And so it I I mean it's remarkable for them.
• 1:09:57
  SPEAKER_00: You know, we're getting a lot of letters and emails, Richard and I, that are really uh moving and make us understand again and again what it means for these patients, and that are born into that.
• 1:10:12
  SPEAKER_00: And 70% approximately, we know this from um um twin studies, are genetics, right?
• 1:10:19
  SPEAKER_00: Um, and um it is not a question of moral or discipline or you know what I find really interesting when I gave give my lectures and you know, uh to public audiences and so on, they're always individuals that are getting really mad at me.
• 1:10:38
  SPEAKER_00: And the way I feel this uh coming up is that these are individuals that have always been lean.
• 1:10:48
  SPEAKER_00: And they're kind of annoyed with the fact that now others can be lean as well, because they they saw this as uh evidence for them being superior, right?
• 1:10:59
  SPEAKER_00: Because I have more discipline, I got my life, you know, in shape, and um I'm I'm morally superior, and and now they can cheat, and all of these people can look like me.
• 1:11:11
  SPEAKER_00: How that that is not what the world's supposed to be like, so they aggressively argue against that um becoming uh available for everybody, and that just shows you um how um that is misunderstood by society.
• 1:11:27
  SPEAKER_00: Yeah.
• 1:11:29
  SPEAKER_01: There's a lot of that in general, I think, either way.
• 1:11:32
  SPEAKER_01: You know, people everyone's got an opinion, and they make sure that you know about it.
• 1:11:37
  SPEAKER_00: Everybody's an expert in food intake, everybody eats.
• 1:11:40
  SPEAKER_01: Yeah, true.
• 1:11:41
  SPEAKER_01: Yeah, it's something that we all have to do multiple times a day.
• 1:11:45
  SPEAKER_00: And by the way, that this is different from you know nicotine addiction.
• 1:11:49
  SPEAKER_00: Yeah, you can go call turkey on smoking, you can't go and stop eating.
• 1:11:55
  SPEAKER_01: Yeah.
• 1:11:55
  SPEAKER_01: I think there's a thing, there's a bit of stigma as well when people decide to make a like a real concerted effort to improve their health.
• 1:12:06
  SPEAKER_01: Sometimes seemingly good actors, like people, they are good actors, they're friends and family who will see you making that change.
• 1:12:14
  SPEAKER_01: And it might be that you say no to the the beer with them or or that you don't take the dessert, you know, because you're trying to make this positive change in your life.
• 1:12:22
  SPEAKER_01: And there's always going to be people who love you, to be clear, who say you don't need to do that.
• 1:12:27
  SPEAKER_01: You know, you're you're you you look great, you are you're already fit enough and healthy enough and lean enough.
• 1:12:33
  SPEAKER_01: And I think it's difficult sometimes for people to you know push back against that and stay on the the straight and narrow, but it it's all subjective, right?
• 1:12:42
  SPEAKER_01: It's yeah if you want to make that change, you should.
• 1:12:44
  SPEAKER_00: Yeah, yeah, yeah.
• 1:12:45
  SPEAKER_01: Of course, in all kinds of directions.
• 1:12:47
  SPEAKER_00: It it changes society, right?
• 1:12:49
  SPEAKER_00: And and I find that uh progress, that that stigma is being removed from so many people, that is uh that is um wonderful.
• 1:13:01
  SPEAKER_00: And um I think more people start to understand that this isn't um something that's based on a character flaw, uh, but obesity is a disease now that we learn more about the signals and the genes.
• 1:13:15
  SPEAKER_00: What I also enjoy is uh sort of observing the um uh changes in society that sort of go into economics, um, so that you know, fast food companies and um companies that are making candy bars are are now in trouble and um you know are adopting new strategies because they feel it now.
• 1:13:38
  SPEAKER_00: Is that right?
• 1:13:39
  SPEAKER_00: We're seeing that change economically now.
• 1:13:41
  SPEAKER_00: You can see that online how they have you know uh already meetings about um how they react to that and they see drinking numbers, uh, but they're reacting quickly.
• 1:13:51
  SPEAKER_00: So I think Nestle, uh the company that makes a lot of these uh types of um uh food to food types that you get at the gas station at night and it's never healthy.
• 1:14:01
  SPEAKER_00: Um they uh make um a new food that's called Vital Pursuit, and they market it as the um perfect weightless drug accompanying food.
• 1:14:14
  SPEAKER_00: Basically, it's sandwiches and salad, but you know, it's uh they're slower calorie.
• 1:14:19
  SPEAKER_00: They have adapted quickly.
• 1:14:21
  SPEAKER_00: Um and the uh other thing that I found remarkable is that there are reports how airlines uh have already calculated how much uh money they're gonna be saving because they will need less gas for their few less fuel for their flights because people weigh less.
• 1:14:40
  SPEAKER_00: Um so you know, definitely change.
• 1:14:43
  SPEAKER_01: Have we got good like world-to-date data about its impact on you know population level threshold for obesity being overweight?
• 1:14:53
  SPEAKER_01: Because the last time I looked, it was pretty frightening still, around 70-ish percent of the US population.
• 1:15:00
  SPEAKER_01: Are we seeing that trend down?
• 1:15:02
  SPEAKER_00: So, of course, you know, it depends on what you study, which numbers uh and uh a global US um there is.
• 1:15:10
  SPEAKER_00: I think Gallup uh put that out, uh, if I'm not mistaken.
• 1:15:13
  SPEAKER_00: I would have to look that up again.
• 1:15:15
  SPEAKER_00: But uh there is for the first time a curve that shows uh body weight increase, increase, increase.
• 1:15:21
  SPEAKER_00: For the first time ever, it's decreasing.
• 1:15:23
  SPEAKER_00: Obesity trends are reversing uh in the US.
• 1:15:28
  SPEAKER_00: Right.
• 1:15:29
  SPEAKER_00: Based on these these drugs that are available.
• 1:15:32
  SPEAKER_01: So then I assume as it becomes more affordable, that should be.
• 1:15:36
  SPEAKER_00: Let's see if that turns out to be um uh lasting and and going continuing to go in the other direction.
• 1:15:42
  SPEAKER_01: What what um what don't we know about these drugs so far?
• 1:15:47
  SPEAKER_00: There's there's a lot we don't know.
• 1:15:49
  SPEAKER_00: So one thing is we really don't know how they work.
• 1:15:53
  SPEAKER_00: So um they work in the uh in the hind brain.
• 1:15:57
  SPEAKER_00: Uh we know that.
• 1:15:58
  SPEAKER_00: And I can you know point you to the neurons we identified where GLP and GIP have their action, gabergic and glutamaturgic.
• 1:16:06
  SPEAKER_00: Well, that's where the receptors are, and you we, you know, the types of experiments you do then is you can genetically now remove receptors from these populations of neurons only, and then you give the drug and then it doesn't do the effect on on appetite anymore.
• 1:16:23
  SPEAKER_00: But that's still pretty uh rough because what's happening after that neuron?
• 1:16:28
  SPEAKER_00: What is that connecting to?
• 1:16:30
  SPEAKER_00: Is it is it going to the dopamine system?
• 1:16:32
  SPEAKER_00: And what we see here, that's in mice.
• 1:16:35
  SPEAKER_00: Is it really the same in humans?
• 1:16:37
  SPEAKER_00: Yeah, humans are quite different than than than mice.
• 1:16:40
  SPEAKER_00: Well, removing a few genes, a few receptors, and a few neurons isn't something we can do in a human population.
• 1:16:48
  SPEAKER_00: So let me phrase it in a different way.
• 1:16:53
  SPEAKER_00: For the last 40 years, ever since leptin was discovered, and um Jeff and others have shown how leptin works in the hypothalamus, in the NPY and AGRP neurons, um, at a certain area of the brain that has fenestrated capillaries, so it's not blood-brain barrier protected.
• 1:17:16
  SPEAKER_00: We have studied that to death as a community because that seemed to be where everything happens.
• 1:17:24
  SPEAKER_00: This is certainly where also Grolin works and where we sense a lot of signals and so on.
• 1:17:29
  SPEAKER_00: And it's this incredible body of work from hundreds, thousands of researchers and hundreds and thousands of conferences where we exchanged opinions on that.
• 1:17:39
  SPEAKER_00: This was basically 90% of what everybody was working on in terms of understanding mechanisms of body weight control.
• 1:17:48
  SPEAKER_00: These drugs don't work there, they work on a different part of the brain.
• 1:17:53
  SPEAKER_00: So everything we know about the pathophysiology, we think we know about the pathophysiology of the disease and how these drugs work is completely disconnected, which is quite amazing.
• 1:18:04
  SPEAKER_00: And again, it just shows you how little we know and how much how much serendipity is involved in success um in biomedical research.
• 1:18:12
  SPEAKER_01: So many examples of that as well in science.
• 1:18:15
  SPEAKER_01: Absolutely.
• 1:18:16
  SPEAKER_01: Science for the woman.
• 1:18:17
  SPEAKER_01: We don't need to know everything to know that it works.
• 1:18:19
  SPEAKER_01: That's absolutely that's a good one.
• 1:18:21
  SPEAKER_01: I had a question from a member today, um, and she asked me to ask you: will we get a version of this that we only ever have to take once?
• 1:18:32
  SPEAKER_00: Yes.
• 1:18:33
  SPEAKER_00: In the far future, there likely is going to be gene therapy versions where what I said earlier, we uh understand much better everything about our genetic makeup and our proteomics, etc., and figure out what our weakness is in terms of not having a perfect metabolism and a perfect appetite control, and then developing, very likely heavily AI-based, the right version of a gene therapy targeting multiple psi at the same time, and then forever we have sort of uh re-orchestrated our system in a way that works for us.
• 1:19:16
  SPEAKER_00: That is far away.
• 1:19:17
  SPEAKER_00: I would, you know, for for anybody who is, you know, out of high school, uh, I think that's not gonna happen in our lifetime anymore.
• 1:19:25
  SPEAKER_01: Yeah, it's so tough to know though, right?
• 1:19:27
  SPEAKER_01: Like these things are moving so quickly now.
• 1:19:30
  SPEAKER_00: But but again, again, yeah, exactly.
• 1:19:33
  SPEAKER_00: I mean, who would have thought that large language models are doing what they're doing five years ago?
• 1:19:36
  SPEAKER_00: So we take whatever essay with at least one grain of salt.
• 1:19:40
  SPEAKER_00: On the other hand, is it really that bad that this is a lifelong treatment?
• 1:19:46
  SPEAKER_00: Um, first of all, I wouldn't be afraid of injections because these aren't the injections that some of us remember as a kid, right?
• 1:19:55
  SPEAKER_00: You get you go to the doctor and it really hurts.
• 1:19:57
  SPEAKER_00: Yeah.
• 1:19:58
  SPEAKER_00: You don't feel this, these injections.
• 1:20:00
  SPEAKER_00: There's this ultra-thin needles.
• 1:20:02
  SPEAKER_00: Um second, think of it as something similar to treating high blood pressure.
• 1:20:09
  SPEAKER_00: If you have hypertension, you're taking a beta blocker or an ACE inhibitor.
• 1:20:16
  SPEAKER_00: Um and your blood pressure then hopefully is in check.
• 1:20:19
  SPEAKER_00: Wonderful.
• 1:20:20
  SPEAKER_00: You know, you're not running into a heart attack at some point, and you you live happily and healthily, and it's it's it's fine.
• 1:20:28
  SPEAKER_00: It's symptomatic treatment, but it works.
• 1:20:31
  SPEAKER_00: Well, if you stop taking a beta blocker, your blood pressure is gonna go back up.
• 1:20:36
  SPEAKER_00: This is how you should think of these drugs.
• 1:20:38
  SPEAKER_00: They they help you, they make you healthy, they prolong your life, they prevent risks.
• 1:20:43
  SPEAKER_00: If you stop taking them, your appetite's gonna go up, your calorie uh um the burning is gonna go down, and you're gonna gain some weight and have high blood sugar and have high lipids.
• 1:20:56
  SPEAKER_01: And that's what we see, right?
• 1:20:57
  SPEAKER_01: Like we see we do see this big rebound of of weight gain, but that's expected.
• 1:21:01
  SPEAKER_01: That's not that's not part of the promise of the treatment, right?
• 1:21:05
  SPEAKER_00: It's not, oh my god, the rebound phenomenon.
• 1:21:07
  SPEAKER_00: Well, you stopped taking the drug, the disease came back.
• 1:21:09
  SPEAKER_00: That's happening uh with with most with most diseases.
• 1:21:12
  SPEAKER_00: By the way, it's not happening as fast as we predicted it to.
• 1:21:16
  SPEAKER_00: Really?
• 1:21:17
  SPEAKER_00: From you know the emerging data now, it seems um it's with a couple of months' delay.
• 1:21:24
  SPEAKER_00: Um, and one reason is likely that um after losing significant amounts of weight, you adopt a more active, healthy lifestyle.
• 1:21:34
  SPEAKER_00: Um, and um that counteracts that rebound phenomenon to some extent, but at some point it's coming back.
• 1:21:43
  SPEAKER_01: Yeah.
• 1:21:44
  SPEAKER_01: But I mean, the same thing would happen if you just started eating more after a long diet.
• 1:21:49
  SPEAKER_01: We see we've seen that for decades.
• 1:21:52
  SPEAKER_01: Can we can we just dispel a myth?
• 1:21:54
  SPEAKER_01: Because I saw a video earlier talking about starvation mode, and uh, you know, when you restrict caloric intake for long enough, your body sort of shuts down its metabolism and you stop burning calories.
• 1:22:07
  SPEAKER_01: Could could you maybe explain to the listeners this concept of you know adaptive thermogenesis, you know, what's actually happening there?
• 1:22:16
  SPEAKER_00: I mean, that actually does exist.
• 1:22:17
  SPEAKER_00: There is very good studies uh from long before you know leptin was discovered to show that if you decrease energy intake, your body adapts and decreases um how much how many calories are being burned and decreases energy expenditure to a point.
• 1:22:35
  SPEAKER_00: Um, and I think many of us who have been trying this and went on caloric restriction for longer term felt, you know, or you start freezing a little bit, you're a little bit colder, and and so on.
• 1:22:46
  SPEAKER_00: That is what that is.
• 1:22:48
  SPEAKER_00: Um, again, that is highly uh individually uh uh different.
• 1:22:54
  SPEAKER_00: Um, some people will have more of that phenomenon, some will have less.
• 1:22:57
  SPEAKER_00: But it's a general normal physiological mechanism.
• 1:23:02
  SPEAKER_00: It is not to that extent that you wouldn't lose weight, right?
• 1:23:05
  SPEAKER_00: If if if you decrease the amount of calories you ingest, um you lose weight.
• 1:23:11
  SPEAKER_00: You're not losing as much as you should by just that because your body is counter-regulating it.
• 1:23:16
  SPEAKER_00: Yeah.
• 1:23:17
  SPEAKER_01: Yeah, and you're losing you're losing mass, and so your necessity to hit a maintenance level goes down, right?
• 1:23:23
  SPEAKER_01: Yeah.
• 1:23:24
  SPEAKER_01: It would be it would be useful if that was a thing, and then no one would starve.
• 1:23:28
  SPEAKER_01: That's true.
• 1:23:29
  SPEAKER_01: Yeah.
• 1:23:30
  SPEAKER_01: What what talking about myths?
• 1:23:32
  SPEAKER_01: What what do people misunderstand when when they think about these drugs?
• 1:23:38
  SPEAKER_01: You know, what are some of the things that you wish people would stop saying?
• 1:23:43
  SPEAKER_00: I think really the the point that there is so much uh surprise or frustration or skepticism uh toward these drugs um when folks learn about the fact that uh they need to continue to take them.
• 1:24:00
  SPEAKER_00: Um because it this is not uh different with with many other cases, as I as I just said with the example of of high blood pressure.
• 1:24:11
  SPEAKER_00: And think about if it would be the case that you take these drugs once and uh you never have to take it again.
• 1:24:21
  SPEAKER_00: Do you have that action forever?
• 1:24:23
  SPEAKER_00: That would scare me to death.
• 1:24:25
  SPEAKER_00: Yeah.
• 1:24:25
  SPEAKER_00: What did we do?
• 1:24:26
  SPEAKER_00: Which which neurons did we kill?
• 1:24:28
  SPEAKER_00: And by the way, how about those folks that actually have massive side effects?
• 1:24:33
  SPEAKER_00: Yeah.
• 1:24:33
  SPEAKER_00: Some folks that start vomiting um like several times a day, I think it's a pretty good thing that they can stop taking the drug.
• 1:24:41
  SPEAKER_00: And it isn't something we did forever.
• 1:24:43
  SPEAKER_00: I think this is also one of the major um um benefits uh or or advan advantages compared to uh gastric bypass.
• 1:24:52
  SPEAKER_00: Because gastric bypass, that's irreversible.
• 1:24:55
  SPEAKER_00: If if you're not doing well with that, this is it.
• 1:24:59
  SPEAKER_00: You're gonna with that be with that for living with that for gastric bypass still?
• 1:25:02
  SPEAKER_00: Is that still a thing?
• 1:25:03
  SPEAKER_00: That's still there's still actually um quite quite impressive numbers.
• 1:25:07
  SPEAKER_01: But while we do that over, take these.
• 1:25:10
  SPEAKER_01: Maybe they're non-responders.
• 1:25:13
  SPEAKER_00: Yeah, I think hopefully that is mostly used for patients that really have a massive obesity problem.
• 1:25:21
  SPEAKER_00: There are patients that need to lose not 20, 25% of their weight, uh, but 40, 45%, 50%.
• 1:25:28
  SPEAKER_00: Yeah.
• 1:25:28
  SPEAKER_00: And for them, probably uh um, let's see what the quantiply agonist does or retardotite does, but for them probably gastric pipers is right the right solutions.
• 1:25:38
  SPEAKER_00: And um also um that is something that will be covered by insurance in in many cases.
• 1:25:46
  SPEAKER_00: And also there's this tradition, right?
• 1:25:49
  SPEAKER_00: Um there are there are surgeons that are doing this and doing this very well um that uh offer the benefits, and there are benefits.
• 1:25:58
  SPEAKER_00: Um so um I think it will be a while until that has recalibrated.
• 1:26:04
  SPEAKER_00: Sure.
• 1:26:05
  SPEAKER_00: Yeah.
• 1:26:05
  SPEAKER_00: The right subpopulations are getting that type of treatment because this works for them.
• 1:26:09
  SPEAKER_00: And and there may be, as we said earlier, patients that um don't benefit, that are resistant against these drugs.
• 1:26:17
  SPEAKER_00: And for them, then the gastric bypass probably is the right option.
• 1:26:20
  SPEAKER_00: Although an interesting academic question, does that overlap, right?
• 1:26:24
  SPEAKER_00: Folks that are resistant against the weight loss drugs, are those actually not getting a lot of benefits out of the gastric bypass?
• 1:26:31
  SPEAKER_00: Because these hormones are involved in the metabolic benefits of these gastric bypass as well.
• 1:26:36
  SPEAKER_00: This isn't just we we make the stomach smaller or we put the stomach aside.
• 1:26:40
  SPEAKER_00: Yeah, that's not how it works.
• 1:26:41
  SPEAKER_00: There's something neuroendocrine signal-wise happening, and that might overlap with the action profile of the drugs.
• 1:26:47
  SPEAKER_01: Matthias, I'm I'm mindful of your time, and I know it's been a long day.
• 1:26:51
  SPEAKER_01: Um, so this is the section of the show where we ask some audience questions if you're open to it.
• 1:26:57
  SPEAKER_01: I like the first one.
• 1:26:58
  SPEAKER_01: If you weren't a scientist, what would you be doing?
• 1:27:01
  SPEAKER_01: You can't say psychiatrist now either.
• 1:27:04
  SPEAKER_00: I really wanted to be a drummer in a rock band, but I lacked the talent.
• 1:27:08
  SPEAKER_00: Can you drum?
• 1:27:10
  SPEAKER_01: Which is not well.
• 1:27:11
  SPEAKER_01: Not well.
• 1:27:12
  SPEAKER_01: Loud.
• 1:27:14
  SPEAKER_01: You can you can bang it loudly.
• 1:27:17
  SPEAKER_01: Are GLP1 drugs a result of a broken nutrition society system that has made it come to this for the human species?
• 1:27:24
  SPEAKER_01: Or should it be viewed as a tool to optimize our health?
• 1:27:28
  SPEAKER_01: That's a deep one.
• 1:27:29
  SPEAKER_00: Well, a little bit of both, right?
• 1:27:31
  SPEAKER_00: I mean, it definitely is something that optimizes our health, and I believe in that.
• 1:27:35
  SPEAKER_00: And uh with the grain of salt I mentioned earlier that it can be abused.
• 1:27:40
  SPEAKER_00: Um 70% of obesity is genetic.
• 1:27:44
  SPEAKER_00: Um but 70%?
• 1:27:46
  SPEAKER_00: 70% approximately, yeah.
• 1:27:49
  SPEAKER_00: Um, but um the way uh our society works with you know abundance of you know hypercaloric.
• 1:28:00
  SPEAKER_00: Environments, with the way advertisements work, the way the industry is pushing things, you know, and offering things that are not healthy to children, et cetera.
• 1:28:15
  SPEAKER_00: We now learn to know more about epigenetics, how environment and behavior are programming which genes are being active and not active, and how that can be translated in the next generation.
• 1:28:31
  SPEAKER_00: There is a contribution of our society where we have artificially promoted these types of metabolic diseases.
• 1:28:39
  SPEAKER_00: As sad as that is, um, I don't see another other way of breaking through that as with these types of drugs.
• 1:28:49
  SPEAKER_00: Then, as nice as it would be, just education, um, most of us know that vegetable is better than uh steak and pudding.
• 1:28:59
  SPEAKER_00: Um it hasn't worked.
• 1:29:02
  SPEAKER_00: Uh you know, obesity rates have been going up and up and up and up.
• 1:29:06
  SPEAKER_00: For the first time ever now, they're being stopped.
• 1:29:08
  SPEAKER_00: And that's based on these drugs.
• 1:29:10
  SPEAKER_01: Wouldn't it be wonderful?
• 1:29:11
  SPEAKER_01: And this could happen if you know we we look forward two generations and we know that there is some epigenetic hand down.
• 1:29:22
  SPEAKER_01: We've seen this happen with the Irish potato famine, right?
• 1:29:26
  SPEAKER_01: That but then there is a kickback, is there not?
• 1:29:29
  SPEAKER_01: Yeah, those people could then reverse their biology back to wanting to consume and retain more weight.
• 1:29:38
  SPEAKER_01: Yeah.
• 1:29:39
  SPEAKER_00: That would be wonderful, right?
• 1:29:40
  SPEAKER_00: If yeah, I mean, who who when you know ordering a burger is thinking, oh, if this is good for my grandchildren, right?
• 1:29:49
  SPEAKER_00: Yeah.
• 1:29:52
  SPEAKER_01: As if life's not hard enough as it is.
• 1:29:54
  SPEAKER_01: Exactly.
• 1:29:56
  SPEAKER_01: Let's not go on a tangent here, Chris.
• 1:30:00
  SPEAKER_01: I love this as well.
• 1:30:01
  SPEAKER_01: If both of my parents are overweight, am I doomed?
• 1:30:05
  SPEAKER_00: No, you're not.
• 1:30:06
  SPEAKER_00: Um, first of all, that's not how genetics work, right?
• 1:30:10
  SPEAKER_00: So there's um crossover of genes, and you might actually the ones uh get the ones from your grandparents.
• 1:30:18
  SPEAKER_00: And uh so there's there's a lot of hope, and you're you're not you're not doomed at all.
• 1:30:23
  SPEAKER_00: And how much of the um uh physiology, the phenotype of your parents is actually genetic or is based on their lifestyle or their epigenetics.
• 1:30:33
  SPEAKER_00: So I I I wouldn't despair that's yeah, that's not an excuse.
• 1:30:38
  SPEAKER_01: No.
• 1:30:39
  SPEAKER_01: But caveat to that, you are a hell of a lot more likely to be overweight or obese if both parents are removing genetics, yeah, right?
• 1:30:49
  SPEAKER_01: Like just growing up in that kind of environment.
• 1:30:52
  SPEAKER_01: Um, so that is a challenge I think that we'll hopefully see less of.
• 1:30:55
  SPEAKER_01: Certainly one factor that's frequently influencing things, but yeah.
• 1:31:00
  SPEAKER_01: Wouldn't call it doomed.
• 1:31:02
  SPEAKER_01: No, I didn't write this, all right.
• 1:31:04
  SPEAKER_01: Um, can you please work on a variation for this for mental health?
• 1:31:10
  SPEAKER_01: That's more of a request than a question.
• 1:31:13
  SPEAKER_00: Yes, I will.
• 1:31:14
  SPEAKER_00: Or yes, somebody should.
• 1:31:16
  SPEAKER_00: Um I'm convinced that that's that is really the next frontier or the the biggest unmet medical need out there.
• 1:31:25
  SPEAKER_00: Agreed.
• 1:31:26
  SPEAKER_00: Um there has been such a revolution and transformation uh in uh cancer treatments with with immunoncology, yeah, antibody-based treatments, etc., that you know we haven't really figured everything out yet, but a lot of diseases that were deadly 20, 10 years ago now start to be uh survivable.
• 1:31:46
  SPEAKER_00: Yeah.
• 1:31:47
  SPEAKER_00: Um metabolic diseases, obesity, major breakthrough.
• 1:31:51
  SPEAKER_00: Neurodegeneration, we haven't seen that yet.
• 1:31:54
  SPEAKER_00: And that doesn't mean there isn't intense studies going on, but uh that breakthrough needs to be next.
• 1:32:01
  SPEAKER_00: And as a matter of fact, there were there were some trials um with some of these drugs now, if they actually work directly and and are really beneficial against these neurodegenerative diseases.
• 1:32:13
  SPEAKER_00: That has been a little bit disappointing so far.
• 1:32:16
  SPEAKER_00: Um, there are similarities um that um I heard some folks saying that um you know the neurodegeneration that's sort of the diabetes of the hippocampus or something like that.
• 1:32:29
  SPEAKER_00: It doesn't seem to be as as as simple.
• 1:32:31
  SPEAKER_01: Yeah, never is, is it?
• 1:32:34
  SPEAKER_01: No, so annoying.
• 1:32:36
  SPEAKER_01: If you could go, if you could spend the next 10 years figuring that out, that would be really helpful.
• 1:32:40
  SPEAKER_00: I'll I'll I'll I'll do my best.
• 1:32:42
  SPEAKER_01: Do you think any of these other peptides that not just limiting to the ones that are seemingly trendy, popular now, um do you think from what you know, any of them are showing like real promise?
• 1:32:56
  SPEAKER_01: That are you are you bullish on any or many of them?
• 1:32:59
  SPEAKER_00: Yeah, I you know, I think there's gonna be a wave of next generation ducks coming, most of them peptides that will do um better in terms of maximal effects.
• 1:33:13
  SPEAKER_00: There's gonna be 40% weight loss possible, etc.
• 1:33:17
  SPEAKER_00: Um some of them will work in populations that so far have been resistant because they're targeting other receptors.
• 1:33:25
  SPEAKER_00: I think we may have something now that uh is uh less side effect prone, that will not cause nausea, emesis, and increase in heart rate and all of that.
• 1:33:36
  SPEAKER_00: Um but ultimately it's gonna be more and more precision metabolic medicine with individualized tailored versions of these drugs that may work for a certain subpopulation or in the end for certain families, individuals.
• 1:33:54
  SPEAKER_00: Um I think over the next uh five, ten, fifteen years, metabolic medicine will be completely different.
• 1:34:01
  SPEAKER_00: Um it's not one works for everybody.
• 1:34:04
  SPEAKER_00: It's you optimistic?
• 1:34:06
  SPEAKER_00: Yeah, absolutely.
• 1:34:07
  SPEAKER_00: For that field, yes.
• 1:34:10
  SPEAKER_01: Cheaper, more effective, less side effects, that'd be nice.
• 1:34:14
  SPEAKER_01: Absolutely.
• 1:34:15
  SPEAKER_01: That will happen.
• 1:34:18
  SPEAKER_01: Last one, that I'm adding this myself.
• 1:34:20
  SPEAKER_01: When when are you getting your Nobel Prize?
• 1:34:26
  SPEAKER_00: Right, on optogenetics.
• 1:34:28
  SPEAKER_00: Very exciting, by the way.
• 1:34:30
  SPEAKER_00: Um now the Nobel Prize tends to tends to be very careful and and be awarded, that the committee is very careful and they award the prize when they're really certain what was the the major finding that really led to benefits.
• 1:34:46
  SPEAKER_00: So I think with there's so many things still we don't know what was the most important contribution, etc.
• 1:34:53
  SPEAKER_00: Yeah, that that will be be a couple more years.
• 1:34:55
  SPEAKER_00: And um the Nobel Committee also tends to reward basic research discoveries that then had an impact, um, but um not necessarily uh you know the discovery of an actual chemical entity or drug.
• 1:35:11
  SPEAKER_00: Um that's historic.
• 1:35:13
  SPEAKER_00: Um, this this isn't why we're we're doing what we're doing.
• 1:35:17
  SPEAKER_00: Yeah.
• 1:35:17
  SPEAKER_00: Um that said, it's always exciting to look at uh who's getting the Nobel Prize.
• 1:35:22
  SPEAKER_00: Come on, guys, sharpen up.
• 1:35:24
  SPEAKER_01: We'll see.
• 1:35:25
  SPEAKER_01: Yeah.
• 1:35:25
  SPEAKER_01: Where do you see yourself in 20 years' time?
• 1:35:28
  SPEAKER_00: Hopefully alive.
• 1:35:29
  SPEAKER_00: Um, that's sort of one main goal.
• 1:35:32
  SPEAKER_00: Um but I predict that um, as I see with many of my colleagues that are now that age, you never really stop thinking about these things and doing these things.
• 1:35:42
  SPEAKER_00: I mean, I I made a major career change and taking on more administrative um leadership functions as leading a big university now.
• 1:35:51
  SPEAKER_00: Um but uh I stay involved intellectually and and to some extent with research in that field.
• 1:35:58
  SPEAKER_00: Um now looking back, this university where I'm now back in Munich gave me the opportunity to follow my dream, my mission, my vision, and made everything possible, inspired me, educated me, and um I want to devote most of my time and energy uh making sure that generations to come have that same opportunity, that we uh protect um the freedom of of science, that we protect the uh uh creative spaces where people can follow their vision for the you know the for a better future.
• 1:36:36
  SPEAKER_00: And frankly, that we protect the the version of society and democracy that we're all enjoying.
• 1:36:42
  SPEAKER_00: And I do believe uh universities play an important role there.
• 1:36:46
  SPEAKER_01: That's a good that's a good place to wrap, I think.
• 1:36:49
  SPEAKER_01: Matthias, we I we I can I think it's safe to say that I can say on behalf of everyone who has benefited from this these incredible drugs that is you're a remarkable man, scientist.
• 1:37:03
  SPEAKER_01: I'm so proud to have you as part of our council and to have got to know you and work with you.
• 1:37:07
  SPEAKER_01: Well, thank you so much.
• 1:37:08
  SPEAKER_01: And I'm even more proud that you suffered through two hours of immigration to get through and done up here.
• 1:37:15
  SPEAKER_00: It's really fun talking to you.
• 1:37:16
  SPEAKER_00: Thank you so much.
• 1:37:17
  SPEAKER_01: Legend.