YT YouTube2Text

YouTube2Text → Transcripts → Obesity Is a Brain Disease, Not a Willpower Problem

Obesity Is a Brain Disease, Not a Willpower Problem — Transcript

by The LIVING Room Podcast | Inside The WNDR Lab · 15,925 words · 2,765 segments · language en · Watch on YouTube

Open in transcriber Summarize with AI Download SRT/VTT

Full transcript

0:00Today, I am joined by Professor Matthias
0:02Tschöp. Professor Tschöp was the
0:04scientist responsible for discovering
0:07the GLP-1 glucagon dual agonist that we
0:10now more commonly know as Mounjaro and
0:12Zepbound. But not only that, Matthias
0:14has gone on to discover the triple
0:16agonist that will be the next
0:18blockbuster drug being named as
0:20retatrutide. In this episode, he's going
0:22to tell us about the next generation of
0:24drugs, the quintuple agonists. If you've
0:26ever had any questions on hunger,
0:29appetite, body weight, body composition,
0:31desire to lose or gain weight, and the
0:34effects of these drugs on your
0:35short-term and long-term health, this is
0:38the episode for you.
0:51Welcome to the living room.
0:53>> Wonderful to be here. Thank you for
0:54having me.
0:55>> I know you've had an incredibly long
0:56day.
0:57Um so, thank you for making time for it.
0:59>> Mhm.
1:00>> Can we start
1:0130 years ago? Let's go back when,
1:05you know, obesity, appetite regulation,
1:09weight management
1:11wasn't a problem that we really had a
1:13good solution for.
1:14>> Mhm.
1:15>> Um you know, millions of people
1:19had nowhere to go, hadn't didn't have a
1:21really good understanding of how to
1:23manage their
1:24weight, their body composition, and were
1:26actually made to feel like it was a
1:28discipline problem. It was all their
1:30fault.
1:31Um
1:32and that's when you started researching
1:34in this field. You know, fast forward to
1:36today, things are very, very different
1:38thanks in large part to the work that
1:39you you've done.
1:41How and why did you get into that in the
1:43first place?
1:45>> Well, I was a young physician working at
1:48university hospital in in Munich, and
1:51when I was not in the lab working on
1:53neuroendocrinology and hormones,
1:56I was seeing patients with, you know,
1:58frequently
1:59um obesity, significant levels of
2:03obesity, diabetes.
2:05And then after a while I just couldn't
2:07believe that in our daily routine
2:10all we had to offer for somebody who was
2:13uh significantly overweight was
2:16the advice that already Hippocrates
2:19gave. You know, eat less and move more.
2:21It didn't work then and it isn't working
2:23today on a epidemiological level.
2:26That was one version or we call a
2:28surgeon and see if maybe a gastric
2:31bypass was was an option.
2:33He said, "Well, there had to be
2:34something else, you know, we
2:36um we have figured out so many fantastic
2:39therapies for so many diseases and we're
2:42sort of capitulating uh with with
2:45obesity."
2:46So, when I started to think about and
2:48talk about we need to find something and
2:52talk about a hormone-based therapy
2:55I was told by everybody, "This isn't
2:57possible. You know, this is too
2:58difficult. Um you know, physiology is is
3:02based on evolution in the sense that we
3:06always needed to save all the calories,
3:08get all the calories in and store them
3:10because of the long winters we had to
3:11survive as a species. So, it's too
3:14important for survival of the survival
3:15of the species that all our redundant
3:17mechanisms are making sure we're gaining
3:19weight, we're not losing weight.
3:21Meaning, when you come up with any
3:23therapy, you will have massive side
3:25effects. So, it's a non-starter. Forget
3:27about it."
3:29So, I thought as an endocrinologist,
3:31"Well, you know, we figured out a bunch
3:33of things, right? We we have figured out
3:35contraception.
3:36You know, reproduction is sort of
3:38important for survival of the species.
3:39And and still that that was something
3:41that could be accomplished with with
3:43hormones. So, I didn't want to give up
3:45and and and started going going into
3:47research."
3:48>> So, then what? So, so you you pushed
3:51back against the notion that this wasn't
3:53possible.
3:54And then
3:55but at the time
3:57were we even using gastric bypass?
4:00Probably just about to start, right?
4:02>> Not not at the level that we are
4:04currently using it or we're using it.
4:07The
4:07last decade or two, but it was there. It
4:10was
4:10something that that could be done and
4:12and was done in in some cases.
4:15But you're right, you know, then what is
4:18is exactly where I was because I was
4:20equally enthusiastic and naive.
4:23There was no signal known. There was no
4:26pathway known that would regulate body
4:27weight and and and food intake.
4:30Um so luckily
4:32um as it sometimes goes in the life of a
4:34scientist through serendipity
4:37that was about the time where Jeff
4:39Friedman here in New York discovered
4:42leptin.
4:43Now that was a paper that really
4:45transformed the entire field. I would
4:47say it started the field of molecular
4:49obesity research.
4:51So for the first time we had a signal,
4:53we had a gene that was known to regulate
4:57body weight and and
5:00drive satiety.
5:01Um and for young endocrinologist, a
5:04hormone specialist, it was oh my god,
5:06there's a new hormone. When that When
5:08did that happen the last time, right?
5:09>> Could you maybe before we go into that
5:13explain to the audience what leptin is?
5:15Because I think everyone's heard of
5:16these, you know, leptin and ghrelin but
5:18>> The way it was discovered was that there
5:20was
5:21a fat mouse called the ob/ob mouse.
5:24Ob/ob standing for the obese gene, ob.
5:28And um everybody wanted to know why that
5:31mouse is fat. You know, there's
5:32something must be missing or that mouse
5:35must have something too much and
5:37and and Jeff Friedman was the one who
5:38figured it out through meticulous
5:40genetics work. I mean, today you
5:42probably would do this in a week. Back
5:44then it took 10 years of him focused and
5:47going into it. Positional cloning was
5:50what it was called what he did and and
5:52he figured out and he found out what
5:53gene that was.
5:55And since that gene coded for a protein
5:58that protein when injected decreased
6:02body weight, it made you lean.
6:04Uh so he he called it leptin from leptos
6:07thin in Greek. Uh,
6:09and leptin is a hormone that's secreted
6:11by fat cells. So, we not only had a new
6:14hormone, we had a new endocrine organ.
6:17Cuz, you know, we thought hormones come
6:20from like the thyroid, right? Or
6:23the pituitary. Um, but fat cells? Aren't
6:27those just sacks that store calories?
6:30They do something?
6:31Now, today we know they're actually
6:33complicated organs that signal a lot of
6:36things.
6:37Um, but back then that was completely
6:40new. So, a new endocrine organ, a new
6:41hormone, the first regulator of satiety
6:44and body weight was exciting, a
6:46breakthrough. I mean, that that paper
6:48that came out in nature in 1994,
6:51um, I still see myself sitting there in
6:54the hallway outside my lab and reading
6:56that and saying, "Okay, this is it. I'm
6:58I'm going to leave clinical medicine. I
6:59want to study this. I want to understand
7:01this." Cuz I did sense there's going to
7:04be more than that. There's going to
7:05There's going to be more than one
7:07hormone.
7:08>> It was 1994.
7:09>> 1994. Tells you how old I am.
7:12>> Wow, I know, but relatively that's, you
7:14know, we didn't know about
7:16the hormone that is responsible for
7:18making us feel full, essentially.
7:21Until 1994.
7:23Okay.
7:24Talk to me about ghrelin.
7:26>> Well, so then that was basically, uh,
7:29the next step of the story because,
7:31well, you know, in science things take a
7:33while, right? You need to understand
7:34what that really means, and then there's
7:36the second and the third paper, and then
7:39um, there are the first individuals that
7:41are actually making, synthesizing
7:43leptin, and, uh, understanding the
7:46chemistry better. And that was
7:48happening, interestingly, at Eli Lilly,
7:51a company we now know a lot about, but
7:54back then they weren't really in that
7:55business, but they were interested in in
7:58that. So, they were the first place
8:00where they actually made a a soluble
8:04active version of leptin. And when I
8:06understood that, I said, "I want to go
8:08there and understand how that's done."
8:10So, back then it was very traditional
8:13the way
8:14uh academicians were thinking about a
8:16post doc fellowship. They said, "You've
8:18got to go to Harvard or Oxford or
8:20something like that, otherwise you're
8:22never going to be a professor."
8:23>> Yeah.
8:24>> I said, you know, well, sure, but I I
8:26want to make drugs. I
8:28And they seem to be figuring out how you
8:30make leptin, and maybe leptin is that
8:32drug. Um
8:34So, I um went for a fellowship at Eli
8:37Lilly in Indianapolis.
8:39And um that was then I would have to
8:42start 1997, 1998. And um
8:46that was quite a culture shock, by the
8:48way, because here's this this young guy
8:50from Munich, Germany, coming out of
8:52academia,
8:54uh being an avid mountaineer,
8:57going to Indianapolis, which is
8:58completely flat. And there's nothing
9:02going on. And the streets are ABC,
9:04once a year, but other than that, there
9:06was no
9:09So, it was perfect for for doing a post
9:11doc, cuz there's no distraction.
9:13>> There's nothing to do.
9:14>> Nothing to do. Um but the science was
9:16fantastic, had a great mentor in in in
9:19Mark Heiman back then, and I met um two
9:22individuals right out of the gates when
9:25I started there. One of them was Jeff
9:28Friedman, and he visited there and gave
9:30a talk, and somehow I was the one who
9:33went to lunch with him, and you know, we
9:36connected, and I told him a little bit
9:37about what I wanted to do, and we became
9:39friends
9:40um you know, over the years.
9:42Um And the other one was Richard
9:44DiMarqui,
9:45uh a peptide chemist, an expert. He was
9:48already vice president at Eli Lilly, and
9:50I was the
9:51the post doc, but we, you know, started
9:54to talk, and then later reconnected, and
9:57um did a lot of research over the last
9:5930 years together. But my my job was as
10:03a post doc to find another um
10:06uh
10:08the hunger hormone.
10:09And um we didn't know what it was at the
10:12time and I was looking in the in the
10:13wrong tissue. I was looking in the brain
10:16cuz I thought well, hunger hormone now
10:17needs to be in the brain.
10:18>> Mhm.
10:19>> Turns out it was in the stomach. And it
10:22was a Japanese group of scientists who
10:24discovered this peptide called ghrelin.
10:27>> Mhm.
10:27>> And they they called it ghrelin because
10:30they thought it had to do with growth
10:31hormone release.
10:33Um
10:33which it does too, but that's not its
10:35main job.
10:37Um
10:38And because of the receptor we were
10:42studying and that's a complicated
10:44signaling world. My post-doc mentor Mark
10:47Heiman and I thought, well, we think
10:49that peptide, that might be the hunger
10:50hormone.
10:51>> Mhm.
10:51>> So we did a bunch of experiments really
10:53quickly, made ghrelin. I still remember
10:56I was supposed to go on on um
10:59uh Christmas holidays with my fiance and
11:02I said, well, you know, I I need to make
11:04ghrelin now. I I don't have that much
11:06time.
11:06>> How did that go down?
11:07>> Well, that was, you know, gave there
11:09were discussions.
11:10Um but it was exciting. So I learned to
11:12make how to make peptides so you know,
11:14with the with with the chemists and we
11:16tested it. It turns out yeah, that that
11:18was it and today it's in the textbooks
11:20that that's the human hunger hormone. If
11:22you inject ghrelin, if you infuse
11:24ghrelin right now, um you'll get hungry.
11:27It increases before meals, it decreases
11:29after meals.
11:31Uh it's certainly um
11:32sort of the the counterpart to leptin.
11:35So
11:35we thought of it as the yin and yang of
11:38of appetite regulation, satiety and
11:40hunger.
11:42But it's not the only one. Uh it neither
11:44is leptin and that's why
11:46likely that that's why
11:49neither of them was the answer for the
11:51obesity
11:53epidemic pandemic.
11:54Um cuz leptin, if you give leptin,
11:57there's leptin resistance. It doesn't do
12:00a whole lot.
12:01Um
12:02>> That was going to be my super naive
12:04question. Why not? Why is leptin not
12:06turning into a blockbuster?
12:08>> Um insulin and type 2 diabetes
12:12because there's insulin resistance,
12:14right? You can still give a bunch of
12:16insulin and get something done, and you
12:17probably can do a little bit with
12:19leptin, but, you know, there weren't
12:21leptin molecules that were that good at
12:23at at the time. And then blocking the
12:25ghrelin pathway was a big
12:27disappointment. First of all, there was
12:28a very complicated we worked on that for
12:3010 years, and and in the end it didn't
12:33do a whole lot. Probably because there's
12:35several receptors, and there's several
12:36other signals. It's a redundant system.
12:40From these frustrating experiences, by
12:42the way, the idea was born that then
12:44Richard and I followed up later, that
12:46you probably need a combination of
12:48signals to really be effective in in in
12:51in in fighting obesity. But we learned
12:54one thing, and we learned a lot of
12:55things, but one thing is the most
12:56important thing
12:58that we learned,
12:59leptin and ghrelin have something in
13:01common. They both act in the brain.
13:05And they achieve 95% of what they do as
13:08a hormone by acting in the brain. And
13:11that fit very well with everything we,
13:13you know, started to learn about
13:15genetics of obesity, because all of the
13:17genes that were associated in the large
13:19GWS studies and and sequencing studies
13:22with obesity seemed to be calling for
13:24something that had a function in the
13:26brain or was expressed in the brain. In
13:28other words,
13:29science said obesity is a brain disease.
13:34So, if you want to target obesity, you
13:36probably have to target the brain.
13:39>> But it was really that discovery that
13:42made science say that, right? Because
13:44until that point,
13:46science didn't say obesity was a brain
13:48disease. It said it's a discipline.
13:50>> There was
13:51there was always the assumption that, of
13:53course, you know, appetite probably
13:55needs central nervous system.
13:57>> Yeah.
13:57>> But, um I mean, for centuries we thought
14:01obesity is a disease of the fat cell,
14:03right?
14:05Fat belly, well, that's that's where you
14:06need to look.
14:08>> What year was that?
14:10>> Um so, the our ghrelin paper saying it's
14:14the hunger hormone came out in 2000.
14:17Now, we're a couple of years later.
14:19Um and then from there, you know, a
14:22bunch of ghrelin research uh that as I
14:24said was academically really
14:26interesting.
14:27Um but uh didn't give us the answer that
14:30we wanted and
14:32you know, a traditionally a scientist is
14:33supposed to follow up once you have a
14:35discovery, follow up on that discovery
14:37for for decades. So, you know, become a
14:39ghrelinologist and become the
14:42>> [clears throat]
14:42>> the guy for that.
14:44>> the guy for that.
14:45>> Um and I was just, you know, getting
14:48frustrated and you know, wanted to go
14:50back to my original mission, finding
14:52ways to treat obesity, you know.
14:55So, I was very happy that I then um I
14:57was already uh out of Eli Lilly and had
15:00finished my post-doc and was at
15:02University of Cincinnati.
15:03>> Mhm.
15:03>> Where there was a great metabolism
15:05research center and I knew there was a
15:06lot of expertise in how
15:09appetite is regulated, etc. So, uh I
15:12reconnected with Richard DiMarzo who I
15:14had met at Lilly cuz he also had left
15:16Lilly and he said Indiana University.
15:18And the two of us talked and said,
15:20"Well, you know, we
15:22can we do something together as a
15:24chemist and as a whatever physician
15:26physiologist that usually is only done
15:29inside big pharma um
15:31in academia
15:33um or with a startup company and find a
15:38novel therapeutic that effectively can
15:41treat obesity and is probably
15:43>> be based on a combination of signals.
15:46>> Um the other hypothesis we had was we
15:48need to target the brain. Mhm. But we
15:51can't do this directly. We shouldn't do
15:53this directly because we had, by the
15:54way, in another set of experiments
15:56learned and there was a couple of other
15:58groups around the world working on this.
16:00Uh if you, for example, target
16:02cannabinoid receptors, there was an
16:04interesting story.
16:05Cannabinoid receptor antagonists were
16:07working quite well but had side effects.
16:10>> Mhm.
16:11>> Well, you know, the
16:13friends tell me when they smoke
16:14marijuana, then they get hungry.
16:16>> Mhm.
16:17>> They told me that. So, could you could
16:19think that's your friend said that.
16:20>> Yeah, my friends told me that.
16:21>> Um and and and then, you know, you say,
16:23"Okay, you can block that." Um and then
16:26you have a drug. And it's it actually
16:28worked to some extent. The effects
16:29weren't that great compared to what we
16:31know today, what we see today.
16:33But there were effects. Now, also but
16:35there was there were side effects. There
16:36were cardiovascular side effects and
16:38there were side effects in terms of
16:40driving depression.
16:41>> Mhm.
16:41>> Well, you know, it turns out my friends
16:43don't smoke it to get hungry. They smoke
16:45it to
16:45>> Mhm.
16:46>> in a in a pleasant state of mind.
16:48>> Mhm.
16:49>> You mess with that pathway, and it's
16:51over.
16:52>> In other words, if you directly target
16:55the brain,
16:56we don't have the means until today to
16:59specifically target only those neurons,
17:02those cells, those astrocytes, those
17:04signals for specifically appetite only.
17:07>> Mhm.
17:08>> Um there's always something else we will
17:10mess with and and that's dangerous and
17:13and and undesired.
17:15Uh so,
17:16we said, Richard and I, "Why don't we
17:18use Mother Nature's toolkit?" We use
17:21these afferent hormones, those are the
17:23hormones that come from the periphery
17:24and talk to the brain
17:26that are made for this, to report to the
17:29brain how much food is coming in and
17:31what's going on with metabolism.
17:33So, you have less of a risk for side
17:36effects cuz you find naturally exactly
17:38those places where you need to go. And
17:40then you need to figure out which ones
17:41those are and you need to combine them
17:43in the in the right manner.
17:46By then, there were so many already
17:48because that field exploded. And then it
17:50became a question, well, which ones are
17:52we going to work on because
17:55this then is a question of how how many
17:58years do you have, right?
17:59>> Right.
18:00>> Making some of them and combining them
18:02and testing them in cells and then in
18:05mice and in rats and going back and
18:07tweaking a little bit here, a little bit
18:09there. That's that's you know, you're
18:11losing months and months and years and
18:13years. So, it was
18:15a wise decision that we started where we
18:17started with the hormone glucagon at
18:20some point. Tested all these things, but
18:22relatively early we focused on glucagon.
18:25Might have been also that we got really
18:27lucky that we started there, right?
18:30>> Yeah, luck.
18:31>> Success is over half chance, right?
18:33>> Serendipity is is an in science.
18:38>> Right.
18:39When was the moment you realized you'd
18:41stumbled upon what ultimately would turn
18:44into
18:45an absolute blockbuster?
18:47>> It was
18:48somewhere I see It might have been
18:49March, April of 2006.
18:52And that I can't remember. That tells
18:54you how much of a moment that was.
18:56>> Right.
18:56>> So, Richard then had figured out how to
19:00how to make glucagon molecules
19:04that were longer acting, soluble, and
19:06specific. And that sounds trivial.
19:08>> Mhm.
19:09>> But, an important hormone like glucagon,
19:11you would think people had made receptor
19:14agonists before.
19:15>> Mhm.
19:16>> So, to explain what that means, all of
19:18these hormones have one problem. They
19:19have a very short half-life. A few
19:22minutes.
19:23So, they're not not drugs at all.
19:25>> Yeah.
19:25>> So, then chemistry got better and
19:27better, and Richard was always at the
19:28forefront of this, making them
19:31act longer and be more stable, and still
19:34do what they're supposed to do and
19:35nothing else.
19:36Um one important clue came from
19:40a a lizard that you find in the
19:42southwestern United States, so-called
19:45Gila monster. Uh by the way, I own one
19:47now cuz my postdocs gave me one. It's
19:49somewhere in the zoo in Germany. I can I
19:51can go and and pet it.
19:53So, in the saliva of that lizard, um
19:56by a guy by the name of John Eng found
19:59that there's a version of a GLP, a
20:01glucagon-like peptide that's more
20:03stable. And that had a chemical
20:05modification that we could also use then
20:07to make glucagon more more uh
20:10>> Is that right? I had no
20:12>> So, these these are This is just one
20:14thing that was done, right? So, that
20:15tells you a little bit how crazy science
20:17sometimes can go with, you know,
20:19inspiration from places where you don't
20:20see it coming.
20:21Um and uh so uh a long-acting glucagon
20:26was made and we put it in our mice
20:30mouse model where our mice were like on
20:32a McDonald's diet for like 6 to 9 months
20:35and then they wouldn't weigh 25 g but 50
20:3855.
20:39>> Yeah.
20:40>> And with with that glucagon we could
20:42make these mice
20:44lose weight substantially.
20:46And that was the goosebump moment
20:47because nobody saw that coming.
20:49Everybody thought at the time first of
20:51all, glucagon
20:53is the glucose hormone that increases
20:55blood glucose. That was in the
20:57textbooks. So what do you got to do if
20:59you treat metabolic disease? You got to
21:00block glucagon. We said, "No, no, no,
21:02no. You got to do the opposite cuz we
21:04think glucagon helps you with burning
21:07calories, with curbing appetite, etc. If
21:10you have a long acting version."
21:12>> Mhm.
21:13>> We were called crazy more than once but
21:15that experiment showed that showed us we
21:17were on on the right track.
21:19Now we needed to do something to counter
21:21the the glucose effects of glucagon and
21:24the idea was to use GLP-1.
21:28You heard that before?
21:29>> Mhm.
21:29>> From the same family
21:31of hormones and you know, by the time it
21:35it started to become known that there
21:37may be a small effect on appetite cuz
21:39these early versions of these hormones
21:41didn't have the massive effects we know
21:43they can achieve today.
21:45And of course GLP-1 would trigger
21:47insulin secretion and decrease blood
21:49glucose so it would override the bad
21:52liabilities of glucagon. So we wanted to
21:54put them together.
21:56Putting them together not in the sense
21:57of gluing them together or sticking them
21:59together but to engineer glucagon by
22:02changing a few amino acids so that it
22:05became a hormone that could activate
22:07both receptors, glucagon and GLP in a
22:10certain ratio.
22:11Now you have the best of both worlds,
22:13synergistic action and get rid of some
22:16side effects. And again, took 2 3 years
22:19but now we have drugs that are about to
22:22be approved that are glucagon GLP
22:26receptor co-agonists. So, what would
22:28tide by Boehringer Ingelheim is one of
22:30them, but there are others.
22:31Um that was the first dual agonist that
22:34uh then um
22:36we discovered. Um and that was
22:38published, I think, in 2009.
22:42Um but it was only the the beginning of
22:45the story.
22:46>> Yeah.
22:47A story we we're all kind of familiar
22:49with the ending of right now. Well,
22:51maybe not the ending of where we are
22:52today. When you doing that, and when you
22:54discover that in the little fat mouse,
22:57um like
22:58are there moments where
23:00obviously it's goosebump moment, you're
23:02extremely excited, it's clearly working.
23:06Do you ever think in that moment
23:10this is too good to be true? Like,
23:11what's going to go wrong? What's the
23:13side There's got to be some kind of side
23:14effect. Because
23:16you know, that is a problem we've been
23:17trying to solve for many decades.
23:20>> Well,
23:21you know,
23:22in a scientist's life, there's so much
23:23frustration and rejection.
23:25>> Mhm.
23:26>> Uh so, when when
23:28uh next generation scientists ask me,
23:30"What do you think it needs to become a
23:32great scientist?" Not that I would
23:34really know, but what I usually tell
23:35them is one thing you definitely need is
23:38you got to be able to handle frustration
23:41and rejection. You got to have
23:43perseverance.
23:44Cuz you know, everything else, you know,
23:46you need some luck, you need some good
23:48ideas, but
23:49you papers are going to be rejected, um
23:52your experiments are going to reject
23:53you, and your hypothesis are going to be
23:56wrong, and you still got to be
23:58passionate and excited and then carry
24:00on. So, that that was daily business
24:02then, you know, you
24:03didn't come out the way you wanted it,
24:05and so but these moments that I
24:07mentioned, this goosebump moment, these
24:09goosebump moments where I had, you know,
24:11maybe only three, four in my life, but
24:13they drive you. You sort of get addicted
24:15to that moment. You're like, "Wow,
24:18nobody saw this before me, and and I
24:21found something." And it's like
24:23discovery. It's like you're on Starship
24:25Enterprise and you see a new star.
24:26That's how you feel when you see these
24:29numbers on your screen. You're like, "Oh
24:31my god, this
24:32the ghrelin levels go up when you fast
24:35the rats. I think this is the hunger
24:37hormone." Yeah, so
24:38and you want that moment again. So, and
24:41then you you go for years and years and
24:43you hunt the next discovery.
24:45>> So, that's 2009.
24:46>> Mhm.
24:48>> How then, you know, we're in 2026 now?
24:51It feels a lot like the last
24:53four or five years we've seen this
24:55insane
24:57adoption of these GLP-1 agonists.
25:00Talk to me about that sort of bridge
25:02between finding that
25:04in the lab and then when, you know,
25:05consumers were then
25:07buying into this idea.
25:09>> So,
25:12it may seem to some like overnight there
25:14was this revolution, this transformative
25:16development, but when you really look
25:19into the history, Jeff Friedman and I
25:22was it 2 years ago
25:24wrote an article
25:25in Science Translational Medicine
25:27reviewing the the history of the peptide
25:30hormones and how the obesity drugs then
25:33came
25:34came to be that successful. And it turns
25:37out, you know,
25:38it's at least 120 years of of science
25:42that went into that. That is the
25:43building incremental
25:45It's not that [laughter] old. I mean, of
25:47course there are breakthrough moments
25:48and there's acceleration,
25:50but yeah, well, you know,
25:53you got to know about that there has
25:55been an incretin hypothesis and well,
25:58GIP was discovered so many years ago and
26:01so on. Then it builds builds on that. Um
26:05but yeah, it started to then accelerate
26:08and in parallel to what we did with
26:11glucagon and and then GIP and combining
26:14with GLP, the GLP-1 research was, you
26:17know,
26:18continuing to improve the quality of
26:21these molecules. Um you know,
26:25putting a fatty acid on the molecule,
26:27making it even more long-acting and more
26:29powerful.
26:30Um it it does go back to one
26:34breakthrough moment
26:36in the mid mid '80s where
26:38I think mostly Svetlana Mojsov at the
26:41Rockefeller here here in New York uh
26:43discovered the bioactive sequence. You
26:46know, what is the exact sequence of the
26:48preproglucagon to GLP-1 that is
26:53that is activating into GLP-1 receptor.
26:55And it took a couple of more years until
26:58somebody, and I believe this was Sir
27:00Stephen Bloom,
27:01uh put it into the brain of a rat and
27:04said, "Well, this does something to food
27:05intake." And and then, you know, step by
27:08step um
27:09this became the story that it is today.
27:13Um our next step was to after glucagon
27:16and GLP work together, put GIP and GLP
27:20together. Again, one molecule looks like
27:23an endogenous hormone more or less, and
27:24that's important because otherwise your
27:26immune system is going to reject that
27:27stuff.
27:28Um just a little bit of change here and
27:30there, and now we had a molecule that
27:32would activate the GLP-1 receptor and
27:35the GIP receptor. GIP, another
27:38hormone of that family of peptides,
27:41which is important chemically because
27:43they're relatively similar. So, you
27:45know, you only need a few changes to
27:47make them make it a dual agonist. So, we
27:49discovered the second dual agonist, and
27:51we saw saw that that works even better.
27:54Well, and and that dual agonist GIP GIP
27:58GLP that became the basis for what we
28:00now know as tirzepatide, Mounjaro, and
28:03and and semaglutide, right?
28:05Um
28:06and of course that also is a story where
28:08then, you know, small improvements in
28:10the chemistry made it more and more
28:11powerful, but
28:12the
28:14the concept um and the first version of
28:17it, we actually put it in in humans
28:19first, the first GIP GLP agonist. Um
28:22that uh we published um I think it was
28:25in 2011.
28:26Uh no, was it 15 years ago, right? And
28:29then it it it it takes a while, but
28:32um it is still of the approved drugs the
28:34the most potent one, the most
28:36efficacious one and
28:38a transformative breakthrough. And then
28:41when I saw in clinical trials a couple
28:43of years ago that this works so well,
28:46that was another you sort of goosebump
28:48moment because I remembered when I
28:50started as a young doctor in the early
28:52'90s, everybody told me never in our
28:55lifetime is there going to be a drug
28:56where you can safely reduce 20 25% of
28:59body weight. You you're going to kill
29:01people to stop thinking about it.
29:03You know, go go and do something else.
29:06And and it's it's possible. So, um, you
29:09know, some sometimes it's worthwhile
29:11going against uh
29:13everybody's recommendation.
29:15>> Well,
29:17as a gangster story for a start, not
29:19only did it not kill people,
29:21it's done the exact opposite, right? And
29:24there must it must have saved
29:27hundreds of thousands of lives. You
29:29know, it's it's a problem that, you
29:30know, we're still combating right now,
29:32of course, because of the just sheer
29:35volume of people that are in that
29:37category of overweight and and and
29:40obese.
29:42But, what a remarkable
29:43accolade, right? It works and it works
29:46well.
29:47It almost
29:49miraculously well for people.
29:53Do you ever see this being the outcome?
29:57I mean, obviously that was the ambition.
29:58Did you
30:00did you ever think it would get adopted
30:01and become this just cr-
30:03absolute revolution in in this field of
30:07weight management?
30:08>> There was there was the ambition um and
30:11of course we had hopes, but
30:13um
30:13time we have here today won't
30:16suffice for me to tell you all the
30:18stories of things that didn't work.
30:20Because we tried a lot of things and a
30:22lot of things didn't work. So, and and
30:24it kind of gets blurry and and when you
30:26look back and and you know, it's 30
30:28years of research, 35 years and
30:31you tend to then
30:33um remember it as a narrative of
30:35success, but um, all the hours, all the
30:39the molecules, all the months, um, all
30:42the grad students that worked on
30:43something else and didn't have the
30:45success they wanted to have, they
30:46>> Yeah.
30:47>> is they they is they're still there and
30:49and um
30:51as I said earlier, serendipity and luck
30:54play an important role.
30:56And while you got to have good
30:58hypothesis and we had the hypothesis to
31:00go indirectly and target the brain and
31:02combine signals,
31:04that was about it in terms of the
31:06hypothesis that were right because
31:09we thought we could combine with a
31:12ghrelin receptor antagonist or, you
31:14know, maybe, um,
31:16there is a a version where we could use
31:18a growth hormone and none of that
31:19worked, right? So, um, yeah. I I I think
31:23the the combination of some solid
31:26hypothesis, hard work, and a lot of luck
31:29uh led us to where we then were. At some
31:31point then you get a feeling for a field
31:34where because of things that worked and
31:38others don't know about it yet, but
31:39you're sort of at the forefront,
31:41you get a gut feeling, pun intended, for
31:44>> pun.
31:45>> for for what would next work. So,
31:48example, we had a GIP GLP dual agonist
31:51that worked great. We had a glucagon GLP
31:55agonist that worked great. How about a
31:57triple receptor hormone hormone receptor
31:59agonist, a GLP GIP glucagon triple
32:02agonist?
32:03>> Mhm.
32:04>> And that worked and we saw that coming
32:06because that seemed so obvious that now,
32:10um, not only you would combine the power
32:12of all three, but you could even dose
32:15down with that and maybe reduce with
32:17that, uh, some some of the side effects
32:19and
32:20my philosophy was always mother nature
32:23doesn't do that with one signal.
32:25>> Mhm.
32:26>> So, if it's sort of a matrix, a pattern
32:28of signals, we want to imitate that. Uh,
32:32not, you know,
32:33press on one signal too hard, but
32:35combine the right signals and be more
32:37physiological about it because when you
32:40eat or or or you fast, um
32:42a bunch of signals change, and you want
32:44to imitate that. And um I think the
32:46triple agonist is is something that
32:48really
32:50um
32:51does that well or better than any of our
32:53other approaches. And I think probably
32:57end of this year, next year, I expect
32:58the first triple agonist to be approved.
33:00That's retatrutide.
33:02>> Retatrutide, yeah.
33:03>> Uh
33:04incredibly difficult name. I don't know
33:06who came up with that, but that's the
33:07Lilly version of a triple agonist.
33:10Um we published it in 2015, and then of
33:13course several pharmaceutical companies
33:15followed suit and
33:16>> I'm sniffing around. Yeah, of course.
33:17>> And and now I mean, but again, there's
33:21this an art form in in big pharma to
33:24develop these things well and to make
33:26them
33:26um the real drugs. That's that's a lot
33:29of work, and it it it
33:30the case of retatrutide really well
33:32done.
33:33Um but that gives you what? 30% weight
33:35loss?
33:36>> That one is 30%.
33:37>> 29%, right?
33:39Um
33:41and uh
33:43not not more side effects. So now we are
33:45the level where with retatrutide being
33:48approved, you can give a once-a-week
33:50injection
33:51and achieve the same outcome like we did
33:53with a gastric bypass, right? About 30%
33:56weight loss.
33:57>> That's remarkable.
33:58Feels like there's a a Moore's law of
34:01peptides going on here. Where does this
34:03stop? Does it ever stop? Is this just
34:06the beginning?
34:06>> Well, we didn't stop. We uh
34:08we continued and published a few months
34:11ago a Nature paper on a quintuple
34:14agonist.
34:15>> Of course.
34:16>> something that is combining a GIP.
34:19>> Five.
34:20>> Yeah, five. GIP, GLP, and a triple PPAR.
34:24Uh this is small molecules now. Now
34:26we're going to add small molecules,
34:29nuclear hormone receptor agonists to the
34:32peptides
34:33and have the peptides deliver them like
34:35a Trojan horse to cells certain cells.
34:38Uh you can tell this is way more
34:39complex, but also a fascinating. I think
34:41this is going to be a version of sort of
34:43personalized metabolic medicine where
34:45you target certain organs or certain
34:47cells and not others
34:49with
34:50different versions of satiety inducing
34:53drugs.
34:54Uh will do to also help burn calories,
34:57but also prevent other things like
34:59inflammatory pathways and this and that.
35:02Um that might be next level.
35:05The thing that I'm most excited about
35:07these days is that we tackled another
35:10problem, I believe, which is the side
35:12effects that these drugs still have,
35:14right?
35:15Um and the most well-known, most
35:17frequent one are nausea and, you know,
35:19maybe emesis, vomiting,
35:22um diarrhea, constipation, stomach pain,
35:25indigestion. It's
35:28and and it's
35:29very individual. Some folks have less of
35:32a problem, um
35:34but most of
35:35patients have a little bit of that, some
35:38level of that. That's why dosing up
35:40slowly is what's done with any version
35:43of a GLP-1 receptor agonist like
35:45semaglutide or Ozempic or or or or
35:47tirzepatide, Mounjaro, Zepbound.
35:50Um so, um that helps
35:53with getting used to these drugs and not
35:55having too much of these
35:57gastrointestinal uh adverse effects.
36:00Now, there are other things you got to
36:04see a physician who prescribes these
36:05drugs because you
36:07you you can't take them when you have
36:09had a history of thyroid carcinoma or
36:11pancreatitis and
36:13um there are other things. Um there is a
36:16little bit of an increase in heart rate
36:18with some of them.
36:19Um Um mono agonists as well as dual
36:22agonists. Um
36:23specifically with tirzepatide is
36:25something where that was seen. It
36:27increases early in treatment and goes
36:29down a little, but there's something
36:30there with cardiovascular effects. So,
36:33our ambition became uh for last 5 to 10
36:37years to come up with versions that
36:39don't have these side effects.
36:42And that again was was you know not
36:45trivial.
36:47Everybody in the world is trying this
36:48now. When we started we were alone.
36:50>> Yeah.
36:50>> Now everybody is doing it.
36:52>> sure. Right. And it's big pharma and
36:54they have a lot of manpower.
36:55>> And and and cash.
36:57>> Yeah.
36:57>> Um and for us it's still Richard and I
37:01and and and a few a few folks on the
37:03team. Um so um
37:06our idea was
37:08a lot of what we see here is happening
37:10with the mono agonists. Semaglutide or
37:13Ozempic has these side effects. The dual
37:15and triple agonists have it. So
37:17logically you would think it has
37:19something to do with GLP.
37:21>> Hm.
37:22Hm.
37:22>> Um
37:24So what if we come up with a version
37:25that's GLP-1 free?
37:28Um how about a GIP glucagon?
37:32And for that it's important to know that
37:34um these drugs like Mounjaro, that's
37:36actually not a GLP-1 drug. Um it's more
37:39of a GIP drug. The the ratio of GIP to
37:42GLP is toward GIP.
37:45And while everybody has GLP because that
37:47was the first one.
37:48>> Yeah, that's just what we think they're
37:50called, right?
37:50>> Mounjaro is more of a GIP thing. So GIP
37:52really important. What if we add
37:54glucagon a little bit glucagon to GIP
37:57and get rid of the GLP?
37:58>> Yeah.
37:59>> We did that. And Richard made the dual
38:02agonist after we did tons of experiments
38:04with knockout mice and co-infusing and
38:07this and that. And it turns out bottom
38:10line it decreases body weight as much as
38:13retatrutide. It it doesn't increase
38:16blood glucose. It improves um metabolism
38:18significantly.
38:20And um
38:22we have tested this now in mice and rats
38:25and in non-human primates and in monkey
38:27studies and don't see any sign of these
38:30adverse effects in terms of
38:31gastrointestinal side effects.
38:33Um we're hoping to have this in the in
38:36the clinic soon next next year.
38:38>> So we could end up with a version of
38:40this
38:41>> Yes.
38:41>> gets us as good a result as the the most
38:44effective version that we know about
38:45today, we're talking about
38:47with no side effects.
38:48>> That's what I believe.
38:50I think we might
38:51>> to be alive.
38:53>> Yeah, and you might be alive longer
38:55because of these drugs.
38:56>> Let's talk about that.
38:57>> [laughter]
38:58>> Let's talk about that. You know, when we
39:00remove the the fact that
39:02you know, that they're helping
39:04to dramatically improve body
39:06composition,
39:08do we know that there are other
39:09benefits? We hear a lot about these
39:11different mechanisms that might be
39:14improving all types of different markers
39:16of health. Do we know that for sure?
39:19>> Now,
39:21I have mixed feelings about this when
39:23like the economist has on the title page
39:26that that title
39:28the everything drugs.
39:30Um,
39:31they're definitely not the everything
39:32drugs.
39:33A lot of the benefits that they do have
39:36beyond just decreasing body weight, um,
39:39are in my opinion, um, a consequence of
39:43improved metabolism and decreased body
39:45weight. That you have, you know,
39:47cardiovascular benefits, uh, fewer heart
39:50attacks and fewer strokes. That's very
39:52obvious for a drug that helps you keep
39:55the lipids down and and keep the glucose
39:58in check and and, um, keep the adipose
40:01tissue low and and the calories stored
40:03in the right place. Well, of course.
40:05Yeah. The same for, you know, decreased
40:07risk of neurodegeneration, the same for
40:09several types of cancer, colon cancer
40:12and and so on.
40:14There are, however, effects that are
40:16likely direct
40:18and most of them have to do with
40:20addiction.
40:21>> Mhm.
40:22>> Cuz in a sense you could argue that the
40:24main effect of these drugs is they're
40:26fighting food addiction.
40:28If you listen to patients tell you about
40:30their experience, um, they would say,
40:32"Well, you know, for my entire life I
40:34had these voices in my head that I need
40:37to eat and I need to think about food."
40:39And now I have like 5 hours more time in
40:41my day because these voices are gone.
40:43>> So, these drugs work on food addiction
40:46in a sense in the brain. They work on
40:48addiction to alcohol,
40:51nicotine,
40:52some say even gambling addiction.
40:55>> Yeah.
40:55>> Now, I'm saying I'm I'm saying this a
40:57little bit more carefully because we
40:58don't have the prospective studies yet,
41:01the long-term studies that we have with
41:03obesity. But, there seems to be
41:05something something to it.
41:06>> And it would certainly make sense that
41:08it impacts all kinds of addiction in the
41:10same way.
41:12Can I ask you a then a sort of follow on
41:14from that? You know, obviously I do
41:16think that in the media we conflate some
41:18of the benefits of these drugs with just
41:20weight loss, but obviously there's more
41:22to it than that, and it makes it a lot
41:24easier to achieve the weight loss. So,
41:26you know, there is a tremendous upside
41:28there because that is one of the most
41:29difficult things for the people who are
41:32struggling with being overweight.
41:35I guess one concern that gets voiced, I
41:37have this concern myself, is that if you
41:40blunt desire in that fashion, you know,
41:43or or the the
41:45um being compelled to consume, does that
41:50blunt the
41:51desire to consume and and take part in
41:54everything, right? So, will that make
41:56people feel less inclined to exercise,
41:59to have intimate relations, like all of
42:02the things that are beneficial for our
42:04health?
42:05Um because there's obviously downstream
42:08effects of that which are negative.
42:10>> It doesn't seem to do that, but that's
42:12something that of course we all thought
42:14about and clinicians were worried about.
42:17You know, basically does it drive you
42:18into depression?
42:20If in a sense all the things that are
42:21fun in life are now being hurt.
42:25Um and there are patients that are
42:27saying, "Well, it's a little bit less
42:29colorful how I experience life now, but
42:31it's it's definitely worth it." But,
42:34you know,
42:35there's so much of a trigger for
42:37depression in obesity because people
42:39being stigmatized,
42:41being you know, deprived of social
42:44interactions because of that stigma,
42:46etc.
42:46>> And just the ability to function in
42:48daily life.
42:49>> And it now for the first time in their
42:51lifetime they're, you know, after losing
42:5330, 40, 50 kg,
42:55they can
42:57do exercise, move more,
42:59be more active, and and
43:01more encouraged to take part in social
43:04life. So, that that is such a positive
43:07drive that to to dissect what are the
43:10effects on on mood and quality of life
43:14that are positively influenced by these
43:16drugs and by the weight loss or that may
43:19also be negatively influenced by what
43:22it's is done to addiction or
43:24levels of of joy.
43:26>> Yeah.
43:26>> Um that that is complex. Overall, there
43:29is no signal that this would drive
43:32depression
43:33at all. And um
43:36it also seems that folks are in in
43:39enjoying their meal. It's just that
43:43they're not having the second plate or
43:44the third, and then they maybe don't
43:47have to have dessert.
43:49>> Yeah.
43:49>> Um so, um
43:51in a sense, this this works just as as
43:54it should. And interestingly, it works
43:58best in
44:00massive overweight. And the more you
44:02lose weight, the less effective it is.
44:06So, even though it's abused, {quote}
44:09{unquote}, as a lifestyle drug,
44:11>> Mhm.
44:11>> it is not a very good lifestyle drug cuz
44:13it works best on a BMI of 45. It doesn't
44:17work that great on a BMI of of 25.
44:20>> It does work depending on the dose, of
44:21course, and on on the individual
44:23response.
44:25>> You use that term abuse. I mean, I think
44:26that's one thing that
44:29all of these different talking points we
44:31get
44:33opposing views on in the media, right?
44:35You can read one article that says,
44:38you know, a Zempic or name any of these
44:41GLP-1 agonists
44:43causes depression, and then another one
44:45saying it alleviates depression, causes
44:47lean tissue loss, and another one
44:49saying, you know, it's good for body
44:51composition as a whole, and that the
44:53loss is through fat. How is it How do
44:56consumers just pass through that noise?
44:58Because it is very confusing.
45:01>> Yeah. They need to listen to your
45:02podcast.
45:03>> That's right. Okay, next question.
45:04>> Then they're
45:05>> [laughter]
45:06>> they're going to be informed. So, let me
45:08talk about uh body composition for a
45:09moment there because there's a lot of
45:11confusion and a lot of confusion and a
45:13lot of misinformation.
45:14>> Yeah.
45:15>> Whichever way you lose weight, whenever
45:17you lose weight, you will lose fat mass
45:20and you will lose lean mass. And lean
45:23mass is, you know, composed of um
45:26muscle mass, water, and and so on.
45:30>> Bone, yeah.
45:31>> Bone.
45:32Um
45:33Now, there is nothing that these drugs,
45:36the mono- and dual-agonists, are doing
45:39directly to muscle that we know of. Um
45:42there are not even receptors there of
45:43these drugs. But, you're going into a
45:47negative energy balance cuz fewer
45:48calories and the same levels or
45:51increased levels of energy expenditure
45:53and burning calories.
45:54So, you will lose in a balance fat and
45:57and and lean mass.
45:59Um
46:01If you are forcing yourself into a diet
46:04and do caloric restriction, the exact
46:06same thing will happen.
46:08>> Yeah.
46:09>> You could also look at it from a
46:11physiological perspective and say,
46:14"You know, if if you carry around 20 kg
46:17of fat in a backpack and you suddenly
46:20get rid of that backpack, um you're
46:23losing a a level of weight lifting when
46:26exercise. You need less muscle.
46:28Um so, is it really that bad that now
46:31you have also lost some muscle mass?
46:33It's a new balance that's probably the
46:35right one for you."
46:37There are, of course, um situations,
46:40especially when you look at a an aging
46:41population,
46:43um where it's desirable to maintain or
46:46increase muscle mass.
46:48Um and that's why in in you know, in in
46:51the academic labs and in in the uh big
46:53pharma these days and in biotech, a lot
46:56of folks are working on
46:58combination
47:00drugs that
47:02also increase muscle mass.
47:04That is tricky, right? If if you work on
47:08myostatin inhibitor or something like
47:11that, um very fascinating, but let me
47:15point out one issue with that. Uh our
47:17heart is also a muscle.
47:19>> Mhm.
47:19>> You want that to grow?
47:20>> Mhm.
47:21>> Um so, you know, something that um will
47:25be complex, uh but again, uh not not
47:28something that may never be solved, but
47:31something where we're not as close as
47:33people think.
47:34>> Mhm. I want to say this because I've
47:37said this on other podcasts, and now
47:38that you're here, I want to I don't want
47:40anyone to call me out for not bringing
47:42it up. Um
47:43but, you know, this uh
47:46the use of these
47:47drugs when people are not
47:52massively overweight. And I don't just
47:54mean a little overweight. I mean like
47:56significantly overweight in this obese
47:59category.
48:00When we see people abusing them, which I
48:02think they do get abused,
48:05and we see
48:07this loss of lean tissue, which is
48:09measurable, right? And and I agree with
48:11you, by the way. I don't I don't think
48:13that's
48:14the the drug is not to blame. It's this
48:15huge energy deficit. There is a there is
48:18a significant loss of lean tissue
48:21that becomes pretty difficult to get
48:23back once you've lost it in your latter
48:25years.
48:26I think there is going to be
48:29for some people, I think it will be
48:31catastrophic. I think it will be
48:34it will be
48:36extremely difficult, if not
48:38impossible, to gain back.
48:40If you If you are in your
48:4250s, 60s, 70s, beyond,
48:46and you're not overweight,
48:47>> Right.
48:47>> I don't know why we would risk the loss
48:49of the lean tissue. I think that is
48:50currency of longevity.
48:51>> Right. So, it becomes more difficult to
48:54gain muscle back, gain muscle
48:57at at my age, you know, I'm I'm 59, so I
49:01I know what the numbers look like and
49:02they're not friendly.
49:03So, a lot of exercise is important and I
49:07hate it when I have like a flu and I
49:08can't exercise.
49:10Oh my god, can I catch it catch up
49:12again?
49:13So, you're right.
49:15So,
49:17these drugs should not be abused.
49:20That's why physicians experts should be
49:23prescribing prescribing them.
49:25Nobody should order them on the web
49:28from China from some catalog
49:31for scientific purposes and then use
49:33them. But apparently this is what's
49:35happening, right? People are getting
49:36their hands on Retatrutide already left
49:38and right and they should they
49:40shouldn't.
49:41This should be guided by by experts in
49:45from the medical
49:47medical business.
49:49But
49:51there is
49:52I think a different perspective on that
49:55possible.
49:58I wouldn't be surprised and I'm not
50:01seeing patients anymore. I'm just just
50:02doing science and looking at it from
50:04that perspective. If there was a future
50:07for
50:08sort of microdosing with these drugs
50:11where you are improving your metabolism
50:14just keep keeping it in in in a certain
50:17dimension more healthy
50:19that makes
50:21that would make an important
50:23contribution to your longevity.
50:27>> More people are doing that now as well,
50:29right?
50:30>> Pardon me?
50:30>> People are microdosing now. What what
50:33what do you what's your perspective on
50:34that? Do you think that is there's value
50:36there?
50:36>> I think there might be value there,
50:38right? From everything we know it
50:40doesn't seem to hurt anything and it
50:42might help.
50:43If if you have slightly better lipids
50:46and slightly more controlled glucose and
50:49maybe
50:50a little bit of a check on not overdoing
50:53it
50:55when you're in a
50:56fabulous restaurant too many times a
50:58week
51:00and maybe a little bit less alcohol,
51:03that's a good thing. So, if you are on
51:062.5 mg of of tirzepatide, um
51:10even though you're not clinically obese,
51:14that might be a good thing. We don't
51:16have the studies yet, right? This this
51:18needs to be studied carefully and
51:20I'm not recommending it that, you know,
51:22don't don't do this at home.
51:23>> Yeah.
51:24>> But, I mean, I academically I'm thinking
51:26there's likely a chance that that that
51:30uh becomes uh relevant in the future. If
51:33If we remember, I mean, even back then,
51:36I think now 20, 30 years back, we
51:39already knew from clinical studies
51:41before we had weight loss drugs that
51:44even if you lose 3 to 5% of your body
51:49weight
51:50uh that had has
51:52massive impact on your cardiovascular
51:56and metabolic health.
51:57>> Yeah.
51:57>> Uh even though you should really should
51:59lose 20%. Just a little bit. So, if you
52:02translate that now into these drugs
52:04today, a little bit of these drug
52:07effects that may actually have a
52:10disproportionate impact on on your
52:12chances for, you know, um health span.
52:15>> Mhm. To straw man my own argument as
52:18well, I think if you start seeing these
52:20marginal gains in the in the way that
52:22you feel, in the way that you look and
52:23perform, it is encouraging. It's
52:26motivating. It's a There is a certainly
52:28a subset of people that that would drive
52:30them to go on to then get more healthy
52:33habits and then maybe spend more time
52:34doing exercise and the things that then
52:36can contribute to building
52:38>> There is something that sort of keeps me
52:40awake at night that is that
52:43it's it's possible to abuse these drugs,
52:46especially when the more powerful
52:47versions now become available. Um uh
52:51early in the in the ghrelin days and
52:53studied ghrelin
52:55I was um investigating if ghrelin itself
52:59or a long-acting version of ghrelin
53:01could be used to fight anorexia
53:04Anorexia nervosa. And because basically
53:08there was no treatment and there still
53:09isn't a real treatment for that. It's
53:11it's a horrible condition.
53:12>> Yeah.
53:13>> And uh turns out that it wasn't the
53:16answer until today. It doesn't seem like
53:18ghrelin is the answer there because
53:21really not not being hungry is not the
53:23main problem of most of these patients
53:25cuz they actually have hunger. Um but
53:27but um they're overriding that. Um now
53:32that the drugs we discovered and that
53:34are helping millions of people and are
53:36saving millions of lives
53:38can be abused
53:40by patients that are fighting anorexia
53:42nervosa and then making their condition
53:45even worse.
53:47That worries me.
53:48>> Mhm.
53:48>> Um and that is why these drugs need to
53:51be really controlled and shouldn't be
53:54available freely.
53:55>> Can we talk about this for a minute
53:57because this is a something that is a
54:00concern for me and and our patients and
54:02you know, discussions that I've had in
54:04this room
54:05that um we are now seeing
54:09not just
54:10these research versions of those drugs
54:13but of any other number of peptides. And
54:16the the sort of floodgates have opened
54:18there where we're seeing this
54:20reclassification of half a dozen of them
54:23under this current administration.
54:26Your your drugs
54:28collectively have decades of research
54:30and data.
54:31These do not.
54:33>> Yeah.
54:33>> Right? And and so now
54:35um
54:36I feel like
54:38I always feel like a villain for saying
54:40this because they've become so popular
54:41online and people are using them and
54:44people swear by them.
54:46But at what cost? We because we don't
54:47know yet. It's way too early. We don't
54:50know what's in these vials. We have no
54:53lit- little to no human clinical data on
54:56any of them to be clear for the
54:58audience.
54:59And yet
55:01we can not only buy them online through
55:03catalogs
55:05but now we have in New York, right here,
55:08licensed physicians that are prescribing
55:11them.
55:12And so, you know, we've always been
55:14told,
55:15you know, before you do or take
55:16anything, you should be getting this
55:18approved by a licensed physician.
55:20But now, what does that even mean if
55:22people are doing that without having
55:23that data? And I think that's unfair on
55:25the
55:26the abundance of incredible physicians
55:28who are not willing to cross that line.
55:32>> You know, I
55:34I get worried when I hear people these
55:36days all be fascinated suddenly about
55:39peptides, even though I've been dealing
55:40with peptides and
55:42uh promoting peptides is on my all my
55:44professional life. Um
55:46as a matter of fact, when I started um
55:48as a young researcher, peptides were
55:51sort of the thing of yesterday. People
55:53like, oh, you got to If you want to make
55:54a drug, you need a small molecule. One
55:56of the drivers for that was small
55:58molecules are not sort of um
56:03taken apart by the stomach acid. So, you
56:05can use them orally.
56:07Peptides are going to be destroyed in
56:09the stomach, so you've got to inject
56:10them. So, everybody thought, well, this
56:11is the thing of the past.
56:13Now, look at where peptides are today.
56:16But peptides, that is that is talks
56:18about a chain of amino acids of a
56:21certain length. And if they're longer
56:24than that certain length, then they're
56:26going to be called proteins. Nobody's
56:28excited about proteins. Yeah. Only in a
56:30different way, but
56:31for for for nutrition.
56:33Um but peptides
56:35folks that are excited about peptides
56:37are a great thing. They need to realize
56:40there is deadly toxins, you know,
56:43poisons. Those are peptides, right? Um
56:46If you eat a dangerous mushroom and you
56:47die, that was a peptide. So, we we got
56:51to be careful that [laughter] that we're
56:53not, you know, generalizing too much. Um
56:56it turns out that some of these drugs
56:58are are are based on a peptide
57:00structure.
57:01>> Mhm.
57:02>> But that doesn't make peptides a good or
57:04a bad thing. Um and that that whole
57:07excitement is is a little bit misleading
57:10and dangerous.
57:11>> I think the cart has got ahead of the
57:12horse there a little.
57:13>> A little bit, yeah, it's
57:15>> I mean, what what about when we we when
57:17they are we do have the capacity to
57:20compound them safely?
57:22Right? And so I and that's part of the
57:25reason for this reclassification
57:28because, you know, some of them
57:30are showing promise in animal models in
57:32the same way that that yours were
57:34two decades ago.
57:36>> But that's why we have this long path of
57:39of complicated, challenging, expensive
57:41studies to make sure
57:44we're not overlooking something.
57:47And and we we know from horrible
57:50examples in history what happens
57:52>> A laundry list of examples.
57:54>> Yeah, maybe in in in in pregnancy and to
57:57to your babies if if we're overlooking
57:59something. So
58:01all of these things make a lot of sense
58:03to be tested thoroughly and intensely
58:07before we go and and
58:10approve it or or use it broadly. And we
58:13we we can't overlook that. That's that's
58:15really really important.
58:19I I trust that the system works and
58:21protects everybody from
58:23their own enthusiasm for peptides.
58:28But I think a little bit of that is
58:31driven by
58:33this combination of the success of these
58:35drugs and
58:37limited access to them because not
58:40everybody can afford them, right?
58:43They're expensive. They're really
58:44expensive. And
58:47I know a lot of folks, even, you know,
58:49friends of mine who
58:51would like to be on it and
58:54it's not covered by their insurance and
58:56they they can't afford it long-term.
58:59So that's why I'm very much looking
59:01forward to and and
59:03wherever I can pushing for these drugs
59:07becoming more affordable. So and it will
59:09happen. More and more competition.
59:12Some of them will go off patent and in a
59:15couple of years we will see much more
59:18affordable versions. They still need to
59:20be prescribed by responsible doctors
59:22that have expertise in that area, but I
59:25think that will hopefully then
59:28take away some of that sort of black
59:31market
59:33activity that that is really dangerous.
59:36>> Do you think they become really
59:37affordable?
59:38>> Yeah, yeah, absolutely. I mean,
59:40the the the the the cost for synthesis
59:42for a month of these drugs is is
59:44significantly less than $10, right?
59:47>> Wow.
59:48>> The cost for developing all of them
59:50there were billions and billions and
59:52that's what needs to come back, but
59:54but
59:56looking at, you know, how how well these
59:58companies are doing, I think they got it
59:59back.
1:00:01>> They're making a few dollars.
1:00:02>> A few more.
1:00:03>> Yeah. Can I ask you a question about the
1:00:05efficacy just for us as individuals?
1:00:08I don't know if this is true, but I'm
1:00:10going to say anyway.
1:00:12The these drugs don't work for a
1:00:14percentage of the population.
1:00:17I heard that's around, you know, 20 to
1:00:1930%. Is that right?
1:00:21>> Different numbers around.
1:00:23I bet there are certainly patients where
1:00:25it doesn't work.
1:00:26Some of them stop or it doesn't work
1:00:29because of the side effects and this is
1:00:30something we're tackling now.
1:00:32But for some of them it doesn't seem to
1:00:35show the same
1:00:38impact on weight loss, the same Yeah,
1:00:39don't get the same weight loss benefits.
1:00:42Now,
1:00:43with almost every drug for every disease
1:00:45you sort of have a Gaussian distribution
1:00:48of, you know,
1:00:49most of them have solid effects, some
1:00:51have super effects, and some seem to be
1:00:54sort of resistant.
1:00:57Biology is complicated. We all have
1:00:59different genetic makeup and
1:01:02polymorphisms and react a little bit
1:01:04better, a little bit less.
1:01:06And then there will be some patients
1:01:07that don't respond
1:01:10because they have a specific
1:01:14genetic
1:01:16composition where for example, they
1:01:18don't have a functioning GIP receptor or
1:01:20the GIP receptor functions only to 10%
1:01:23and we start to know about these cases.
1:01:25It's not that frequent, but it explains
1:01:28some of of these phenomena. And for
1:01:30those, then you need different versions,
1:01:32right? Those then need, uh, a GLP with
1:01:36an Amylin or or something like that. And
1:01:39luckily now there's so many versions
1:01:41coming of of future combinations that we
1:01:44will be able to offer that personalized
1:01:46medicine where we will be screening, uh,
1:01:49quicker and quicker and in more depth
1:01:51and with AI-based analysis get quick
1:01:54results to say, "You need this version
1:01:56because you will not respond to this."
1:01:59>> Right.
1:01:59>> Um, that's something, um,
1:02:01you know, biomedical researchers are
1:02:03talking about for 20 years now. Hasn't
1:02:05happened yet. Um,
1:02:08basically it's at the level from you can
1:02:10get your whole genome sequenced at the
1:02:11end your doctor's going to tell you, you
1:02:13know, eat an apple and go go go for a
1:02:15run.
1:02:16>> Oh, well, that was worth it.
1:02:17>> Yeah. Um, but we we will get there.
1:02:19>> Yeah. Those those genetic tests are
1:02:21getting better now that we can we can
1:02:24deduce more from them than we used to be
1:02:26able to. What do what do you think that
1:02:28screening looks like a beyond
1:02:31genetics? Do you do you think that
1:02:35that is, uh, you know, an assay, uh,
1:02:37subjective measures, combination of
1:02:40those things?
1:02:42>> I think
1:02:43>> I'm just trying to get you out of the
1:02:44lab eventually because otherwise you're
1:02:46going to have to keep developing these.
1:02:47>> I think, um,
1:02:50there's going to be a whole other, you
1:02:52know, dimension of a combination of
1:02:55proteomics and,
1:02:57uh, exosomes and metabolomics going in
1:03:00there. I personally am not a big fan of
1:03:03of, um, i- over interpreting the
1:03:07microbiome.
1:03:08>> Mhm.
1:03:10>> There was a lot of hype about the
1:03:12microbiome being so important for
1:03:14metabolism, but then there were clinical
1:03:16studies done where the entire gut
1:03:18microbiome was killed with antibiotics
1:03:22for months.
1:03:23And you know what happened to metabolism
1:03:25and weight?
1:03:26Absolutely nothing. Which, you know,
1:03:29makes me question how how important it
1:03:32really is for that part of medicine.
1:03:34But there's um
1:03:37even so much more that we don't know
1:03:40about. And one version that made me
1:03:42think about this is a friend of mine,
1:03:45Ferenc Krausz, at Ludwig Maximilians
1:03:47University where I'm now in Munich. Um
1:03:50he is a is a physicist who uses his
1:03:54laser-based methods now
1:03:56to to
1:03:58um
1:03:59analyze blood samples.
1:04:02And
1:04:03he doesn't even want to know is this
1:04:05proteins or peptides or he just gets
1:04:08physical signals out and combines those
1:04:11with large amounts of data predicting
1:04:13diseases. And he's showing first success
1:04:16that goes beyond anything I've ever
1:04:18seen. Which just tells us there's
1:04:20there's so much other stuff that we
1:04:22haven't understood yet that he, you
1:04:24know, just ignores and just goes with
1:04:26his methods. Helps that he already has a
1:04:27Nobel Prize in physics that he's pretty
1:04:29smart guy. Um
1:04:31and and um
1:04:34I think um
1:04:36this is just the tip of the iceberg um
1:04:38even though we have more data than we
1:04:41can analyze. Now, with AI we start to be
1:04:44able to, but
1:04:45this is
1:04:47weirdly enough, this is still early
1:04:48days.
1:04:49>> Yeah, there's a lot of unanswered
1:04:50questions.
1:04:52Can we can we touch on some that are
1:04:54answered?
1:04:56What are the things that you do, if
1:04:57you're open to talking about it, to
1:04:59protect your own health, your own health
1:05:02span, longevity, whatever buzzword we
1:05:04want to use to to talk about that? Tell
1:05:07me about the things that you believe in
1:05:08enough to weave into your own life.
1:05:11>> I don't do enough.
1:05:12I do crazy things like flying across the
1:05:14Atlantic, uh waiting in immigration,
1:05:18going on a taxi ride for 2 hours only to
1:05:21talk to you, that's not good for my
1:05:23health.
1:05:23>> I feel like it is.
1:05:25>> [laughter]
1:05:26>> But um
1:05:28So, I don't do anything miraculous that
1:05:31others won't do. I try to exercise um
1:05:35five, six times a week. Try to get in my
1:05:387, 8 hours a week.
1:05:40>> Um What type of exercise are we talking
1:05:41about?
1:05:42>> And uh you know, um
1:05:45weight
1:05:46uh um
1:05:47ex- exercise, but mostly sort of
1:05:50calisthenics and
1:05:51functional training. Um
1:05:54I used to train completely different
1:05:56heavy weights in the past, like many of
1:05:58us, I guess. Uh
1:06:00Um but um some cardiovascular
1:06:04some tennis. Some fun needs to be in
1:06:06there as well. I try to look after my
1:06:09diet. Unfortunately, I have a sweet
1:06:11tooth.
1:06:12Um and it is a is a constant fight
1:06:16against ingesting too much sugar.
1:06:18>> Mhm.
1:06:18>> Um but
1:06:20um
1:06:21there's nothing miraculous that I do
1:06:23beyond that. I you know
1:06:25don't overdo the supplements.
1:06:28Some healthy levels of vitamins and um
1:06:32some fish oil.
1:06:34Um but not not nothing nothing too
1:06:38fancy.
1:06:38>> You take creatine?
1:06:40>> Um used to. Stopped mostly because I'm
1:06:43lazy and forget to buy it.
1:06:45>> Yeah.
1:06:46>> I've got busy days and um No, that's an
1:06:49interesting question. Um
1:06:51when I look at folks that you know, have
1:06:53had a full life of
1:06:56say positive stress
1:06:58they tend to be and getting pretty old.
1:07:01Um
1:07:03I'm not so sure that stress in a general
1:07:05sense in terms of hard work is is
1:07:11is standing against a a you know, um
1:07:17long health span or something like that.
1:07:19Uh I love to work and um
1:07:22my feeling is that if you're excited
1:07:24about what you do,
1:07:26uh
1:07:26you can do a lot of hours.
1:07:28>> Yeah.
1:07:29>> Not saying that my my job is always just
1:07:32fun and games, but
1:07:34um
1:07:35I I I I work long hours and uh just fit
1:07:39in that exercise
1:07:41um
1:07:42if I force it in in the early mornings.
1:07:45>> You're a morning workout guy. Yeah, I
1:07:48am, too.
1:07:49Otherwise, it's too easy to
1:07:51>> find excuse.
1:07:52>> Yeah, tomorrow.
1:07:53>> Yeah, exactly. Yeah, so I I do it first
1:07:55thing in the morning.
1:07:57>> Can I ask you, and you don't have to
1:07:58answer this,
1:07:59do you
1:08:00take
1:08:01GLP-1
1:08:02agonist of any kind?
1:08:03>> I've uh I've tried, of course, dual
1:08:06agonists cuz after 30 years of research,
1:08:08I wanted to know how it feels, and it
1:08:09was really interesting.
1:08:11Um
1:08:12>> How does it feel?
1:08:13>> It's a It's a It's a fun story. Um
1:08:15cuz I
1:08:17I don't know why, but it worked out that
1:08:19way that I started taking for the first
1:08:21time
1:08:22on vacation.
1:08:24And and we're in Italy, and big big
1:08:26family, and and
1:08:28so
1:08:30And suddenly, I'm like, first of all, I
1:08:31didn't like the tiramisu anymore, and
1:08:34uh I I want plate of pasta, well, maybe
1:08:37half a plate is enough, and then I
1:08:39didn't want alcohol anymore. Actually,
1:08:42that went away after a while, but in the
1:08:43beginning, it was like, oh, I don't
1:08:44know, I don't want to drink. I don't
1:08:45like that gin tonic.
1:08:46>> Mhm.
1:08:48>> And
1:08:49what do I do then? I went to bed early,
1:08:51and I felt great, uh but my
1:08:53brother-in-law uh talks to me 2 weeks
1:08:56later and says, "You know what? You used
1:08:58to be more fun."
1:08:59>> [laughter]
1:09:00>> Uh
1:09:01so,
1:09:01that was interesting, but
1:09:03>> It works, then.
1:09:03>> It really amazing how it felt. I did
1:09:05this for a while, and I stopped, but I'm
1:09:07you know, I'm I'm considering going back
1:09:10on a on a microdosing version of this.
1:09:12Um
1:09:13>> I've never tried it, but I would
1:09:15consider it.
1:09:16I
1:09:17one thing
1:09:19I I always sound like a bit of a
1:09:20naysayer, and I find myself sounding bit
1:09:22of a naysayer, and major in the majors,
1:09:24and do all the things we know to work.
1:09:26One thing that is for certain, I I have
1:09:29seen and and continue to see
1:09:31some people whose some people whose life
1:09:34is night and day different because of
1:09:36this and have been trying for many years
1:09:39if not decades to manage their weight
1:09:41and you know,
1:09:43we're almost gaslit into
1:09:45being told that it wasn't possible or it
1:09:47was a desire problem or a discipline
1:09:51problem and so it I mean this
1:09:54remarkable for them.
1:09:57>> You know,
1:09:58we're getting a lot of letters and
1:09:59emails Richard and I that they're really
1:10:02moving
1:10:04and and make us understand again and
1:10:05again
1:10:07what it means for these patients
1:10:10that that are born into that and 70%
1:10:13approximately we know this from
1:10:16twin studies are genetics, right?
1:10:19And um
1:10:21it is not a question of moral or
1:10:23discipline or you know
1:10:26what I find really interesting when I
1:10:28gave give my lectures and you know,
1:10:31to public audiences and so on they're
1:10:34always individuals
1:10:36that are getting really mad at me
1:10:38and the way I feel this
1:10:42coming up is that these are individuals
1:10:44that have always been lean
1:10:47and they're kind of annoyed with the
1:10:50fact that now others can be lean as well
1:10:52because they
1:10:54they saw this as a evidence for them
1:10:57being superior cuz I have more
1:10:59discipline. I got my life, you know, in
1:11:02in in in shape and I'm I'm morally
1:11:05superior and and now they can cheat and
1:11:09all of these people can look like me.
1:11:10How that that is not what the world's
1:11:13supposed to be like. So they
1:11:15aggressively argue against that
1:11:18becoming available for everybody and
1:11:21that just shows you
1:11:23um how
1:11:25um that is misunderstood by society.
1:11:27>> Yeah.
1:11:28That there's a lot of that in general, I
1:11:30think, either way. You know, peop-
1:11:32everyone's got an opinion.
1:11:35And they make sure that you know about
1:11:36it.
1:11:37>> Everybody's an expert in food intake.
1:11:39Everybody eats.
1:11:40>> Yeah, true.
1:11:41Yeah. It's something that we all have to
1:11:43do multiple times a day.
1:11:45>> And by the way, that that this is
1:11:46different from, you know, nicotine
1:11:48addiction. Yeah. You can go cold turkey
1:11:51on smoking. Mhm. You can't go and stop
1:11:54eating.
1:11:55>> Yeah. I think there's the thing there's
1:11:56a bit of stigma as well when people
1:11:58decide to
1:12:00make like a real
1:12:03concerted effort to improve their
1:12:05health.
1:12:06Sometimes
1:12:07seemingly good actors, like people They
1:12:10are good actors. They're friends and
1:12:11family who will see you making that
1:12:13change and it might be that you say no
1:12:15to the the beer with them or that you
1:12:17don't take the dessert, you know,
1:12:19because you're trying to make this
1:12:20positive change in your life. And
1:12:22there's always going to be people who
1:12:24love you, to be clear, who say you don't
1:12:26need to do that. You know, you're you're
1:12:28you you look great. You are You're
1:12:30already fit enough and healthy enough
1:12:31and lean enough.
1:12:33And I think it's difficult sometimes for
1:12:34people to
1:12:36you know, push back against that and
1:12:39stay on the the straight and narrow, but
1:12:40it's all subjective, right? It's If you
1:12:42want to make that change, you should.
1:12:44>> Yeah. Yeah. Yeah.
1:12:45Of course, in all kinds of directions.
1:12:47It It changes society, right? And And I
1:12:49find
1:12:51that
1:12:52progress that that stigma is being
1:12:54removed from so many people. That is
1:12:57uh that is um
1:13:00wonderful. And um I think more people
1:13:03start to understand that this isn't um
1:13:07something that's based on a character
1:13:09flaw, uh
1:13:10but obesity is a disease. Now, they've
1:13:12been learn more about the signals and
1:13:14the genes.
1:13:16What I also enjoy is uh sort of
1:13:18observing the um
1:13:20uh changes in society that sort of go
1:13:22into in
1:13:23economics. Um So, that you know, fast
1:13:26food companies and um companies that are
1:13:30making candy bars are are now in trouble
1:13:33and um, you know, are
1:13:35adapting new strategies cuz they feel
1:13:37it. Now, we're seeing that change
1:13:39economically now. You can see that
1:13:41online how they have, you know, uh,
1:13:43already meetings about um,
1:13:46how they react to that and they see
1:13:48trending numbers. Uh, but they reacting
1:13:50quickly. So, I think Nestle, uh, the
1:13:52company that makes a lot of these types
1:13:54of um,
1:13:56uh, food food types that you get at the
1:13:58gas station at night and it's never
1:14:00healthy. Um,
1:14:02they, uh, make, um,
1:14:04a new food that's called Vital Pursuit
1:14:07and they market it as the, um,
1:14:10perfect weight loss drug accompanying
1:14:12food.
1:14:13>> Mhm.
1:14:14>> Basically, it's sandwiches and salad,
1:14:16but you know, it's uh,
1:14:18>> It's low calorie.
1:14:19>> They have adapted quickly. Um,
1:14:22and the other thing that I found
1:14:24remarkable is that they report how
1:14:27airlines uh,
1:14:29have already calculated how much, uh,
1:14:32money they're going to be saving because
1:14:35they will need less gas for their fuel
1:14:37less fuel for their flights because
1:14:38people weigh less.
1:14:40Um, so, you know, definitely changing
1:14:43changing
1:14:43>> good like up-to-date data about its
1:14:46impact on you know, population level
1:14:50threshold for obesity, being overweight
1:14:53because the last time I looked it was
1:14:55pretty frightening still around 70-ish
1:14:57percent of the US population.
1:15:00Have we seen that trend down?
1:15:02>> So, of course, you know, it depends on
1:15:04what you study, which numbers, uh, and,
1:15:07uh, global US, um, there is I think
1:15:10Gallup put that out, uh, if I'm not
1:15:13mistaken. I would have to look that up
1:15:14again. But, there is for the first time
1:15:17a curve that shows
1:15:19uh, body weight increase increase
1:15:20increase for the first time ever it's
1:15:22decreasing. Obesity trends are
1:15:25reversing.
1:15:26Um, in the US.
1:15:28>> Right.
1:15:29>> Based on these these drugs that are
1:15:31available.
1:15:32>> Mhm. And then I assume as it becomes
1:15:34more more affordable, that should
1:15:36>> Let's Let's see if that turns out to be
1:15:38um
1:15:39lasting and and going continuing to go
1:15:41in that direction.
1:15:42>> What What um
1:15:44what don't we know about these drugs so
1:15:46far?
1:15:47>> There's There's a lot we don't know. So,
1:15:49one thing is
1:15:50we really don't know how they work.
1:15:52>> [laughter]
1:15:53>> Um
1:15:54they work in the in the hindbrain. We
1:15:57know that and I can, you know, point you
1:15:59to the neurons we have identified where
1:16:02GLP and GIP have their action, GABAergic
1:16:04and glutamatergic.
1:16:06Well, that's where the receptors are and
1:16:08we you know, the types of experiments
1:16:10you do then is you can genetically now
1:16:12remove the receptors from these
1:16:14populations of neurons only and then you
1:16:17give the drug and then it doesn't do
1:16:19the effect on on appetite anymore.
1:16:23But it's still pretty rough because
1:16:26what's happening after that neuron? What
1:16:28is that connecting to? Is it Is it going
1:16:30to the dopamine system and what we see
1:16:33here, that's in mice. Is it really the
1:16:35same in humans?
1:16:37>> Yeah.
1:16:37>> Humans are quite different than than
1:16:39than mice. Well,
1:16:40removing a few genes, a few receptors,
1:16:43and a few neurons isn't something we can
1:16:45do in in a
1:16:46in a human population. So,
1:16:49um let me phrase it in a different way.
1:16:52For the last 40 years, ever since leptin
1:16:57was discovered and
1:16:59Jeff and others have shown
1:17:02how leptin works in the hypothalamus in
1:17:05the NPY and AGRP neurons
1:17:09at a certain area of the brain that has
1:17:12fenestrated capillaries, so it's not
1:17:14blood-brain barrier protected. We have
1:17:17studied that to death as a community
1:17:20because that seemed to be where
1:17:22everything happens. This is certainly
1:17:24where also ghrelin works and where we
1:17:26sense a lot of signals and so on.
1:17:29And it's this incredible body of work
1:17:32from hundreds, thousands of researchers,
1:17:35and and hundreds and thousands of
1:17:36conferences where exchanged opinions on
1:17:38that.
1:17:39This was basically 90% of what everybody
1:17:42was working on in terms of understanding
1:17:45mechanisms of body weight control.
1:17:48These drugs don't work there. They're
1:17:51working on a different part of the
1:17:52brain. So, everything we know about the
1:17:55pathophysiology, we think we know about
1:17:57the pathophysiology of the disease and
1:17:59how these drugs work
1:18:01uh is completely disconnected, which is
1:18:03quite quite amazing. And again, just
1:18:04shows you how little we know
1:18:06>> Wow.
1:18:06>> in terms of how much serendipity is
1:18:08involved in success
1:18:11in biomedical research.
1:18:12>> So many examples of that as well in
1:18:14science.
1:18:15>> Absolutely.
1:18:16>> Science for the win. We don't need to
1:18:17know everything to know that it works.
1:18:19That's That's a good one.
1:18:21Uh I had a question from a member today.
1:18:23Um
1:18:24and she asked me to ask you,
1:18:27will we get a version of this that we
1:18:29only ever have to take once?
1:18:32>> Yes.
1:18:33In the far future,
1:18:35there likely is going to be gene therapy
1:18:37versions where what I said earlier, we
1:18:41understand much better everything about
1:18:44our genetic makeup and and our
1:18:46proteomics, etc. and figure out what our
1:18:50weakness is in terms of not having a
1:18:53perfect metabolism and a perfect
1:18:55appetite control,
1:18:57and then developing very likely heavily
1:19:00AI based the right version of a gene
1:19:04therapy targeting multiple loci at the
1:19:07same time,
1:19:09and then forever we have sort of
1:19:12re-orchestrated our system in in a way
1:19:14that works for us. That is far away. I I
1:19:17know for for anybody who is, you know,
1:19:21out of high school, I think that's not
1:19:23going to happen in our lifetime anymore.
1:19:25>> Yes, so tough to know though, right?
1:19:27Like these things are moving so quickly
1:19:29now.
1:19:30>> Yeah, but but again, again, yeah,
1:19:32exactly. I mean, who
1:19:33>> would have thought that large language
1:19:34models are doing what they're doing 5
1:19:36years ago. So, we'll whatever I say with
1:19:38at least one grain of salt.
1:19:40On the other hand, is it really that bad
1:19:43that this is a lifelong treatment? Um
1:19:47first of all,
1:19:48I wouldn't be afraid of injections cuz
1:19:51these aren't the injections that some of
1:19:53us remember as a kid when you get you go
1:19:56to the doctor and it really hurts.
1:19:57>> Yeah.
1:19:58>> You don't feel this these injections.
1:20:00There's there's ultra-thin needles.
1:20:02>> Yeah.
1:20:03>> Uh second,
1:20:05think of it as something similar to
1:20:07treating high blood pressure.
1:20:09If you have hypertension,
1:20:11you take an a beta blocker or an ACE
1:20:14inhibitor.
1:20:15Um
1:20:17and your blood pressure then hopefully
1:20:18is in check. Wonderful. You know, you
1:20:20you're not running into a heart attack
1:20:23at some point and you you live happily
1:20:25and and healthily and it's it's it's
1:20:27fine. It's symptomatic treatment, but it
1:20:30works.
1:20:30>> Yeah.
1:20:31>> Well, if you stop taking a beta blocker,
1:20:33your blood pressure is going to go back
1:20:35up. This is how you should think of
1:20:37these drugs.
1:20:38>> Yeah.
1:20:38>> They They help you. They make you
1:20:40healthy. They prolong your life. They
1:20:42prevent risks.
1:20:43If you stop stop taking them,
1:20:46your appetite's going to go up. Your
1:20:48calorie
1:20:49um burning is going to go down and you
1:20:51are going to
1:20:53gain some weight and have high blood
1:20:54sugar and have high lipids.
1:20:55>> And that's what we see, right? Like we
1:20:57see we do see this big rebound of of
1:20:59weight gain, but that's expected. That's
1:21:01not That's not part of the promise of
1:21:03the treatment, right?
1:21:04>> It's not Oh my god, the rebound
1:21:06phenomenon. Well, you stopped taking the
1:21:08drug. The disease came back. That's
1:21:09happening
1:21:10uh with with most with most diseases. By
1:21:12the way, it's not happening as fast as
1:21:14we predicted it to.
1:21:16>> Really?
1:21:16>> Mm from, you know, the emerging data now
1:21:19it seems
1:21:20um it's with a couple of months delay.
1:21:23>> Hm.
1:21:24>> Um and one reason is likely that
1:21:27um after losing a significant amounts of
1:21:29weight, you adopt a more active healthy
1:21:32lifestyle.
1:21:33Um
1:21:35and um
1:21:37that counteracts that rebound phenomenon
1:21:39to some extent, but at some point it's
1:21:42coming back.
1:21:43>> Yeah.
1:21:44But I mean the same thing would happen
1:21:46if you just started eating more after a
1:21:48long diet. We see we've seen that for
1:21:50decades.
1:21:52Can we can we just dispel a myth because
1:21:54I saw a video earlier talking about
1:21:56starvation mode?
1:21:58And uh you know, when you restrict
1:22:01caloric intake for long enough, your
1:22:03body sort of shuts down its metabolism
1:22:05and you stop burning calories. Could
1:22:07could you maybe explain to the listeners
1:22:10this concept of you know, adaptive
1:22:12thermogenesis, you know, what's actually
1:22:14happening there?
1:22:16>> I mean that actually does exist. There
1:22:17there is very good studies uh from long
1:22:20before, you know, leptin was discovered
1:22:22show that
1:22:24if you decrease energy intake, your body
1:22:26adapts and decreases um how much how
1:22:30many calories are being burned. It
1:22:31decreases energy expenditure to a point.
1:22:35Um and I think many of us who have been
1:22:37trying this and went on caloric
1:22:39restriction um for longer term felt, you
1:22:42know, how you start freezing a little
1:22:44bit, you're a little bit colder and and
1:22:45so on.
1:22:46That is what that is.
1:22:48Um
1:22:49again, that is highly individually uh
1:22:53different. Um some people will have more
1:22:55of that phenomenon, some will have less.
1:22:57But it's a general normal physiological
1:23:00mechanism.
1:23:02It is not to that extent that you
1:23:03wouldn't lose weight, right? If if you
1:23:06decrease the amount of calories you
1:23:08ingest,
1:23:09um you lose weight. You're not losing as
1:23:11much as you should by just that because
1:23:14your body is counter regulating.
1:23:16>> Yeah.
1:23:16Yeah, you're losing you're losing mass,
1:23:18and so your necessity to hit a
1:23:21maintenance level goes down, right?
1:23:22>> Right.
1:23:23>> Yeah.
1:23:24It'd be It'd be useful if that was a
1:23:25thing and then no one would starve.
1:23:28>> That's true. That's true.
1:23:30>> What what
1:23:31talking about myths, what
1:23:34what do people misunderstand when when
1:23:37they think about these drugs? You know,
1:23:39what are some of the things that you
1:23:40wish people would stop saying?
1:23:42>> Mhm.
1:23:43I think really the the point that
1:23:46there's so much surprise or frustration
1:23:49or skepticism
1:23:52toward these drugs when folks learn
1:23:55about the fact that they need to
1:23:58continue to take them.
1:23:59>> Mhm.
1:24:00>> Because
1:24:02this is not different with with many
1:24:06other cases as I as as I just said with
1:24:08the example of of high blood pressure.
1:24:11And think about if it would be the case
1:24:14that you take these drugs once
1:24:17and
1:24:19you never have to take it again. You
1:24:21have that action forever.
1:24:23That would scare me to death. What did
1:24:25we do? Which which neurons did we kill?
1:24:28And by the way, how about those folks
1:24:30that actually have massive side effects?
1:24:32>> Yeah.
1:24:33>> Some folks that start vomiting
1:24:35like several times a day.
1:24:38I think it's a pretty good thing that
1:24:39they can stop taking the drug. And this
1:24:41isn't something we did forever. I think
1:24:43this is also one of the major
1:24:46benefits or or
1:24:49advantages compared to gastric bypass.
1:24:52Because gastric bypass, that's
1:24:54irreversible.
1:24:55>> Mhm.
1:24:55>> If if you're not doing well with that
1:24:57this is it. You're going to with that be
1:24:59with that living with that forever.
1:25:02>> still? Is that still a thing?
1:25:03>> Yeah, still still actually
1:25:05quite quite impressive numbers.
1:25:07>> But why would someone do that over take
1:25:10this? Maybe they're non-respondent.
1:25:13>> Yeah, I think hopefully that is mostly
1:25:15used for patients that really have a
1:25:18massive obesity problem.
1:25:21There are patients that need to lose not
1:25:2320 to 25% of their weight but 40 45 to
1:25:2750%. And and for them probably uh
1:25:31um
1:25:32let's see what the quintuple agonist
1:25:33does or or what retatrutide does. But
1:25:35for them probably gastric bypass is
1:25:37right the right solutions and um
1:25:40also
1:25:41um
1:25:42that is something that will be covered
1:25:44by insurance in in in many cases.
1:25:46And also there's
1:25:48this tradition, right? Um
1:25:50there are there are surgeons that are
1:25:51doing this and doing this very well.
1:25:53>> Mhm.
1:25:53>> Um that uh offer the benefits and there
1:25:56are benefits.
1:25:58Um so
1:25:59um
1:26:00I think it will be a while until that
1:26:03has recalibrated.
1:26:04>> Sure.
1:26:05>> The right sub-populations are getting
1:26:06that type of treatment cuz this works
1:26:08for them. And and there may be as we
1:26:11said earlier patients that um don't
1:26:14benefit, that are resistant against
1:26:15these drugs.
1:26:17And for them then the gastric bypass
1:26:18probably is the right option. Although
1:26:20an interesting academic question,
1:26:23does that overlap, right? Folks that are
1:26:25resistant against the weight loss drugs,
1:26:27are those actually not getting a lot of
1:26:29benefits out of the gastric bypass cuz
1:26:31these hormones are involved in the
1:26:33metabolic benefits of gastric bypass as
1:26:35well. This isn't just we we make the
1:26:38stomach smaller or we put the stomach
1:26:39aside.
1:26:40>> not how it is.
1:26:40>> There's something neuroendocrine
1:26:42signal-wise happening.
1:26:44And that might overlap with the action
1:26:46profile of the drugs.
1:26:47>> Matthias, I'm I'm mindful of your time
1:26:49and I know it's been a long day. Um so
1:26:52this is the section of the show where we
1:26:54ask some audience questions if you're
1:26:56open to it. I like the first one.
1:26:58If you weren't a scientist, what would
1:27:00you be doing?
1:27:01You can't say psychiatrist now either.
1:27:03>> I really wanted to be a drummer in a
1:27:05rock band but I lacked the talent.
1:27:08>> Can you drum?
1:27:10Just not well.
1:27:11>> Not well. Loud.
1:27:13>> [laughter]
1:27:14>> You
1:27:14You can bang it loudly.
1:27:17Are GLP-1 drugs a result of a broken
1:27:20nutrition society system that has made
1:27:22it come to this for this human species?
1:27:24Or should it be viewed as a tool to
1:27:26optimize our health?
1:27:28That's a deep one.
1:27:29>> Well, a little bit of both, right? I
1:27:31mean definitely is something that
1:27:33optimizes our health and I believe in
1:27:34that. And uh with the the grain of salt
1:27:37I mentioned earlier that it can be
1:27:38abused.
1:27:39Um
1:27:4170% of obesity is genetic. Um but
1:27:45>> 70%?
1:27:46>> 70% approximately, yeah.
1:27:48>> Huh.
1:27:49Um but
1:27:50um
1:27:51the way uh our society works
1:27:55with, you know, abundance of, you know,
1:27:58hypercaloric environments, uh with the
1:28:02way advertisements work, uh
1:28:04um
1:28:05the way the industry is pushing things,
1:28:07uh you know, and offering things that
1:28:10are not healthy to children, etc. Uh we
1:28:15now learned more about epigenetics.
1:28:18>> Mhm.
1:28:19>> How uh environment and behavior are
1:28:23programming which genes are being active
1:28:26and not active, and how that can be
1:28:27translated in the next generation. Um
1:28:31there is a contribution of our society
1:28:34where we have artificially promoted uh
1:28:37these types of metabolic diseases.
1:28:39As sad as that is, um
1:28:42I don't see any other other way
1:28:45uh of breaking through that
1:28:46>> Mhm.
1:28:47>> as with these types of drugs. Then, as
1:28:50as nice as it would be, just education,
1:28:53um most of us know that vegetable is
1:28:56better than uh steak and pudding.
1:28:59>> Mhm.
1:28:59>> Um
1:29:00it hasn't worked.
1:29:01>> Mhm.
1:29:02>> You know, obesity rates have been going
1:29:04up and up and up and up. For the first
1:29:06time ever, now they're being stopped,
1:29:08and that's based on these drugs.
1:29:10>> Wouldn't it be wonderful, and
1:29:12this could happen,
1:29:14if, you know, we we look forward two
1:29:17generations, and we know that there is
1:29:19some epigenetic hand down. We've seen
1:29:22this
1:29:22>> Mhm.
1:29:23>> happen with the
1:29:24Irish potato famine, right? The
1:29:27But then there is a kickback, is there
1:29:28not?
1:29:29>> Yeah.
1:29:29>> That those people could then
1:29:32reverse [snorts]
1:29:33their biology back to wanting to
1:29:35consume and retain more
1:29:37weight.
1:29:37>> Yeah.
1:29:39That would be wonderful, right? If
1:29:41I mean, who who when, you know, ordering
1:29:44a burger is thinking, "Oh, if this is
1:29:46good for my grandchildren"
1:29:47>> Yeah, right.
1:29:49Yeah. [laughter]
1:29:50>> Mhm.
1:29:52>> As if life's not hard enough as it is.
1:29:54>> Exactly.
1:29:55>> [laughter]
1:29:57>> Let's not go on a tangent here, Chris.
1:30:00I love this as well. If both of my
1:30:02parents were overweight, am I doomed?
1:30:05>> [snorts]
1:30:05>> No, you're not. Um
1:30:07first of all, that's not how genetics
1:30:09work, right? So, there's
1:30:11um
1:30:13crossover of genes and you might
1:30:15actually the ones uh get the ones from
1:30:16your grandparents.
1:30:17>> Mhm.
1:30:18>> And uh so, there's there's a lot of hope
1:30:20in you're not you're not doomed at all.
1:30:23And how much of the um
1:30:26uh physiology, the phenotype of your
1:30:28parents, is actually genetic or is based
1:30:30on their lifestyle?
1:30:31>> Mhm.
1:30:31>> Or their epigenetics. So,
1:30:34>> I I I wouldn't despair. That's That's
1:30:36not an excuse.
1:30:38>> No.
1:30:39But,
1:30:40caveat to that,
1:30:42you are a hell of a lot more likely to
1:30:44be overweight or obese if both parents
1:30:46are, removing genetics, right? Like just
1:30:49growing up in that kind of environment.
1:30:51Um so, that is a challenge, I think,
1:30:53that we'll hopefully see less of.
1:30:55>> It's certainly one one factor that's
1:30:57frequently influencing things.
1:30:58>> Yeah.
1:31:00>> Wouldn't call it doomed.
1:31:02>> No, I didn't write this, all right?
1:31:04Um can you please work on a variation
1:31:08for this for mental health?
1:31:10That's more of a request than a
1:31:11question.
1:31:13>> Yes, I will. Or yes, somebody should.
1:31:15>> Mhm.
1:31:16>> Um
1:31:17I'm convinced that that this that is
1:31:20really the next frontier or the the
1:31:22biggest unmet medical need out there.
1:31:25>> Great.
1:31:25>> Um
1:31:26there has been such a revolution and
1:31:29transformation in
1:31:31cancer treatments
1:31:32with with immuno-oncology,
1:31:34antibody-based treatments, etc.
1:31:36>> That you know,
1:31:37we haven't really figured everything out
1:31:39yet, but
1:31:40a lot of diseases that were deadly 20,
1:31:4210 years ago, now start to be uh
1:31:45survivable.
1:31:46>> Um metabolic diseases, obesity, major
1:31:49breakthrough.
1:31:51Neurodegeneration,
1:31:52we haven't seen that yet. And that
1:31:54doesn't mean there isn't intense studies
1:31:56going on. But that breakthrough needs
1:31:59needs to be next. And as a matter of
1:32:02fact, there were there were some trials
1:32:05with some of these drugs now. If they
1:32:07actually work directly and and are
1:32:09really beneficial against these
1:32:11neurodegenerative diseases, that has
1:32:13been a little bit disappointing so far.
1:32:16There are similarities
1:32:18that I
1:32:21heard some folks saying that you know,
1:32:24the neurodegeneration, that's sort of
1:32:26the diabetes of the hippocampus or
1:32:27something like that.
1:32:28>> diabetes.
1:32:29>> seem to be as as as simple.
1:32:31>> Yeah.
1:32:32Never is, is it?
1:32:34>> No.
1:32:34>> So annoying.
1:32:35If you could go if you could spend the
1:32:37next 10 years figuring that out, that
1:32:39would be really helpful.
1:32:40>> I'll I'll I'll do my best.
1:32:42>> Do you think any of these other peptides
1:32:44that
1:32:45not just limiting to the ones that are
1:32:48seemingly trendy, popular now.
1:32:51Do you think
1:32:53from what you know, any of them are
1:32:54showing like real promise that you are
1:32:56you bullish on any or many of them?
1:32:59>> Yeah, I you know, I think there's going
1:33:01to be a wave of next generation drugs
1:33:04coming, most of them peptides yeah,
1:33:07that will do
1:33:10better in terms of maximal effects. Then
1:33:13they're just going to be 40% weight loss
1:33:14possible, etc.
1:33:16Um
1:33:19some of them will work in populations
1:33:21that so far have been resistant cuz
1:33:22they're targeting other receptors.
1:33:25I think we may have something now that
1:33:28is less side effect prone, that will not
1:33:31cause nausea, emesis, and
1:33:33increase in heart rate and and all of
1:33:35that. Um but ultimately, it's going to
1:33:39be more and more precision metabolic
1:33:42medicine with individualized tailored
1:33:45versions of these drugs that may work
1:33:48for a certain subpopulation or in the
1:33:50end
1:33:51for certain families, individuals.
1:33:54Um
1:33:55and I think over the next 5, 10, 15
1:33:58years metabolic medicine will be
1:34:00completely different. Um, it's not one
1:34:03works for everybody. It's
1:34:05>> You optimistic? [snorts]
1:34:06>> Yeah, absolutely. For that field, yes.
1:34:10>> Cheaper, more effective.
1:34:13Less side effects, that'd be nice.
1:34:14>> Absolutely. That will happen.
1:34:16>> Mhm.
1:34:18Last one, I'm adding this myself. When
1:34:21when are you getting your Nobel Prize?
1:34:23>> Ha, well.
1:34:25We we just had a Nobel Prize this week,
1:34:26right? On on optogenetics, very exciting
1:34:28by the way.
1:34:29>> Was it?
1:34:29>> Um,
1:34:30now, you know,
1:34:32the Nobel Prize tends to tends to
1:34:35be very careful and and be awarded and
1:34:38that committee is very careful and they
1:34:40award the prize when they're really
1:34:42certain what was the the major finding
1:34:45that really led to benefit. So, I think
1:34:47with
1:34:47there's so many things still we don't
1:34:49know what was the most important
1:34:51contribution, etc.
1:34:53That that will be be a couple more years
1:34:55and um,
1:34:57the Nobel Committee also tends to reward
1:35:00basic research discoveries that then had
1:35:02an impact. Um, but um, not necessarily,
1:35:07uh, you know, the discovery of an actual
1:35:09chemical entity or drug.
1:35:11That's historic.
1:35:13This this isn't why we're we're doing
1:35:16what we're doing.
1:35:17>> Yeah.
1:35:17>> Um, that said, it's always exciting to
1:35:19look at
1:35:20who's getting the Nobel Prize and
1:35:22>> Come on, guys, sharpen up.
1:35:24>> We'll see.
1:35:24>> Yeah. Where do you see yourself in 20
1:35:27years time?
1:35:28>> Hopefully alive. Um, that's sort of one
1:35:31main goal. Um,
1:35:33but I predict that, um,
1:35:36as I see with many of my colleagues that
1:35:38are now that age, you never really stop
1:35:39thinking about these things and and
1:35:41doing these things. I mean, I I made a
1:35:43major career change in taking on more
1:35:45administrative, um, leadership functions
1:35:48as leading a big university now.
1:35:50Um, but, uh, I stay involved
1:35:53intellectually and and to some extent
1:35:55with research in in that field. Um,
1:35:59now looking back
1:36:02this university where I'm now back in in
1:36:05Munich gave me the opportunity to follow
1:36:08my dream, my mission, my vision and made
1:36:11everything possible, inspired me,
1:36:13educated me and um I want to devote most
1:36:17of my time and energy
1:36:19uh making sure that generations to come
1:36:22have that same opportunity, that we
1:36:24uh protect um the freedom of of science,
1:36:28that we protect the
1:36:30uh creative spaces where people can
1:36:32follow their vision for the you know
1:36:34for a better future.
1:36:36And frankly that we protect the the
1:36:38version of society and democracy that
1:36:40we're all enjoying and I do believe uh
1:36:43universities play important role there.
1:36:46>> That's a good That's a good place to
1:36:48wrap, I think. Matthias, we we I can I
1:36:51think
1:36:52it's safe to say that
1:36:54I can
1:36:55say on behalf of everyone who's
1:36:57benefited from this these incredible
1:36:59drugs that is you're a remarkable man,
1:37:02scientist. I'm so proud to have you as
1:37:04part of our council and to have got to
1:37:06know you and work with you.
1:37:07>> Well, thank you so much.
1:37:08>> And I'm even more proud that you
1:37:09suffered through two hours of
1:37:10immigration to get through
1:37:12>> [laughter]
1:37:13>> and turn up here.
1:37:14>> It's really fun talking to you. Thank
1:37:16you so much.
1:37:17>> Legend.

About this transcript

This page contains the full transcript of Obesity Is a Brain Disease, Not a Willpower Problem by The LIVING Room Podcast | Inside The WNDR Lab, generated from the public captions YouTube serves with the video. The transcript has 15,925 words across 2,765 segments, with the original timestamps preserved so you can click any line to jump to that moment in the embedded player.

What you can do with it

Use the transcript to take notes, quote the speaker, build a study guide, generate a summary with ChatGPT or Claude via the YouTube Summary tool, or export it as a timed subtitle file with YouTube to SRT. You can also re-open it in the transcriber to translate the transcript into 100+ languages.

Free YouTube transcript tool

YouTube2Text is a free YouTube transcript generator — no signup, no daily limit. Paste any YouTube link and get the full transcript instantly, with timestamps, click-to-jump, translation to 100+ languages, AI prompts for ChatGPT, Claude, and Gemini, and exports to TXT, SRT, VTT, or Markdown.