Putting mysterious cellular structures to use, and when brown fat started to warm us up

This episode delves into the biology and potential applications of mysterious cellular structures known as vaults, and explores the evolution and function of brown fat in mammals.

1. Vaults are cellular structures whose functions are still not fully understood, but they show potential for drug delivery and environmental remediation.
2. Brown fat plays a crucial role in thermoregulation by generating heat, a function that has evolved significantly among mammals.
3. The episode highlights ongoing research into using vaults to improve gene therapy effectiveness by bypassing immune system detection.
4. It discusses how brown fat's ability to burn energy for heat could be utilized to treat obesity and metabolic diseases.
5. The evolutionary journey of brown fat and its functional protein, UCP1, is mapped out, providing insights into its development and importance in mammalian biology.

1. Introduction to Vaults

Explores the history and current research on vaults, cellular structures with unknown functions that are being tested for therapeutic delivery. Sarah Crespi: "Vaults, first discovered in the 1980s, are now being eyed for drug delivery despite their mysterious nature."

2. The Role of Brown Fat

Discusses the evolution and function of brown fat in mammals, focusing on its role in heat generation and potential implications for treating obesity. Sarah Crespi: "Brown fat, a recent discovery in adults, plays a critical role in thermoregulation and energy expenditure."

3. Applications and Implications

Covers potential applications of vaults in medicine and environmental cleanup, and the implications of brown fat research on metabolic health. Sarah Crespi: "Researchers are exploring how vaults can carry therapeutic agents and how brown fat can be targeted to combat obesity."

1. Stay informed about the latest research on cellular structures like vaults for potential health applications.
2. Consider the implications of brown fat in energy metabolism and weight management strategies.
3. Follow developments in gene therapy that utilize innovative methods like vaults for more effective delivery.
4. Engage with scientific literature to understand the evolutionary significance of physiological features like brown fat.
5. Explore ways to apply emerging biotechnologies in environmental conservation efforts.

Despite not having a known function, cellular “vaults” are on the verge of being harnessed for all kinds of applications, and looking at the evolution of brown fat into a heat-generating organ

First on this week’s show, Managing News Editor John Travis joins host Sarah Crespi to discuss mysterious cellular complexes called “vaults.” First discovered in the 1980s, scientists have yet to uncover the function of these large, common, hollow structures. But now some researchers are looking to use vaults to deliver cancer drugs and viruses for gene therapy.

Next, what can we learn about the evolution of brown fat from opossums? Unlike white fat, which stores energy in many mammals, brown fat cells use ATP to generate heat, helping babies maintain their body temperature and hibernators kick-start their summers. Susanne Keipert, a researcher in the Department of Molecular Biosciences at Stockholm University’s Wenner-Gren Institute, talks about when in evolutionary history brown fat took on this job of burning energy.

Finally, this week we are launching our music refresh! If you are interested in what happened to our music—where it came from and how it’s different (and the same)—stay tuned for a chat with artist Nguyên Khôi Nguyễn.

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Sarah Crespi
This podcast is supported by the Icon School of Medicine at Mount Sinai, one of America's leading research medical schools. Icon Mount Sinai is the academic arm of the eight hospital Mount Sinai Health System in New York City. It's consistently among the top recipients of NIH funding. Researchers at Icon Mount Sinai have made breakthrough discoveries in many fields vital to advancing the health of patients, including cancer, Covid and long Covid, cardiology, neuroscience, and artificial intelligence. The Icahn School of Medicine at Mount Sinai we find a way.

Sarah Crespi
This is the science podcast for June 7, 2024. I'm Sarah Crespi, and yeah, this is new music.

Sarah Crespi
We've had a refresh. Be sure to stick around for a.

Sarah Crespi
Bonus segment at the end of the episode for a look behind the scenes at our audio update. But first on this week's show, managing news editor John Travis joins me to discuss mysterious cellular complexes called vaults, first discovered in the eighties. Scientists have yet to uncover the function of these common, highly expressed hollow structures. But now some researchers are looking to use vaults to get things into cells like drugs, gene therapy, and more. Next, what can we learn about the evolution of heat generating brown fat from opossums? Researcher Suzanne Kuipert. Here to talk about when in evolutionary history, Brown fat took on the job of burning energy and warming us up.

Sarah Crespi
This week in science, managing news editor John Travis put on his reporter hat to revisit a topic he first wrote about in 1996. That was about ten years after the discovery of these mysterious organelles called vaults, which are found in all kinds of eukaryotic cells, including ours. And there's still some mysteries about them today. Hi, John. Welcome back to the Science Podcast.

John Travis
Thanks, Sarah. I'm happy to revisit one of my favorite stories of all time.

Sarah Crespi
Oh, man. You know, I have never heard of vaults before. You pitched a story, and I was a cell biology student in the nineties, and we definitely learned about organelles. What gives? Why was I not informed?

John Travis
Well, as I tell people in the story, it's not in the textbooks. And even one of the most famous textbooks, I think one that you studied, have never mentioned vaults.

Sarah Crespi
Yeah. So I blame Bruce Alberts, one of the authors of that big textbook on molecular biology of the cell, our former editor of science.

John Travis
Definitely. I blame him. He has a good reason.

Sarah Crespi
Okay, what's his reasoning? That we don't need to know about waltz in college because we don't know.

John Travis
What they do 40 years after their discovery, we still don't know what they do. And he doesn't want to confuse the students out there, which you can understand, but it's kind of remarkable that this very big, very prevalent, there are thousands of vaults in a cell that most people don't know about them. Even in the scientific community, we know.

Sarah Crespi
What they look like. We know what they're made of protein wise, the genes, the process of assembly, and yet we still don't.

Sarah Crespi
It's just kind of freaking me out.

Sarah Crespi
That we don't know what they do. So were you surprised you reported on this in 96? Here we are, 2024. Were you surprised when you looked into this, that this hadn't been resolved?

John Travis
Definitely. I came across vaults again recently in a preprint where a team had done something very unusual. They had stuffed a virus in the.

Sarah Crespi
Vault because it's a little hollow guy.

John Travis
Yeah.

If you think of it as like a barrel or somebody said it looked like a hand grenade or a football. But it's largely empty space and we can make synthetic versions that are completely empty. And so people keep trying to put things in them. Drugs, enzymes to decontaminate water. And this group had stuffed a virus into the vault. When I looked on the paper, I came across a name, Leonard Rome. And I went, oh, my God, he's the discoverer vault. What's going on with them? I should give him a call.

And it turned out he was officially retired. And he said, we still don't know what vaults do, but I'm still working on it. I haven't given up.

Sarah Crespi
Wow.

John Travis
After talking to Lenny and realizing kind of the ups and downs and that this mystery was going on, I pitched a bigger story to my boss and said, let's talk about the mystery and kind of the struggle to understand this component of the cell. It illustrates a lot of what goes on in science, how something can be hot one day and then forgotten the next day. So I thought it illustrated a lot of themes.

Sarah Crespi
Did Lenny remember you from your first story that you did on vaults back in the nineties?

John Travis
Definitely. I think I had done the first big story on vaults, and so he had always, I guess, somewhat been thankful, but, yeah, he had remembered me. And there seemed to be a lot of interesting new stuff, even though the big central mystery was still there.

Sarah Crespi
So I think we should start with the central mystery, and then we'll go to looking at applications for vaults. How are vaults first identified in a cell? What happened?

John Travis
A postdoc named Nancy Kadurza in Lenny's lab was trying to purify another component called coated vesicles in the cell. They transport enzymes back and forth within the cell and she came across essentially a contaminant. They thought it was kind of deformed coated vesicles. But when they did some studies and some electron micrographs, they came across this weird particle that looked like a football. So Nancy and Lenny did a lot more studies to try to analyze the vaults, and they found a really unusual structure with three different proteins and rna. It was centered on a key protein called the major vault protein. There are 78 copies of it in the vault or on the vault, 39 per half. And they kind of form kind of like the staves of a whiskey barrel. On each half, inside are the other two proteins in the rna. It was just very odd. They'd never seen anything like it. It was bigger than ribosomes.

Sarah Crespi
What kinds of theories were there about what these little vaults were doing?

John Travis
The earliest ones were that it was carrying a cargo, and maybe it was the rna inside or the other proteins, but they could never figure out functions for those components. So they thought maybe it was picking up things like maybe enzymes and transporting them, and they could never find anything. There was a period where they thought it might be expelling toxic chemicals from the cell, because cancer cells appear to make a lot of vaults, and the cancer cells that do it are drug resistant. And the thought was maybe the cell upregulated vaults to get rid of all that. But that hypothesis, like many others, fell away over time. There's still a possibility, but there hasn't been good evidence for it.

Sarah Crespi
I mean, really, like, it's such a strange puzzle. I love it. What did they call it when you have something that evolves, but it's not because of adaptation?

John Travis
Are you talking about like a spandrel?

Sarah Crespi
Yeah.

John Travis
Yeah. So the idea that it's not something that evolved, it's just kind of a byproduct of other things. And John Cohen kept asking. He's like, maybe it's just a spandrel. And Lenny's like, there are four genes devoted to making it, and it takes all these resources.

Sarah Crespi
Right.

John Travis
That's not a spandrel.

Sarah Crespi
Yeah. Was it? One person said it was rocks, which I didn't really understand.

John Travis
The idea is they're basically warehouses of amino acids throughout the cell. If you need an amino acid to build a synapse or to build a protein to build a synapse, do you need to go wait for the cell to make that protein? Or can you just break apart the vaults and use those amino acids to assemble something?

Sarah Crespi
As a good molecular biologist, what happens when you knock it out? What happens when you turn off these proteins or. Or not these genes.

John Travis
Well, that's the frustrating thing. Not much. So they've created a mouse that has no mvp, the main protein, and it seems to be pretty normal. It develops normally, it's fertile, it has a couple of cell abnormalities that they don't quite understand, and if you knock out the other protein components, the same thing.

And I just talked with the NIH team that knocked out the rna, and it's perfectly normal. The researcher just was like, it's crazy.

Yeah, they're very conserved. I mean, slide molds have vaults as well.

Sarah Crespi
Yeah.

Sarah Crespi
All right, so this is kind of.

Sarah Crespi
Where we're at this. We have something, an interesting phenomenon that we can point to and say, this exists in cells. It's got to be important because the cells are invested, it's conserved over the family tree, and yet our methods for determining its function are kind of exhausted.

That actually coincides with funding running out.

John Travis
Yeah, I mean, after he found the vault, Lenny put in an NIH grant, and he said it was his best scored grant ever. So they spent a few years trying to figure out the vault, and then they had to apply for another NIH grant, and it got rejected initially, but it got approved eventually. And then the third time, they had an even tougher challenge to get NIH. And after the third grant, NIH stopped funding basic research into them. That's when Lenny was like, I want to keep going. And so he started turning to National Science Foundation, Department of Defense, private foundations, and he started thinking more about applications of vaults, because by that point, they had figured out something very surprising, that if you expressed a major vault protein alone and none of the other components, it would form an empty vault.

Sarah Crespi
One thing that came up in your.

Sarah Crespi
Story was that these vaults aren't really.

Sarah Crespi
Targeted by the immune system, that they noticed that when they were trying to characterize them, it wasn't easy to label them with antibodies. And it turns out that our bodies just kind of ignore them.

Sarah Crespi
So I certainly can't figure out why.

Sarah Crespi
They would naturally be in the cell, but I'm starting to see some applications.

John Travis
Definitely, there are potential advantages to vaults as kind of a delivery vehicle, because they're in all your cells, your immune system is not going to respond to them. It's not going to say, oh, this is foreign, I need to get rid of it or do something to it. It has a pretty big volume. You can get big proteins into it, lipid nanoparticles, which we all may know about because of COVID vaccines.

You can get messenger rna into it and small proteins when they're doing it with this potential cancer drug.

Sarah Crespi
So it's just cellular tupperware. We don't know.

We don't know its function. Besides carrying things, it does seem that research these days has really turned more to that carrying function. You mentioned cancer viruses and environmental cleanup. So which one do you want to take on first?

John Travis
Let's start with the environmental cleanup. Yeah, it's a pretty simple idea. There are enzymes that can remediate, basically, toxins, synthetic dyes and so forth. But if you spray it out into the environment, it gets broken down very quickly. And so one of Lenny's collaborators is like, let's put this stuff into a vault, make it more stable and longer lasting. And she has some grants from, I think, the EPA and maybe the defense department.

Sarah Crespi
And so on the clinical side, what else are people trying?

John Travis
The long collaboration Lenny has had is with a UCLA physician who wants to basically teach the immune system to attack tumors.

And he's been using a immune signal called ccl 24.

He started by injecting that into tumors, and it would attract immune cells to the tumor, but the protein gets cleared away pretty quickly. So Lenny came to him, because Lenny always has an idea and said, why don't you put CCL 21 into my vaults and then inject those vaults into the tumor? And so they've been working on this probably for ten years. There's a small company called Vault Pharma that Lenny is partnering with, and they are at the point, if they can find the funding, where they want to launch a clinical trial, and that could happen this year.

Sarah Crespi
It's in animals.

John Travis
Yeah. They've shown that if you inject the vaults into animals, you can stimulate the antitumor response, the same one you get if you inject the protein. So injecting the protein, and I think the dendritic cells, has been done in people. So the next step is to test the vaults in people, because vaults have never been injected into a person.

Sarah Crespi
Whoa. We make our own, but we don't. We have.

John Travis
We make our own.

Sarah Crespi
We haven't had exogenous vaults, so it should be safe. That's super interesting. Okay. And why was someone putting a virus in a vault?

John Travis
Yeah. So that's a very creative solution to a big problem in gene therapy. Gene therapy is delivering a therapeutic gene into your body, maybe to a specific tissue. And a lot of teams are using viruses to do that. In particular, they're using something called adeno associated virus, which is a harmless virus, as far as we know. For most people.

And you stitch a gene into the aav and deliver the aav. But most of us have been exposed to aavs and so we have antibodies to it. And so either you can't give a person aav or you have to give them such a high dose that they might have an immune reaction to it. So this postdoc student at Washington University St. Louis had read about vaults long ago and was talking to his lab head, David Curriel. What if we put the aav inside a vault? Could we turn it into kind of a stealth delivery vehicle? And they called up Lenny and said, I think a virus can fit in a vault. And Lenny was like, yeah, maybe.

And they're like, well, let's do it. And they tried. Lo and behold, you can get an aav into a vault. And if you do that and you put vaults with the virus together with cells and with antibodies that target the virus, the vaults slip by the antibodies and go into the cell.

Sarah Crespi
Oh, wow.

John Travis
So this is a long way from any testing. They haven't tested it in mice, they haven't tested it in people.

But it's a pretty creative way to get over a big problem in gene therapy.

Sarah Crespi
Absolutely. So you don't want to just put the desired genes in the vault because the virus has all this other apparatus that will help it integrate and express the genes and the cells?

John Travis
Well, that's a good question. Lenny has long dreamed of just putting DNA or rna into a vault and using that for gene therapy.

Sarah Crespi
So he's just going to make a virus out of vault, is what you're saying?

John Travis
Essentially, he thinks the vault can be the perfect virus for gene delivery. But we can't get DNA and RNA to stay in a vault, even though it naturally takes certain rna. If you try to put a whole gene into it or longer messenger rna, we have not succeeded. They're working on it, so give them time.

Sarah Crespi
So many puzzles. They keep coming. So, John, are we going to get together again in ten years and still not know their natural function?

What do you see?

John Travis
I'll be very depressed if that is true. I won't be surprised because a lot of people said, this shows how hard it is to figure out what things do in the body.

Lenny's retired, but he's trying to train the next generation. He's the vault guy. Look him up on YouTube. And he's trying to get the next generation of people to take on his quest. Although for his sake and my sake, I hope we figure it out soon, I would love to do that story as well.

Sarah Crespi
Me, too. That's so great.

Sarah Crespi
All right.

Sarah Crespi
Thanks so much, Jon. It was really fun talking.

John Travis
Oh, I appreciate it, Sarah. I hope to come back and talk vaults again.

Sarah Crespi
Yeah. Jon Travis is the news managing editor at science. You can find a link to the story we talked about and many, many pictures and illustrations of vaults@science.org.

Sarah Crespi
Podcast up next, I talk with Suzanne Kuipert about the evolution of brown fat, our heat generating organ.

This week's episode is brought to you in part by the Eppendorf and Science Prize for Neurobiology.

Are you or one of your colleagues doing great neuroscience? If so, then we encourage you to apply for the prestigious Eppendorf and Science Prize for Neurobiology, an international prize which honors young scientists for outstanding neurobiological research based on methods of molecular cellular systems or organismic biology.

Submissions are due June 15. Visit science.org eppendorf to apply today we are warm blooded.

Sarah Crespi
This is us mammals, but also birds. We maintain a specific temperature, usually warmer than our surroundings, except for those very, very hot days. But how do we warm our blood? How do we keep our cells, our interior, at a specific temperature?

My first thought is, while we move muscles, those warm us up. But, you know, reptiles have muscles, and they even, they have fat, too. What makes us different? Well, we do have special ways of insulating ourselves, and we also have a few ways of generating heat, including shivering, including that muscle movement, and also through something called brown fat, which is a heat generating organ first found in adult humans about 20 years ago. This week in science, Suzanne Kuypert and colleagues wrote about when in evolutionary history, brown fat took on this job of heat generation. Hi Suzanne, welcome to the podcast.

Suzanne Kuypert
Hi Sarah. Thanks for having me.

Sarah Crespi
I was so surprised that brown fat is kind of a recent development that we have this on our bodies, that it might actually help us keep ourselves warm. Why was this overlooked so long? How do we find out about it now?

Suzanne Kuypert
Brown fat is known already for quite a long time, but it was mainly studied in rodents and hibernating animals because there it is really critical for rewarming after hibernation, for example. But in humans, it came up quite late. So we know that it is in infants. So also in babies, it plays an important role when it comes to thermoregulation. However, when we are growing older, also our surface to volume ratio changes, and we don't need it so much anymore. So because of that, it was, in adults, a little bit overlooked.

Sarah Crespi
Yeah, it's almost like a little pilot light, right? Like it's something that is there to kick on the heat generation and hibernating animals and to kind of protect babies from the fact that they are so small, they can just lose their heat in a big gust of wind or something. So the other thing that surprised me about this was that it's in a specific location. So brown fat is not spread throughout our body or in the areas we think of as, like, fat harboring. Right. It's in a special area.

Suzanne Kuypert
It's a little bit like a heating west. So the biggest depot is somehow in the neck, but then you can also find it in the axillary region. So it's really keeping your body core warm.

Sarah Crespi
Yeah. So between the shoulders, down your spine, you have a little vest of proud fat. It's just so crazy.

Suzanne Kuypert
Exactly.

Sarah Crespi
So how is brown fat, or more formally, brown adipose tissue, different from white fat? White adipose tissue?

Suzanne Kuypert
Yeah, it's quite funny because they share the same name, like adipose tissue, but they are completely different in function, because white adipose tissue is mainly there to store energy. So when you eat too much, then white adipose tissue stores your surplus energy, whereas brown adipose tissue burns the energy to generate heat. Morphologically, it looks also a little different. You have a lot of mitochondria, which are needed to produce the heat. So there are definitely a lot of differences, but they also share some topics.

Sarah Crespi
That zero in on those mitochondria. That's where the magic happens, in the brown fat. So they have all these mitochondria and a special protein turned on that basically takes advantage of the proton motive forces, normally how we make ATP. But instead of taking the energy from protons moving down their gradient, turning it into ATP, we're using it to generate heat to give us warmth.

Suzanne Kuypert
And this is exactly the most important difference, because the protein is called uncoupling protein one. And as you nicely explained, it can uncouple the respiratory chain, and then there is no ATP production. The protonmotive force is used to generate heat.

This is very unique for brown adipose tissue, so it's really highly expressed in this tissue and gives the tissue this heat producing capacity.

Sarah Crespi
We know that brown fat is part of the mammalian warm blooded biology. Is this process also active in other animals?

Suzanne Kuypert
We know from studies that UCP one is quite an ancient gene, so it is already expressed, for example, in teleostia fish, but the heat producing function is not given, so we don't really know what it is doing in fish. These animals also don't have brown fat, so it's also not expressed in brown adults tissue, for example. This was also one of the main interesting questions we asked. So when did brown adipose tissue evolve and when did UCP one gain this thermogenic function?

Sarah Crespi
Right. I actually want to do, like, a little side quest here.

All of us animals, all of us descended from a common ancestor that I'm assuming was not warm blooded. Do we know anything about, you know, the evolutionary advantage of having a heated interior? What are some of the theories for why it was a good idea to start heating up bodies and keeping them warm year round?

Suzanne Kuypert
Yeah, this is a so called endothelial, and it comes with a lot of benefits. For example, you're somehow more independent of climate and temperatures because you can move freely, you can reproduce easier, and it's also even associated with brain size.

Sarah Crespi
Yeah, I'm just imagining iguanas falling out of trees.

You're just not very active when it's cold. So you have a lot of ways you can keep foraging, you can stay awake, all that good stuff.

Suzanne Kuypert
Exactly.

Sarah Crespi
Okay, so that's kind of like, broadly getting warm bodies. But the focus of this work is on this protein, uncoupling protein, which in many mammals uncouples the mitochondrial processes and, you know, turns that work into warmth instead of ATP. This is found in animals like fish, so they're not using that this way, which makes it hard to figure out when brown fat started doing this. How did you, you know, start to investigate this question, start to pick apart uncoupling protein as well as thermogenesis in brown fat?

Suzanne Kuypert
What we did, we went down the mammalian tree and looked at marsupials, because we know that marsupials diverged already, almost 150 million years ago from the placental mammals. And the idea was, when we can find this protein and also the organ already in marsupials, then this means that it already developed very, very early in evolution.

Sarah Crespi
Yeah, I like there's. I think it's in the paper, it says, well, we found in hedgehogs, which is 80 million years ago. So we had to go back further to possums, which is 150 million years ago. So you did look into opossums and compare them with mice. And this is. It's a gray, short tail possum, which is a very cute kind of pocket critter. This is more of the laboratory possum.

So when you compare these, you know, the marsupial versus the placental mammalian, what did you see?

Suzanne Kuypert
The first step we did was really looking. Okay, do we found UCP one? This uncoupling protein in adipose tissue depots.

We took different samples during development from these animals and had a look at a bunch of organs to see where is this protein expressed. We could really exactly see that it's only expressed in adipose tissue and we also only saw it at a really critical time period during development.

And this was when the animals started to really keep their body temperature stable, because when they are younger, they can't. So when they are still together with their mom, they somehow lose body temperature when you separate them from the mom, but at a specific time point, they really can stabilize and maintain their body temperature. And this was exactly the time period where we saw that UCP one was expressed in adipose tissue. So this is very identical, what you find in mice. The specificity here was that the opossum itself doesn't have really brown adipose tissue. So when we look at the morphology of the tissue, it looks more like white oedipus tissue. But as I said, the proteins somehow expressed or coming up at this specific time point.

Sarah Crespi
So you found something that was in between, not the kind of more condensed organ that you see in placental mammals, but something more diffuse that seems more active during development, is that right?

Suzanne Kuypert
Exactly, yeah.

Sarah Crespi
Just because opossum has certain kinds of cells, or it has this uncoupled one protein, doesn't mean that it's doing the same job creating warmth. You know, we know it's in fish. So how did you look at whether or not it was doing this job in possums, we then really took the.

Suzanne Kuypert
Protein and overexpressed it in a cell line to study it in vitro, because this gave us a good chance to see what it is really doing. And what we found out was quite surprising because it was not producing heat. So it is the same protein, it is in adipose tissue, but the function seems to be different. And that was very surprising to us also.

Sarah Crespi
The elements are in place, but they're not yet harnessed together and doing the job that you see in mammals.

Suzanne Kuypert
Exactly. Our gene signature and everything points in the direction of brown fat. UCP one pointed in the direction of brown fat, but this heat producing function, which is so essential for brown adipose tissue, was not there.

Sarah Crespi
So that.

Sarah Crespi
Can you say, aha.

Sarah Crespi
It was definitely after the diversions from marsupials that the brown fat, as a heat generating organ, came to be.

Suzanne Kuypert
This is what we concluded from that, exactly.

Sarah Crespi
First, it was cold blooded, that it was a mixture between white and brown fat with a coupled protein hanging out in there, but not heating things up. And then the next stage was okay, now we're going to start heating things up.

Suzanne Kuypert
This is what we thought. What we also wanted to know then, as a next step, is when did it start? So when did really, this thermogenic function was somehow introduced into the protein?

We did something quite fancy. A PhD student at our lab, Michael Godry, he compared the genomes of more than 200 mammalian species, and then he somehow generated in silico a sequence which predicted and reconstructed the ancestral UCP one sequence.

Sarah Crespi
So you actually translated that into a protein and tried to figure out whether or not it would generate heat?

Suzanne Kuypert
Exactly, because we wanted to go back as much as possible close to the marsupials, but still being in the mammalian space.

Sarah Crespi
Okay, so what happened?

Suzanne Kuypert
This one uncoupled.

Sarah Crespi
So this is.

Suzanne Kuypert
We can clearly say now that the UCP one, the thermogene function of UCP one, really developed later, but it definitely developed at the beginning of this, divergent from the marsupials.

Sarah Crespi
Okay, and so what else do you want to learn about this particular protein or this process?

Suzanne Kuypert
I'm coming from the field of obesity and diabetes research, where this protein or the brown adipose tissue seems to be also a very interesting target to get somehow rid of excess energy. And because of that, I think what we also can learn from this study is that we now know the underlying molecular network was already there before UCP one turned into this thermogenic function. I think with this knowledge, we then can perhaps find even other targets and learn a little bit about the development, how this thermogenic function was then really incorporated into the protein, into adipose tissue.

Sarah Crespi
How would brown fat relate to obesity? When you say, oh, this person is overweight, it's because they have a lot of white adipose tissue, not a lot of brown adipose tissue.

Suzanne Kuypert
Right, exactly. Adult humans almost don't have brown adoption anymore, so there are some gender differences, age differences, so in some people, you can still find it. But the idea is that this process of wasting energy in form of heat could be really something interested for fighting against the obesity pandemic.

Sarah Crespi
So you could somehow turn on uncoupling one in a subset of cells to just diffuse away all this excess energy?

Suzanne Kuypert
No. It's also interesting to see what's happening when you really uncouple your mitochondria. So in the form that you produce and UCP one, is there a natural product where you can really study the function and the impact of the tissues also?

Sarah Crespi
Yeah, it's a little bit scary to think that your mitochondria could suddenly be like, you know, what I'm going to do instead of making ATP.

Suzanne Kuypert
When you think about evolution at the beginning, you don't want to waste energy. So this is what most animals want. And in humans, we are now looking for ways to waste energy. So perhaps this could be a potential way to waste energy. But, yeah, we have to learn a lot about it. And I guess our study somehow contributed to the understanding how this molecular network somehow forced UCP one also to turn into thermogenic function.

Sarah Crespi
Thank you so much, Suzanne.

Suzanne Kuypert
Yeah, thank you very much, Sarah. It was a lot of fun.

Sarah Crespi
Suzanne Kuypert is a researcher in the department of molecular biosciences at the Winogren Institute at the University of Stockholm. You can find a link to the paper we discussed@science.org.

Sarah Crespi
Podcast if you're interested in what happened to our music, where it came from, how it's different, and also kind of the same, stay tuned for my chat with musician and composer and artist Wen Khoi wen.

So this week, for the first time since 2006, the podcast has different music. I mean, somewhat different. It's the same as what was called composed for the show back then, but with some updates. I have our composer here, and we're gonna talk mostly about the show's intro, but we also had him take on the outro and the interstitials that go between the segments.

Sarah Crespi
Can you just say who you are and what you do?

Sarah Crespi
Hi.

Wen Khoi Nguyen
My name is Win Khoi Nguyen, and I'm at digital media teacher at Loyola University Maryland.

Sarah Crespi
And what's your affiliation with science?

Wen Khoi Nguyen
Well, way back when I was a video producer at Science, one of my favorite things as a video producer was to make original music for the videos.

Sarah Crespi
Yeah. And we use it on the podcast all the time. We have narrative pieces now where music needs to be scored. And Kelly Cervic actually just did a piece. She did a whole segment on loneliness. And she, of course, picked a song that you wrote.

Wen Khoi Nguyen
No way. That's so cool.

Sarah Crespi
Yeah. So, yeah, we still use your music to this day.

Wen Khoi Nguyen
I'm very glad.

Sarah Crespi
Just a little background here. The podcast music was actually written by Jeffrey Cook, a copy editor working on the journal side on research papers back in 2006. He wrote all the music, our intro, outro and interstitials, and we've been using it ever since.

Sarah Crespi
We didn't have the files. Jeff was like, I will look in my basement for an old hard drive. And he pulled one out, and then we got closer to doing this. And Jeff, unfortunately, Jeff died in 2022, and we really didn't have much to start with. We had that one file.

Sarah Crespi
Jeff had such a deep history with science with the podcast. We didn't want to change that.

Sarah Crespi
He had a deep history with music. Jeff had a master's degree in harpsichord chord performance.

Wen Khoi Nguyen
Wow.

Sarah Crespi
From the University of Minnesota.

Wen Khoi Nguyen
How cool is that? Oh my gosh.

Sarah Crespi
He's a lifelong musician and composer.

We didn't really get to collaborate with him or kind of continue this tradition of someone at science making the music for the podcast. But next best thing, when he used to work at science and really had an appreciation for this music, because when I said, we should do something with this music, and he said, oh, but it's great. What did you like about it?

Wen Khoi Nguyen
Well, it is lively and it's kind of a little bit surprising. The theme is in a weird time signature.

It's in five 8th notes per measure, which is not typical at all.

Sarah Crespi
Yeah. Holden, our editor in chief, said it was a very nerdy time signature.

Wen Khoi Nguyen
Yeah.

Sarah Crespi
Let's play a part that actually demonstrates that, you know, your first impression of it was, this is lively, this is unusual, this is interesting, and don't get rid of it. Sarah, then I asked you to recreate it. Did your opinion of the music change when that came about?

Wen Khoi Nguyen
It didn't change for me, but as just someone interpreting someone else's music posed a challenge of what do I change, what do I keep?

Sarah Crespi
Yeah.

Wen Khoi Nguyen
And originally, because I didn't have the sheet music, I had to transcribe it by ear. Just that, getting all the notes together and then playing that.

Sarah Crespi
Listen to the density of this music.

Wen Khoi Nguyen
Yeah, it's very dense.

Sarah Crespi
There's not a computer that can do this. There's not an AI that can do this. It's like when someone gives you a jpeg of a map, there's a raster file, there's no data in it. Yeah, we need to basically extract the data, but with the mind of a composer, you can't just. Not anybody can do that.

What was your mission when you were told to transcribe this music and make it different somehow?

Wen Khoi Nguyen
Well, I think at first the instructions I got were do just a light revision of it and try to stick closely to it. But I think after the first round, I was encouraged to go a little further. And I come from a jazz background too, so that's a little different than I think the original music was informed by.

Sarah Crespi
Yeah.

Do you think it's jazzy now?

Wen Khoi Nguyen
Slightly. There are some swinging 8th notes in there. A little bit.

Sarah Crespi
So technical. So a couple people have said it sounded a little bit like a video game.

Wen Khoi Nguyen
Yeah.

Sarah Crespi
Do you think that there's a little bit of that? And that would make me very happy, I think just.

Wen Khoi Nguyen
Yeah, by the nature of.

There is enough polyphony happening at the same time. So, yeah, it makes me think a little bit of Mario Bros. Or something.

Sarah Crespi
What's polyphony?

Wen Khoi Nguyen
So more than one note being played at once?

Sarah Crespi
Oh, okay.

Wen Khoi Nguyen
Yeah.

Sarah Crespi
That's so funny. So it's in the original. That kind of like.

Wen Khoi Nguyen
Yeah, the density of that originally. Yeah.

Sarah Crespi
That's so cool.

That was Wen Khoi Wen. He's a teacher at Loyola University in Maryland. He's also a filmmaker, a composer, a performer. He also does graphic novels and all kinds of art cartoons.

We'll link to his website from the episode.

Sarah Crespi
And that concludes this edition of the Science podcast. If you have any comments or suggestions, write to us at sciencepodcast@aaas.org dot. You have any comments or suggestions about the content or the music, write to us at sciencepodcast aaas.org dot. To find us on podcasting apps like overcast or Apple Podcasts, search for Science magazine, or you can listen on our website, science.org podcast. This show was edited by me, Sarah Crespi, Megan Cantwell, and Kevin McLean. We also have production help from Megan Tucker at Prodigy. Our music is by Jeffrey Cook and Wen Koi wen on behalf of science and its publisher, AaA. Thanks for joining us.