Announcer:
Welcome to the Salk Institute’s 治愈的起点 podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.

Brittany Fair:
I’m here today with Dr. Uri Manor. He is a staff scientist at Salk and the director of the Waitt Advanced Biophotonics Core Facility. Dr. Manor, welcome to 治愈的起点.

Uri Manor:
Thank you very much. Happy to be here.

Brittany Fair:
And just to start out, what exactly is the Waitt Advanced Biophotonics Core Facility? That’s quite a long name there.

Uri Manor:
Yeah, I was still trying to figure out what it is. No, I kid I kid. Um, so I guess maybe we should start with what a core facility is. So, um, science is very much driven by technology these days. Now this equipment is really a high end and it’s very complicated and it’s just not feasible for every single lab to have their own equipment financially or practically. So these core facilities are shared resources for institutes. So, the biophotonics core facility is a facility where we house all of the high end of microscopy equipment, which allows us to image biological samples with really high resolution.

Brittany Fair:
So, it’s an imaging facility for scientific research.

Uri Manor:
Exactly. Which is critical to understanding what we’re studying.

Brittany Fair:
Why is it critical to be able to see it?

Uri Manor:
Well, I’m obviously biased because I am a microscopist and I am the director of the biophotonics core, but there’s a direct relationship between the structure of a biological system and its function in both health and disease. So, in order to understand how, for example, to cure a disease, you have to understand how it works. And in order to understand how it works, you have to see how it is put together. We also do live imaging in the biophotonics center, so we can see how things are dynamically changing because life is dynamic.

Brittany Fair:
And you’re basically a photographer of these really, really tiny structures. How big are these structures that you’re looking at?

Uri Manor:
They can range from a single protein, you know, nanometers scale all the way up to entire brains or even entire organisms. I just think it’s so cool that we can actually look into a cell and see how all the different parts of the cell work together, how they interact with one another. Um, for example, the cell has hundreds of mitochondria and now with some of our microscopes, we can actually look into parts of a single mitochondria.

Brittany Fair:
And why do mitochondria matter?

Uri Manor:
They’re amazingly important. Um, for example, I don’t know if you’ve heard of the theory of endosymbiosis. This was famously put forward by a scientist named Lynn Margulis. Um, she came up with this theory based on lots and lots of data that what we now call mitochondria used to be a separate organism. It was actually a bacteria that are single celled ancestors somehow engulfed. And then it became the mitochondria and they developed a symbiotic relationship. So mitochondria provide energy for the cell cause they can do certain types of metabolic processes that our cells cannot do without them. Because of this ancient relationship, they don’t just provide energy for the cells to actually incredibly important signaling hubs. They even tell the cell when to die. And if you think about it, you know, in life and death, that’s one of the most important things that a cell can do is die. And the fact that that can be dictated by mitochondria almost raises some interesting philosophical questions. Who’s really running the show here? Is it us using mitochondria or are mitochondria using us? I don’t know.

Brittany Fair:
I didn’t realize mitochondria has such a fascinating history. How are mitochondria deciding when a cell should die or what other processes do they control?

Uri Manor:
Well, um, mitochondria had been described by others as the canary in the coal mine. They’re one of the first ones to send stress and damage in the cell. When they become damaged beyond repair, they then tell the cell, “time to go.” And the cell initiates this cell death pathway called apoptosis. But mitochondria also play a role in something called autophagy, which is when the cell starts to eat itself. So, there’s self-cannibalism and there is suicide all dictated by mitochondria. So that’s just sort of one example of how important they are. And now we know that mitochondria, if they become overly damaged or if there are defects in mitochondria, that’s one of the leading associations with neurodegeneration and aging.

If you put a cell in a microscope and you label the mitochondria and you keep that cell alive and you image it for awhile, you’ll see that there’s actually hundreds of mitochondria in the cell. And they’re wriggling around like worms, not looking very different from what an ancestral bacteria might look like. It just looked like the cell is full of these bacteria that are independently moving around. And they even have their own DNA.

Brittany Fair:
That’s different?

Uri Manor:
Mmm. Yeah. That’s like basically descended from this ancestral holey separate organism that was the bacteria, that became mitochondria. So, we actually have two genomes in our bodies.

Brittany Fair:
And do you study mitochondria in your own work?

Uri Manor:
Yes. So for my postdoc, I studied a protein on mitochondria that helps mitochondria interact with something called the ER, the endoplasmic reticulum and something called the actin cytoskeleton. So, the actin cytoskeleton is it’s a skeleton of the cell and it produces forces in the cell that actually dictates the shape of the cell. It’s critical for cell migration. The actin cytoskeleton also plays a role in driving mitochondrial dynamics and fission. If it goes awry that leads to things like neurodegeneration, cancer, metabolic disorders, aging. So yeah, it’s really important that we understand how this happens. The realization that the actin cytoskeleton is involved in that was key. So part of what my work is focused on now is developing probes, fluorescent tools that allow us to see how and when and where the actin cytoskeleton actually interacts with the mitochondria to drive fission.

Brittany Fair:
And is that what you are currently working on at Salk?

Uri Manor:
That is one thing I’m working on it.

Brittany Fair:
So, what else are you working on?

Uri Manor:
I also work on hearing loss.

Brittany Fair:
Oh, that’s very different than mitochondria.

Uri Manor:
Well, it is. And it isn’t.

Brittany Fair:
好的.

Uri Manor:
Yeah. So, so first of all, our hearing is mediated by cells, right? Which have mitochondria.  And one thing we’re finding is that mitochondria as with all the other things that described are actually very important for dictating how a cell will respond to aging. And one particular area of interest of mine is noise. Uh, one thing we’re working on is trying to understand what are the similarities and differences between noise induced, hearing loss and age related, hearing loss. And one central hypothesis is that age related hearing loss is simply accumulation of damage of noise over a lifetime. And there is some sort of anecdotal evidence for that.

So, for example, there is a tribe in Sudan, fairly isolated from all industrialization. They have none of the noises around them that we have here. And this tribe has a very different hearing loss as a function of aging, then the rest of the world.

Brittany Fair:
That’s really fascinating.

Uri Manor:
Yeah. So anyway, it seems to us that mitochondria are a key signaling hub, for responding to noise, and we have some preliminary data actually using an FDA-approved drug that we can actually mitigate noise, induced damage by manipulating these mitochondria-mediated signaling pathways. So we’re hoping that we’ll be able to give people a pill before, for example, soldiers go out to battle or before you go to a concert that can actually reduce the amount of damage you’ll get as a result of that noise.

Brittany Fair:
That would be really cool. So how did you become interested in studying hearing loss?

Uri Manor:
I’m actually hearing impaired.

Brittany Fair:
Oh, are you?

Uri Manor:
I was born with severe to profound hearing loss.

Brittany Fair:
好的.

Uri Manor:
And they didn’t figure it out until I was two and a half.

Brittany Fair:
Oh, wow.

Uri Manor:
Which created some problems for me in my development. So, when a plane flew above me, when I was a baby, I heard it and I would look up, and I would point.

My dad was an aerospace engineer and he really noticed that. He was excited, whatever. So, I obviously could hear something, but when they would call me, when I was playing with things, they would say, “Uri….Uri….Uri.” I wouldn’t respond. And finally they screamed, “URI!!!”

And then, you know, I would look. So, they didn’t get it. That I was, I actually had really bad hearing until I was two and a half. People are screened at birth now, but when I was born, they weren’t doing that.

Brittany Fair:
So, what did that mean for you when you were diagnosed at two and a half? How did that change your life?

Uri Manor:
I didn’t know any words. So I had a lot of catching up to do and you know, there’s a famous quote by Helen Keller. You know, she was famously deaf and blind. And she said that blindness separates people from things, deafness, separates people from people. And I think she said or was implying or had said other points that if she could choose one, she would choose hearing.

You know, I was kind of isolated, you know, and now we know, you know, that a lot of the elderly who are really losing their hearing and it’s happening at an earlier age for a lot of people, because of things like headphones and rock concerts and stuff, they start to get depressed. They can’t hear, they can’t interact in a social environment. So, it has a lot of ripple effects on your entire wellbeing. So, I feel very passionately about hearing loss and being able to do something about it. And as it turns out the inner ear, in particular, the hair cells, those are the sensory cells of the inner ear. That’s just amazing to image to the most beautiful cells in the body of my opinion.

Brittany Fair:
What do they look like?

Uri Manor:
They, there are these kind of like cylindrical shaped cells, but on top of them, they have this little hair bundle.

It’s like a tuft of tens to hundreds of individual, little hairs, so to speak. And they moved back and forth in response to sound. And that movement is what sends an electrical signal to the brain. But they’re organized in such a beautiful, repetitive, patterned way. That’s very interesting. So first of all, within a single cell, there are at least three rows of hairs. And in each row, they’re all exactly same length. And then the next row, they’re a little bit taller and the natural other a little bit taller. So it’s like a staircase shape. And, you know, as a photographer, artist, microscopist patterns and repetition, those are really pleasing motifs. So these hair cells are just gorgeous, but then also across the whole tissue, the whole, the whole cochlea is organized kind of like a grand piano. Where the hairs are longer on one end and they get progressively shorter towards the other end of the cochlea. And those lengths are tuned to the frequency of sound they detect.

Brittany Fair:
Interesting.

Uri Manor:
So just like a grand piano, the really long strings are really low frequencies. The really short strings are really high frequencies.

The same thing with our hair cell. So, there’s this tissue wide organization, and then there’s a sub cellular organization and it’s all mediated by our favorite friend, the actin cytoskeleton, who I mentioned before. So that’s why I was always interested in understanding how the cell says, “this is how long you’re going to be. And you’re going to be this long, by the way, for a hundred years.” Cause people live for a hundred or more years and those hairs have to last that long.

Brittany Fair:
So, it’s the same cell that you have when you’re born.

Uri Manor:
Exactly. Those cells do not replace themselves as far as we can tell.

Brittany Fair:
Okay, so once it’s gone, it’s gone.

Uri Manor:
It’s gone once it’s gone, it’s gone. And that’s why hearing loss is permanent.

Brittany Fair:
I see.

Uri Manor:
And progressive. It’s a really interesting problem. Do these hairs repair themselves, do they replace themselves? Is there turnover? Is there fixing or they just built so robustly that they can last a hundred years, which is pretty mind boggling.

Most proteins have a lifetime of maybe minutes to hours. So the proteins in these hairs are supposed to last a hundred years. That’s remarkable in of itself.

Brittany Fair:
So how are they doing that?

Uri Manor:
How are they doing that? Especially kids are being pushed back and forth over a lifetime. Not like they’re just sitting there, they’re not passive. So it’s a really interesting problem as well. One way we can understand how it works is by looking at it when it doesn’t work. So there are mice that are born deaf. There are people that are born deaf.  Very often they have mutations in the same gene. And some of those mutations cause those little hairs to be really short. So they basically don’t work anymore. So we are studying these mice that had these really short stereocilia, that’s what those hairs are called stereocilia. And we’re exploring the possibility of using gene therapy, basically virus delivered genes to see if we can grow those hairs back.

Brittany Fair:
Interesting.

Uri Manor:
So that has an obvious clinical medical use. And then the other area is understanding, um, noise-induced or age-related hearing loss, where we’re kind of looking at these mice as they get older and older and or experienced noise and trying to understand what’s happening to the mitochondria. Because I have all these different things happening, but they all have that common thread of really high resolution, advanced microscopy.

Brittany Fair:
Okay. So let’s swing back to your microscopy and you kept saying that you’re a photographer, you’re a photographer. So you’re obviously taking, as I said before, images of these tiny, tiny little structures, do you ever just go out on the street with a camera and take photos of big things too?

Uri Manor:
Not as much as I used to. In DC, I had a really sweet gig where I was photographing concerts.

Brittany Fair:
Oh ok.

Uri Manor:
That was a lot of fun because I got to go to all these shows for free and be in the front row and take pictures of the artists. I listen to music a lot and I like loud music. My philosophical excuse there is that I have hearing probably for a limited period of time because everyone loses hearing with aging and I’ve got much less to start from, but while I have it, I’m going to enjoy it.

Brittany Fair:
Well, Dr. Manor, thank you so much for coming on our podcast. It was a pleasure having you and thank you so much for being here today.

Uri Manor:
Yep. Thank you for having me.

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Join us next time for more cutting-edge Salk science. At Salk, world-renowned scientists work together to explore big bold ideas from cancer to Alzheimer’s aging to climate. 治愈的起点 is a production of the Salk Institute’s Office of Communications. To learn more about the research discussed today, visit Salk dot EDU slash podcast.